「Parkin」の版間の差分

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Parkin遺伝子は、常染色体性潜性(劣性)若年性パーキンソニズム(autosomal recessive-juvenile parkinsonism: AR-JP) の原因遺伝子である。Parkin遺伝子の正式名称はPRKNであり、PARK2とも表記される。遺伝子産物Parkinはユビキチン転移酵素(ユビキチンリガーゼ)であり、損傷したミトコンドリアを排除するミトコンドリアの品質管理に関与すると考えられている。一方、がん抑制遺伝子、らい菌の感受性遺伝子としても報告され、未解明の生理的機能も示唆される。
{{box|text= Parkin遺伝子は、常染色体性潜性(劣性)若年性パーキンソニズム(autosomal recessive-juvenile parkinsonism: AR-JP) の原因遺伝子である。Parkin遺伝子の正式名称はPRKNであり、PARK2とも表記される。遺伝子産物Parkinはユビキチン転移酵素(ユビキチンリガーゼ)であり、損傷したミトコンドリアを排除するミトコンドリアの品質管理に関与すると考えられている。一方、がん抑制遺伝子、らい菌の感受性遺伝子としても報告され、未解明の生理的機能も示唆される。}}


==背景、歴史的推移==
==背景、歴史的推移==
パーキンソン病は振戦、無動・寡動、筋固縮、姿勢保持障害などの運動機能障害を特徴とする神経変性疾患である。運動症状は中脳黒質のドーパミン神経の選択的変性脱落に起因する。高齢になるほど発病率が増加し、60歳以上では約1%が罹患する。パーキンソン病の一部に、40歳以下で発症する若年性パーキンソン病と呼ばれる群があり、そのうち家族性(遺伝性)のものがいくつかみつかっている。
 パーキンソン病は振戦、無動・寡動、筋固縮、姿勢保持障害などの運動機能障害を特徴とする神経変性疾患である。運動症状は中脳黒質のドーパミン神経の選択的変性脱落に起因する。高齢になるほど発病率が増加し、60歳以上では約1%が罹患する。パーキンソン病の一部に、40歳以下で発症する若年性パーキンソン病と呼ばれる群があり、そのうち家族性(遺伝性)のものがいくつかみつかっている。


1998年、若年性パーキンソン病の一つである常染色体性潜性(劣性)若年性パーキンソニズム(Autosomal Recessive-Juvenile Parkinsonism: AR-JP)の原因遺伝子としてParkin (PRKN, PARK2)が同定された<ref name=Kitada1998><pubmed>9560156</pubmed></ref> 。パーキンソン病原因遺伝子としては、α-Synuclein (SNCA; PARK1/PARK4)に次いで、2番目に同定された遺伝子である。Parkinは、6番染色体(6q26)にある1.38 Mbの巨大な遺伝子で、欠失変異、フレームシフト変異、ミスセンス変異が、遺伝子全体にわたって見つかっている。Parkin変異は人種を越えてみられ、遺伝性若年性パーキンソン病の約50%を占めると報告されている<ref name=Lucking2000><pubmed>10824074</pubmed></ref><ref><pubmed>name=Hattori2004><pubmed>15325839</pubmed></ref> 。
 1998年、若年性パーキンソン病の一つである常染色体性潜性(劣性)若年性パーキンソニズム(Autosomal Recessive-Juvenile Parkinsonism: AR-JP)の原因遺伝子としてParkin (PRKN, PARK2)が同定された<ref name=Kitada1998><pubmed>9560156</pubmed></ref> 。パーキンソン病原因遺伝子としては、α-Synuclein (SNCA; PARK1/PARK4)に次いで、2番目に同定された遺伝子である。Parkinは、6番染色体(6q26)にある1.38 Mbの巨大な遺伝子で、欠失変異、フレームシフト変異、ミスセンス変異が、遺伝子全体にわたって見つかっている。Parkin変異は人種を越えてみられ、遺伝性若年性パーキンソン病の約50%を占めると報告されている<ref name=Lucking2000><pubmed>10824074</pubmed></ref><ref><pubmed>name=Hattori2004><pubmed>15325839</pubmed></ref> 。


Parkinタンパク質は基質タンパク質にユビキチンを転移するユビキチンリガーゼで、多くの病因変異でその活性が損なわれている<ref name=Shimura2000><pubmed>10888878</pubmed></ref><ref><pubmed>name=Imai2000><pubmed>10973942</pubmed></ref><ref><pubmed>name=Zhang2000><pubmed>11078524</pubmed></ref> 。これまでにユビキチン化基質候補として数多くのタンパク質が報告されている<ref name=Zhang2015><pubmed>26793099</pubmed></ref> 。
 Parkinタンパク質は基質タンパク質にユビキチンを転移するユビキチンリガーゼで、多くの病因変異でその活性が損なわれている<ref name=Shimura2000><pubmed>10888878</pubmed></ref><ref><pubmed>name=Imai2000><pubmed>10973942</pubmed></ref><ref><pubmed>name=Zhang2000><pubmed>11078524</pubmed></ref> 。これまでにユビキチン化基質候補として数多くのタンパク質が報告されている<ref name=Zhang2015><pubmed>26793099</pubmed></ref> 。
2004年、PINK1(PTEN induced kinase 1; PARK6)が、常染色体性潜性若年性パーキンソン病原因遺伝子として同定された<ref name=Valente2004><pubmed>15087508</pubmed></ref> 。遺伝性若年性パーキンソン病のうち、PINK1変異はParkinに次いで頻度が高く、Parkinと臨床像は類似している<ref name=Kumazawa2008><pubmed>18541801</pubmed></ref> 。ショウジョウバエを用いた遺伝学的研究から、常染色体性潜性(劣性)若年性パーキンソン病原因遺伝子PINK1がParkinの上流因子であり、PINK1とParkinがミトコンドリアの機能維持に関与することが明らかとなった<ref name=Clark2006><pubmed>16672981</pubmed></ref><ref><pubmed>name=Park2006><pubmed>16672980</pubmed></ref><ref><pubmed>name=Yang2006><pubmed>16818890</pubmed></ref> 。その後、ヒト培養細胞を用いた研究から、PINK1がParkinをリン酸化し<ref name=Kondapalli2012><pubmed>22724072</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2012><pubmed>23256036</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2014><pubmed>24901221</pubmed></ref> 、協働して膜電位の低下したミトコンドリアを除去するマイトファジー(ミトコンドリアを対象とするオートファジー)に関与することが明らかになった(図1)<ref name=Narendra2008><pubmed>19029340</pubmed></ref><ref><pubmed>name=Narendra2010><pubmed>20126261</pubmed></ref><ref><pubmed>name=Matsuda2010><pubmed>20404107</pubmed></ref><ref><pubmed>name=Geisler2010><pubmed>20098416</pubmed></ref> 。
 
 2004年、PINK1(PTEN induced kinase 1; PARK6)が、常染色体性潜性若年性パーキンソン病原因遺伝子として同定された<ref name=Valente2004><pubmed>15087508</pubmed></ref> 。遺伝性若年性パーキンソン病のうち、PINK1変異はParkinに次いで頻度が高く、Parkinと臨床像は類似している<ref name=Kumazawa2008><pubmed>18541801</pubmed></ref> 。ショウジョウバエを用いた遺伝学的研究から、常染色体性潜性(劣性)若年性パーキンソン病原因遺伝子PINK1がParkinの上流因子であり、PINK1とParkinがミトコンドリアの機能維持に関与することが明らかとなった<ref name=Clark2006><pubmed>16672981</pubmed></ref><ref><pubmed>name=Park2006><pubmed>16672980</pubmed></ref><ref><pubmed>name=Yang2006><pubmed>16818890</pubmed></ref> 。その後、ヒト培養細胞を用いた研究から、PINK1がParkinをリン酸化し<ref name=Kondapalli2012><pubmed>22724072</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2012><pubmed>23256036</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2014><pubmed>24901221</pubmed></ref> 、協働して膜電位の低下したミトコンドリアを除去するマイトファジー(ミトコンドリアを対象とするオートファジー)に関与することが明らかになった(図1)<ref name=Narendra2008><pubmed>19029340</pubmed></ref><ref><pubmed>name=Narendra2010><pubmed>20126261</pubmed></ref><ref><pubmed>name=Matsuda2010><pubmed>20404107</pubmed></ref><ref><pubmed>name=Geisler2010><pubmed>20098416</pubmed></ref> 。


==構造==
==構造==
ヒトParkinタンパク質は465 アミノ酸残基からなり、N末端のユビキチン様ドメイン(Ubl)、C末端に2つのRING fingerモチーフ(RING1, RING2)とIn-Between-RINGs (IBR)という構造をもつ(図2)。その後、UblとRNIG1-IBR-RING2の間に、RING様構造が見つかり、RING0(またはUPD; unique parkin domain)と呼ばれる<ref name=Hristova2009><pubmed>19339245</pubmed></ref> (図2)。Parkinは、RING-IBR-RINGドメインを有するRBR型ユビキチンリガーゼに分類され、同様の構造をもヒトユビキチンリガーゼに、HOIL-1, HHARI, DORFINがある。タンパク質の全体構造は2013-2015年に解かれ、コンパクトに折り畳まれた状態であることが明らかとなった<ref name=Trempe2013><pubmed>23661642</pubmed></ref><ref><pubmed>name=Wauer2015><pubmed>26161729</pubmed></ref> (図3)。
 ヒトParkinタンパク質は465 アミノ酸残基からなり、N末端のユビキチン様ドメイン(Ubl)、C末端に2つのRING fingerモチーフ(RING1, RING2)とIn-Between-RINGs (IBR)という構造をもつ(図2)。その後、UblとRNIG1-IBR-RING2の間に、RING様構造が見つかり、RING0(またはUPD; unique parkin domain)と呼ばれる<ref name=Hristova2009><pubmed>19339245</pubmed></ref> (図2)。Parkinは、RING-IBR-RINGドメインを有するRBR型ユビキチンリガーゼに分類され、同様の構造をもヒトユビキチンリガーゼに、HOIL-1, HHARI, DORFINがある。タンパク質の全体構造は2013-2015年に解かれ、コンパクトに折り畳まれた状態であることが明らかとなった<ref name=Trempe2013><pubmed>23661642</pubmed></ref><ref><pubmed>name=Wauer2015><pubmed>26161729</pubmed></ref> (図3)。
 
==活性化機構==
==活性化機構==
コンパクトに折り畳まれたParkinは、活性中心がマスクされ不活性型である。Parkinの活性化は2つのステップで起こる。1段階目として、PINK1によってSer65がリン酸化されたユビキチン<ref name=Kane2014><pubmed>24751536</pubmed></ref><ref><pubmed>name=Kazlauskaite2014><pubmed>24660806</pubmed></ref><ref><pubmed>name=Koyano2014><pubmed>24784582</pubmed></ref> がParkinのリン酸基結合ポケットに結合し、Ublのリン酸化サイト(Ser65)が露出する。2段階目に、露出したUblのSer65がPINK1によりリン酸化され、リン酸化UblがRING0/UPDに結合することで、RING2にある活性中心とRING1にあるユビキチン結合酵素(E2)結合部位が安定的に露出する<ref name=Wauer2015><pubmed>26161729</pubmed></ref>  (図3)。
 コンパクトに折り畳まれたParkinは、活性中心がマスクされ不活性型である。Parkinの活性化は2つのステップで起こる。1段階目として、PINK1によってSer65がリン酸化されたユビキチン<ref name=Kane2014><pubmed>24751536</pubmed></ref><ref><pubmed>name=Kazlauskaite2014><pubmed>24660806</pubmed></ref><ref><pubmed>name=Koyano2014><pubmed>24784582</pubmed></ref> がParkinのリン酸基結合ポケットに結合し、Ublのリン酸化サイト(Ser65)が露出する。2段階目に、露出したUblのSer65がPINK1によりリン酸化され、リン酸化UblがRING0/UPDに結合することで、RING2にある活性中心とRING1にあるユビキチン結合酵素(E2)結合部位が安定的に露出する<ref name=Wauer2015><pubmed>26161729</pubmed></ref>  (図3)。


==発現==
==発現==
ヒトParkin mRNAはユビキタスに発現しているが、筋組織、腎臓、脳で比較的高発現をしている<ref name=Kitada1998><pubmed>9560156</pubmed></ref><ref><pubmed>name=Uhlen2015><pubmed>25613900</pubmed></ref> 。哺乳類ゲノムにおいて、PRKNはPACRG (Parkin co-regulated gene)と双方向プロモーターを共有する<ref name=West2003><pubmed>12547187</pubmed></ref> 。Parkinの発現を制御する転写因子として、N-myc <ref name=West2004><pubmed>15078880</pubmed></ref> , p53 <ref name=Zhang2011><pubmed>21930938</pubmed></ref> , ATF4 <ref name=Bouman2011><pubmed>21113145</pubmed></ref> が報告されている。小胞体ストレス・ミトコンドリアストレス <ref name=Imai2000><pubmed>10973942</pubmed></ref><ref><pubmed>name=Bouman2011><pubmed>21113145</pubmed></ref><ref><pubmed>name=Wang2007><pubmed>17465879</pubmed></ref> 、成長因子・栄養制限 <ref name=Klinkenberg2012><pubmed>22028146</pubmed></ref> などの環境要因でも発現上昇が見られる。
 ヒトParkin mRNAはユビキタスに発現しているが、筋組織、腎臓、脳で比較的高発現をしている<ref name=Kitada1998><pubmed>9560156</pubmed></ref><ref><pubmed>name=Uhlen2015><pubmed>25613900</pubmed></ref> 。哺乳類ゲノムにおいて、PRKNはPACRG (Parkin co-regulated gene)と双方向プロモーターを共有する<ref name=West2003><pubmed>12547187</pubmed></ref> 。Parkinの発現を制御する転写因子として、N-myc <ref name=West2004><pubmed>15078880</pubmed></ref> , p53 <ref name=Zhang2011><pubmed>21930938</pubmed></ref> , ATF4 <ref name=Bouman2011><pubmed>21113145</pubmed></ref> が報告されている。小胞体ストレス・ミトコンドリアストレス <ref name=Imai2000><pubmed>10973942</pubmed></ref><ref><pubmed>name=Bouman2011><pubmed>21113145</pubmed></ref><ref><pubmed>name=Wang2007><pubmed>17465879</pubmed></ref> 、成長因子・栄養制限 <ref name=Klinkenberg2012><pubmed>22028146</pubmed></ref> などの環境要因でも発現上昇が見られる。


哺乳類細胞内では主に細胞質に局在するが、PINK1の活性化に伴って、ミトコンドリアへの集積が見られる<ref name=Narendra2010><pubmed>20126261</pubmed></ref><ref><pubmed>name=Matsuda2010><pubmed>20404107</pubmed></ref> 。PINK1によるParkinのミトコンドリアへの集積の分子メカニズムは、2014-2015年に明らかされた(図4)<ref name=Ordureau2014><pubmed>25284222</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2014><pubmed>25474007</pubmed></ref><ref><pubmed>name=Okatsu2015><pubmed>25609704</pubmed></ref> 。
 哺乳類細胞内では主に細胞質に局在するが、PINK1の活性化に伴って、ミトコンドリアへの集積が見られる<ref name=Narendra2010><pubmed>20126261</pubmed></ref><ref><pubmed>name=Matsuda2010><pubmed>20404107</pubmed></ref> 。PINK1によるParkinのミトコンドリアへの集積の分子メカニズムは、2014-2015年に明らかされた(図4)<ref name=Ordureau2014><pubmed>25284222</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2014><pubmed>25474007</pubmed></ref><ref><pubmed>name=Okatsu2015><pubmed>25609704</pubmed></ref> 。


==機能==
==機能==


===不良(不要)ミトコンドリア排除のためのマイトファジー===
===不良(不要)ミトコンドリアのマイトファジー===
細胞での機能として、PINK1と協働してマイトファジーに関与することが、培養細胞でキャラクタライズされている。
 細胞での機能として、PINK1と協働してマイトファジーに関与することが、培養細胞でキャラクタライズされている。
 
ミトコンドリア局在性キナーゼPINK1は、ミトコンドリア膜電位依存的に健常なミトコンドリアの内膜まで輸送され、ミトコンドリア内プロテアーゼMPP(mitochondrial processing peptidase) <ref name=Greene2012><pubmed>22354088</pubmed></ref> とPARL <ref name=Zhou2008><pubmed>18687899</pubmed></ref><ref><pubmed>name=Jin2010><pubmed>21115803</pubmed></ref> によって2段階の切断を受け、その後、細胞質にてユビキチン-プロテアソーム経路で分解されると考えられている<ref name=Yamano2013><pubmed>24121706</pubmed></ref> 。ミトコンドリア膜電位が低下すると、膜電位依存的な輸送効率が低下し、ミトコンドリア外膜に蓄積、自己会合および自己リン酸化により、キナーゼが活性化する<ref name=Okatsu2015><pubmed>25609704</pubmed></ref><ref><pubmed>name=Okatsu2012><pubmed>22910362</pubmed></ref><ref><pubmed>name=Okatsu2013><pubmed>24189060</pubmed></ref> (図5)。以上から、PINK1は膜電位が低下した(機能低下した)ミトコンドリアを検出するセンサーとして働くと考えられる。


活性化したPINK1は、近傍のポリユビキチン化修飾を受けたタンパク質(主にミトコンドリア外膜のタンパク質)をリン酸化する(リン酸化ポリユビキチン鎖の種の形成)。Parkinはリン酸化ポリユビキチンへの親和性が高く、細胞質からミトコンドリア上のリン酸化ポリユビキチンへ繋留され活性化する。活性化されたParkinは、近傍のミトコンドリアタンパク質をユビキチン化する。さらに、PINK1がParkinによるポリユビキチン鎖をリン酸化し、新たなリン酸化ポリユビキチン鎖をミトコンドリア外膜上に形成する(リン酸化ポリユビキチン鎖の増幅)。増幅されたリン酸化ポリユビキチン鎖に、細胞質に残っている不活性型Parkinが繋留され活性化し、PINK1と協働して、さらにリン酸化ポリユビキチン鎖を形成する(リン酸化ポリユビキチン鎖の再増幅)。PINK1とParkinの役割は、上述のようなフィードフォワードループを形成して、不良ミトコンドリアをリン酸化ポリユビキチン鎖にて速やかにマーキングすることだと考えられる(図4)<ref name=Ordureau2014><pubmed>25284222</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2014><pubmed>25474007</pubmed></ref>
 ミトコンドリア局在性キナーゼPINK1は、ミトコンドリア膜電位依存的に健常なミトコンドリアの内膜まで輸送され、ミトコンドリア内プロテアーゼMPP(mitochondrial processing peptidase) <ref name=Greene2012><pubmed>22354088</pubmed></ref> とPARL <ref name=Zhou2008><pubmed>18687899</pubmed></ref><ref><pubmed>name=Jin2010><pubmed>21115803</pubmed></ref> によって2段階の切断を受け、その後、細胞質にてユビキチン-プロテアソーム経路で分解されると考えられている<ref name=Yamano2013><pubmed>24121706</pubmed></ref> 。ミトコンドリア膜電位が低下すると、膜電位依存的な輸送効率が低下し、ミトコンドリア外膜に蓄積、自己会合および自己リン酸化により、キナーゼが活性化する<ref name=Okatsu2015><pubmed>25609704</pubmed></ref><ref><pubmed>name=Okatsu2012><pubmed>22910362</pubmed></ref><ref><pubmed>name=Okatsu2013><pubmed>24189060</pubmed></ref> (図5)。以上から、PINK1は膜電位が低下した(機能低下した)ミトコンドリアを検出するセンサーとして働くと考えられる。


マイトファジー時のParkinのユビキチン化基質は数多く報告され、ミトコンドリア外膜・内膜・マトリクスタンパク質のほか、細胞質や核のタンパク質も含まれる<ref name=Sarraf2013><pubmed>23503661</pubmed></ref> 。そのうち、Dynamin-like GTPase, Mitofusin(哺乳類ではMitofusin 1とMitofusin 2がある)は、Parkinによって早期にユビキチン化とその後のプロテアソーム経路での分解を受けるミトコンドリア外膜分子として知られる。Mitofusinの分解により、ミトコンドリアが断片化する<ref name=Gegg2010><pubmed>20871098</pubmed></ref><ref><pubmed>name=Poole2010><pubmed>20383334</pubmed></ref><ref><pubmed>name=Rakovic2011><pubmed>21408142</pubmed></ref><ref><pubmed>name=Tanaka2010><pubmed>21173115</pubmed></ref><ref><pubmed>name=Ziviani2010><pubmed>20194754</pubmed></ref> 。ミトコンドリアの断片化は、隔離膜形成とオートファジーによる除去を容易にすると考えられる<ref name=Tanaka2010><pubmed>21173115</pubmed></ref> 。実際、ミトコンドリア断片化に働くDynamin-like GTPase, Drp1の過剰発現は、ParkinやPINK1ノックアウトハエのミトコンドリア変性を緩和する<ref name=Deng2008><pubmed>18799731</pubmed></ref><ref><pubmed>name=Yang2008><pubmed>18443288</pubmed></ref> 。このDrp1の効果は、Parkin非介在マイトファジーによる補完を促進するからと考えられる。
 活性化したPINK1は、近傍のポリユビキチン化修飾を受けたタンパク質(主にミトコンドリア外膜のタンパク質)をリン酸化する(リン酸化ポリユビキチン鎖の種の形成)。Parkinはリン酸化ポリユビキチンへの親和性が高く、細胞質からミトコンドリア上のリン酸化ポリユビキチンへ繋留され活性化する。活性化されたParkinは、近傍のミトコンドリアタンパク質をユビキチン化する。さらに、PINK1がParkinによるポリユビキチン鎖をリン酸化し、新たなリン酸化ポリユビキチン鎖をミトコンドリア外膜上に形成する(リン酸化ポリユビキチン鎖の増幅)。増幅されたリン酸化ポリユビキチン鎖に、細胞質に残っている不活性型Parkinが繋留され活性化し、PINK1と協働して、さらにリン酸化ポリユビキチン鎖を形成する(リン酸化ポリユビキチン鎖の再増幅)。PINK1とParkinの役割は、上述のようなフィードフォワードループを形成して、不良ミトコンドリアをリン酸化ポリユビキチン鎖にて速やかにマーキングすることだと考えられる(図4)<ref name=Ordureau2014><pubmed>25284222</pubmed></ref><ref><pubmed>name=Shiba-Fukushima2014><pubmed>25474007</pubmed></ref>


 マイトファジー時のParkinのユビキチン化基質は数多く報告され、ミトコンドリア外膜・内膜・マトリクスタンパク質のほか、細胞質や核のタンパク質も含まれる<ref name=Sarraf2013><pubmed>23503661</pubmed></ref> 。そのうち、Dynamin-like GTPase, Mitofusin(哺乳類ではMitofusin 1とMitofusin 2がある)は、Parkinによって早期にユビキチン化とその後のプロテアソーム経路での分解を受けるミトコンドリア外膜分子として知られる。Mitofusinの分解により、ミトコンドリアが断片化する<ref name=Gegg2010><pubmed>20871098</pubmed></ref><ref><pubmed>name=Poole2010><pubmed>20383334</pubmed></ref><ref><pubmed>name=Rakovic2011><pubmed>21408142</pubmed></ref><ref><pubmed>name=Tanaka2010><pubmed>21173115</pubmed></ref><ref><pubmed>name=Ziviani2010><pubmed>20194754</pubmed></ref> 。ミトコンドリアの断片化は、隔離膜形成とオートファジーによる除去を容易にすると考えられる<ref name=Tanaka2010><pubmed>21173115</pubmed></ref> 。実際、ミトコンドリア断片化に働くDynamin-like GTPase, Drp1の過剰発現は、ParkinやPINK1ノックアウトハエのミトコンドリア変性を緩和する<ref name=Deng2008><pubmed>18799731</pubmed></ref><ref><pubmed>name=Yang2008><pubmed>18443288</pubmed></ref> 。このDrp1の効果は、Parkin非介在マイトファジーによる補完を促進するからと考えられる。


生理的なミトコンドリア排除へのParkinの関与も報告されている。寒冷暴露に応じて発達するベージュ脂肪細胞は、熱産生のためにミトコンドリアが豊富である。しかし寒冷ストレスがなくなると、脂肪滴貯蔵のためミトコンドリアが少ない白色脂肪細胞へと変化する。ベージュ脂肪細胞の白色脂肪細胞化の際に不要となったミトコンドリアがParkinによって除去される<ref name=Lu2018><pubmed>29692364</pubmed></ref> 。
 生理的なミトコンドリア排除へのParkinの関与も報告されている。寒冷暴露に応じて発達するベージュ脂肪細胞は、熱産生のためにミトコンドリアが豊富である。しかし寒冷ストレスがなくなると、脂肪滴貯蔵のためミトコンドリアが少ない白色脂肪細胞へと変化する。ベージュ脂肪細胞の白色脂肪細胞化の際に不要となったミトコンドリアがParkinによって除去される<ref name=Lu2018><pubmed>29692364</pubmed></ref> 。


===ミトコンドリア輸送制御===
===ミトコンドリア輸送制御===
ミトコンドリア外膜Rho-GTPase, Miro (哺乳類ではMiro 1とMiro 2がある)は、キネシンタンパク質KIF5と協働して、微小管を介したミトコンドリアの順行輸送に関与する<ref name=Wang2011><pubmed>22078885</pubmed></ref><ref><pubmed>name=Liu2012><pubmed>22396657</pubmed></ref> 。神経細胞においては、神経軸索、前シナプスへのミトコンドリア供給機構として重要である。MiroがPINK1-Parkinによりユビキチン化、プロテアソーム経路での分解を受けることにより、ミトコンドリア輸送が停止する<ref name=Wang2011><pubmed>22078885</pubmed></ref><ref><pubmed>name=Liu2012><pubmed>22396657</pubmed></ref> 。その生理的意義として、不良ミトコンドリアを神経終末へ輸送しないミトコンドリア品質管理と考えられる(図6)。
 ミトコンドリア外膜Rho-GTPase, Miro (哺乳類ではMiro 1とMiro 2がある)は、キネシンタンパク質KIF5と協働して、微小管を介したミトコンドリアの順行輸送に関与する<ref name=Wang2011><pubmed>22078885</pubmed></ref><ref><pubmed>name=Liu2012><pubmed>22396657</pubmed></ref> 。神経細胞においては、神経軸索、前シナプスへのミトコンドリア供給機構として重要である。MiroがPINK1-Parkinによりユビキチン化、プロテアソーム経路での分解を受けることにより、ミトコンドリア輸送が停止する<ref name=Wang2011><pubmed>22078885</pubmed></ref><ref><pubmed>name=Liu2012><pubmed>22396657</pubmed></ref> 。その生理的意義として、不良ミトコンドリアを神経終末へ輸送しないミトコンドリア品質管理と考えられる(図6)。


===ゼノファジーへの関与===
===ゼノファジーへの関与===
ParkinはPACRG (Parkin co-regulated gene)とともにサルモネラ菌、らい菌感染の感受性遺伝子座に位置する<ref name=Mira2004><pubmed>14737177</pubmed></ref><ref><pubmed>name=Ali2006><pubmed>16734611</pubmed></ref> 。実験的にParkinが結核菌のゼノファジー(異物排除のためのオートファジー)に関与することが示されたが、Parkinが活性化するメカニズムは不明である<ref name=Manzanillo2013><pubmed>24005326</pubmed></ref> 。
 ParkinはPACRG (Parkin co-regulated gene)とともにサルモネラ菌、らい菌感染の感受性遺伝子座に位置する<ref name=Mira2004><pubmed>14737177</pubmed></ref><ref><pubmed>name=Ali2006><pubmed>16734611</pubmed></ref> 。実験的にParkinが結核菌のゼノファジー(異物排除のためのオートファジー)に関与することが示されたが、Parkinが活性化するメカニズムは不明である<ref name=Manzanillo2013><pubmed>24005326</pubmed></ref> 。


===個体レベルでの機能===
===個体レベルでの機能===
ミトコンドリアゲノム変異<ref name=Pickrell2015><pubmed>26182419</pubmed></ref> ・異常タンパク質のミトコンドリアへの蓄積<ref name=Pimenta de Castro2012><pubmed>22301916</pubmed></ref> を示す動物モデルで、Parkinが不良ミトコンドリアの除去に関与することが示されている。しかし、マイトファジーを可視化できるmito-QCマウスの中脳黒質ドーパミン神経では、Parkinを介したマイトファジーは検出されていない<ref name=McWilliams2018><pubmed>29337137</pubmed></ref> 。一方、マイトファジーを可視化するmt-Keimaを用いたマウスでは、PINK1の欠失によって、強負荷運動後の心筋におけるマイトファジーが減少することが報告されている<ref name=Sliter2018><pubmed>30135585</pubmed></ref> 。
 ミトコンドリアゲノム変異<ref name=Pickrell2015><pubmed>26182419</pubmed></ref> ・異常タンパク質のミトコンドリアへの蓄積<ref name=Pimenta de Castro2012><pubmed>22301916</pubmed></ref> を示す動物モデルで、Parkinが不良ミトコンドリアの除去に関与することが示されている。しかし、マイトファジーを可視化できるmito-QCマウスの中脳黒質ドーパミン神経では、Parkinを介したマイトファジーは検出されていない<ref name=McWilliams2018><pubmed>29337137</pubmed></ref> 。一方、マイトファジーを可視化するmt-Keimaを用いたマウスでは、PINK1の欠失によって、強負荷運動後の心筋におけるマイトファジーが減少することが報告されている<ref name=Sliter2018><pubmed>30135585</pubmed></ref> 。


ショウジョウバエでは、加齢依存的な中枢ドーパミン神経のマイトファジーにParkinが関与するという報告<ref name=Cornelissen2018><pubmed>29809156</pubmed></ref> 、しないという報告<ref name=Lee2018><pubmed>29500189</pubmed></ref><ref><pubmed>name=Kim2019><pubmed>31120803</pubmed></ref> がある。ただし文献<ref name=Kim2019><pubmed>31120803</pubmed></ref> では、非神経組織において、低酸素処理によるマイトファジーや、ミトコンドリアから活性酸素種を発生させるロテノン処理で誘導されるマイトファジーにPINK1、Parkinが関与すると報告している。ショウジョウバエモデルにおいて、PINK1やParkinが中枢ドーパミン神経のマイトファジーに関与するという文献<ref name=Cornelissen2018><pubmed>29809156</pubmed></ref> ではmt-Keimaを、関与しないという文献<ref name=Lee2018><pubmed>29500189</pubmed></ref> ではmt-Keimaとmito-QCを、非神経組織でのPINK1-Parkin依存的なマイトファジーをみた文献<ref name=Kim2019><pubmed>31120803</pubmed></ref> ではmt-Keimaを、マイトファジーのレポーターとして用いている。今後、新たなマイトファジー解析手法が待たれる状況である。
 ショウジョウバエでは、加齢依存的な中枢ドーパミン神経のマイトファジーにParkinが関与するという報告<ref name=Cornelissen2018><pubmed>29809156</pubmed></ref> 、しないという報告<ref name=Lee2018><pubmed>29500189</pubmed></ref><ref><pubmed>name=Kim2019><pubmed>31120803</pubmed></ref> がある。ただし文献<ref name=Kim2019><pubmed>31120803</pubmed></ref> では、非神経組織において、低酸素処理によるマイトファジーや、ミトコンドリアから活性酸素種を発生させるロテノン処理で誘導されるマイトファジーにPINK1、Parkinが関与すると報告している。ショウジョウバエモデルにおいて、PINK1やParkinが中枢ドーパミン神経のマイトファジーに関与するという文献<ref name=Cornelissen2018><pubmed>29809156</pubmed></ref> ではmt-Keimaを、関与しないという文献<ref name=Lee2018><pubmed>29500189</pubmed></ref> ではmt-Keimaとmito-QCを、非神経組織でのPINK1-Parkin依存的なマイトファジーをみた文献<ref name=Kim2019><pubmed>31120803</pubmed></ref> ではmt-Keimaを、マイトファジーのレポーターとして用いている。今後、新たなマイトファジー解析手法が待たれる状況である。


ショウジョウバエでは、ParkinやPINK1変異でミトコンドリア呼吸鎖複合体サブユニット群の半減期が長くなっており、マイトファジー以外の選択的なミトコンドリアタンパク質分解機構も提唱されている<ref name=Vincow2013><pubmed>23509287</pubmed></ref><ref><pubmed>name=McLelland2016><pubmed>27458136</pubmed></ref> 。
 ショウジョウバエでは、ParkinやPINK1変異でミトコンドリア呼吸鎖複合体サブユニット群の半減期が長くなっており、マイトファジー以外の選択的なミトコンドリアタンパク質分解機構も提唱されている<ref name=Vincow2013><pubmed>23509287</pubmed></ref><ref><pubmed>name=McLelland2016><pubmed>27458136</pubmed></ref> 。


AR-JP脳アストロサイトの形態的異常や患者iPS細胞で作製した中脳オルガノイドでのアストロサイトの分化能低下<ref name=Kano2020><pubmed></pubmed></ref> 、Parkinノックアウトマウスにおいてアストロサイトのミトコンドリア損傷の報告<ref name=Schmidt2011><pubmed>21212098</pubmed></ref> がある。
 AR-JP脳アストロサイトの形態的異常や患者iPS細胞で作製した中脳オルガノイドでのアストロサイトの分化能低下<ref name=Kano2020><pubmed></pubmed></ref> 、Parkinノックアウトマウスにおいてアストロサイトのミトコンドリア損傷の報告<ref name=Schmidt2011><pubmed>21212098</pubmed></ref> がある。


免疫・炎症へのParkinの関与が示唆されている。PINK1とParkinは、ミトコンドリアの抗原提示経路に関わる分子Sorting nexin-9を分解し、T細胞への抗原提示を阻害する。Parkinのこの機能が過剰な免疫反応を抑制している可能性が報告された<ref name=Matheoud2016><pubmed>27345367</pubmed></ref> . PINK1, Parkinノックアウトマウスでは、ミトコンドリアへの強い負荷(激しい運動やミトコンドリアDNAへの構成的な変異の蓄積)により、STING経路を介した炎症性サイトカインの上昇がみられる <ref name=Sliter2018><pubmed>30135585</pubmed></ref> 。STINGは血清中に遊離した損傷ミトコンドリアのDNAを認識し、自然免疫を活性化する。ミトコンドリアストレスで生した損傷ミトコンドリアのPINK1-Parkin経路を介したマイトファジーでの除去が、炎症の沈静化に寄与していることが示唆されている。
 免疫・炎症へのParkinの関与が示唆されている。PINK1とParkinは、ミトコンドリアの抗原提示経路に関わる分子Sorting nexin-9を分解し、T細胞への抗原提示を阻害する。Parkinのこの機能が過剰な免疫反応を抑制している可能性が報告された<ref name=Matheoud2016><pubmed>27345367</pubmed></ref> . PINK1, Parkinノックアウトマウスでは、ミトコンドリアへの強い負荷(激しい運動やミトコンドリアDNAへの構成的な変異の蓄積)により、STING経路を介した炎症性サイトカインの上昇がみられる <ref name=Sliter2018><pubmed>30135585</pubmed></ref> 。STINGは血清中に遊離した損傷ミトコンドリアのDNAを認識し、自然免疫を活性化する。ミトコンドリアストレスで生した損傷ミトコンドリアのPINK1-Parkin経路を介したマイトファジーでの除去が、炎症の沈静化に寄与していることが示唆されている。


==疾患との関わり==
==疾患との関わり==
PRKNのホモ接合性変異、複合ヘテロ接合性変異で、若年発症のパーキンソン病を発症する。ヘテロ接合性変異により、パーキンソン病を晩発で発症する例も見られる<ref name=Klein2007><pubmed>17582365</pubmed></ref> 。PRKNの病因変異やレアバリアントの報告は、世界中で多数あり、以下のデータベースで検索できる。
 PRKNのホモ接合性変異、複合ヘテロ接合性変異で、若年発症のパーキンソン病を発症する。ヘテロ接合性変異により、パーキンソン病を晩発で発症する例も見られる<ref name=Klein2007><pubmed>17582365</pubmed></ref> 。PRKNの病因変異やレアバリアントの報告は、世界中で多数あり、以下のデータベースで検索できる。


MDS gene の Parkin
[https://www.mdsgene.org/d/1/g/4 MDS gene の Parkin]
https://www.mdsgene.org/d/1/g/4


LOVD の  PARK2
[https://databases.lovd.nl/shared/variants/PARK2/unique LOVD の  PARK2]
https://databases.lovd.nl/shared/variants/PARK2/unique


バリアントデータベースとして以下も利用できる。
バリアントデータベースとして以下も利用できる。


ClinVar
[https://www.ncbi.nlm.nih.gov/clinvar/ ClinVar]
https://www.ncbi.nlm.nih.gov/clinvar/
 
[http://www.hgmd.cf.ac.uk/ac/index.php HGMD(有料)]


HGMD(有料)
[https://decipher.sanger.ac.uk/browser DECIPHER Genome Browser]
http://www.hgmd.cf.ac.uk/ac/index.php


DECIPHER Genome Browser
 PRKNミスセンス病因変異・レアバリアントとタンパク質の安定性・マイトファジーとの相関を培養細胞で調べた研究がある<ref name=Yi2019><pubmed>30994895</pubmed></ref> 。病態が比較的重篤なミスセンス病因変異は、すべてマイトファジー活性が50%以下に低下していた。しかし、病態が軽度・病態への意義が不明なミスセンス病因変異・レアバリアントでは、マイトファジーへの影響がほとんどなく、まれに亢進しているものも観察された。ユビキチンリガーゼ活性やタンパク質の安定性に影響しない病因変異については、不活性状態を解くアミノ酸への置換(REPを不安定化させるF146AやW403A、図3参照)の導入により、マイトファジー活性が戻ることが示された。この観察は、Parkinの不活性状態を解く化合物がパーキンソン病の疾患修飾薬となる可能性を示唆している。
https://decipher.sanger.ac.uk/browser


PRKNミスセンス病因変異・レアバリアントとタンパク質の安定性・マイトファジーとの相関を培養細胞で調べた研究がある<ref name=Yi2019><pubmed>30994895</pubmed></ref> 。病態が比較的重篤なミスセンス病因変異は、すべてマイトファジー活性が50%以下に低下していた。しかし、病態が軽度・病態への意義が不明なミスセンス病因変異・レアバリアントでは、マイトファジーへの影響がほとんどなく、まれに亢進しているものも観察された。ユビキチンリガーゼ活性やタンパク質の安定性に影響しない病因変異については、不活性状態を解くアミノ酸への置換(REPを不安定化させるF146AやW403A、図3参照)の導入により、マイトファジー活性が戻ることが示された。この観察は、Parkinの不活性状態を解く化合物がパーキンソン病の疾患修飾薬となる可能性を示唆している。
 Parkin変異によるパーキンソン病の典型的な臨床像として、40歳未満での発症、緩慢な病態進行、正常な認知機能、下肢ジストニア、良好なL-ドーパへの反応性、が挙げられる <ref name=久保紳一郎、波田野琢、服部信孝2013><pubmed></pubmed></ref> 。神経病理学的特徴として、黒質および青斑核に限局した神経細胞減少を示し、グリオーシスは通常見られない。孤発性パーキンソン病の特徴的病理所見であるレビュー小体は通常みられない<ref name=久保紳一郎、波田野琢、服部信孝2013><pubmed></pubmed></ref> 。10歳未満での発症の報告もあり、Parkinはドーパミン神経発生の段階で機能していることが推察される<ref name=Matsumine1997><pubmed>9042918</pubmed></ref><ref><pubmed>name=Takei2000><pubmed>11086400</pubmed></ref> 。


Parkin変異によるパーキンソン病の典型的な臨床像として、40歳未満での発症、緩慢な病態進行、正常な認知機能、下肢ジストニア、良好なL-ドーパへの反応性、が挙げられる <ref name=久保紳一郎、波田野琢、服部信孝2013><pubmed></pubmed></ref> 。神経病理学的特徴として、黒質および青斑核に限局した神経細胞減少を示し、グリオーシスは通常見られない。孤発性パーキンソン病の特徴的病理所見であるレビュー小体は通常みられない<ref name=久保紳一郎、波田野琢、服部信孝2013><pubmed></pubmed></ref> 。10歳未満での発症の報告もあり、Parkinはドーパミン神経発生の段階で機能していることが推察される<ref name=Matsumine1997><pubmed>9042918</pubmed></ref><ref><pubmed>name=Takei2000><pubmed>11086400</pubmed></ref> 。
 Parkin変異患者由来のiPS細胞から作製したドーパミン神経では、リン酸化ユビキチンのシグナルが低下し、不良ミトコンドリアの神経軸索輸送停止が障害されている<ref name=Shiba-Fukushima2017><pubmed>28541509</pubmed></ref> 。
Parkin変異患者由来のiPS細胞から作製したドーパミン神経では、リン酸化ユビキチンのシグナルが低下し、不良ミトコンドリアの神経軸索輸送停止が障害されている<ref name=Shiba-Fukushima2017><pubmed>28541509</pubmed></ref> 。
その他、がん抑制遺伝子として、いくつか報告がある<ref name=Denison2003><pubmed>12874785</pubmed></ref><ref><pubmed>name=Cesari2003><pubmed>12719539</pubmed></ref><ref><pubmed>name=Fujiwara2008><pubmed>18574468</pubmed></ref><ref><pubmed>name=Veeriah2010><pubmed>19946270</pubmed></ref><ref><pubmed>name=Gong2014><pubmed>24793136</pubmed></ref> 。
その他、がん抑制遺伝子として、いくつか報告がある<ref name=Denison2003><pubmed>12874785</pubmed></ref><ref><pubmed>name=Cesari2003><pubmed>12719539</pubmed></ref><ref><pubmed>name=Fujiwara2008><pubmed>18574468</pubmed></ref><ref><pubmed>name=Veeriah2010><pubmed>19946270</pubmed></ref><ref><pubmed>name=Gong2014><pubmed>24793136</pubmed></ref> 。


==関連項目==
==関連項目==

2020年11月5日 (木) 20:47時点における版

 Parkin遺伝子は、常染色体性潜性(劣性)若年性パーキンソニズム(autosomal recessive-juvenile parkinsonism: AR-JP) の原因遺伝子である。Parkin遺伝子の正式名称はPRKNであり、PARK2とも表記される。遺伝子産物Parkinはユビキチン転移酵素(ユビキチンリガーゼ)であり、損傷したミトコンドリアを排除するミトコンドリアの品質管理に関与すると考えられている。一方、がん抑制遺伝子、らい菌の感受性遺伝子としても報告され、未解明の生理的機能も示唆される。

背景、歴史的推移

 パーキンソン病は振戦、無動・寡動、筋固縮、姿勢保持障害などの運動機能障害を特徴とする神経変性疾患である。運動症状は中脳黒質のドーパミン神経の選択的変性脱落に起因する。高齢になるほど発病率が増加し、60歳以上では約1%が罹患する。パーキンソン病の一部に、40歳以下で発症する若年性パーキンソン病と呼ばれる群があり、そのうち家族性(遺伝性)のものがいくつかみつかっている。

 1998年、若年性パーキンソン病の一つである常染色体性潜性(劣性)若年性パーキンソニズム(Autosomal Recessive-Juvenile Parkinsonism: AR-JP)の原因遺伝子としてParkin (PRKN, PARK2)が同定された[1] 。パーキンソン病原因遺伝子としては、α-Synuclein (SNCA; PARK1/PARK4)に次いで、2番目に同定された遺伝子である。Parkinは、6番染色体(6q26)にある1.38 Mbの巨大な遺伝子で、欠失変異、フレームシフト変異、ミスセンス変異が、遺伝子全体にわたって見つかっている。Parkin変異は人種を越えてみられ、遺伝性若年性パーキンソン病の約50%を占めると報告されている[2][3]

 Parkinタンパク質は基質タンパク質にユビキチンを転移するユビキチンリガーゼで、多くの病因変異でその活性が損なわれている[4][5][6] 。これまでにユビキチン化基質候補として数多くのタンパク質が報告されている[7]

 2004年、PINK1(PTEN induced kinase 1; PARK6)が、常染色体性潜性若年性パーキンソン病原因遺伝子として同定された[8] 。遺伝性若年性パーキンソン病のうち、PINK1変異はParkinに次いで頻度が高く、Parkinと臨床像は類似している[9] 。ショウジョウバエを用いた遺伝学的研究から、常染色体性潜性(劣性)若年性パーキンソン病原因遺伝子PINK1がParkinの上流因子であり、PINK1とParkinがミトコンドリアの機能維持に関与することが明らかとなった[10][11][12] 。その後、ヒト培養細胞を用いた研究から、PINK1がParkinをリン酸化し[13][14][15] 、協働して膜電位の低下したミトコンドリアを除去するマイトファジー(ミトコンドリアを対象とするオートファジー)に関与することが明らかになった(図1)[16][17][18][19]

構造

 ヒトParkinタンパク質は465 アミノ酸残基からなり、N末端のユビキチン様ドメイン(Ubl)、C末端に2つのRING fingerモチーフ(RING1, RING2)とIn-Between-RINGs (IBR)という構造をもつ(図2)。その後、UblとRNIG1-IBR-RING2の間に、RING様構造が見つかり、RING0(またはUPD; unique parkin domain)と呼ばれる[20] (図2)。Parkinは、RING-IBR-RINGドメインを有するRBR型ユビキチンリガーゼに分類され、同様の構造をもヒトユビキチンリガーゼに、HOIL-1, HHARI, DORFINがある。タンパク質の全体構造は2013-2015年に解かれ、コンパクトに折り畳まれた状態であることが明らかとなった[21][22] (図3)。

活性化機構

 コンパクトに折り畳まれたParkinは、活性中心がマスクされ不活性型である。Parkinの活性化は2つのステップで起こる。1段階目として、PINK1によってSer65がリン酸化されたユビキチン[23][24][25] がParkinのリン酸基結合ポケットに結合し、Ublのリン酸化サイト(Ser65)が露出する。2段階目に、露出したUblのSer65がPINK1によりリン酸化され、リン酸化UblがRING0/UPDに結合することで、RING2にある活性中心とRING1にあるユビキチン結合酵素(E2)結合部位が安定的に露出する[26] (図3)。

発現

 ヒトParkin mRNAはユビキタスに発現しているが、筋組織、腎臓、脳で比較的高発現をしている[1][27] 。哺乳類ゲノムにおいて、PRKNはPACRG (Parkin co-regulated gene)と双方向プロモーターを共有する[28] 。Parkinの発現を制御する転写因子として、N-myc [29] , p53 [30] , ATF4 [31] が報告されている。小胞体ストレス・ミトコンドリアストレス [32][33][34] 、成長因子・栄養制限 [35] などの環境要因でも発現上昇が見られる。

 哺乳類細胞内では主に細胞質に局在するが、PINK1の活性化に伴って、ミトコンドリアへの集積が見られる[36][37] 。PINK1によるParkinのミトコンドリアへの集積の分子メカニズムは、2014-2015年に明らかされた(図4)[38][39][40]

機能

不良(不要)ミトコンドリアのマイトファジー

 細胞での機能として、PINK1と協働してマイトファジーに関与することが、培養細胞でキャラクタライズされている。

 ミトコンドリア局在性キナーゼPINK1は、ミトコンドリア膜電位依存的に健常なミトコンドリアの内膜まで輸送され、ミトコンドリア内プロテアーゼMPP(mitochondrial processing peptidase) [41] とPARL [42][43] によって2段階の切断を受け、その後、細胞質にてユビキチン-プロテアソーム経路で分解されると考えられている[44] 。ミトコンドリア膜電位が低下すると、膜電位依存的な輸送効率が低下し、ミトコンドリア外膜に蓄積、自己会合および自己リン酸化により、キナーゼが活性化する[45][46][47] (図5)。以上から、PINK1は膜電位が低下した(機能低下した)ミトコンドリアを検出するセンサーとして働くと考えられる。

 活性化したPINK1は、近傍のポリユビキチン化修飾を受けたタンパク質(主にミトコンドリア外膜のタンパク質)をリン酸化する(リン酸化ポリユビキチン鎖の種の形成)。Parkinはリン酸化ポリユビキチンへの親和性が高く、細胞質からミトコンドリア上のリン酸化ポリユビキチンへ繋留され活性化する。活性化されたParkinは、近傍のミトコンドリアタンパク質をユビキチン化する。さらに、PINK1がParkinによるポリユビキチン鎖をリン酸化し、新たなリン酸化ポリユビキチン鎖をミトコンドリア外膜上に形成する(リン酸化ポリユビキチン鎖の増幅)。増幅されたリン酸化ポリユビキチン鎖に、細胞質に残っている不活性型Parkinが繋留され活性化し、PINK1と協働して、さらにリン酸化ポリユビキチン鎖を形成する(リン酸化ポリユビキチン鎖の再増幅)。PINK1とParkinの役割は、上述のようなフィードフォワードループを形成して、不良ミトコンドリアをリン酸化ポリユビキチン鎖にて速やかにマーキングすることだと考えられる(図4)[38][48]

 マイトファジー時のParkinのユビキチン化基質は数多く報告され、ミトコンドリア外膜・内膜・マトリクスタンパク質のほか、細胞質や核のタンパク質も含まれる[49] 。そのうち、Dynamin-like GTPase, Mitofusin(哺乳類ではMitofusin 1とMitofusin 2がある)は、Parkinによって早期にユビキチン化とその後のプロテアソーム経路での分解を受けるミトコンドリア外膜分子として知られる。Mitofusinの分解により、ミトコンドリアが断片化する[50][51][52][53][54] 。ミトコンドリアの断片化は、隔離膜形成とオートファジーによる除去を容易にすると考えられる[55] 。実際、ミトコンドリア断片化に働くDynamin-like GTPase, Drp1の過剰発現は、ParkinやPINK1ノックアウトハエのミトコンドリア変性を緩和する[56][57] 。このDrp1の効果は、Parkin非介在マイトファジーによる補完を促進するからと考えられる。

 生理的なミトコンドリア排除へのParkinの関与も報告されている。寒冷暴露に応じて発達するベージュ脂肪細胞は、熱産生のためにミトコンドリアが豊富である。しかし寒冷ストレスがなくなると、脂肪滴貯蔵のためミトコンドリアが少ない白色脂肪細胞へと変化する。ベージュ脂肪細胞の白色脂肪細胞化の際に不要となったミトコンドリアがParkinによって除去される[58]

ミトコンドリア輸送制御

 ミトコンドリア外膜Rho-GTPase, Miro (哺乳類ではMiro 1とMiro 2がある)は、キネシンタンパク質KIF5と協働して、微小管を介したミトコンドリアの順行輸送に関与する[59][60] 。神経細胞においては、神経軸索、前シナプスへのミトコンドリア供給機構として重要である。MiroがPINK1-Parkinによりユビキチン化、プロテアソーム経路での分解を受けることにより、ミトコンドリア輸送が停止する[59][61] 。その生理的意義として、不良ミトコンドリアを神経終末へ輸送しないミトコンドリア品質管理と考えられる(図6)。

ゼノファジーへの関与

 ParkinはPACRG (Parkin co-regulated gene)とともにサルモネラ菌、らい菌感染の感受性遺伝子座に位置する[62][63] 。実験的にParkinが結核菌のゼノファジー(異物排除のためのオートファジー)に関与することが示されたが、Parkinが活性化するメカニズムは不明である[64]

個体レベルでの機能

 ミトコンドリアゲノム変異[65] ・異常タンパク質のミトコンドリアへの蓄積引用エラー: 無効な <ref> タグです。数が多すぎるなどの理由で名前が無効です を示す動物モデルで、Parkinが不良ミトコンドリアの除去に関与することが示されている。しかし、マイトファジーを可視化できるmito-QCマウスの中脳黒質ドーパミン神経では、Parkinを介したマイトファジーは検出されていない[66] 。一方、マイトファジーを可視化するmt-Keimaを用いたマウスでは、PINK1の欠失によって、強負荷運動後の心筋におけるマイトファジーが減少することが報告されている[67]

 ショウジョウバエでは、加齢依存的な中枢ドーパミン神経のマイトファジーにParkinが関与するという報告[68] 、しないという報告[69][70] がある。ただし文献[71] では、非神経組織において、低酸素処理によるマイトファジーや、ミトコンドリアから活性酸素種を発生させるロテノン処理で誘導されるマイトファジーにPINK1、Parkinが関与すると報告している。ショウジョウバエモデルにおいて、PINK1やParkinが中枢ドーパミン神経のマイトファジーに関与するという文献[68] ではmt-Keimaを、関与しないという文献[69] ではmt-Keimaとmito-QCを、非神経組織でのPINK1-Parkin依存的なマイトファジーをみた文献[71] ではmt-Keimaを、マイトファジーのレポーターとして用いている。今後、新たなマイトファジー解析手法が待たれる状況である。

 ショウジョウバエでは、ParkinやPINK1変異でミトコンドリア呼吸鎖複合体サブユニット群の半減期が長くなっており、マイトファジー以外の選択的なミトコンドリアタンパク質分解機構も提唱されている[72][73]

 AR-JP脳アストロサイトの形態的異常や患者iPS細胞で作製した中脳オルガノイドでのアストロサイトの分化能低下[74] 、Parkinノックアウトマウスにおいてアストロサイトのミトコンドリア損傷の報告[75] がある。

 免疫・炎症へのParkinの関与が示唆されている。PINK1とParkinは、ミトコンドリアの抗原提示経路に関わる分子Sorting nexin-9を分解し、T細胞への抗原提示を阻害する。Parkinのこの機能が過剰な免疫反応を抑制している可能性が報告された[76] . PINK1, Parkinノックアウトマウスでは、ミトコンドリアへの強い負荷(激しい運動やミトコンドリアDNAへの構成的な変異の蓄積)により、STING経路を介した炎症性サイトカインの上昇がみられる [67] 。STINGは血清中に遊離した損傷ミトコンドリアのDNAを認識し、自然免疫を活性化する。ミトコンドリアストレスで生した損傷ミトコンドリアのPINK1-Parkin経路を介したマイトファジーでの除去が、炎症の沈静化に寄与していることが示唆されている。

疾患との関わり

 PRKNのホモ接合性変異、複合ヘテロ接合性変異で、若年発症のパーキンソン病を発症する。ヘテロ接合性変異により、パーキンソン病を晩発で発症する例も見られる[77] 。PRKNの病因変異やレアバリアントの報告は、世界中で多数あり、以下のデータベースで検索できる。

MDS gene の Parkin

LOVD の PARK2

バリアントデータベースとして以下も利用できる。

ClinVar

HGMD(有料)

DECIPHER Genome Browser

 PRKNミスセンス病因変異・レアバリアントとタンパク質の安定性・マイトファジーとの相関を培養細胞で調べた研究がある[78] 。病態が比較的重篤なミスセンス病因変異は、すべてマイトファジー活性が50%以下に低下していた。しかし、病態が軽度・病態への意義が不明なミスセンス病因変異・レアバリアントでは、マイトファジーへの影響がほとんどなく、まれに亢進しているものも観察された。ユビキチンリガーゼ活性やタンパク質の安定性に影響しない病因変異については、不活性状態を解くアミノ酸への置換(REPを不安定化させるF146AやW403A、図3参照)の導入により、マイトファジー活性が戻ることが示された。この観察は、Parkinの不活性状態を解く化合物がパーキンソン病の疾患修飾薬となる可能性を示唆している。

 Parkin変異によるパーキンソン病の典型的な臨床像として、40歳未満での発症、緩慢な病態進行、正常な認知機能、下肢ジストニア、良好なL-ドーパへの反応性、が挙げられる [79] 。神経病理学的特徴として、黒質および青斑核に限局した神経細胞減少を示し、グリオーシスは通常見られない。孤発性パーキンソン病の特徴的病理所見であるレビュー小体は通常みられない[79] 。10歳未満での発症の報告もあり、Parkinはドーパミン神経発生の段階で機能していることが推察される[80][81]

 Parkin変異患者由来のiPS細胞から作製したドーパミン神経では、リン酸化ユビキチンのシグナルが低下し、不良ミトコンドリアの神経軸索輸送停止が障害されている[82] 。 その他、がん抑制遺伝子として、いくつか報告がある[83][84][85][86][87]

関連項目

参考文献

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    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
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    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
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    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
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    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
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    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  15. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  16. Narendra, D., Tanaka, A., Suen, D.F., & Youle, R.J. (2008).
    Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. The Journal of cell biology, 183(5), 795-803. [PubMed:19029340] [PMC] [WorldCat] [DOI]
  17. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  18. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  19. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
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    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

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    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
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    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

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    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

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    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

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    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
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    Moin-Vaziri, V., & Badakhshan, M. (2023).
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    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
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    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
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    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
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    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
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    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

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    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
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    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
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    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
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    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
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    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
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    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

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    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
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    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

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    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

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    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
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    Moin-Vaziri, V., & Badakhshan, M. (2023).
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    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
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    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
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    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
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    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
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    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

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    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
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    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
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    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
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    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
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    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
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    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
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    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
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    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
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    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

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    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

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    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
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    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
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  84. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  85. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  86. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]
  87. Grabowska, M.E., Huang, A., Wen, Z., Li, B., & Wei, W.Q. (2023).
    Drug repurposing for Alzheimer's disease from 2012-2022-a 10-year literature review. Frontiers in pharmacology, 14, 1257700. [PubMed:37745051] [PMC] [WorldCat] [DOI]

    Abdalla, S., Abdalla, M., Saad, M., Jones, D., Podolsky, S., & Abdalla, M. (2023).
    Ethnicity and gender trends of UK authors in The British Medical Journal and the Lancet over the past two decades: a comprehensive longitudinal analysis. EClinicalMedicine, 64, 102174. [PubMed:37711218] [PMC] [WorldCat] [DOI]

    Asif, F., Sultan, F., Masood, I., Baig, S., Ekmecki, P.E., Vaswani, V., ..., & Crawley, F. (2023).
    A Scoping Review Of The Literature Of Research Ethics Committees And Ethics Review Framework In Pakistan: What We Know And What We Still Need To Learn. JPMA. The Journal of the Pakistan Medical Association, 73(8), 1667-1674. [PubMed:37697760] [WorldCat] [DOI]

    Demeli, A., & Meyer, J.C. (2023).
    The assessment of haematologic and serum chemistry parameters in canine pyometra: a systematic review and meta-analysis. The Journal of small animal practice, 64(9), 543-551. [PubMed:37691297] [WorldCat] [DOI]

    Shariat, A., Najafabadi, M.G., Kelly Dos Santos, I., Anastasio, A.T., Milajerdi, H.R., Hassanzadeh, G., & Nouri, E. (2023).
    The effectiveness of aquatic therapy on motor and social skill as well as executive function in children with neurodevelopmental disorder: A systematic review and meta-analysis. Archives of physical medicine and rehabilitation. [PubMed:37690741] [WorldCat] [DOI]

    Bailly, C. (2023).
    Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). Journal of ethnopharmacology, 319(Pt 1), 117127. [PubMed:37683930] [WorldCat] [DOI]

    Moghadasi, A.N., Ebrahimi, N., Haghparast, E., Rastkar, M., Mokhberdezfuli, M., & Ghajarzadeh, M. (2023).
    The prevalence of multiple sclerosis (MS) in Oceania, a systematic review, and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. [PubMed:37682389] [WorldCat] [DOI]

    Shahraki, Z., Rastkar, M., Rastkar, E., Mohammadifar, M., Mohamadi, A., & Ghajarzadeh, M. (2023).
    Impact of menopause on relapse rate and disability level in patients with multiple sclerosis (MS): a systematic review and meta-analysis. BMC neurology, 23(1), 316. [PubMed:37667181] [PMC] [WorldCat] [DOI]

    Wu, J., Cao, M., Peng, Y., Dong, B., Jiang, Y., Hu, C., ..., & Chen, Z. (2023).
    Research progress on the treatment of epilepsy with traditional Chinese medicine. Phytomedicine : international journal of phytotherapy and phytopharmacology, 120, 155022. [PubMed:37647670] [WorldCat] [DOI]

    Moin-Vaziri, V., & Badakhshan, M. (2023).
    The Impact of COVID-19 Pandemic on Arthropod-Related Diseases. Journal of arthropod-borne diseases, 17(1), 28-35. [PubMed:37609568] [PMC] [WorldCat] [DOI]

    Issa, P.P., Munshi, R., Albuck, A.L., Omar, M., Abu Alhuda, R.F., Metz, T., ..., & Kandil, E. (2023).
    Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance. American journal of otolaryngology, 44(6), 103994. [PubMed:37607459] [WorldCat] [DOI]

    Ayalew, T.L., Haile, K.E., Feleke, M.G., Zewudie, B.T., & Chichiabellu, T.Y. (2023).
    A systematic review and meta-analysis of cardiovascular diseases and associated factors among diabetes mellitus patients in Ethiopia. BMC cardiovascular disorders, 23(1), 413. [PubMed:37605128] [PMC] [WorldCat] [DOI]

    Tanzadehpanah, H., Lotfian, E., Avan, A., Saki, S., Nobari, S., Mahmoodian, R., ..., & Mahaki, H. (2023).
    Role of SARS-COV-2 and ACE2 in the pathophysiology of peripheral vascular diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 166, 115321. [PubMed:37597321] [WorldCat] [DOI]

    Teixeira, C.A., Morais, A.N.P., Moura, G.A., Gomes, I.A., Souza, S.V., Dias, M.O.M., ..., & Monteiro, P.B. (2023).
    The impact of thyroid disorders on the clinical outcome of assisted reproductive techniques: a systematic approach over the last 10 years. JBRA assisted reproduction. [PubMed:37579266] [WorldCat] [DOI]

    Narayanan, A., Garza-Berlanga, A., & Lopera, J. (2023).
    Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective. Annals of palliative medicine. [PubMed:37574584] [WorldCat] [DOI]

    Prado, M.C., Dotto, L., Agostini, B., & Sarkis-Onofre, R. (2023).
    Meta-research study highlights the gender gap in randomized controlled trials in dentistry. Journal of clinical epidemiology. [PubMed:37574081] [WorldCat] [DOI]

    Chagas, A.P., da Silva, N.G., Ribeiro, C.M., & Amato, A.A. (2023).
    Early-life exposure to antibiotics and excess body weight in childhood and adolescence: A systematic review and meta-analysis. Obesity research & clinical practice, 17(4), 318-334. [PubMed:37573229] [WorldCat] [DOI]

    Su, J., Chen, X.M., Xie, Y.L., Li, M.Q., Shang, Q., Zhang, D.K., ..., & Han, L. (2023).
    Clinical efficacy, pharmacodynamic components, and molecular mechanisms of antiviral granules in the treatment of influenza: A systematic review. Journal of ethnopharmacology, 318(Pt B), 117011. [PubMed:37567423] [WorldCat] [DOI]

    Gan, H., Su, Y., Zhang, L., Huang, G., Lai, C., Lv, Y., & Li, Y. (2023).
    Questionnaire-based analysis of autism spectrum disorders and gastrointestinal symptoms in children and adolescents: a systematic review and meta-analysis. Frontiers in pediatrics, 11, 1120728. [PubMed:37565245] [PMC] [WorldCat] [DOI]

    Cahill, A.M., & Carlson, J.C. (2023).
    A Scoping Review of Physician Advocacy on Twitter. Cureus, 15(7), e41632. [PubMed:37565125] [PMC] [WorldCat] [DOI]