FEBS Letters最新文献

{"title":"The Lily Foundation: supporting patients, raising awareness and funding research into mitochondrial diseases.","authors":"Liz Curtis, Maria E O'Hanlon, Katie Waller, Duncan E Wright","doi":"10.1002/1873-3468.15107","DOIUrl":"https://doi.org/10.1002/1873-3468.15107","url":null,"abstract":"<p><p>Primary mitochondrial diseases ('mito') are a group of genetically and phenotypically diverse disorders caused by defects in mitochondrial structure or function. Although they are individually rare, they collectively have an incidence of around 1 : 4300. Mitochondrial diseases can arise from mutations in either mitochondrial or nuclear genes, complicating genetic diagnosis. The Lily Foundation was founded by Liz Curtis in the UK in 2007 in order to raise awareness of mitochondrial diseases and to fund research into diagnosis and treatment. In this first of a new series on patient advocacy, FEBS Letters interviews Founder and CEO Liz Curtis MBE, Head of Patient Programmes Katie Waller and Research Manager Dr. Maria O'Hanlon on the aims, achievements and activities of the Lily Foundation.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inclusion, belonging, and institutional climate - overlooked factors driving diverse STEM faculty turnover?","authors":"Mali D Doles, Joseph T Cornelius, Jason D Doles","doi":"10.1002/1873-3468.70005","DOIUrl":"https://doi.org/10.1002/1873-3468.70005","url":null,"abstract":"<p><p>Faculty turnover at institutes of higher learning disrupts educational continuity, compromises scholarly activity, has negative impacts on learner experiences, and is costly. As such, understanding the reasons why faculty leave-especially in cases where they plan to stay in academia-is critically important with respect to designing and implementing informed retention initiatives. We conducted a survey of STEM faculty who recently switched institutions to gain insights into factors driving their decision to leave. Across all respondents, we found that factors relating to culture/climate were more important than factors relating to pay/compensation or position title. This relative prioritization was even more apparent among women faculty and faculty from disadvantaged backgrounds. We contextualize and discuss the implications of our findings and provide strategies for cultivating inclusive climates to promote faculty retention.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6 mediated CD206⁺ARG-1⁺ tumor associated macrophage polarization induces Treg infiltration in non-responder luminal A breast cancer.","authors":"Ananya Das, Sraddhya Roy, Aparajita Bairagi, Neyaz Alam, Nabanita Chatterjee","doi":"10.1002/1873-3468.70000","DOIUrl":"https://doi.org/10.1002/1873-3468.70000","url":null,"abstract":"<p><p>Drug non-responsiveness is the major reason for the poor prognosis of hormonal receptor-positive breast cancer (ER⁺/PR⁺ BCa), particularly the luminal A subtype. However, the underlying mechanism of drug non-responsiveness remains unknown. Flow cytometry and t-SNE analysis followed by ELISA validation of responder and non-responder unveiled lower secretion of IFN-γ, IL-12, and higher levels of IL-6 and TGF-β in CD4⁺ T cells (P < 0.001), CD8⁺ T cells (P < 0.001), FOXP3⁺ Tregs (P < 0.001) and CD206⁺ TAMs (P < 0.001) in non-responders. Treatment of isolated CD206⁺ TAMs with recombinant IL-6 upregulated the expression of ARG-1 (arginase-1) and subsequent increase of TGF-β⁺ Tregs (P < 0.001) and IL-6⁺ Tregs (P < 0.001) in luminal A BCa. Our findings showed IL-6 mediated ARG-1⁺CD206⁺ TAMs polarization induced FOXP3⁺ Tregs infiltration in TME of non-responder in luminal A BCa.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight into the function of the Golgi membrane protein GOLM1 in cholangiocytes through interactomic analysis.","authors":"Meghana Nagaraj, Sharath Kumar Goud Emmagouni, Vaishali Chaurasiya, Luyang Li, Van Dien Nguyen, Salla Keskitalo, Markku Varjosalo, You Zhou, P A Nidhina Haridas, Vesa M Olkkonen","doi":"10.1002/1873-3468.70001","DOIUrl":"https://doi.org/10.1002/1873-3468.70001","url":null,"abstract":"<p><p>GOLM1, a Golgi membrane protein, is upregulated in cancers and liver diseases. Analysis of public RNAseq data from healthy human liver suggested that GOLM1 is predominantly expressed in cholangiocytes. Therefore, this study was initiated to understand the molecular functions of GOLM1 in cholangiocytes through protein interactomics. The findings reveal a number of putative GOLM1-interacting partners involved in cellular regimes such as mitochondrial and Golgi functions, ribonucleoprotein biogenesis, cell cycle, and basement membrane organization. Further, to validate select key roles, GOLM1 was silenced in MMNK-1 cholangiocytes and the effects on cell functions were studied. The silencing resulted in impaired mitochondrial function, reduced mitochondrial and P-body markers, increased apoptosis, and reduced cell adhesion, suggesting crucial roles of GOLM1 in maintaining normal cholangiocyte metabolism and function.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics of the Kelch domain containing (KLHDC) subfamily and relationships with diseases.","authors":"Courtney Pilcher, Paula Armina V Buco, Jia Q Truong, Paul A Ramsland, Monique F Smeets, Carl R Walkley, Jessica K Holien","doi":"10.1002/1873-3468.15108","DOIUrl":"https://doi.org/10.1002/1873-3468.15108","url":null,"abstract":"<p><p>The Kelch protein superfamily is an evolutionary conserved family containing 63 alternate protein coding members. The superfamily is split into three subfamilies: Kelch like (KLHL), Kelch-repeat and bric-a-bracs (BTB) domain containing (KBTBD) and Kelch domain containing protein (KLHDC). The KLHDC subfamily is one of the smallest within the Kelch superfamily, containing 10 primary members. There is little known about the structures and functions of the subfamily; however, they are thought to be involved in several cellular and molecular processes. Recently, there have been significant structural and biochemical advances for KLHDC2, which has aided our understanding of other KLHDC family members. Furthermore, small molecules directly targeting KLHDC2 have been identified, which act as tools for targeted protein degradation. This review utilises this information, in conjunction with a thorough exploration of the structural aspects and potential biological functions to summarise the relationship between KLHDCs and human disease.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ablation of LRP6 in alpha-smooth muscle actin-expressing cells abrogates lung inflammation and fibrosis upon bleomycin-induced lung injury.","authors":"Eun-Ah Sung, Mikhail G Dozmorov, SuJeong Song, Theingi Aung, Min Hee Park, Patricia J Sime, Wook-Jin Chae","doi":"10.1002/1873-3468.15106","DOIUrl":"10.1002/1873-3468.15106","url":null,"abstract":"<p><p>Tissue fibrosis is a progressive pathological process with excessive deposition of extracellular matrix proteins (ECM). Myofibroblasts, identified by alpha-smooth muscle actin (αSMA) expression, play an important role in tissue fibrosis by producing ECM. Here, we found that the Wnt antagonist Dickkopf1 (DKK1) induced gene expressions associated with inflammation and fibrosis in lung fibroblasts. We demonstrated that genetic deletion of LRP6, a receptor for Wnt ligands and DKK1, in αSMA-expressing cells using Acta2-cre Lrp6^fl/fl (Lrp6^AKO) mice abrogated the bleomycin (BLM)-induced lung inflammation and fibrosis phenotype, suggesting an important role for LRP6 in modulating inflammation and fibrotic processes in the lung. Our results highlight the crucial role of LRP6 in fibroblasts in regulating inflammation and fibrosis upon BLM-induced lung injury.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcription: friend or foe of genome stability","authors":"Emmanuel Compe,&nbsp;Donata Orioli","doi":"10.1002/1873-3468.15091","DOIUrl":"10.1002/1873-3468.15091","url":null,"abstract":"&lt;p&gt;Over the past 60 years, tremendous progress has been made in elucidating the highly regulated process of transcription, a cellular mechanism during which RNA polymerases copy specific DNA sequences into RNA. Initially considered as simple messengers between DNA and protein synthesis, it is now undeniable that RNA transcripts play fundamental roles in various aspects of DNA metabolism, ranging from gene expression regulation to chromatin remodelling [&lt;span&gt;[1, 2]&lt;/span&gt;]. Furthermore, a convergence of molecular and genomic evidence reveal that pre-existing RNA and &lt;i&gt;de novo&lt;/i&gt; RNA may directly or indirectly contribute to DNA damage signalling pathways and preservation of genome integrity [&lt;span&gt;[3]&lt;/span&gt;]. This is well-illustrated by the long noncoding &lt;i&gt;telomeric&lt;/i&gt; repeat-containing RNA (TERRA), which directly participates in genomic integrity by contributing to telomere maintenance [&lt;span&gt;[4-6]&lt;/span&gt;]. Besides the genome-protective function of RNAs, the transcriptional process itself is crucial for genome maintenance. By unwinding and scanning the DNA double helix, the transcription process contributes towards the identification and repair of a wide variety of DNA lesions. Indeed, impediments of transcription elongation caused by DNA lesions result in stalling of RNA polymerases, whose outcome can be detrimental to cell survival. The stalling of RNA polymerases can nevertheless promote the recruitment of DNA repair machineries to the damaged sites. Depending on the nature of the lesions, a wide variety of transcription-coupled repair mechanisms thus exist, which enable efficient repair of transcribed regions as well as fast restart of transcription after genotoxic stress [&lt;span&gt;[7-11]&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;However, transcription can also be a source of genomic instability. Indeed, it can directly induce DNA damage by generating torsional stress on the double helix structure or exposing single-strand DNA to genotoxic agents [&lt;span&gt;[12]&lt;/span&gt;]. In addition, a collision between transcription and other processes occurring on DNA, such as DNA replication, may have a nefarious outcome on genome integrity [&lt;span&gt;[13]&lt;/span&gt;]. Both transcription and DNA replication machineries are large multiprotein assemblies that cannot simultaneously stand on the same DNA strand. Their collision gives rise to conflicts that, if not properly resolved, may result in transcription and replication stalling as well as the generation of DNA double-strand breaks (DSBs) [&lt;span&gt;[13, 14]&lt;/span&gt;]. Furthermore, the unwinding of guanine (G)-rich DNA sequences during transcription may result in the formation of stable noncanonical DNA structures, such as G-quadruplexes (G4), which normally contribute to transcription as well as telomere maintenance, recombination and epigenetic regulation [&lt;span&gt;[15]&lt;/span&gt;]. However, depending on their localization or persistence, the G4 structures may induce genome instability by causing DNA breaks. Similarly, transcription of GC-rich DNA se","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 2","pages":"143-146"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.15091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insights into the modulation of the 5HT_2A receptor by serotonin, psilocin, and the G protein subunit Gqα.","authors":"Niklas Viohl, Ali Asghar Hakami Zanjani, Himanshu Khandelia","doi":"10.1002/1873-3468.15099","DOIUrl":"https://doi.org/10.1002/1873-3468.15099","url":null,"abstract":"<p><p>5HT_2AR is a G-protein-coupled receptor that drives many neuronal functions and is a target for psychedelic drugs. Understanding ligand interactions and conformational transitions is essential for developing effective pharmaceuticals, but mechanistic details of 5HT_2AR activation remain poorly understood. We utilized all-atom molecular dynamics simulations and free-energy calculations to investigate 5HT_2AR's conformational dynamics upon binding to serotonin and psilocin. We show that the active state of 5HT_2AR collapses to a closed state in the absence of Gqα, underscoring the importance of G-protein coupling. We discover an intermediate \"partially-open\" receptor conformation. Both ligands have higher binding affinities for the orthosteric than the extended binding pocket. These findings enhance our understanding of 5HT_2AR's activation and may aid in developing novel therapeutics. Impact statement This study sheds light on 5HT_2AR activation, revealing intermediate conformations and ligand dynamics. These insights could enhance drug development for neurological and psychiatric disorders, benefiting researchers and clinicians in pharmacology and neuroscience.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction between bacterial phytochromes Agp1 and Agp2 of Agrobacterium fabrum by fluorescence resonance energy transfer and docking studies.","authors":"Afaf El Kurdi, Gero Kaeser, Patrick Scheerer, David Hoffmann, Ebru Akkus, Marcus Elstner, Norbert Krauß, Tilman Lamparter","doi":"10.1002/1873-3468.15102","DOIUrl":"https://doi.org/10.1002/1873-3468.15102","url":null,"abstract":"<p><p>Phytochromes are biliprotein photoreceptors found in bacteria, fungi, and plants. The soil bacterium Agrobacterium fabrum has two phytochromes, Agp1 and Agp2, which work together to control DNA transfer to plants and bacterial conjugation. Both phytochromes interact as homodimeric proteins. For fluorescence resonance energy transfer (FRET) measurements, various Agp1 mutants and wild-type Agp2 were labeled with specific fluorophores to study their interaction. FRET efficiencies rose from position 122 to 545 of Agp1. The photosensory chromophore module (PCM) of Agp1 did not show a FRET signal, but the PCM of Agp2 did. Docking models suggest that Agp1 and Agp2 interact with their histidine kinase and PCM perpendicular to each, around 45 amino acids of Agp1 or Agp2 are involved.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of interface interactions between a dehydratase domain and an acyl carrier protein in cremimycin polyketide synthase.","authors":"Kaede Kotagiri, Haruka Tachibana, Daisuke Kawasaki, Taichi Chisuga, Toma Kashima, Shinya Fushinobu, Fumitaka Kudo, Tadashi Eguchi, Akimasa Miyanaga","doi":"10.1002/1873-3468.15103","DOIUrl":"https://doi.org/10.1002/1873-3468.15103","url":null,"abstract":"<p><p>Modular polyketide synthases (PKSs) are multi-domain enzymes involved in the biosynthesis of polyketide natural products. The dehydratase (DH) domain catalyzes the dehydration of the β-hydroxyacyl unit attached to the acyl carrier protein (ACP) domain in modular PKS. Although the DH domain likely recognizes the cognate ACP domain during the dehydration reaction, the molecular basis of DH-ACP interactions remains elusive. In this study, we conducted cross-linking analysis using a pantetheine-type probe for investigating the ACP recognition of a fusion-DH protein generated from a split-DH domain of cremimycin PKS. Based on the AlphaFold 3-predicted model structure of the fusion-DH-ACP complex, DH-ACP interface residues were identified and validated by mutational analysis. Our findings provide the first detailed insights into domain-domain interactions between DH and ACP in modular PKSs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}