Function (Oxford, England)最新文献

{"title":"Elucidating a Complex Mechanism.","authors":"Victor Wray","doi":"10.1093/function/zqad051","DOIUrl":"10.1093/function/zqad051","url":null,"abstract":"ur understanding of the complex dynamic system dri v en by onformational change during adenosine triphosphate (ATP) ydr ol ysis by F 1 -ATPase is of fundamental biochemical imporance. 1 , 2 Cr yo-electr on micr oscopy (Cr yo-EM) studies 3 −5 have ontributed v alua b le structural information on how the F 1 TPase functions, although, in themselves, these have not led o a definiti v e mechanism. The F 1 -ATPase is a multi-subunit sysem containing 3 β-catalytic sites that have been studied by biohysical single-molecule experiments based on direct visualizaion of the rotation of its central γ -subunit. 6 However, it is difcult to esta b lish which interconverting site or sites contribute nergy for the observ ed r otation, gi v en that a site can perform he elementary chemical steps of ATP binding, ATP hydr ol ytic ond cleav a ge, and pr oduct (Pi and adenosine diphosphate, ADP) elease. 7 Originally, the molecular mechanism of ATP syntheis/hydr ol ysis w as studied using classical biochemical pproaches that provided a wealth of fundamental data. A i-site Boyer’s binding change mechanism of ATP syntheis/hydr ol ysis (Nobel Prize for Chemistry, 1997) was postulated etween 1973 and 1993 based on biochemical unisite/multisite atalysis and oxygen exchange experiments. 8 An alternati v e ri-site Nath’s torsional mechanism of energy transduction nd ATP synthesis/hydr ol ysis w as first pr oposed in 1999 and ev eloped ov er the next 25 yr using a nov el m ultidisciplinar y pproac h, 9 whic h inte gr ated physics, c hemistry, bioc hemistry, nd engineering. The dir ect measur ements by Senior and oworkers of the fluorescence quenching of tryptophan probes","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad051"},"PeriodicalIF":0.0,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10548849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41164820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently?","authors":"","doi":"10.1093/function/zqad052","DOIUrl":"10.1093/function/zqad052","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/function/zqad009.].</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad052"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10532101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41172212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inactivation of TRPM7 Kinase Targets AKT Signaling and Cyclooxygenase-2 Expression in Human CML Cells.","authors":"Birgit Hoeger,&nbsp;Wiebke Nadolni,&nbsp;Sarah Hampe,&nbsp;Kilian Hoelting,&nbsp;Marco Fraticelli,&nbsp;Nadja Zaborsky,&nbsp;Anna Madlmayr,&nbsp;Viktoria Sperrer,&nbsp;Laura Fraticelli,&nbsp;Lynda Addington,&nbsp;Dirk Steinritz,&nbsp;Vladimir Chubanov,&nbsp;Roland Geisberger,&nbsp;Richard Greil,&nbsp;Andreas Breit,&nbsp;Ingrid Boekhoff,&nbsp;Thomas Gudermann,&nbsp;Susanna Zierler","doi":"10.1093/function/zqad053","DOIUrl":"10.1093/function/zqad053","url":null,"abstract":"<p><p>Cyclooxygenase-2 (COX-2) is a key regulator of inflammation. High constitutive <i>COX-2</i> expression enhances survival and proliferation of cancer cells, and adversely impacts antitumor immunity. The expression of <i>COX-2</i> is modulated by various signaling pathways. Recently, we identified the melastatin-like transient-receptor-potential-7 (TRPM7) channel-kinase as modulator of immune homeostasis. TRPM7 protein is essential for leukocyte proliferation and differentiation, and upregulated in several cancers. It comprises of a cation channel and an atypical α-kinase, linked to inflammatory cell signals and associated with hallmarks of tumor progression. A role in leukemia has not been established, and signaling pathways are yet to be deciphered. We show that inhibiting TRPM7 channel-kinase in chronic myeloid leukemia (CML) cells results in reduced constitutive <i>COX-2</i> expression. By utilizing a CML-derived cell line, HAP1, harboring CRISPR/Cas9-mediated TRPM7 knockout, or a point mutation inactivating TRPM7 kinase, we could link this to reduced activation of AKT serine/threonine kinase and mothers against decapentaplegic homolog 2 (SMAD2). We identified AKT as a direct in vitro substrate of TRPM7 kinase. Pharmacologic blockade of TRPM7 in wildtype HAP1 cells confirmed the effect on <i>COX-2</i> via altered AKT signaling. Addition of an AKT activator on TRPM7 kinase-dead cells reconstituted the wildtype phenotype. Inhibition of TRPM7 resulted in reduced phosphorylation of AKT and diminished <i>COX-2</i> expression in peripheral blood mononuclear cells derived from CML patients, and reduced proliferation in patient-derived CD34⁺ cells. These results highlight a role of TRPM7 kinase in AKT-driven <i>COX-2</i> expression and suggest a beneficial potential of TRPM7 blockade in COX-2-related inflammation and malignancy.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad053"},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6d/e8/zqad053.PMC10541797.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41160752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extravasation of Blood and Blood Toxicity Drives Tubular Injury from RBC Trapping in Ischemic AKI.","authors":"Sarah R McLarnon, Chloe Johnson, Jingping Sun, Qingqing Wei, Gabor Csanyi, Phillip O'Herron, Brendan Marshall, Priya Giddens, Jennifer C Sullivan, Amanda Barrett, Paul M O'Connor","doi":"10.1093/function/zqad050","DOIUrl":"10.1093/function/zqad050","url":null,"abstract":"<p><p>Red blood cell (RBC) trapping is common in ischemic acute kidney injury (AKI) and presents as densely packed RBCs that accumulate within and engorge the kidney medullary circulation. In this study, we tested the hypothesis that \"RBC trapping directly promotes tubular injury independent of extending ischemia time.\" Studies were performed on rats. Red blood cell congestion and tubular injury were compared between renal arterial clamping, venous clamping, and venous clamping of blood-free kidneys. Vessels were occluded for either 15 or 45 min with and without reperfusion. We found that RBC trapping in the medullary capillaries occurred rapidly following reperfusion from renal arterial clamping and that this was associated with extravasation of blood from congested vessels, uptake of blood proteins by the tubules, and marked tubular injury. To determine if this injury was due to blood toxicity or an extension of ischemia time, we compared renal venous and arterial clamping without reperfusion. Venous clamping resulted in RBC trapping and marked tubular injury within 45 min of ischemia. Conversely, despite the same ischemia time, RBC trapping and tubular injury were minimal following arterial clamping without reperfusion. Confirming the role of blood toward tubular injury, injury was markedly reduced in blood-free kidneys with venous clamping. Our data demonstrate that RBC trapping results in the rapid extravasation and uptake of blood components by tubular cells, causing toxic tubular injury. Tubular toxicity from extravasation of blood following RBC trapping appears to be a major component of tubular injury in ischemic AKI, which has not previously been recognized.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad050"},"PeriodicalIF":5.1,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41161519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intermittent Hypoxia and Respiratory Plasticity: The Good, the Bad, and the Unknown.","authors":"Andrew William Sheel","doi":"10.1093/function/zqad045","DOIUrl":"10.1093/function/zqad045","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad045"},"PeriodicalIF":0.0,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41160793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beliefs Made It into Science: Believe It or Not.","authors":"Rüdiger J Seitz,&nbsp;Raymond F Paloutzian","doi":"10.1093/function/zqad049","DOIUrl":"10.1093/function/zqad049","url":null,"abstract":"© t n c long-standing discourse in philosophy dating back to antiqity concerns the nature of beliefs and believing. Until today, he notion “belief” has been of importance in philosophy, as evient from the definition of knowledge as justified true belief. In act, the notion “belief” was understood as a topic of resear c h ocused on people’s attitudes or opinions about what was or was ot true in the w orld. 1 Resear c h questions were summarized by he formula “ S A that P ,” where S denotes the mental state, A he attitude of a putati v el y rational a gent, and P the v erball y xpr essed pr oposition r eflecting the belief. 1 By contrast, the tudy of beliefs was generally assumed to be incompatible with he natural sciences. Ver y r ecentl y, howev er, the term “belief” as been described as to be used widespread in the cogniti v e cience literature to explain human reasoning and behavior. 2 pecifically, it has been described that beliefs act as fundamenal hypotheses about the world that result from any amount of ogniti v e pr ocessing and ar e held with any degr ee of certainty. 3 hus, beliefs are apparently not propositions expressed by conciousl y aw ar e , so-called r ational agents, but, on the contrary, eterminants of people’s spontaneous and intuiti v e behavior in complex world, as highlighted in a recent interdisciplinary esear c h topic. 4 Here , w e put the implications of the recent dvancements in this rapidly evolving field in perspective for the ciences and beyond.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad049"},"PeriodicalIF":0.0,"publicationDate":"2023-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6f/e5/zqad049.PMC10519273.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41171008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of phosphatidylethanolamine synthesis: consequences for skeletal muscle.","authors":"Robin Elaine Duncan","doi":"10.1093/function/zqad044","DOIUrl":"10.1093/function/zqad044","url":null,"abstract":"hosphatidylethanolamine (PE) is a major gl ycer ophospholipid PL) in cellular and organellar membranes, and dysregulation of E synthesis has been associated with ener gy o v er-stora ge and nsulin resistance. 1 Due to the small size of its ethanolamine eadgr oup r elati v e to the v olume occupied by its long and, in articular, unsaturated fatty acyl side chains (which impart a kink” to the molecule), PE forms a conical shape. 2 This moleclar structure is key to sculpting the curv atur e of the inner layer f cellular and organellar membranes, where PE is quantitati v el y he most abundant type of PL. 3 In organelles where a high degree of membrane curv atur e s critical for the translation of structure to function, such s in the cristae that form the inner mitochondrial memranes, increases in PE content can impr ov e performance, hile losses can result in dysfunction that is so critical as o be incompatible with cellular and organismal life. 4 While his provides a direct connection between PE and the conrol of energy metabolism, recent studies demonstrate addiional roles for this gl ycer olipid in the regulation of wholeody metabolic homeostasis that are both complex and overlaping. For example, PE is primarily synthesized in the Kennedy athw ay thr ough the cytidine diphosphate (CDP)-ethanolamine athw ay, wher e CTP:phosphoethanolamine c ytid ylyltr ansfer ase Pcyt2) catalyzes the second and rate-limiting step. Because iacylgl ycer ol (DAG) is a substrate in the third and final step f the PE-K ennedy pathw ay, limitations in Pcyt2 activity are ssociated with reduced utilization, and therefore increased t","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad044"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41158101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Tetraspanins: From Markers to Mechanisms Driving Systemic Exercise Adaptation.","authors":"Darby S Easterday,&nbsp;Daniel S Lark","doi":"10.1093/function/zqad048","DOIUrl":"10.1093/function/zqad048","url":null,"abstract":"Exercise impr ov es cardiometa bolic health thr ough a range of systemic [ie , bey ond w orking skeletal muscle (SkM)] mec ha-nisms typically attributed to small molecules and peptide hormones. Recent discoveries have shown that the abundance and cargo of circulating small extracellular vesicles (sEVs) like exosomes ar e alter ed by exer cise , but linking these c hanges to SkM-deri v ed systemic exercise adaptations has been challenging. A key barrier to linking SkM sEVs to exercise adaptations is determining which of the hundreds of molecules that may be transported by SkM sEVs have functional relevance in the context of exer cise . One surprisingly untested str ate gy is to start with the most abundant sEV car go . Tetraspanins like CD81 are tr ansmembr ane protein hallmarks of sEVs. To date, CD81 has only been described as an sEV marker, not an instrument of sEV function. However, ∼ 30 yr of resear c h has established CD81 as a tr ansmembr ane adaptor protein that influences a variety of cellular functions by altering the organization of r ece ptor pr oteins within membranes. Multiple groups","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad048"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41163799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiogenic Microvascular Wall Shear Stress Patterns Revealed Through Three-dimensional Red Blood Cell Resolved Modeling.","authors":"Mir Md Nasim Hossain, Nien-Wen Hu, Maram Abdelhamid, Simerpreet Singh, Walter L Murfee, Peter Balogh","doi":"10.1093/function/zqad046","DOIUrl":"10.1093/function/zqad046","url":null,"abstract":"<p><p>The wall shear stress (WSS) exerted by blood flowing through microvascular capillaries is an established driver of new blood vessel growth, or angiogenesis. Such adaptations are central to many physiological processes in both health and disease, yet three-dimensional (3D) WSS characteristics in real angiogenic microvascular networks are largely unknown. This marks a major knowledge gap because angiogenesis, naturally, is a 3D process. To advance current understanding, we model 3D red blood cells (RBCs) flowing through rat angiogenic microvascular networks using state-of-the-art simulation. The high-resolution fluid dynamics reveal 3D WSS patterns occurring at sub-endothelial cell (EC) scales that derive from distinct angiogenic morphologies, including microvascular loops and vessel tortuosity. We identify the existence of WSS hot and cold spots caused by angiogenic surface shapes and RBCs, and notably enhancement of low WSS regions by RBCs. Spatiotemporal characteristics further reveal how fluctuations follow timescales of RBC \"footprints.\" Altogether, this work provides a new conceptual framework for understanding how shear stress might regulate EC dynamics in vivo.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad046"},"PeriodicalIF":5.1,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41123551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase.","authors":"Alexandria B Marciante, Yasin B Seven, Mia N Kelly, Raphael R Perim, Gordon S Mitchell","doi":"10.1093/function/zqad041","DOIUrl":"10.1093/function/zqad041","url":null,"abstract":"<p><p>Plasticity is a fundamental property of the neural system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity elicited by acute intermittent hypoxia (AIH). pLTF can arise from distinct cell signaling cascades initiated by serotonin versus adenosine receptor activation, respectively, and interact via powerful cross-talk inhibition. Here, we demonstrate that the daily rest/active phase and the duration of hypoxic episodes within an AIH protocol have profound impact on the magnitude and mechanism of pLTF due to shifts in serotonin/adenosine balance. Using the historical \"standard\" AIH protocol (3, 5-min moderate hypoxic episodes), we demonstrate that pLTF magnitude is unaffected by exposure in the midactive versus midrest phase, yet the mechanism driving pLTF shifts from serotonin-dominant (midrest) to adenosine-dominant (midactive). This mechanistic \"flip\" results from combined influences of hypoxia-evoked adenosine release and daily fluctuations in basal spinal adenosine. Since AIH evokes less adenosine with shorter (15, 1-min) hypoxic episodes, midrest pLTF is amplified due to diminished adenosine constraint on serotonin-driven plasticity; in contrast, elevated background adenosine during the midactive phase suppresses serotonin-dominant pLTF. These findings demonstrate the importance of the serotonin/adenosine balance in regulating the amplitude and mechanism of AIH-induced pLTF. Since AIH is emerging as a promising therapeutic modality to restore respiratory and nonrespiratory movements in people with spinal cord injury or ALS, knowledge of how time-of-day and hypoxic episode duration impact the serotonin/adenosine balance and the magnitude and mechanism of pLTF has profound biological, experimental, and translational implications.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad041"},"PeriodicalIF":0.0,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/76/d9/zqad041.PMC10519274.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41124716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}