Function (Oxford, England)最新文献

{"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":null,"pages":null},"PeriodicalIF":0.0,"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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,&nbsp;Nien-Wen Hu,&nbsp;Maram Abdelhamid,&nbsp;Simerpreet Singh,&nbsp;Walter L Murfee,&nbsp;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":null,"pages":null},"PeriodicalIF":0.0,"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":null,"pages":null},"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}

{"title":"Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension.","authors":"Natalia M Mathieu, Eva M Fekete, Patricia C Muskus, Daniel T Brozoski, Ko-Ting Lu, Kelsey K Wackman, Javier Gomez, Shi Fang, John J Reho, Connie C Grobe, Ibrahim Vazirabad, Gary C Mouradian, Matthew R Hodges, Jeffrey L Segar, Justin L Grobe, Curt D Sigmund, Pablo Nakagawa","doi":"10.1093/function/zqad043","DOIUrl":"10.1093/function/zqad043","url":null,"abstract":"<p><p>Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRR^RVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRR^RVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRR^RVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the \"maintenance\" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10206983","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":"Breaking New Ground: The Crucial Role of Animal Research in the Advancement of Rhabdomyolysis-Induced AKI Treatment and Prevention.","authors":"Marharyta Semenikhina, Joshua H Lipschutz, Oleg Palygin","doi":"10.1093/function/zqad039","DOIUrl":"10.1093/function/zqad039","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006225","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":"Computational Modeling of Substrate-Dependent Mitochondrial Respiration and Bioenergetics in the Heart and Kidney Cortex and Outer Medulla.","authors":"Shima Sadri,&nbsp;Xiao Zhang,&nbsp;Said H Audi,&nbsp;Allen W Cowley,&nbsp;Ranjan K Dash","doi":"10.1093/function/zqad038","DOIUrl":"10.1093/function/zqad038","url":null,"abstract":"<p><p>Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates <i>in-silico</i>. These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis-Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH₂-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH₂-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006232","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}