Function (Oxford, England)最新文献

{"title":"Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice.","authors":"Beng San Yeoh,&nbsp;Rachel M Golonka,&nbsp;Piu Saha,&nbsp;Mrunmayee R Kandalgaonkar,&nbsp;Yuan Tian,&nbsp;Islam Osman,&nbsp;Andrew D Patterson,&nbsp;Andrew T Gewirtz,&nbsp;Bina Joe,&nbsp;Matam Vijay-Kumar","doi":"10.1093/function/zqad040","DOIUrl":"https://doi.org/10.1093/function/zqad040","url":null,"abstract":"<p><p>Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a <i>bona fide</i> biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad040"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d4/cc/zqad040.PMC10413929.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10062481","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":"What Does Physiological Mean?","authors":"Ole H Petersen","doi":"10.1093/function/zqad042","DOIUrl":"https://doi.org/10.1093/function/zqad042","url":null,"abstract":"S © t a r ecentl y r e vie wed an original paper with a title including he words “physiological stimulation.” In this particular case, t turned out that the stim ulation w as far fr om physiological. he concentration of the hormone used for acti v ation w as w ay bov e the maximal level ever observed in vivo, and this made e think about the use, and misuse, of the word “physiologial.” It is a word that we (physiologists) employ fr equentl y and erhaps too fr equentl y. Papers in physiological, and other, jourals often refer to “physiological conditions,” which sometimes s taken to indicate experiments in vi v o, but also fr equentl y ust means that experiments on single cells or tissue fragents were carried out with stimulation protocols and under ircumstances that are not unlike those that could happen n vi v o. We hav e li v ed thr ough a long and pr oducti v e period of singleell biology. Very important discoveries of real significance have een made, but it is now becoming incr easingl y clear that ther e r e many criticall y important inter actions betw een different djacent cell types in most tissues. To c har acterize these proesses, it is necessary to observe simultaneously more than one ell type in individual organs or tissues. Furthermore, the behavor of a particular cell type in isolation may not be the same as hen it is embedded in its normal environment. Of particular oncern is the tacit assumption in many studies that processes n cell lines reflect those in normal cells in situ. It may therefore e useful to reflect on the usefulness of working under real physological conditions, notwithstanding the obvious difficulties of oing so. In what follows, I’ll try to illuminate these issues by xamples from immunology, epithelial physiology, and neurocience. Ca 2 + signaling studies in imm une cells hav e been immensel y uccessful in unravelling key Ca 2 + transport events and, in articular, the properties of the Ca 2 + r elease acti v ated Ca 2 + CRAC) channel of the Orai type and its molecular control echanism. 1 Unlike the situation in epithelial cells, where Ca 2 +","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 5","pages":"zqad042"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10433090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10424847","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":"A Perspective on \"Hypoxia Resistance is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle\".","authors":"Camila Padilha,&nbsp;Ashleigh M Philp","doi":"10.1093/function/zqad024","DOIUrl":"https://doi.org/10.1093/function/zqad024","url":null,"abstract":"; Hypoxias; r esistance; inher ent; phenotype; mouse Skeletal muscle is reliant on a constant oxygen supply for mov ement, cellular r espiration, and thermogenesis. Heter oge-neous fibre types exist in skeletal muscle as a continuum from slow- to fast-twitch to facilitate specialized function. Type I (oxidati v e fibr es) pr esent a slow-twitc h phenotype , c har acterized by high oxygen capacity and increased fatigue resistance. In contrast, type IIa (fast oxidati v e gl ycol ytic phenotype) and type IIx (fast gl ycol ytic) pr esent faster twitc h speeds and contr","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad024"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713055","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":"Redox Bridling of GIRK Channel Activity.","authors":"Anna Boccaccio,&nbsp;Rocio K Finol-Urdaneta","doi":"10.1093/function/zqad027","DOIUrl":"https://doi.org/10.1093/function/zqad027","url":null,"abstract":"pr otein-gated inw ardl y r ectifying potassium (GIRK, Kir3.x) hannels belong to the large family of inw ardl y r ectifying potasium (Kir) channels expressed throughout the body. Activation nd consequent opening of GIRK channels allow inward flow of otassium (K + ) ions into the cell resulting in membrane potenial hyperpolarization and decr eased excita bility. Thus, GIRK hannels play a key role in regulating the activity of neurons and ontrolling important physiological processes including neuonal excita bility, heart r ate , and pain per ception. 1 GIRK channels are integral membrane proteins, existing s homoor heterotetr amers. Eac h monomer features two embrane-spanning helices (M1 and M2), a re-entrant P-loop or controlling ion permeation and selectivity, and extensive ntracellular aminoand carboxy-termini crucial for channel ating. Permeation is regulated by an inner helix gate formed y the M2 segments and a cytoplasmic G-loop gate. 1 Acti v ation of GIRK channels is mediated by the direct interction of G βγ subunits, released from various G protein-coupled ece ptors (GPCRs) upon the acti v ation of inhibitory neuroransmitter r ece ptors. Howev er, the acti vity of GIRK channels epends on the presence of the membrane anionic phospholipid hosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 or PIP 2 ) while it s also modulated by ubiquitously present sodium (Na + ) ions. urthermore , GIRK c hannels ar e too r e gulated by c holesterol, hosphorylation, ethanol, etcetera. 1 The crystal structures of ecombinant GIRK channels have offered valuable insights into ow they are functionally regulated by various ligands. Thus, hannel opening is facilitated by PIP 2 at the plasma membrane, hereas G βγ and Na + modulate the c hannel’s inter action with IP 2 through conformational changes that govern the gating proess. 2 The intracellular milieu is a reducing environment charcterized by a balanced redox state. This state is crucial to upport cellular processes while serving as a pr otecti v e shield","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad027"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713057","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":"Serendipity in senescence.","authors":"R A North","doi":"10.1093/function/zqac064","DOIUrl":"https://doi.org/10.1093/function/zqac064","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac064"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/86/66/zqac064.PMC9809900.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10494832","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":"Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K_ATP channel gain-of-function.","authors":"Michael J Davis,&nbsp;Jorge A Castorena-Gonzalez,&nbsp;Hae Jin Kim,&nbsp;Min Li,&nbsp;Maria Remedi,&nbsp;Colin G Nichols","doi":"10.1093/function/zqad017","DOIUrl":"https://doi.org/10.1093/function/zqad017","url":null,"abstract":"<p><p>Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of K_ATP channels. K_ATP overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by >50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad017"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10194823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10057746","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":"Overactive ATP-Sensitive K⁺ Channels Compromise Lymphatic Contractile Function in Cantú Syndrome.","authors":"Qadeer Aziz","doi":"10.1093/function/zqad030","DOIUrl":"https://doi.org/10.1093/function/zqad030","url":null,"abstract":"he lymphatic system is an extensive network of vessels that uns in parallel to the blood vasculature. Both networks play cruial roles in nourishing and protecting the body. Alongside its ole in “draina ge,” the l ymphatic system is also associated with ultisystem functions and disorders, including metabolic disrders, obesity, neurological disorders, and cardiac growth and e pair. Hence, a better understanding of its structural and funcional physiology and pathophysiology could help in the develpment of future therapeutics for not only traditional lymphatic isorders such as primary and secondary lymphedema but also n the potential treatment of organ-specific functions. Lymphatic vessels, like blood vessels, are composed of a ayer of endothelial cells surrounded by a thin layer of smooth uscle cells. Electrophysiologically, lymphatic smooth muscle LSM) exhibits intrinsic pacemaker properties that allow sponaneous action potential firing, sync hronized contr action w av es, nd facilitation of lymph propulsion against pressure gradients. hile the ion channels r esponsib le for the pacemaker proprties of LSM cells have not been clearly defined, L-type Ca 2 + hannels and ATP-sensiti v e K + (K ATP ) channels are present and rucial for LSM contractility and modulation of spontaneous ontractility, r especti v el y. 1 As well as being present in tissues hroughout the body, K ATP channels are prominently expressed n vascular smooth muscle where they regulate vascular tone nd ther efor e b lood flow. 2–4 Functional K ATP channels ar e a etero-octomeric complex of 4 pore-forming potassium chanel subunits (either Kir6.1 or Kir6.2) and 4 r egulator y sulphonyur ea r ece ptor subunits (either SUR1, SUR2A, or SUR2B). It is now ell esta b lished that the “v ascular smooth m uscle” K ATP chanel is formed of Kir6.1 and SUR2B. 2–4 Evidence from molecular","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad030"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713061","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":"Dissociation Between Neuronal and Astrocytic Calcium Activity in Response to Locomotion in Mice.","authors":"Anna Fedotova,&nbsp;Alexey Brazhe,&nbsp;Maxim Doronin,&nbsp;Dmytro Toptunov,&nbsp;Evgeny Pryazhnikov,&nbsp;Leonard Khiroug,&nbsp;Alexei Verkhratsky,&nbsp;Alexey Semyanov","doi":"10.1093/function/zqad019","DOIUrl":"https://doi.org/10.1093/function/zqad019","url":null,"abstract":"<p><p>Locomotion triggers a coordinated response of both neurons and astrocytes in the brain. Here we performed calcium (Ca²⁺) imaging of these two cell types in the somatosensory cortex in head-fixed mice moving on the airlifted platform. Ca²⁺ activity in astrocytes significantly increased during locomotion from a low quiescence level. Ca²⁺ signals first appeared in the distal processes and then propagated to astrocytic somata, where it became significantly larger and exhibited oscillatory behaviour. Thus, astrocytic soma operates as both integrator and amplifier of Ca²⁺ signal. In neurons, Ca²⁺ activity was pronounced in quiescent periods and further increased during locomotion. Neuronal Ca²⁺ concentration ([Ca²⁺]_i) rose almost immediately following the onset of locomotion, whereas astrocytic Ca²⁺ signals lagged by several seconds. Such a long lag suggests that astrocytic [Ca²⁺]_i elevations are unlikely to be triggered by the activity of synapses among local neurons. Ca²⁺ responses to pairs of consecutive episodes of locomotion did not significantly differ in neurons, while were significantly diminished in response to the second locomotion in astrocytes. Such astrocytic refractoriness may arise from distinct mechanisms underlying Ca²⁺ signal generation. In neurons, the bulk of Ca²⁺ enters through the Ca²⁺ channels in the plasma membrane allowing for steady-level Ca²⁺ elevations in repetitive runs. Astrocytic Ca²⁺ responses originate from the intracellular stores, the depletion of which affects subsequent Ca²⁺ signals. Functionally, neuronal Ca²⁺ response reflects sensory input processed by neurons. Astrocytic Ca²⁺ dynamics is likely to provide metabolic and homeostatic support within the brain active milieu.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad019"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713065","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":"Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone.","authors":"Calum Wilson,&nbsp;Matthew D Lee,&nbsp;Charlotte Buckley,&nbsp;Xun Zhang,&nbsp;John G McCarron","doi":"10.1093/function/zqac063","DOIUrl":"https://doi.org/10.1093/function/zqac063","url":null,"abstract":"<p><p>Arteries and veins are lined by nonproliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis, rather than mitochondrial oxidative phosphorylation, to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells, and little is known about energy production in endothelial cells within the fully formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial respiration disrupts endothelial control of vascular tone. Basal, mechanically activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. Agonist-evoked calcium activity was also inhibited by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for mitochondria in endothelial cell energy production is independent of species, sex, or vascular bed. These data show that a mitochondrial ATP supply is necessary for calcium-dependent, nitric oxide-mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqac063"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10799995","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":"Towards Astroglia-based Noradrenergic Hypothesis of Alzheimer's Disease.","authors":"Giampiero Leanza,&nbsp;Robert Zorec","doi":"10.1093/function/zqac060","DOIUrl":"https://doi.org/10.1093/function/zqac060","url":null,"abstract":"1Dept. of Drug and Health Sciences, University of Catania, Piazza Università, 2, 95131 Catania, Italy, 2Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia and 3Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia ∗Address correspondence to R.Z. (e-mail: robert.zorec@mf.uni.lj.si)","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac060"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/82/eb/zqac060.PMC9789502.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10680269","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}