Journal of Physiology-London最新文献

{"title":"Vertebral artery hypoplasia: small artery, large implications for cerebral blood flow.","authors":"Paige M Williams, Cynthia M Weiner","doi":"10.1113/JP288878","DOIUrl":"https://doi.org/10.1113/JP288878","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of PKA-mediated SNAP-25b phosphorylation destabilizes exocytotic fusion pores and reduces the interactions of t-SNAREs.","authors":"Yu-Tien Hsiao, Yu-Lin Su, Pin-Chun Chen, Chien-Ting Huang, Ya-Yun Hsieh, Ning Chiang, Yu-Chun Lin, Juu-Chin Lu, Chih-Tien Wang","doi":"10.1113/JP286760","DOIUrl":"https://doi.org/10.1113/JP286760","url":null,"abstract":"<p><p>Ca²⁺-dependent exocytosis initiates with the formation of fusion pores comprising the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Although cellular signalling typically occurs in transient oscillations on the order of tens of seconds, it remains unclear how such rapid SNARE phosphorylation influences fusion pore kinetics, analogous to transient regulation observed in ion channels. Here we demonstrate that protein kinase A (PKA)-mediated phosphorylation of SN25b (the neuronal isoform of synaptosome-associated protein of 25 kD) modulates secretion rate and fusion pore kinetics in PC12 cells (rat pheochromocytoma derivatives). Upon acute application of KCl and forskolin, cells overexpressing SN25b exhibited a reduced secretion rate compared to the control. This reduction was occluded by overexpressing a PKA-phosphodeficient mutant, SN25b-T138A, rather than a PKA-phosphomimetic mutant, SN25b-T138E. Notably, SN25b, SN25b-T138A or SN25b-T138E did not alter the fraction of incomplete fusion events or quantal size compared to the control. Further kinetic analysis indicated that SN25b-T138A destabilized initial fusion pores by promoting the closure and dilatation of fusion pores. Mechanistically, in situ proximity ligation assays showed that SN25b-T138A reduced its interaction with the other t-SNARE syntaxin-1 compared to the control and SN25b, correlating with destabilized fusion pores. Moreover, compared to SN25b-T138E, SN25b-T138A decreased whole-cell Ca²⁺ currents and weakened its interaction with synaptobrevin-2 and L-type Ca²⁺ channel subunits. These changes in interaction were associated with increased secretion and full-fusion rate, implying efficient disassembly after dilatation. Together, PKA-mediated phosphorylation of SN25b rapidly modulates fusion pore kinetics in response to transient signalling oscillations, thereby fine-tuning exocytotic efficiency in real time. KEY POINTS: Protein kinase A (PKA)-mediated SNAP-25 phosphorylation rapidly reduces the rate of secretion. PKA-phosphodeficiency of SNAP-25 destabilizes the kinetics of initial fusion pores, correlating with its decreased interaction with syntaxin-1. PKA-phosphodeficiency of SNAP-25 decreases the interaction with synaptobrevin-2 and the L-type calcium channel subunit, leading to efficient priming. PKA-mediated SNAP-25 phosphorylation rapidly regulates fusion pore kinetics and shapes exocytotic kinetics on the order of tens of seconds.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central terminals of primary afferents coordinate the spontaneous activity of dorsal horn neurons.","authors":"Javier Lucas-Romero, Jose Antonio Lopez-Garcia, Ivan Rivera-Arconada","doi":"10.1113/JP287970","DOIUrl":"https://doi.org/10.1113/JP287970","url":null,"abstract":"<p><p>Central terminals of primary afferents and dorsal horn neurons usually exhibit spontaneous activity, the two phenomena being interrelated. Spontaneous activity may constitute a system for adjusting the level of excitation of spinal circuits and the processing of somatosensory information. Superficial dorsal horn neurons fire action potentials in a coordinated form, giving rise to population events. These population events are altered by peripheral inflammation, suggesting their implication in central sensitisation. In this work, we aimed to define the role of primary afferents in the occurrence of this coordinated activity. Channelrhodopsin-2, archaerhodopsin-3 or the hM4Di-DREADD receptor were expressed in primary afferents by Cre-recombination under control of the advillin promoter. Dorsal roots and superficial dorsal horn neurons were simultaneously recorded using in vitro spinal cord slices from neonatal mice. Depolarisation of primary afferents by activation of channelrhodopsin-2 inhibited dorsal root activity and the coordinated firing of dorsal horn neurons. DREADD activation reduced the activity in the afferents and depressed coordinated activity in dorsal horn neurons. In contrast, hyperpolarisation of afferents by archaerhodopsin-3 augmented dorsal root responses and increased the coordinated activity of spinal neurons. The present results demonstrate a direct implication of primary afferents in the generation of coordinated spontaneous firing in superficial dorsal horn neurons. KEY POINTS: The input of somatosensory information through primary afferents is a process subjected to regulation at the level of the spinal cord, even before it reaches second-order neurons. Primary afferent and spinal cord neurons exhibit spontaneous activity, which is altered in pathological models of pain. This study demonstrates the role of primary afferents as a fundamental coordinating element for the spontaneous activity of dorsal horn neurons. These results show that modulating the activity of the central terminals of primary afferents may have profound implications in both the excitability of spinal cord circuits and the processing of somatosensory information.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrophysiological characterization of pre-adolescents born with intrauterine growth restriction: insights from clinical and computational data.","authors":"Freddy L Bueno-Palomeque, Ernesto Zacur, Esther Pueyo, Fàtima Crispi, Pablo Laguna, Ana Mincholé","doi":"10.1113/JP288197","DOIUrl":"https://doi.org/10.1113/JP288197","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Anatomical changes associated with intra-uterine growth restriction (IUGR) have been observed in different age groups and linked to cardiovascular complications. This study analysed the electrocardiogram (ECG) in pre-adolescents with severe IUGR, comparing QRS complex and T-wave biomarkers with controls. Computer simulations explored links between anatomical re-modelling and ECG biomarkers, providing insights into the potential cardiovascular risk associated with IUGR-induced re-modelling. Clinical recordings were analysed using principal component analysis (PCA) to compute spatially transformed leads, enhancing QRS complex and T-wave delineation for depolarization and repolarization assessment. Transformed leads analysis revealed a 4-ms increase in QRS complex duration (QRS &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mrow&gt;&lt;/mrow&gt; &lt;mi&gt;d&lt;/mi&gt;&lt;/msub&gt; &lt;annotation&gt;$_d$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) and a 2-ms increase in the T peak-to-end interval (T &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mrow&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mi&gt;p&lt;/mi&gt; &lt;mi&gt;e&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;annotation&gt;$_{pe}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) in IUGR subjects compared to controls. We conducted electrophysiological in silico simulations using anatomical models based on clinical IUGR data. These models, derived from a reference control, incorporated key geometric changes associated with IUGR, the apex-base length, basal diameter, wall thickness ( &lt;math&gt;&lt;semantics&gt;&lt;mi&gt;W&lt;/mi&gt; &lt;annotation&gt;$mathcal {W}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) and ventricular tissue volume, to assess their impact on depolarization and repolarization intervals. In silico PCA leads showed increased QRS &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mrow&gt;&lt;/mrow&gt; &lt;mi&gt;d&lt;/mi&gt;&lt;/msub&gt; &lt;annotation&gt;$_d$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; , QRS amplitude and T &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mrow&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mi&gt;p&lt;/mi&gt; &lt;mi&gt;e&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;annotation&gt;$_{pe}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; in globular models, consistent with clinical data. Despite the QRS &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mrow&gt;&lt;/mrow&gt; &lt;mi&gt;d&lt;/mi&gt;&lt;/msub&gt; &lt;annotation&gt;$_d$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; increase, the QT interval increases but is not linearly related to the &lt;math&gt;&lt;semantics&gt;&lt;mi&gt;W&lt;/mi&gt; &lt;annotation&gt;$mathcal {W}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; change. These findings suggest that cardiac re-modelling primarily influences the depolarization cycle, notably QRS &lt;math&gt; &lt;semantics&gt;&lt;msub&gt;&lt;mrow&gt;&lt;/mrow&gt; &lt;mi&gt;d&lt;/mi&gt;&lt;/msub&gt; &lt;annotation&gt;$_d$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; , while repolarization intervals increase but are not directly related to the &lt;math&gt;&lt;semantics&gt;&lt;mi&gt;W&lt;/mi&gt; &lt;annotation&gt;$mathcal {W}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; increase. The study highlights the impact of geometric and volumetric changes in IUGR-related cardiac re-modelling, also emphasizing the need for further research on electrophysiological re-modelling and its effects on cardiac function. KEY POINTS: Intrauterine growth restriction (IUGR) is associated with long-term cardiovascular complications, including changes in the heart's electrical ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of non-coding RNAs derived from macrophage exosomes in cardiovascular diseases.","authors":"Wenyan Ding, Xiaofang Chen, Yuan Tian, Yanyue Wang, Chi Zhang","doi":"10.1113/JP288459","DOIUrl":"https://doi.org/10.1113/JP288459","url":null,"abstract":"<p><p>Cardiovascular disease is the predominant cause of mortality globally, with both morbidity and mortality rates escalating annually. Non-coding RNAs are essential in the regulation of cardiovascular disease. Exosomes are lipid bilayer vesicles that are released by many types of cells. They carry biomolecules such as proteins and nucleic acids (e.g. microRNAs, circular RNAs and long non-coding RNAs). The physiological condition of the mother cell significantly affects their composition and biological activity. In cardiovascular disorders, macrophages generate exosomes that facilitate intercellular communication, potentially resulting in new therapeutic strategies for these conditions. In this article, we examine the impact of exosomal non-coding RNAs derived from macrophages on the functionality and condition of immune cells, vascular smooth muscle cells, endothelial cells, cardiomyocytes and cardiac fibroblasts. They facilitate intercellular communication via several mechanisms. Non-coding RNAs generated from macrophage exosomes significantly influence cellular functional states and might offer new approaches for preventing and treating cardiovascular disorders. Owing to insufficient clinical evidence, additional extensive investigations are required to assess the therapeutic potential of these non-coding RNAs in cardiovascular disorders.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional control of heteromeric Kv2.1/6.4 channels by the voltage sensor domain of the silent Kv6.4 subunit.","authors":"Debanjan Tewari, Christian Sattler, Klaus Benndorf","doi":"10.1113/JP288376","DOIUrl":"https://doi.org/10.1113/JP288376","url":null,"abstract":"<p><p>In the activation process of Kv channels, the S4 segment of the voltage-sensing domain (VSD) moves in the outward direction. A conserved phenylalanine in the transmembrane S2 helix of the VSD is viewed as operating as a charge transfer centre (CTC) that interacts with a positively charged arginine of the S4 helix. This phenylalanine is highly sensitive to diverse substitutions. Kv2.1 subunits can form functional homotetrameric channels on their own whereas 'silent' Kv6.4 subunits can only contribute to functional heterotetrameric channels. We used concatenated dimers of Kv2.1 and Kv6.4 subunits to define the stoichiometry and position of these subunits in functional heterotetrameric channels. Our results demonstrate that mutating the phenylalanine F273 of the Kv6.4 subunits in Kv 2.1_6.4 channels built of dimers to diverse other amino acids at the CTC affects steady-state activation only moderately whereas it strongly shifts steady-state inactivation by 40 mV toward more depolarized potentials compared to Kv2.1_6.4 wild-type channels. Mutating the Kv6.4 subunits in this heterotetramer slowed down the recovery from closed-state inactivation without impacting open-state inactivation. Moreover, results with the specific Kv2.1 blocker guangxitoxin suggest that Kv6.4 subunits may partly activate Kv2.1_6.4 channels. It is concluded that F273 in the silent Kv6.4 subunit of Kv2.1_6.4 channels has a unique role in controlling activation and the recovery from inactivation. HIGHLIGHTS: This study quantifies the functional effects of Kv6.4 mutations in Kv2.1_6.4 channels on activation and inactivation. Highly diverse mutations of the phenylalanine in the charge transfer centre of Kv6.4 reveal its unique role in Kv2.1_6.4 channels in closed state inactivation. The specific Kv2.1 blocker guangxitoxin unmasks that Kv6.4 subunits can partly activate Kv2.1_6.4 channels.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Control of lymphatic pacemaking and pumping by mechanobiological signals","authors":"M. J. Davis,&nbsp;C. D. Bertram","doi":"10.1113/JP288477","DOIUrl":"10.1113/JP288477","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;The spontaneous, phasic contractions of collecting lymphatic vessels are critical for lymph transport and interstitial fluid homeostasis. Phasic contractions are initiated by action potentials in lymphatic muscle and conduct along the vessel to trigger contraction waves. Contractions are regulated by pressure and shear stress (SS), but only limited aspects of that regulation are understood. Numerical models predict that pressure promotes retrograde propagation of contraction waves, whereas nitric oxide (NO) production associated with phasic contractions (pulsatile NO) promotes antegrade conduction and extends the pressure range over which contractions propel lymph. These predictions were tested using 3−4-valve segments of rat mesenteric lymphatic vessels using pressure myography and protocols that imposed forward flow, elevated inflow pressure (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;in&lt;/sub&gt;) or elevated outflow pressure (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;out&lt;/sub&gt;), each with/without intact NO signalling. NO bioavailability and flow-induced responses were enhanced by &lt;span&gt;l&lt;/span&gt;-arginine supplementation. Spatiotemporal maps generated from video images were used to quantify the direction and extent of contraction wave conduction. Our results show that (1) contraction waves are normally biased towards retrograde conduction at equal &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;in&lt;/sub&gt;/&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;out&lt;/sub&gt; levels. (2) &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;in&lt;/sub&gt; elevation promotes antegrade conduction, whereas &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;out&lt;/sub&gt; elevation promotes retrograde conduction. (3) Imposed flow is inhibitory, reducing contraction amplitude and frequency and limiting the extent of contraction wave conduction without a significant effect on conduction direction. (4) Pulsatile NO does not significantly influence the conduction direction or extend the pressure range over which spontaneous contractions occur. Our findings support the idea that pressure is the dominant regulator of lymphatic pacemaking and pumping, with pulsatile NO having only minimal influence.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The degree to which spontaneous, phasic contractions of lymphatic collecting vessels are regulated by pressure and shear stress is not fully understood.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Numeric models predict that nitric oxide (NO) production associated with phasic contractions (pulsatile NO) promotes antegrade conduction of contraction waves, whereas pressure elevation promotes retrograde conduction; pulsatile NO production is also thought to extend the pressure ra","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3307-3327"},"PeriodicalIF":4.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288477","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding CPVT pathogenic mechanisms based on mutation location within RyR2: towards personalized medicine?","authors":"Jean-Pierre Benitah, Esther Zorio, Ana María Gómez","doi":"10.1113/JP288927","DOIUrl":"https://doi.org/10.1113/JP288927","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modifying microbially derived short chain fatty acids to promote health.","authors":"Alfredo Ornelas, Jacob A Countess, Ji Yeon Kim, Sean P Colgan","doi":"10.1113/JP287585","DOIUrl":"https://doi.org/10.1113/JP287585","url":null,"abstract":"<p><p>The intestinal mucosa has evolved to facilitate interactions between the host and the constellation of intestinal microbes, collectively termed the microbiota. A well-orchestrated balance exists in the healthy mucosa where microbes and microbial products first encounter a barrier formed by a single layer of intestinal epithelial cells (IECs). This homeostasis exists at a harsh interface between the highly vascularized mucosa and the anaerobic intestinal lumen. This steep oxygen gradient establishes 'physiological hypoxia' as a central metabolic characteristic of the mucosa. Recently, interest in understanding the dynamic host-microbe interplay has identified microbial metabolites that support host functions at several different levels. Of singular relevance are short-chain fatty acids, particularly butyric acid. Studies have demonstrated that IECs have evolved to benefit from butyrate through a plethora of functions, including energy procurement, metabolism, barrier and wound healing regulation, production of antimicrobial peptides, etc. Butyrate is consumed by differentiated colonic epithelial cells preferentially for energy, creating a distinct butyrate gradient along the intestinal cryp-tvillus axis. The depletion of butyrate and butyrate-producing microbes during active inflammation, termed dysbiosis, promotes disease and attenuates tissue healing responses. Furthermore, in a disease state, the butyrate gradient is disrupted leading to reduced utilization of butyrate and inhibition of proliferation of colonic stem cells. Emerging studies suggest that chemical modifications to butyrate could be useful in targeting select IEC functions for particular benefits to the host. In this review, we consider how butyrate molecular mimicry may play out in the setting of mucosal health and disease and discuss current discoveries on endogenous and synthetic butyrate-like compounds and their pathways.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repolarization adaptation to rapid change in heart rate in human models - a review.","authors":"Lennart Bergfeldt, Karl-Jonas Axelsson, Pia Dahlberg, Farzad Vahedi, Gunilla Lundahl, Lennart Gransberg","doi":"10.1113/JP288585","DOIUrl":"https://doi.org/10.1113/JP288585","url":null,"abstract":"<p><p>Hysteresis is a ubiquitous phenomenon and a salient feature of the adaptation of cardiac ventricular repolarization (VR) duration to changes in heart rate (HR), an expression of ultra-rapid cardiac memory. Against a background of a handful of previous studies, this review focuses on non-invasive electrophysiological assessment of the adaptation of VR duration and heterogeneity (aka dispersion) to changes in HR. Four different modalities were used: atrial pacing (incremental and step up/down), ventricular pacing (step up/down), and atropine-induced continuous HR increase in healthy subjects and patients who either had permanent pacemakers or were scheduled for ablation of supraventricular tachycardia or had long QT syndrome type 1 (LQT1). Vectorcardiography according to Frank, with orthogonal leads X, Y, and Z, was used for signal recording and beat-to-beat analysis. The RR interval (instantaneous HR) was the input. VR duration was assessed by the QT and QT_peak intervals and VR dispersion by T amplitude, T area, and the ventricular gradient. The main results were that independent of modality, VR duration adaptation follows a mono-exponential pattern, is reproducible, and at a stable HR it takes 2-3 min to reach steady state. In contrast, VR dispersion adaptation is more rapid and roller-coaster-like, presumably due to local differences in adaptation time. In LQT1 patients, VR duration adaptation time is reduced giving less time for electro-mechanical adaptation and coronary perfusion at HR increase. In conclusion, the patterns of adaptation of VR duration and VR dispersion differ, and further studies might provide information on these phenomena of both pathophysiological and therapeutic relevance.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}