Against the background of global climate change, increasingly severe drought stress exerts a significant impact on plant growth and yield. This study aimed to clarify the leaf anatomical structure, physiology and biochemistry and transcriptome-level metabolic adaptation mechanisms of ancient P. szechuanica to environmental stress. We selected cuttings of ancient P. szechuanica with a diameter of breast-height (DBH) ≥ 1 m and a tree age of 300-500 years as experimental materials. Natural drought stress was applied to investigate the responses of leaf anatomical structure, physiological and biochemical traits, and transcriptome-level metabolic processes of ancient P. szechuanica under drought stress. The results showed the following changes in leaf anatomical structure under drought stress (compared with the control group, the same below): leaf thickness, pith length and palisade tissue thickness decreased by 49.60 %, 20.1 % and 28.68 %, respectively. The thickness of upper and lower epidermis and spongy tissue first increased and then decreased, with final reductions of 53.13 %, 54.26 % and 50.30 %, respectively. Stomatal length and width also decreased, by 15.67 % and 24.26 % respectively. For physiological and biochemical traits, with the prolongation of drought stress, the soluble sugar content decreased significantly by 7.49 %, while the soluble protein content increased significantly by 44 %.At the transcriptome level, significant differentially expressed genes (DEGs) were screened at different drought stages: 3,353 upregulated and 3,161 downregulated DEGs on the day 4 of drought, 5,208 up-regulated and 9,560 down-regulated DEGs on the day 8, and 15,659 up-regulated and 14,870 down-regulated DEGs on the day 12. These DEGs mediated the drought stress response of P. szechuanica via positive up- or down-regulation.
Essential hypertension remains a major global health problem with poorly defined mechanisms. Increased vascular sympathetic activity and sleep-disordered breathing are common features in hypertensive patients and adult spontaneously hypertensive rats (SHRs), an experimental model of essential hypertension. We hypothesized that SHRs exhibit inherent respiratory dysfunctions during postnatal development, leading to irregular breathing and hypoxaemia that contribute to later sympathetic hyperactivity. We assessed pulmonary ventilation, oxygen consumption, systemic and tissue oxygen levels and cardiovascular parameters in male and female normotensive (Wistar-Kyoto and Sprague-Dawley, NT) rats and SHRs from birth to adulthood. Newborn SHRs (0-2 days old) exhibited hypoventilation, fluctuating respiratory frequency and increased episodes of apnoea and breath-hold, resulting in hypoxaemia and reduced brain oxygen levels in comparison to NT pups. These irregularities and hypoxaemia persisted until postnatal day 12. During hypoxic challenges, SHR pups from 0 to 12 days of life displayed an impaired ventilatory response, contrasting with the developmental increase in hypoxic ventilatory response seen in NT animals. In adult animals, the higher mean arterial pressure levels in SHRs were correlated with postnatal hypoventilation, suggesting a developmental link between postnatal respiratory dysfunction and hypertension. Chronic exposure to hyperoxia (50% O2) during the first 2 weeks of life attenuated respiratory irregularities in neonatal SHRs and reduced sympathetic vasoconstrictor tone in adult SHRs. Our results show that SHRs show early-life respiratory deficits that lead to breathing irregularities and hypoxaemia during postnatal development, which might contribute to the development of sympathetic hyperactivity in essential hypertension. KEY POINTS: Arterial hypertension is a common cardiovascular disease globally; however, its underlying mechanisms are still not fully understood. In spontaneously hypertensive rats (SHRs), a widely used experimental model of arterial hypertension, we identified inherent respiratory dysfunctions that cause breathing irregularities during the postnatal period. Neonatal SHR pups exhibit hypoventilation, fluctuating respiratory frequency and increased episodes of apnoea and breath-hold, leading to hypoxaemia and reduced oxygen levels in the brain. Exposure to high oxygen levels during postnatal life attenuates the respiratory irregularities in neonatal SHRs and reduces sympathetic vasoconstrictor tone in adult SHRs. Our study shows that early-life respiratory irregularities and hypoxaemia are present in SHRs from birth and might contribute to the development of sympathetic hyperactivity in arterial hypertension.
Fracture healing may be influenced by concomitant traumatic brain injury (TBI). Both clinical and experimental studies have reported accelerated union and enhanced callus formation in the presence of TBI. The Wnt/β-catenin signaling pathway is thought to play a role in this process; however, the relationship between serum β-catenin mRNA relative expression and fracture healing in the context of TBI remains unclear. Thirty-six female Wistar albino rats were randomly assigned to four groups: control, TBI only, femoral fracture only, and combined TBI + femoral fracture. Radiographic healing was evaluated using the Radiographic Union Scale for Tibial fractures (RUST) at weeks 3 and 6. Serum β-catenin mRNA relative expression was quantified by real-time polymerase chain reaction at baseline (week 0) and during follow-up (weeks 3 and 6). Histological analysis was performed at week 6. Radiographic evaluation demonstrated progressive healing in all fracture groups, with significantly higher RUST scores in the TBI + fracture group compared to the fracture-only group at both time points (p<0.05). Serum β-catenin mRNA relative expression decreased significantly over time in both fracture groups, whereas no significant temporal changes were observed in the control or isolated TBI groups. Because this decline occurred in both fracture groups, it did not indicate a TBI-specific molecular effect. Histologi-cal analysis showed a tendency toward more mature osseous callus formation in the TBI + fracture group; however, these differences were not statistically significant. Concomitant TBI was associated with enhanced radiographic fracture healing and showed a non-significant trend toward more advanced osseous callus formation. The observed decline in serum β-catenin mRNA relative expression in the fracture groups suggests phase-dependent regulation of Wnt/β-catenin-related activity during repair. However, serum β-catenin mRNA represents an indirect systemic marker and does not establish a mechanistic, TBI-specific pathway. These findings highlight the complex systemic influence of TBI on skeletal repair and support further mechanistic studies-particularly those incorporating fracture-site (local) analyses-to clarify the biological pathways underlying the observed radiographic association.
Hemostasis lies at the edge between physiology and cancer, where the coagulation cascade-initiated by tissue factor, thrombin generation, and fibrin deposition-shifts from vascular repair to tumor promotion. The interplay between coagulation and cancer is now recognized as a two-way street, with tumor cells activating the clotting system and coagulation components feeding back to promote malignancy. Tumor cells not only foster proliferation and invasion by overexpressing tissue factor and activating Protease-Activated Receptors (PAR1/PAR2) signalling, but they also induce endothelial cells and fibroblasts in the tumor microenvironment (TME) to produce coagulation factors (TF, FV, prothrombin) through cytokines (VEGF, IL-1β), NF-κB signalling, and hypoxia factor (HIF-1α). Generated thrombin and FXa drive MAPK/PI3K pathways, angiogenesis (VEGF upregulation), and immune evasion by suppressing T-cell chemokines (CXCL9/10/11) and fostering M2 macrophages. Platelets, activated by tumor-associated coagulation, release PDGF, TGF-β, and VEGF to promote stromal remodeling and exclude cytotoxic T cells via PD-L1 transfer, while fibrin matrices shield tumors and recruit suppressive myeloid cells. This bidirectional interplay creates a protumoral niche supporting both primary growth and metastatic dissemination, where circulating tumor cells (CTCs) exploit platelet cloaking against shear stress and NK cells. Cancer hypercoagulability is a known state which elevates venous thromboembolism, with D-dimer as a prognostic biomarker linking thrombosis to aggressive disease. Targeting this hemostasis-cancer axis-via TF inhibition, anticoagulation, or antiplatelet therapy-offers therapeutic promise to disrupt proliferation, immune escape, and metastasis.
Sleep quality declines with age and is a known contributor to multiple chronic health conditions, including Alzheimer disease. Emerging evidence suggests that certain electroencephalography (EEG) neural signatures measured during sleep may be predictive of cognitive decline in older adults. Sleep EEG signals are traditionally measured using bulky, rigid, and uncomfortable equipment in an unfamiliar laboratory setting, which can negatively impact sleep signals. Due to these limitations, sleep EEG data acquisition is typically limited to a single night. This study aimed to validate our recently developed portable, skin-like EEG monitoring patch for 7 nights in the home environment in a pilot sample of young and older adults by evaluating usability and acceptance, and replicating age-related differences in sleep architecture observed in the polysomnography literature. Eighteen young adults and 18 cognitively unimpaired older adults without sleep disorders were enrolled (data from 11 young adults and 12 older adults were included in the analyses) in a 7-night study during which they wore novel, gel-free, wireless, ultrathin, skin-conforming, sleep monitoring, fabric-based patches. These patches were self-applied to the forehead and face for optimal usability and comfort. The patches incorporate laser-cut mesh electrodes with low-profile electronics (including a rechargeable battery and amplifier) and transmit EEG signals to a participant-controlled, Bluetooth-enabled, tablet-based data acquisition app. An automated algorithm was used to stage sleep and assess microarchitecture features from the EEG commonly impacted for each participant. Averages across nights were computed for these sleep features for each participant. Young and older adults reported that the sleep patch was easy to use and comfortable to wear. There was no loss of signal power over 7 nights of wear across participants (retained-data signal-to-noise ratio over the 7-d period: young adult, mean 20.69, SD 12.78, maximum 52.13, minimum 5.19; older adult, mean 22.10, SD 9.39, maximum 49.96, minimum 13.79). Most datasets not retained were lost due to poor reference electrode adhesion on the nose (75/101, 74% of lost datasets in young adults and 57/88, 65% in older adults). Trained sleep technologists verified that the retained datasets were of sufficient quality to be scored without difficulty. Expected age-group differences in sleep features were observed, including age-related reductions in stage N3 sleep (young adult, mean 18.55, SD 6.70; older adult, mean 10.40, SD 6.43; Mann-Whitney U=42.0; P=.01) and reduced sleep spindle density (young adult, mean 2.92, SD 2.24; older adult, mean 0.94, SD 1.33; Mann-Whitney U=45.0; P=.006). This study demonstrates that our novel, comfortable, wearable patch can reliably measure physiological sleep data over multiple nights at home in adults across the lifespan, thereby making multinight sleep assessment in cognitive aging studies and clinical research more accessible than traditional polysomnography. In future studies, the small, lightweight system, which is highly scalable, can be shipped inexpensively to participants' homes, making this technology and research accessible to individuals who may have difficulty traveling or who are hesitant to travel to a laboratory or clinic.
Metastasis remains the primary cause of cancer-related deaths and is characterized by complex reprogramming of systemic processes. Emerging evidence indicates that extraosseous tumors can rewire bone marrow physiology and disrupt hematopoiesis, thereby compromising effective systemic immune responses. However, how tumor-induced immune alterations in bone marrow contribute to skeletal metastasis remains poorly defined. Here, using immunocompetent mouse models of mammary tumor bone metastasis, we show that mammary cancer cells precondition the bone marrow niche prior to metastatic colonization, driving early remodeling of the microenvironment and depleting bone marrow lymphoid populations. Specifically, cancer cells induce a dramatic B cell reduction, the most abundant lymphoid subset in bone marrow, resulting from dysregulated cell cycle gene expression in pre-B cells, along with impaired B-cell proliferation and differentiation. These findings are further validated in breast cancer bone metastasis patients, who exhibit significant bone marrow B-cell loss alongside disrupted molecular and developmental programs. A causal role for B cells in restraining skeletal metastasis is supported by the finding that experimental B-cell depletion significantly increases both incidence and severity of bone metastasis. Mechanistically, we find that B-cell loss is driven by systemic elevation of G-CSF. Accordingly, pharmacological neutralization of G-CSF significantly reduces both B-cell depletion and bone metastasis susceptibility. Collectively, our data reveal that breast cancer cells can distantly hijack B-cell developmental trajectories, promoting skeletal metastasis. This work identifies B cells and G-CSF as potential therapeutic targets in bone metastasis and highlights the importance of targeting early bone marrow immune dysregulation to prevent or limit skeletal metastasis. Mammary tumor cells reshape the bone marrow niche inducing B cell lossBone marrow B cell development is impaired in mammary tumor metastasisExperimental depletion of B cells promotes bone metastasisG-CSF mediates B cell loss in mammary tumor metastasis.
Circadian rhythms are endogenous biological cycles with a period of approximately 24 h that integrate a wide range of physiological and behavioral processes in living organisms. In addition to circadian rhythms, many other biological processes also exhibit diurnal (24 h) rhythms driven by external environmental cues. With the significance of circadian and diurnal regulation becoming increasingly recognized, the field of chronobiology is exhibiting unprecedented growth in the life sciences and translational medicine. Over the past 2 decades, a variety of computational methods have been developed to detect and extract rhythmic signals from the time-series data of different species. However, existing rhythmic analysis tools are often fragmented, demand programming expertise, exhibit limited visualization capabilities, and impose inconsistent requirements on data types and sampling intervals. Therefore, there is an urgent need to establish a convenient and comprehensive tool for detecting and analyzing the circadian and diurnal rhythmicity. To meet this demand, RhythmInsight was developed as an open access, web-based platform for comprehensive analysis and visualization of circadian and diurnal rhythms across various species and data types, including physiological, omics, and experimental data. RhythmInsight includes 3 modules: Rhythmic Analysis, Differential Rhythmicity Analysis, and Rhythmic Visualization. The Rhythmic Analysis module incorporates 9 algorithms (JTK_CYCLE, Cosinor, CircaCompare, meta2d, Lomb-Scargle, RAIN, ARSER, Fisher's G-test, and Robust G-test) to detect and characterize rhythmic signals. The Differential Rhythmicity Analysis module, based on CircaCompare, detects and compares rhythmic parameters (amplitude, phase, and the Midline Estimating Statistic of Rhythm) between 2 experimental conditions. The Rhythmic Visualization module provides powerful graphical tools, including line plots, fitted curves, heatmaps, polar plots, and boxplots, for the intuitive visualization of time-dependent trends. By integrating rhythmic algorithmic analysis with interactive visualization, RhythmInsight simplifies the analysis process and enhances accessibility for researchers without programming backgrounds, particularly experimental biologists and early-career scientists. RhythmInsight is freely available at https://RhythmInsight.com.
Digital twins are an emerging concept in healthcare that envisions integration of molecular, physiological, functional and clinical data to create computational models of biological systems such as cells, organs and individuals. However, the lack of large, multimodal datasets has so far precluded the realization of comprehensive digital twins in medicine. Ex vivo lung perfusion (EVLP) allows the study of human lungs outside the body under physiological conditions and generates multimodal data from imaging, physiologic monitoring and molecular assays. Here we report lung digital twins developed from the largest known clinical EVLP dataset. We show that the digital twin framework accurately models >75 parameters spanning lung physiology, biochemistry, radiography, transcriptomics, metabolomics and proteomics. Furthermore, direct comparison to experimental data on EVLP lungs treated with alteplase demonstrates that digital twins can precisely assess therapeutic efficacy. Together, these results establish human lung digital twins developed using EVLP as a data-rich approach to improve the evaluation of therapeutic effects.
Mitochondrial dynamics play a critical role in the development of aging-related diseases such as type 2 diabetes mellitus. To investigate how mitochondrial dynamics influence cellular behavior in pancreatic beta-cells, we developed a rule-based, multi-level simulation model of insulin secretion. The pancreatic beta-cell model encompasses metabolic pathways (glycolysis and oxidative phosphorylation), compartmental processes (mitochondrial fusion and fission), and cellular processes (insulin secretion), allowing for the investigation of their interplay. The rule-based simulation model captures the high plasticity of these organelles and integrates and builds upon insights from various experimental studies and previous simulation models. Its rule-based specification facilitates the exploration of new hypotheses, the integration of new knowledge and data, and the successive extension of the model. The results of our simulation experiments underscore the importance of peripheral, sorted mitochondrial fission in maintaining mitochondrial health. Downregulation of the fission-associated anchor proteins Fis1 and MFF impacts mitochondrial structure and function differently, highlighting their distinct roles in maintaining mitochondrial health and cellular biogenesis, respectively. With respect to insulin secretion, Drp1 suppression shows that beta-cells become unresponsive to glucose, whereas Fis1 downregulation only attenuates the cellular response. The simulation model and simulation results corroborate experimental findings and contribute to a deeper understanding of the mechanisms involved in mitochondrial dynamics of pancreatic beta-cells and their relation to metabolic dysregulation in type 2 diabetes mellitus.
This study aimed to compare the acute and residual physiological responses elicited by three different priming exercise strategies, including high-intensity priming exercise (HIPE), low-intensity priming exercise (LIPE), and low-intensity priming exercise with blood flow restriction (LIPE-BFR), on oxygen uptake kinetics, muscle oxygenation, and metabolic load during severe-intensity cycling in trained anaerobic athletes. Sixteen trained anaerobic athletes completed a randomized crossover protocol with three priming conditions (HIPE, LIPE, and LIPE-BFR) in a randomized order. The experimental protocol began with an incremental exercise test to determine maximal oxygen uptake (VO2max), followed by five submaximal constant-load cycling trials to derive individual power-VO2 regression equations. The three priming interventions included HIPE, LIPE, and LIPE-BFR. Key physiological parameters, including pulmonary oxygen uptake kinetics, muscle oxygen saturation (SmO2), accumulated blood lactate (ABLa) concentration, accumulated oxygen uptake (AVO2), and accumulated oxygen deficit (AOD), were assessed to quantify oxygen utilization and metabolic demand across sessions. Compared with HIPE, both LIPE and LIPE-BFR induced significantly lower amplitude (A) and longer time delay (TD), along with reduced reduced minimum SmO2 (SmO2min) and steady-state SmO2 (SmO2ss) during exercise (P < 0.05). HIPE elicited greater metabolic responses, including higher AVO2, AOD, and ABLa. Significant correlations were observed between VO2kinetics and metabolic demand, as well as between SmO2-derived indices and ABLa (P < 0.05). However, no significant differences were found among the three conditions in VO2 kinetics or metabolic outcomes during the subsequent severe-intensity cycling bout (P > 0.05), except for a higher VO2 baseline in the HIPE group (P < 0.05). Although the three priming strategies elicited distinct acute physiological responses, their residual effects on oxygen uptake kinetics and metabolic outcomes during subsequent severe-intensity exercise were largely comparable. Future studies should further explore alternative priming protocols and refine experimental designs to better clarify the effects of priming.
Neuromuscular fatigability impairs motor performance in both healthy and neurological populations. Corticomuscular coherence (CMC), derived from EEG and EMG recordings, reflects the brain-muscle interaction during movement. However, the impact of neuromuscular fatigability on CMC in healthy and neurological populations remains unclear. A systematic search of PubMed, Web of Science, and Embase was conducted up to 02/02/2026. Eligible studies investigated CMC changes related to fatiguing tasks in healthy or neurological participants. Two reviewers independently screened, extracted data, and assessed the risk of bias. Fifteen non-randomized experimental studies were included, comprising predominantly neurologically healthy adults (n= 174) and a limited number of individuals with neurological conditions (n= 14). Fatiguing tasks varied widely in muscle group, contraction type, mode, and intensity. Across studies, neuromuscular fatigability was associated with heterogeneous changes in CMC, most commonly involving reductions in beta band coherence as fatigue progressed. However, preserved or increased beta band CMC was also reported in both upper- and lower-limb tasks, particularly during sustained or low- to moderate-intensity contractions. Alpha and gamma band CMC were less reported across the included studies. No consistent or limb-specific pattern of CMC modulation emerged, with observed responses depending on task demands, contraction intensity, muscle group, and stage of fatigue. Evidence from neurological populations was sparse but suggested generally lower CMC magnitude and greater disruption during fatiguing tasks compared with healthy controls. These findings indicate that fatigue-related changes in CMC do not reflect a uniform loss of corticomuscular coupling but rather task- and context-dependent adaptations in brain-muscle communication. Reductions in CMC may reflect diminished efficacy of corticospinal synchronization, whereas preserved or increased coherence may represent stabilization to maintain motor output with fatigue. By synthesizing how neuromuscular fatigability reshapes CMC across different experimental contexts and highlighting key methodological limitations, this review provides a framework to inform the design of future rehabilitation or neuromodulation trials targeting fatigability in both healthy and neurological populations.
The increasing prevalence of methicillin and vancomycin-resistant Staphylococcus aureus (MRSA/VRSA) necessitates new antibacterial agents. Penicillin-binding protein 2a (PBP2a) plays a crucial role in bacterial cell wall synthesis. In this work, 125 imidazole-based tetrapeptides were rationally designed and evaluated in silico and experimentally. Molecular docking studies revealed binding energies from -6.6 to -4.0 kcal/mol against MRSA target. The six most promising compounds (A-F) were synthesized and screened against methicillin-susceptible S. aureus (MSSA), MRSA and VRSA. Compound C showed the most promising antibacterial analogue with minimum inhibitory concentration (MIC) of 29.8 ± 4.2 μg/mL among the analogues. Time-kill assays demonstrated bactericidal activity against MSSA and MRSA and bacteriostatic activity against VRSA. All compounds showed < 5% haemolysis, suggesting low toxicity. ADME predictions indicated favourable physicochemical properties and safety profiles. The molecular dynamics simulation (MDS) for compound C shows stable interactions with Ser403, Tyr446, Glu447, Ser462, Lys597, Ser598 and Thr600 key residues in the PBP2a active site. The DFT study confirms the stability of compound C in the PBP2a active site with a binding energy of -42.73 kcal/mol. Overall, compound C is a promising lead for anti-staphylococcal drug development; however, the mechanism of action requires further experimental validation.
Thyroid hormones are essential regulators of cardiac excitability, contractility, and rhythm. Hypothyroidism induces profound electrophysiological remodeling through both genomic and non-genomic pathways, leading to altered expression and function of key ion channels, including HCN, Kv, and Ca²⁺-handling proteins. These changes result in reduced pacemaker activity, prolonged repolarization, and impaired excitation-contraction coupling, which collectively contribute to bradycardia, QT prolongation, and increased arrhythmogenic risk. Elevated thyroid-stimulating hormone (TSH) levels further exacerbate electrical instability through direct myocardial signaling. Experimental and clinical evidence indicates that many of these abnormalities could be reversible upon thyroid hormone replacement, emphasizing the importance of early diagnosis and multidisciplinary management. Understanding the molecular basis of thyroid-induced electrical remodeling provides insight into arrhythmogenesis and may guide therapeutic strategies to prevent cardiac complications in hypothyroidism.
Given the impact of kinetoplastid diseases, the limited therapeutic options and risk of treatment failure, continued research efforts to discover novel drug entities are required. The ambition to deliver drug development candidates has mainly been taken on board by academia and public private partnerships, but remains highly challenging because of the lack of adequate funding and standardized laboratory procedures. Establishing a systematic roadmap of experiments and decision criteria to attain high-quality leads and drug candidates with lower risk profiles remains the logical path to deliver more compelling proof-of-concepts for impactful diseases, such as African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. In a three-part series, a structured roadmap from 'hit finding' to 'drug development candidate' is presented with a focus on the minimal essential data package, laboratory experimental models and endpoints. Part 1 introduces the concept of a pragmatic framework with reference to specific preclinical R&D stages: (i) hit finding, (ii) hit profiling, (iii) lead definition and (iv) drug development candidate to support a more focused early development path that remains accessible to engaged stakeholders. The experiment-oriented roadmap is presented in the next parts addressing the discovery and characterization of confirmed hits (Part 2) and the lead discovery phase towards identification of a drug development candidate (Part 3). Although specifically focusing on kinetoplastid diseases, the principles also apply to small-molecule preclinical R&D against other microbial diseases, evidently with specific adaptation of the primary pharmacology models.
Sepsis frequently involves early gastrointestinal dysfunction, in which intestinal barrier breakdown and microbiota dysbiosis amplify systemic inflammation and contribute to multi-organ failure. Emerging evidence indicates that the gut is not merely a bystander in sepsis but an active driver of pathogenic cascades through epithelial injury, mucosal immune dysregulation, ischemia-reperfusion stress, and impaired motility, collectively promoting microbial translocation and immune deviation. In parallel, sepsis is associated with profound remodeling of the gut microbiome, characterized by reduced commensal diversity, expansion of pathobionts, and functional shifts in key microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan-derived products, which further compromise mucosal integrity and host immune tone. This narrative review synthesizes experimental, translational, and clinical findings to elucidate the bidirectional interaction gut barrier-microbiota interplay in sepsis and to summarize mechanistic links across epithelial, immune, and metabolic signaling pathways, including gut-liver and gut-brain axes relevant to sepsis-associated organ dysfunction. dysfunctional microbial community leads to systemic immune deviation, multi-organ dysfunction and sepsis-associated encephalopathy, a common and severe neurological complication of sepsis. We also discuss emerging therapeutic strategies targeting the gut-microbiota axis-such as early enteral nutrition, prebiotics/postbiotics, defined microbial consortia, fecal microbiota transplantation, and metabolite-based supplementation-and evaluate their potential and limitations in septic populations. Finally, we highlight key challenges, including unresolved causality, inter-individual variability, context-dependent responses, and safety concerns, underscoring the need for longitudinal multi-omic profiling, host-microbiome phenotyping, and mechanism-informed interventional trials to enable precision microbiome-based approaches for sepsis.
Boron plays significant roles in various biological systems, including mineral, lipid, and energy metabolism, immune and endocrine systems, and brain function. It has been suggested to enhance performance and may prevent conditions such as osteoporosis, osteoarthritis, and arthritis. Despite these known benefits, its effects on growth performance and mineral metabolism in horses remain understudied, particularly in young animals like Purebred Arabian foals. The primary objective of this study was to investigate the effects of different doses of boron supplementation (0, 5, 10, and 15 mg/day per animal) on the performance (live weight gain, feed intake, feed conversion ratio) and bone and mineral metabolism in Purebred Arabian foals. A total of 32 Purebred Arabian foals with similar initial live weights were randomly divided into four groups, each consisting of eight animals. The experimental groups were as follows: Control Group (K Group): No boron supplementation. B5 Group: Received 5 mg/day of elemental boron. B10 Group: Received 10 mg/day of elemental boron. B15 Group: Received 15 mg/day of elemental boron. Boric acid was used as the boron source, and the study spanned 90 days. Feed intake, live weight gain, and feed conversion ratio were monitored. Measurements of metacarpal diameter, withers height, and chest circumference were recorded. Serum samples were analyzed for ALP, P, Mg, Ca, B, PTH, cortisol, calcitonin, osteocalcin, and vitamin D3 levels. Performance: Feed intake was similar across all groups (P > 0.05). However, the B15 group exhibited the highest live weight gain, daily weight gain, and feed conversion efficiency (P < 0.05). Bone and Mineral Metabolism: Serum levels of ALP, P, and Mg showed no significant differences between groups (P > 0.05). While no significant main effect of group was found for metacarpal diameter (P > 0.05), a highly significant time × group interaction was detected (P < 0.001), indicating that boron supplementation modulated the developmental trajectory of the skeleton. Serum calcium (Ca) levels on day 90 were significantly higher in the B15 group compared to the control group (P = 0.03). Serum boron (B) levels increased linearly with the administered dose (P < 0.001). Serum cortisol levels on day 90 were significantly higher in the B10 and B15 groups compared to the control (P = 0.004). Calcitonin and osteocalcin levels showed a dose-dependent linear increase, peaking in the B15 group on day 90 (P < 0.001). Vitamin D3 and PTH levels did not differ significantly among the groups (P > 0.05). Boron supplementation positively influenced growth performance and bone and mineral metabolism in Purebred Arabian foals, with the 15 mg/day dose showing the most pronounced benefits. These findings suggest that boron supplementation could be an a promising nutritional strategy to enhance growth performance and mineral metabolism in young horses. Further research is warranted to explore long-term effects and potential applications in equine nutrition and management. However, further long-term studies are required to confirm these findings and determine optimal supplementation levels.
The use of a startling acoustic stimulus during a simple reaction time task results in the rapid initiation of a prepared response at extremely short latencies (< 80 ms). This so-called "StartReact effect" has been increasingly employed to probe subcortical contributions to response preparation, as it is thought to occur due to increased activation in reticulospinal pathways associated with engagement of the startle reflex. However, the lack of an agreed-upon definition of what exactly constitutes a StartReact effect, combined with differences in methodological protocols, has resulted in inconsistent interpretation of experimental results. Based on a comprehensive review of the literature, including evidence for the physiological mechanism underlying the effect, we propose that the clearest definition of the StartReact effect is "the early and involuntary triggering of a prepared movement in the presence of a startle reflex". Reflexive startle activity has been shown to be strongly associated with involuntary response initiation and avoids other potential confounding variables that have been shown to speed reaction time. Here we argue that classification of trials based on startle-related activation in sternocleidomastoid is the most robust method to confirm a StartReact effect. Special situations, such as pre-pulse inhibition, movements involving musculature that require additional considerations, and lowered response preparation levels, are also considered with regards to how to confirm the presence of a StartReact effect. Future directions, including the use of a StartReact protocol as a potential adjuvant therapy for movement disorders, are discussed.
Advances in AI hold considerable promise for organ transplantation. While every transformation brings change, not all change is transformative. Despite the rapid growth of AI in medicine, most applications remain in developmental or experimental stages, with relatively few having been successfully integrated into routine clinical practice. As a professional society, ESOT recognises that achieving meaningful impact will require more than technical progress. This position paper outlines five critical domains for successful implementation. (1) High-quality development: Coordinated collaboration and methodological rigour are prerequisites for trust; AI is only as robust as the data used to train it. (2) Ethical considerations: We must address risks to equity and access to care, and move from generic ethical principles to transplantation-specific ethical guidance. (3) Regulatory landscape: AI in transplantation is regulated under both EU medical device and AI legislation; compliance is central to stakeholder trust. (4) Responsible adoption: AI should augment, not replace, human expertise. Strengthening AI literacy is essential for meaningful adoption. (5) Participatory design: Active involvement of transplant professionals and patients is essential to address real clinical needs. These statements serve as a strategic framework to guide clinicians, researchers, and policymakers in making AI a genuine force multiplier for the transplant community.
Microglia dynamically remodel their cytoskeleton to surveil the brain, respond to injury, and shape synaptic connectivity. While actin drives rapid process motility and phagocytic cup formation, emerging evidence indicates that microtubules are critical regulators of microglial morphology, trafficking, and inflammatory signaling. In homeostatic microglia, microtubules are nucleated at Golgi outposts, supporting ramified architectures and low inflammatory tone. Upon activation, microglia undergo a switch to a centrosome-nucleated, radial microtubule array, driven in part by cyclin-dependent kinase 1 (Cdk1) and associated with polarized cytokine release, NLRP3 inflammasome engagement, and altered phagocytic behavior. We discuss how key regulators of this transition-including Cdk1, centrosomal γ-tubulin recruitment, Golgi-derived microtubule nucleation, and the kinase MARK4 may constitute druggable nodes to tune microglial reactivity in neuro-degenerative diseases. Finally, we outline experimental priorities for translating microglial microtubules into therapeutic targets.
Whereas the brain-heart axis is an emerging field in neuropsychocardiology, a central autonomic network including the insular cortex (Ic) regulates the cardiovascular system via the intrinsic cardiac nervous system. Cardiac interoception, represented in Ic, has been studied in cardiovascular diseases and inflammation. Therefore, it is important to investigate how interoception is related to cardiovascular disease in terms of its prevention and treatment. To examine the role of the Ic in cardiovascular and immune regulation, we focus on converging evidence from human stroke cohorts, lesion-symptom mapping studies, and experimental models that implicate the Ic as a causal hub within the brain-heart-immune axis. In particular, Ic plays a pivotal role in processing interoception as well as immunoception, and based on this information, Ic regulates cardiovascular and immune systems via efferent autonomic networks. Furthermore, vagally mediated neuromodulation is likely to influence interoception and immunoception and plays a pivotal role in improving cardiovascular dysregulation.