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Cancer cells can exploit developmental lineage programs to generate phenotypic heterogeneity under therapeutic pressure. Although a subset of resistant tumors preserves its founding lineage, receptor, or oncogenic dependency, accumulating evidence shows that others enter reversible persister states or stabilize alternative lineage programs. Here we frame malignant plasticity as developmentally constrained, not limitless: cell of origin, lineage history, injury memory, genetic gates, chromatin state, transcription-factor circuits, and tumor-ecosystem feedback help delimit and probabilistically bias which state transitions are accessible under therapy. We distinguish physiological expansion of state space during repair from premalignant permissiveness and malignant fixation, and classify resistance into three modes: lineage-maintained resistance, adaptive reversible plasticity, and fixed reprogramming through lineage switching or histological transformation. These modes should be read as diagnoses rather than rigid therapeutic silos. Prime-then-kill strategies are most defensible when a resistant state is reversible, targetable, and paired with readouts; they may also be considered as biomarker-defined add-on hypotheses in lineage-maintained or lineage-rerouted disease when an evidence-supported state or immune-visibility module is present. Conversely, tumors that retain driver, receptor, or lineage dependency should keep the preserved axis or bypass pathway as the therapeutic backbone, and fixed histological transformation often requires treatment according to the new lineage. We also discuss how single-cell and spatial multi-omics can map state-space breadth and ecosystem context and, when paired with perturbational designs, help test transition capacity and reversibility; static marker expression alone cannot establish plasticity. A resistance-mode-guided approach can sharpen therapeutic hypotheses and limit overgeneralization across tumor types.

We explore alternative hypotheses regarding the association between activity space racial composition and risk behavior among Black-identifying urban youth. Racial isolation perspectives argue that exposure to Black segregated neighborhoods limits access to mainstream institutions and influence, increasing participation in risk behavior (violence, delinquency, and substance/alcohol use). An alternative compelled mobility perspective argues that Black youth spend a substantial amount of time in low proportion Black, largely white neighborhoods seeking organizational resources typically less available in segregated areas. These exposures may lead to discrimination-related strain, detachment from conventional norms, and elevated physiological stress, increasing the likelihood of risk behavior compared to Black youth who spend more time in same-race dominated activity spaces. We test these competing hypotheses employing data from the Columbus, Ohio, USA-based Adolescent Health and Development in Context study on the geospatial exposures and both survey and Ecological Momentary Assessment (EMA)-reported behaviors of 506 Black youth ages 11-17. Contrary to the expectations of the isolation model, we find that greater exposure to residentially low proportion Black areas is associated with an increased likelihood of risk behavior for Black males. We consider implications of findings for extant theories and data collection approaches in research examining spatial effects on adolescent risk behavior.

Positron emission tomography (PET) imaging is widely used in a number of clinical applications, including cancer and Alzheimer's disease (AD) diagnosis, monitoring of disease development, and treatment effect evaluation. Statistical modeling of PET imaging is essential to address continually emerging scientific questions in these research fields, including hypotheses related to evaluation of effects of disease modifying treatments on amyloid reduction in AD and associations between amyloid reduction and cognitive function, among many others. In this paper, we provide background information and tools for statisticians interested in developing statistical models for PET imaging to pre-process and prepare data for analysis. We introduce our novel pre-processing and visualization tool TRAECR (Template registration, MRI-PET co-Registration, Anatomical brain Extraction and COMBAT/RAVEL harmonization) to facilitate data preparation for statistical analysis.

The subthalamic region consists of a complex intersection of many different axonal pathways. Emerging hypotheses in deep brain stimulation (DBS) for Parkinson's disease (PD) suggest that direct stimulation of specific axonal pathways may be linked to the control of specific motor symptoms (e.g. cerebellothalamic (CT) - tremor; motor hyperdirect (mHD) - bradykinesia; pallidothalamic (PT) - rigidity). However, the typical frontal DBS lead trajectory limits opportunities to co-activate all of these pathways. We used advanced biophysical DBS models to evaluate the theoretical utility of a parietal lead trajectory into the subthalamic region that could facilitate activation of the PT, mHD, and CT pathways. We compared a typical frontal DBS lead trajectory with a traditional 8-contact directional DBS lead to the parietal alternative with a 16-contact directional DBS lead. The analyses were performed within the context of the CIT168 human atlas brain populated with the Petersen axonal pathway models. PT, mHD, and CT fibers are distributed in an anterior-to-posterior fashion within the subthalamic white matter. Given this anatomical feature, traditional frontal trajectories limit opportunities for multi-pathway DBS because the electrode contacts are primarily aligned dorsal-ventrally. Alternatively, the span of DBS contacts along a parietal trajectory can provide better opportunities to activate all of the pathways of interest, while also avoiding unwanted activation of the internal capsule. Parietal DBS trajectories warrant consideration in PD therapy as the research concepts of pathway-targeted stimulation begin migrating into clinical practice.

Scapholunate dissociation is usually the result of failure of multiple wrist ligaments. With continued use other structures attenuate, which results in change in position of the carpal bones. It is presumed that load characteristics in the wrist joint change with changes in carpal bone position. This is thought to result in localized pressure overload and arthritic change. The purpose of this study was to evaluate radioscaphoid joint pressures and carpal kinematics after sectioning specific wrist ligaments. Our hypotheses are that there would be increased scaphoid flexion and ulnar deviation, increased lunate extension and radial deviation, increased contact pressure in the radioscaphoid fossa, and increased tendon forces. Eight cadaver wrists were instrumented with an electromagnetic motion tracking device and a pressure sensor was inserted into the radioscaphoid joint. Using a wrist joint motion simulator, motion and pressure data were obtained in the moving wrist in the intact state and after sectioning the dorsal radiocarpal, dorsal intercarpal, and scapholunate interosseous ligaments. After ligament sectioning there was increased scaphoid flexion, scaphoid ulnar deviation, lunate extension, and lunate radial deviation resulting in carpal instability. There was also an increase in pressure in the radioscaphoid fossa. Several specimens showed evidence of scaphoid subluxation. It is our conclusion that this combination of ligament sectioning produces scapholunate instability and increased pressures in the radioscaphoid fossa in the laboratory setting. We believe that if left untreated in the clinical setting, scapholunate advanced collapse could result.

Driven by the global rise in obesity and lifestyle transitions, cardiovascular-kidney-metabolic (CKM) syndrome has emerged as a pathophysiological continuum characterized by metabolic dysregulation and involving multi-organ interactions. Within the comprehensive management of CKM syndrome, dietary patterns represent a cornerstone of intervention due to their high modifiability and cost-effectiveness. Adopting the perspective of the CKM syndrome pathophysiological continuum, this narrative review provides a thematic overview of the current literature on the Mediterranean, DASH, plant-based, and ketogenic diets in relation to metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. Evidence indicates that the Mediterranean and DASH diets, through established anti-inflammatory, antioxidant, and endothelial protective mechanisms, are the most consistently supported dietary patterns for CKM risk mitigation. The efficacy of plant-based diets is strictly quality-dependent: while healthful patterns rich in whole grains and vegetables are associated with improved cardiorenal outcomes, unhealthful patterns dominated by refined carbohydrates may exacerbate metabolic derangements. Although the ketogenic diet may improve glucose metabolism in the short term, concerns regarding elevated low-density lipoprotein cholesterol, potential hepatotoxicity, and limited long-term adherence suggest that its role may be more relevant in selected short-term settings than as a sustained long-term dietary pattern. Furthermore, structured dietary quality indices may provide useful tools for characterizing dietary exposure in relation to CKM and for generating mechanistic hypotheses. By integrating clinical and mechanistic evidence, this review outlines a stage-oriented conceptual framework to discuss how different dietary patterns may relate to distinct phases of the CKM syndrome.

Breast cancer immunity depends on more than the number of immune cells in a tumor. It is also shaped by where those cells sit, which neighbors they contact, and what functional states they adopt locally. Tumor-associated macrophages (TAMs) and T cells are a key pairing in this setting. Depending on tissue context, their crosstalk may support cytotoxic immunity, reinforce immune exclusion, promote T-cell exhaustion, or weaken therapeutic response. Spatial technologies now allow these states to be examined in intact tumor sections rather than inferred from dissociated or bulk samples. Antibody-based imaging approaches, including imaging mass cytometry, MIBI, and CODEX, together with high-plex transcriptomic platforms such as MERFISH, Xenium, CosMx, Visium, GeoMx, and related methods, have revealed inflamed, excluded, myeloid-rich, stromal-barrier, and tertiary lymphoid structure-associated niches in breast cancer. However, spatial maps alone cannot establish mechanism. Cells that lie close together may not necessarily interact, and computational tools, including ligand-receptor scoring, graph-based neighborhood modeling, and spatial biomarker prediction, can only prioritize candidate macrophage-T cell programs. Functional validation remains essential. In this mini review, we discuss how spatial omics, computational modeling, organoid and explant cultures, microfluidic models, perturbation assays, and therapeutic testing can be linked to study macrophage-T cell crosstalk. We highlight a practical workflow in which spatial maps generate hypotheses, experimental systems test causality, and post-treatment profiling determines whether candidate interactions are remodeled by therapy.

The molecular architecture underlying diverse vertebrate sex-determining systems remains elusive despite fragmentary evidence of changes in upstream regulators and downstream mediators. Here we modeled species-specific regulatory networks of urogonadal development for turtles with contrasting mechanisms [Apalone spinifera - ZZ/ZW genotypic sex determination (GSD), and Chrysemys picta - temperature-dependent sex determination (TSD)] using matched data from time-course sampling. We uncovered key steps in the evolutionary transition of sex determination by testing for conservation or divergence of network modular components. Specifically, we tested these alternative hypotheses: first, transcription factor (TF) hubs and their target genes are conserved between species (null H0); second, the same TF hub acquired a new set of target genes in a species, retaining or not ancestral functions (H1 and variants); third, a new TF hub took over the regulation of the former gene targets of an ancestral TF (H2); and finally, complete overhaul occured where both ancestral TF hubs and their target genes were replaced in a species (H3). Results implicate primary cilia as integrators of environmental signals underlying TSD, because known thermosensitive TSD components (e.g., calcium-redox, pSTAT3, Wnt/Rspo1/β-catenin, Dhh) overrepresented in our results are linked to primary cilia. TFs that evolved between species also regulate primary cilia and point to key changes in their sensory machinery that accompanied TSD-GSD transitions (e.g., calcium/ion channels or membrane transport components in Chrysemys versus structural elements and ciliogenesis in Apalone). This novel Primary Cilia Integration hypothesis expands current models of epigenetic regulation of turtle sexual development, the evolution of plasticity versus canalization, and warrants functional validation.

Benzodiazepines and sedative hypnotics such as zolpidem ("z-drugs") are commonly prescribed for anxiety and sleep disorders. Epidemiologic evidence links their use to increased risk of venous thromboembolism. We investigated venous thromboembolism risk among concomitant users of individual benzodiazepines/z-drugs (examined separately) with other prescription medications to generate data-driven hypotheses about drug interactions resulting in clinically meaningful harm to inform future etiologic studies of specific drug combinations. We conducted a series of self-controlled case series studies within a 50% random sample of US Medicaid and Medicare data. Each cohort comprised person-time exposed to a benzodiazepine/z-drug, dichotomized into focal versus referent periods based on concomitant drug use versus non-use. We used conditional Poisson regression to estimate incidence rate ratios for hospital or emergency department presentation for venous thromboembolism. We generated ratios of incidence rate ratios, leveraging negative control analyses of eye drop-concomitant drug pairs, to minimize confounding by indication for the concomitant drug. We used semi-Bayes shrinkage to minimize false positives. Among 1590 self-controlled case series studies involving 8853 individuals with venous thromboembolism, 38 (2.4%) potential drug interaction signals were identified before calibration. After adjustment for multiple testing and negative control findings, five (0.3%) signals remained, involving gabapentin combined with eszopiclone, lorazepam, clonazepam, or alprazolam, and apixaban combined with diazepam (ratio of incidence rate ratio range: 1.92-3.57). Four (80%) involved concurrent use of gabapentin, a medication largely used to treat neuropathic pain. Most benzodiazepine/z-drug combinations conferred no increased venous thromboembolism risk. However, concurrent use of a benzodiazepine/z-drug with gabapentin may increase the relative rate of venous thromboembolism up to 3.5-fold. As this work was hypothesis generating, a future etiologic study should confirm this potential drug interaction.

Cognitive fatigue (CF), characterized by decrements in executive function and heightened subjective exhaustion resulting from prolonged cognitive exertion, has emerged as a critical determinant of athletic performance and psychophysiological wellbeing. Despite the exponential growth in research output, systematic quantitative analyses of the intellectual structure, evolutionary trajectory, and emerging frontiers within this domain remain scarce. Drawing upon the Web of Science Core Collection and Scopus databases, this study retrieved publications addressing exercise and cognitive fatigue from 1998 to 2025 using the search strategy: TS = ("physical activity" OR exercise OR sport*) AND TS = ("mental fatigue" OR "cognitive fatigue" OR "mental fog" OR "cognitive weariness*" OR "cognitive exhaustion*"). Following systematic screening, 820 articles were included for bibliometric analysis utilizing Bibliometrix and VOSviewer. Publication output rose modestly (1.84% annually), peaking in 2025 (n = 106), likely reflecting post-pandemic mental health research expansion and portable neurotechnology adoption. The US and China led productivity; the UK showed highest citation impact (48.16/article), suggesting influential contributions, though this may reflect publication timing and foundational works. Vrije Universiteit Brussel and University of Birmingham topped institutional output, reflecting sustained contributions within the Marcora, Meeusen, and Roelands traditions. Frontiers in Psychology was most influential. Keywords shifted from laboratory tasks to ecologically valid sport contexts ("football," "team sports"). Thematic evolution moved from "chronic fatigue syndrome" to "perceived exertion" and "depression," then to "executive function" and "combat sports"-indicating a gradual shift from descriptive symptoms to integrated cognitive-affective-physiological mechanisms. "Cognitive effort," "physical fatigue," and "executive function" occupied the motor themes quadrant in 2024-2025, signaling mature, structurally central topics. Findings suggest emerging brain-body-performance integration. This study traces an evolution from pathological fatigue measurement to executive function precision assessment. Bibliometric indicators reveal growing emphasis on cognitive effort as a motor modulator, with co-occurrence patterns identifying dual clusters around subjective perception and performance parameters. Whether this bibliographic convergence reflects validated physiological mechanisms or emerging theoretical hypotheses requires further primary experimental investigation. This analysis provides a complementary, field-level perspective that complements, rather than replaces, primary experimental research.

Oropouche virus (OROV), an emerging orthobunyavirus in the Americas, has historically been associated with self-limited febrile illness in endemic Amazon basin regions. However, recent epidemiological updates from the Pan American Health Organization (PAHO) and World Health Organization (WHO) document a marked increase in case counts and geographic expansion, with over 16,000 confirmed cases reported in 2024 and continued transmission across multiple countries in 2025, including regions where transmission had not been previously recognized. The detection of cases in the Caribbean, Central America, and imported infections in North America and Europe underscores its evolving epidemiological profile and growing global relevance. In parallel with this expansion, neurological involvement-including meningitis and encephalitis-has been reported in a subset of patients. Experimental and ex vivo studies demonstrate neural permissiveness and suggest the capacity for interaction with central nervous system (CNS) tissue. Based on established principles of viral neuroimmunology, a conservative conceptual framework is proposed linking acute neuroimmune activation during OROV infection to potential neurological manifestations. Although long-term neurological sequelae have not been systematically characterized, existing clinical observations and biological mechanisms provide plausibility for further investigation. This framework is intended to generate testable hypotheses and guide prospective studies rather than establish causality.

Chronic stress disrupts the gut-brain axis (GBA) through coordinated dysfunction of the intestinal barrier and of the vascular interfaces that protect the brain, fostering a neuroinflammatory state implicated in mood disorders, neuropsychiatric conditions, and chronic pain. This narrative review synthesizes evidence across five domains. First, the inflammatory cascade by which stress-induced disruption of the epithelial and gut vascular barriers activates the NLRP3 inflammasome and sustains central neuroinflammation. Second, microbial metabolites, namely short-chain fatty acids (SCFAs), tryptophan-kynurenine products, and indole derivatives, as modulators of gut-brain homeostasis. Third, the gut microbiome-endocannabinoidome axis, including the capacity of commensal bacteria to generate endocannabinoid-like N-acyl amides that engage host receptors. Fourth, the receptor-specific pharmacology of phytocannabinoids, distinguishing Δ9-tetrahydrocannabinol (THC), which acts principally at CB1 and CB2 with comparable affinity, from cannabidiol (CBD), which has low affinity for these receptors and signals mainly through TRPV1, TRPA1, GPR55, PPARs, and 5-HT1A. Fifth, sexual dimorphism in barrier vulnerability and treatment response. In rodent models, chronic stress reduces intestinal and blood-brain barrier tight junction expression, elevates circulating lipopolysaccharide, and activates the NLRP3 inflammasome, while tryptophan metabolism shifts toward neurotoxic kynurenine products. Cannabinoid modulation of the kynurenine pathway and cannabinoid-mediated restoration of blood-brain barrier integrity remain mechanistic hypotheses extrapolated from indirect evidence rather than demonstrated mechanisms in chronic psychological stress paradigms. Human data are largely limited to small trials of microbiota-targeted interventions and of CBD in anxiety, and to observational endocannabinoidome-microbiome studies. These observations provide a preclinical rationale for GBA-targeted pharmacological strategies, with translational claims explicitly separated from mechanistic plausibility.

The comparative efficacy of acceptance and commitment therapy (ACT) relative to other bona fide psychotherapies has been obscured by methodological limitations and variability in how ACT and active comparators are operationalized. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing full-model ACT (therapist-delivered, multi-session interventions targeting the core ACT processes) to bona fide psychotherapies. We identified 34 RCTs meeting our inclusion criteria. In line with prior critiques of the ACT literature, we identified several common methodological shortcomings, such as lack of preregistration of primary outcomes and hypotheses, inadequate statistical power for detecting differential effects, limited use of intent-to-treat analyses, and interpretive overreach. Random-effects three-level meta-analyses indicated that full-model ACT was not superior to bona fide psychotherapies on mental and behavioral health outcomes (g = -0.01, p = .86). Secondary, hypothesis-generating post hoc analyses examined clinical significance, ACT-targeted processes, and an exploratory TOST comparison against a prespecified equivalence region (g = ±0.20). Current RCT evidence does not justify recommending full-model ACT over other established treatments. Further progress will require more rigorous comparative trials and idiographic designs that better align with the ACT model.

Introduction Maintaining nasal tip projection and rotation while preserving physiological mobility remains challenging in rhinoplasty. Objectives & Hypotheses This study aimed to evaluate the clinical feasibility and biomechanical behavior of the columellolobular strut. We hypothesized that an angled configuration would demonstrate balanced mechanical behavior under load. Study Design This was a retrospective observational case series (N=115) supported by finite element modeling, conducted in accordance with STROBE guidelines. Methods Patients undergoing primary rhinoplasty between January 2021 and April 2024 were included. Finite element modeling assessed deformation and stress at 120°, 150°, and 180° under standardized compressive loading. Clinical outcomes were evaluated descriptively. Results Stable nasal tip projection and columellar position were clinically observed during a mean follow-up of 32 months. Finite element analysis demonstrated reduced deformation and stress with decreasing angulation, with the 120° configuration showing the most balanced response. Conclusions The columellolobular strut represents a biomechanically supported option for nasal tip stabilization while preserving controlled tip mobility.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor of the digestive system with a very low five-year survival rate. The limited efficacy and significant toxicity of existing chemotherapy regimens make the development of novel natural therapeutic agents an urgent priority. Lycopene is a natural carotenoid that has been shown to inhibit multiple cancers. However, research specifically targeting PDAC remains relatively scarce. This study first employed bibliometric analysis to examine the research landscape and emerging trends in lycopene-related cancer research from 2016 to 2026. Subsequently, network pharmacology methods are applied to screen potential lycopene targets and PDAC-related targets from databases such as CTD, ChEMBL and HERB. Following the identification of overlapping targets, drug-target and protein-protein interaction (PPI) networks are constructed, as well as a disease network. The mechanisms were explored using Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was used to predict the potential interactions between lycopene and representative hub targets, and molecular dynamics simulations were performed for selected high-ranking docking complexes to provide supportive information on complex-level conformational stability. In vitro experiments were then conducted to evaluate the predicted anti-PDAC effects and to perform focused validation of apoptosis-related proteins and the PI3K/Akt/P53 signaling axis. Publications on lycopene research in the field of cancer have shown a sustained upward trend. The focus of this research has gradually shifted from areas such as oxidative stress and antioxidant effects towards anti-cancer mechanisms. A total of 132 overlapping targets for lycopene's anti-PDAC activity were screened, leading to the identification of 10 core targets, including BCL2, AKT1, and TP53. GO enrichment analysis revealed that these targets are involved in biological processes such as the response to oxidative stress and cellular senescence. Meanwhile, KEGG enrichment analysis identified the PI3K-Akt signaling pathway as a key pathway. Molecular docking results showed that the binding energies of lycopene with core targets such as TP53 and BCL2 were below -4.5 kcal/mol. Molecular dynamics simulations provided supportive evidence for the conformational stability of representative lycopene-target complexes. In vitro experiments showed that lycopene inhibited the proliferation and migration of PDAC cells and promoted apoptosis-associated cell death, accompanied by decreased p-PI3K and p-AKT expression and increased P53 expression. This study systematically combined bibliometrics, network pharmacology, molecular docking, representative molecular dynamics simulations, and focused experimental validation to explore the potential anti-PDAC activity of lycopene. The inflammation-related hub targets identified by network analysis provide additional hypotheses for future experimental investigation. These findings provide preliminary mechanistic evidence for further preclinical investigation of lycopene in PDAC, but its translational application will require optimized formulations, pharmacokinetic validation, and in vivo efficacy studies to overcome its limited bioavailability.

Surfactants stabilize liquid-liquid interfaces, and their temperature-dependent behavior is highly relevant for applications involving emulsions. While temperature-induced phase transitions of interfacial films are well known, their detection depends strongly on the applied experimental technique. We hypothesize that combining interfacial shear rheology with a temperature-dependent thermodynamic description based on the Gibbs adsorption framework enables a more sensitive and quantitative identification of such transitions. Furthermore, we expect that molecular architecture, specifically head-group chemistry and alkyl chain length, governs the mechanical stability and temperature-induced phase behavior of surfactant films. Temperature-dependent interfacial shear rheology and pendant drop tensiometry were performed for a series of alkyl-chain surfactants with systematic variation of head group (amine, alcohol, acid) and chain length (C14, C16, C18) over a range of 15-80 °C. Interfacial tension data obtained from pendant drop measurements were analyzed using a newly derived temperature-dependent adsorption equation to extract adsorption free energies ∆Gads and identify phase transition temperatures. Interfacial shear rheology reveals pronounced temperature-induced transitions in surfactant films, reflected by a loss of elasticity and changes in interfacial structure. The transition temperature depends strongly on molecular architecture, with systematic variations in head group and chain length. In contrast, pendant drop tensiometry captures these changes only partially, indicating that interfacial tension alone does not fully reflect structural rearrangements. The combined thermodynamic and rheological analysis highlights the importance of interfacial mechanics for understanding temperature-dependent phase behavior at liquid-liquid interfaces.

This study aimed to correlate levels of salivary and serum glutamate in patients with/without generalized periodontitis and Type 2 diabetes mellitus (T2DM) and to evaluate the effect of scaling and root planing (SRP) on glutamate and cognition. We hypothesized that periodontitis and T2DM are associated with altered glutamate levels and poorer cognitive performance and explored whether SRP-related changes in glutamate relate to cognitive performance. Eighty patients aged 45-70-yr were allocated into four groups: healthy, periodontitis, T2DM and periodontitis with T2DM (n = 20 each). Periodontal parameters, Trail Making Tests (TMT-A and TMT-B) and salivary and serum glutamate levels were recorded at baseline and 1-month post-SRP. Diabetic patients showed higher glutamate levels, poorer periodontal status and prolonged TMT times than non-diabetics at baseline. Glutamate levels decreased significantly after SRP, whereas TMT completion times showed only small reductions. Serum glutamate levels showed a significant, moderate positive correlation with TMT-B scores. Fasting plasma glucose and glutamate were significant predictors of periodontitis. Glutamate was altered but did not mediate the periodontitis-TMT association. In T2DM and non-T2DM patients, serum glutamate was the most accurate marker to differentiate periodontitis. SRP improved periodontal status, reduced glutamate levels and was associated with improved executive function and processing speed.

Intramuscular fat (IMF) in beef contains abundant sweet and umami compounds, which largely determine the flavor and commercial value of beef. Previous studies have demonstrated that lncBNIP3 regulates bovine IMF deposition; however, whether and how it affects the metabolism of flavor-related lipids remains poorly understood. In this study, we hypothesized that lncBNIP3 influences the lipid metabolic profile of intramuscular adipocytes. To test this, we performed an integrated metabolome-transcriptome analysis on bovine intramuscular adipocytes transfected with siRNA against lncBNIP3, aiming to characterize the metabolic shifts and identify candidate genes and pathways associated with lncBNIP3 function. Firstly, Quantitative Real-Time PCR (qRT-PCR) confirmed the efficient knockdown of lncBNIP3 using small interfering RNA (siRNA) in bovine intramuscular adipocytes. Subsequently, metabolomic sequencing was performed on lncBNIP3-knockdown intramuscular adipocytes on day 6 of differentiation. A total of 1433 metabolites were identified, including 101 differentially accumulated metabolites (DAMs). These DAMs encompassed various phospholipids (e.g., Glycophosphoinositol) and unsaturated fatty acids (UFAs) such as Docosapentaenoic acid (22n-6) and Docosahexaenoic acid. Functional enrichment analysis of DAMs highlighted key pathways: Glycerophospholipid metabolism, Phospholipase D signaling pathway, and Arachidonic acid metabolism. Integrated analysis of DAMs and previously identified differentially expressed genes (DEGs) further confirmed the most significant enrichment in Glycerophospholipid metabolism. LncBNIP3 knockdown significantly reduced the levels of multiple phospholipids and while upregulating the mRNA expression of three phospholipid hydrolysis-related genes (PLA2G16, PLA2R1, and DGKG). Concurrently, most UFAs showed increased abundance, whereas the fatty acid desaturase genes FADS1, FADS2, and FADS3 were significantly suppressed. In conclusion, our integrative analysis reveals that lncBNIP3 knockdown is associated with enhanced phospholipid hydrolysis and increased UFA content, potentially mediated by altered expression of phospholipid hydrolysis-related genes and the FADS gene family. These findings provide a metabolic and transcriptomic landscape for lncBNIP3 function in bovine intramuscular adipocytes and offer a foundation for future mechanistic studies.

Following brain injury, neurons receiving afferent input from the site of injury become denervated. An established model for studying denervation-induced changes of neurons is the denervation of dentate granule cells following unilateral transection of the perforant pathway. In response to denervation, granule cells show a characteristic sequence of spine loss followed by spine recovery. Notably, some spines are more resistant to denervation than others, and the basis of this resilience is unknown. As in vitro data suggest that the actin-modulating protein synaptopodin stabilizes denervated spines, we hypothesized that the resilient granule cell spines contain this protein. To test this hypothesis in vivo, we performed entorhinal denervation in mice (3, 7, 14, and 28 days), intracellularly injected granule cells in fixed slices with Alexa 568-hydrazide dye, stained for synaptopodin and subsequently analyzed granule cell spines in the denervated outer and non-denervated inner molecular layer of the denervated dentate gyrus. In the denervated zone, synaptopodin-positive spines exhibited resilience to denervation, whereas synaptopodin-negative spines showed a transient ~40% drop in spine density. Furthermore, surviving synaptopodin-negative spines exhibited an increased head size. Within the non-denervated zone, spine density was maintained. However, the subpopulation of synaptopodin-negative spines also showed larger spine heads. Together, our morphological data are in line with (i) a spine-stabilizing role of synaptopodin, (ii) functional data indicating strengthening of surviving spines in the denervated outer molecular layer, and (iii) a functional reorganization of the network within the non-denervated inner molecular layer of the dentate gyrus.