Browse Articles
Discover research articles across all indexed journals
Bacterial biofilms in calcium oxalate kidney stones: Where do we stand?
Hypergravity reduces F-actin accumulation in osteoclasts, with attenuated bone resorption
Bone loss occurs in astronauts during prolonged spaceflight, thus indicating the sensitivity of skeletal homeostasis to altered gravitational environments. Previous studies have shown that microgravity affects osteoclast differentiation and bone resorption, which suggests that osteoclasts possess mechanisms to sense and respond to gravity-generated mechanical forces. For testing of the related mechanisms, hypergravity can be experimentally reproduced with use of a centrifuge. In the present study, osteoclasts derived from mouse bone marrow were subjected to hypergravity under three conditions: 30G exposure using a non-CO 2 centrifuge system, and short- or long-term exposure to 3G or 5G using an incubator-compatible centrifuge system. Cytoskeletal organization and resorptive function were assessed using TRAP (tartrate-resistant acid phosphatase) staining, F-actin visualization, and dentin pit assays. In addition, phosphoproteomic analysis was performed after short-term exposure to 5G hypergravity. Hypergravity exposure for as brief as 30 minutes compromised F-actin ring integrity, reduced fluorescence intensity, and promoted nuclear repositioning toward actin rings, whereas tubulin and vinculin localization remained unchanged, and the structural alterations corresponded to attenuated resorption pit formation. Quantitative phosphoproteomic profiling revealed coordinated hypergravity-dependent changes in phosphorylation across multiple cellular modules, including cytoskeletal organization, membrane trafficking, intracellular signaling, and nuclear regulatory pathways. Together, these results indicate that osteoclasts are sensitive to gravity-generated mechanical loading, with hypergravity rapidly modifying F-actin-associated cytoskeleton properties and reprogramming phosphorylation-dependent signaling networks, ultimately attenuating bone-resorptive activity. These findings provide mechanistic insight into how osteoclasts respond to altered gravitational loading conditions and have implications for skeletal adaptation during spaceflight and under altered mechanical loading conditions on Earth.
Broadly reactive human monoclonal antibodies targeting influenza a nucleoprotein lack protective activity in vivo
G-protein regulatory network governs receptor internalization dynamics
G protein–coupled receptors (GPCRs) enable chemical communication between cells and are involved in nearly all essential functions. They transduce signals via heterotrimeric G proteins and are regulated by internalization, a process which redirects them from the cell surface to internal compartments and enables diversified signaling through spatial reorganization. Beyond the receptor, a vast regulatory network exists to further control G-protein signaling. However, it is unclear whether these modes of G-protein regulation also impact the upstream GPCR. Here, we systematically address how G-protein cycle regulation shapes GPCR internalization and establish several key principles and mechanisms governing this process. We find that timing of G-protein activation and deactivation and changes in G-protein cycle lifetime imparted by guanine nucleotide exchange factors, activators of G-protein signaling, and regulators of G-protein signaling can alter internalization outcomes. Furthermore, we determine how the activity and balance of discrete G-protein components interact with the G protein–coupled receptor kinase system to influence GPCR spatial distribution. Finally, we uncover that disease-associated variants of the most abundant G protein in the brain, GαoA, affect the regulatory network that drives GPCR internalization. Altogether, this study reveals that GPCR internalization is not a fixed receptor property but is dynamically governed by receptor–G-protein activation order, cycle lifetime, and the balance of Gα and Gβγ availability. As such, alterations in receptor internalization dynamics may contribute to the complex disease phenotypes associated with dysregulated G-protein networks.
Developing internationally agreed core indicators for surveillance of preconception health: protocol for a consensus study
Background Interventions and policies to optimise preconception health are increasing internationally. This stems from growing recognition that improving preconception health can improve maternal and child health outcomes and advance equity by reducing inequalities and address inequities for people of reproductive age and any children they may have. Interventions and policies should be evaluated through population-level surveillance of preconception health to inform the development of new initiatives, monitor effectiveness, and support advocacy for international adoption of successful strategies. However, there is currently no internationally agreed set of preconception health indicators available and suitable for international surveillance. The International Core Indicators for Preconception Health and Equity (iCIPHE) Alliance was established to address this gap. Aim To prioritise core indicators that can be used in low-, middle- and high-income countries for surveillance of preconception health and equity. Methods We held two workshops with the iCIPHE Alliance (multi-sectoral stakeholders from low-, middle- and high-income countries) to inform the design of this international consensus study. The development of core indicators will consist of three steps: (1) identifying an initial long-list of candidate surveillance indicators, and defining principles for scoring the importance of each indicator, through a literature review, public involvement, and workshops with iCIPHE Alliance members; (2) scoring each candidate indicator in terms of its importance for surveillance through a two-round Delphi survey among study participants; and (3) agreeing on the final core indicators through a series of consensus meetings with a selected group of study participants. We will recruit study participants from all World Health Organization (WHO) regions across four stakeholder groups: people of reproductive age (who do not belong to any of the other stakeholder groups); health and social care professionals; policy and programme professionals; and researchers. Dissemination We will disseminate the priority core indicators through peer-reviewed publication, lay summaries, policy briefs and presentations. An implementation strategy, to enable monitoring of inequalities, inequities, and changes in preconception health over time within and between countries, will be developed with relevant national and international organisations to inform next steps.
Three-dimensional voltage imaging in live larval zebrafish brains using fully genetically encoded voltage indicator
Abstract Voltage imaging has emerged as a powerful tool for recording membrane potential changes in living cells, offering a direct measurement of rapid neuronal events with high temporal precision. Since the brain is a three-dimensional circuit, it is essential to record signals across a volume. However, achieving effective three-dimensional voltage imaging over large neuronal populations remains challenging due to the need for high imaging speed, high signal-to-noise ratio, and extensive volume coverage. In this study, we demonstrate in vivo three-dimensional voltage imaging in larval zebrafish using oblique plane microscopy and QFDBD-QUAS-driven expression of the genetically encoded voltage indicator Ace-mNeon2-Kv2.1, achieving volumetric imaging rates of up to 200 volumes per second (VPS). This approach enables dye-free voltage imaging, simplifying experimental workflows and improving the reproducibility of in vivo voltage imaging experiments for investigating neuronal circuit dynamics in the living zebrafish animal model.
Mechanisms of ubiquitylation of the mitotic regulatory protein Cdc20
A multisubunit ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C) controls progress through mitosis in eukaryotic cells. The activity of APC/C in mitosis is subject to both positive and negative regulation by the co-activator protein Cdc20. On exit from mitosis, Cdc20 is targeted for degradation by APC/C-catalyzed ubiquitylation. It has been proposed that the ubiquitylation of Cdc20 is carried out by an intramolecular “cis” mechanism, in which Cdc20 bound to the co-activator site of APC/C is directly ubiquitylated [I. T. Foe et al. , Curr. Biol. 21 , 1870–1877 (2011)]. This proposal was mainly based on the observation that mutation in the IR tail of Cdc20, an isoleucine-arginine C-terminal sequence involved in its binding to APC/C, markedly impaired Cdc20 ubiquitylation. We find that the IR tail of Cdc20 is also required for Cdc20 ubiquitylation promoted by Cdh1, an APC/C co-activator that acts in the G1 phase of the cell cycle. This suggested the involvement of the IR motif in a trans mechanism of Cdc20 ubiquitylation. A trans mechanism is also suggested by the observation that Cdc20 ubiquitylation by APC/C Cdc20 , as that by APC/C Cdh1 , requires both KEN-box and CRY-box degrons of Cdc20. A model is proposed according to which the IR tail of substrate Cdc20, along with its KEN-box and CRY-box motifs, interact with corresponding binding sites of APC/C-coactivator complexes.
Frailty in older maintenance hemodialysis patients: A latent class analysis revealing personalized management
Background Elderly patients undergoing maintenance hemodialysis (MHD) exhibit an elevated risk of frailty, which is strongly associated with adverse clinical outcomes, including increased mortality. However, current frailty assessment tools often overlook intrinsic patient heterogeneity, limiting their clinical utility. This study employs latent class analysis to identify distinct frailty profiles in elderly MHD patients, aiming to explore heterogeneity in frailty phenotypes and identify associated factors, thereby informing the development of targeted interventions. Methods Data were collected from 227 elderly patients receiving MHD in Guangdong Province, China, from January to April 2023. Participants were assessed using a general information questionnaire and the Fried scale. Latent class analysis was applied to identify subgroups based on frailty characteristics, and Firth logistic regression was used to examine factors associated with frailty class membership. Results Two distinct frailty subgroups were identified: Class 1 (low physical activity–high frailty group, 55.1%) and Class 2 (high physical activity–low frailty group, 44.9%). Firth logistic regression demonstrated that combined hypertension (odds ratio [OR] = 0.023; 95% confidence interval [CI]: 0.002–0.119; P < 0.001), older age (OR = 0.746; 95% CI: 0.618–0.840; P < 0.001), longer dialysis duration (OR = 0.935; 95% CI: 0.874–0.976; P = 0.001), lower serum albumin concentration (OR = 0.884; 95% CI: 0.775–0.973; P = 0.010), and lower serum creatinine concentration (OR = 0.996; 95% CI: 0.992–0.999; P = 0.017) were significantly associated with belonging to the high-frailty group. Overweight showed a trend toward a protective association but did not reach statistical significance (OR = 5.874; 95% CI: 0.900–55.438; P = 0.065). Conclusions This study highlights the heterogeneity of frailty among elderly maintenance hemodialysis patients. Combined hypertension was strongly and inversely associated with the low-frailty group, indicating its predominance in the high-frailty phenotype. Older age, longer dialysis duration, lower serum albumin levels, and lower serum creatinine levels were significantly associated with the high-frailty phenotype. These findings underscore the importance of personalized frailty assessment and interventions, such as blood pressure management, nutritional support, and tailored exercise programs, to improve health outcomes in this vulnerable population. Future multicenter longitudinal studies are warranted to validate these frailty phenotypes and evaluate their predictive value for clinical outcomes.
Explainable CNN framework for accurate crop disease detection using plant leaf images
Cognition does not automatically influence perception: Evidence from neural encoding of colors belonging to different categories
The firmest evidence in favor of models that posit early high-level influences of cognition on perception comes from electroencephalography (EEG). Enhanced early, preattentive processing of light and dark blue feature changes compared to light and dark green changes was reported in Greek speakers, who have two basic terms for “blue” ( ghalazio/ble ). In the present three-experiment study, we systematically reevaluate this evidence and test an alternative model that the early difference waves in the human EEG instead mainly reflect contrast adaptation phenomena. We use the same classical oddball paradigm presenting alternating standards and deviants that systematically differ in color and/or luminance and chromatic contrast. We then calculate the visual mismatch negativity (vMMN), a putative index of preattentive feature change processing and predictive coding derived from EEG data, by subtracting the activity elicited by standards from that elicited by task-irrelevant deviants. Our experiments demonstrate the following: 1) vMMN is driven by contrast adaptation, being observable only in the presence of contrast differences between the stimuli and not reliably observed for categorically different hues equated in contrast; 2) there is no reliable difference between green- and blue-related difference waves in speakers (Russian) with two basic blue color categories, the difference waves, again, being driven by contrast rather than their categorical content. Our findings are highly significant for the debate concerning the interface between perception and cognition, as the absence of early categorical effects speaks against models that predict Whorfian-type preattentive cognitive influences on perception.
Echocardiographic characterization and markers of cardiovascular risk in adults with sickle cell disease in a Colombian tertiary referral centre: A cross-sectional study
Sickle cell disease (SCD) is associated with substantial cardiovascular morbidity, but echocardiographic data from Latin American populations remain scarce. We aimed to characterise the structural, functional, and haemodynamic echocardiographic profile of adults with SCD attending a tertiary referral centre in Cali, Colombia. We conducted an observational, cross-sectional study based on systematic review of medical records and transthoracic echocardiography reports of consecutive adult patients (≥18 years) with confirmed SCD evaluated between January 2022 and December 2024. Patients with complex congenital heart disease, severe valvular disease of unrelated aetiology, pregnancy, or echocardiograms of insufficient quality were excluded. Of 669 patients screened, 57 met inclusion criteria. Reporting followed STROBE recommendations. The median age was 24 years (interquartile range [IQR] 21–32) and 59.6% were female; the SS genotype was the most frequent (76.4%) and 68.5% were on hydroxyurea. Median haemoglobin was 8.5 g/dL (IQR 7.1–10.0) and median NT-proBNP 491 pg/mL (IQR 98–1290). Most patients had preserved left ventricular dimensions and systolic function (median ejection fraction 63%, IQR 57–66.5; mean global longitudinal strain −18.9% ± 2.9). Right ventricular function was preserved (mean tricuspid annular plane systolic excursion 25.4 ± 4.6 mm). Left ventricular geometry was normal in 42.1%, with concentric remodelling in 10.5%, concentric hypertrophy in 21.1%, and eccentric hypertrophy in 26.3%. Diastolic function was normal in 71.4%. Valvular disease, when present, was predominantly mild. Tricuspid regurgitation velocity exceeded 2.5 m/s in 14 of 36 patients with measurable TRV (38.9%; 24.6% of the whole cohort) and exceeded 3.0 m/s in 6 patients (16.7% of those with measurable TRV), identifying a substantial subgroup at intermediate-to-high probability of pulmonary hypertension. In this Colombian cohort of relatively young adults with SCD, cardiac structure and biventricular function were largely preserved, but nearly one-third of patients had echocardiographic findings suggestive of pulmonary hypertension. These findings support the routine use of transthoracic echocardiography as an accessible tool for early cardiovascular risk stratification in adults with SCD in low- and middle-income settings.
EST-SSR based genetic polymorphism among Lablab (Lablab purpureus L. Sweet) accessions contrasting for drought stress at seedling stage
Oxytocin selectively biases sensory–prefrontal communication through network-level suppression and theta coupling
Oxytocin modulates social information processing by altering excitatory-inhibitory balance at the microcircuit level, but how such local modulation gives rise to selective processing at the level of distributed brain systems remains unclear. Here, we investigated the effects of oxytocin on large-scale neurodynamics across cortico-limbic network in the mouse brain using multisite local field potential recordings. Oxytocin selectively enhanced neural responses to infant calls in the auditory cortex (AC) and medial prefrontal cortex (mPFC). These enhancements occurred while baseline activity was reduced, indicating increased signal-to-noise ratio rather than a global increase in excitability. During auditory steady-state responses (ASSRs), oxytocin increased prefrontal phase coherence without altering ASSR power. During rest, oxytocin induced a transient, broadband reduction in spontaneous spectral power across regions. Despite this reduction in activity, analyses of interregional interactions revealed a selective increase in low-theta phase coupling and directional connectivity of AC→mPFC. Session-level analyses showed that stronger bottom–up AC→mPFC coupling was associated with lower prefrontal power, consistent with a gating or disinhibitory network regime favoring sensory-to-prefrontal information transfer. Multivariate analyses showed that oxytocin/saline conditions were reliably discriminable using supervised classification models, with specific contributions from spectral power, phase-locking, and Granger-causal connectivity features. Conversely, unsupervised dimensionality reduction did not identify a distinct low-dimensional manifold separating conditions, although a modest shift in the centroid of neural state space was observed. Together, these results indicate that oxytocin reduces background neural activity while selectively enhancing sensory–prefrontal network interactions, providing a systems-level account linking local inhibitory modulation to selective processing of socially salient infant cues.
Long COVID risk by pre-infection symptoms and functional status: A retrospective cohort study of data from the All of Us Research Program
Importance Over seven million U.S. adults experience persistent health issues after COVID-19, known as “long COVID”. Although multiple guidelines recommend the inclusion of functional status in long COVID diagnostic criteria, more evidence is needed to guide this recommendation. This study explored the adjusted odds of developing long COVID by pre-infection symptoms and functional status, and the feasibility of estimating functional status using health records data. Design & Methods Retrospective cohort study of U.S. adults with history of COVID-19 enrolled in a multicenter national cohort study through July 2022 ( All of Us Controlled Tier CDR 7.0), using diagnostic, procedure, and billing codes from the health record, and baseline survey responses. The risk of long COVID was estimated using logistic regression by pre-infection (−5 years) incidences of (a) at least one symptom common in long COVID, and (b) functional impairment, and adjusted for disease and demographic characteristics. Results n = 65,464 met inclusion criteria; n = 40,655 had post-infection occurrences of at least one symptom (long COVID group), n = 24,809 had none (recovered). Adjusted odds ratios of developing long COVID increased with older age, female sex, Black racial identity, earlier variant, non-vaccination, lower pre-infection self-reported mental and cognitive health, and number of pre-infection symptoms. Adjusted odds were not significantly affected by any single pre-infection symptom, self-rated physical ability, or EHR-derived indicators of prior functional impairment. Conclusions In this model, there were no significant differences in risk of long COVID based on either pre-infection total incidences of long COVID symptoms (compared to the average of 4) or pre-infection functional impairment. This suggests that long COVID was associated with a change from baseline functioning and health, including in people with pre-infection incident symptoms and functional impairments. The impacts of co-occurring pre-infection symptoms requires further investigation. Both harmonized electronic health records data and patient-reported outcomes contribute important data for developing the diagnostic utility of functional status changes in long COVID.
Phytochemical fingerprinting, antioxidant activity and cytotoxic evaluation of marketed Thalictrum foliolosum (Pili Jadi) root against MCF-7 breast cancer cells
Void-X: A generative void-filling model for predicting atomic packing in proteins
Generative AI algorithms such as the transformer and diffusion models have greatly empowered de novo design of proteins capable of specifically interacting with designated structural sites on another protein. Most of these design methods employ a top–down approach, in which an overall protein shape is generated by an AI model to pack against a given structural site, followed by sequence design to optimize the interaction. Despite being trained on limited protein complex structures available in the database, the top–down approach has yielded encouraging results. Here, we propose a bottom–up approach that generates atom clusters for optimal packing against a specified structured region for informing the design of protein–protein interactions. To this end, we trained a masked discrete diffusion model, named Void-X, that uses the diffusion transformer to learn atomic-level interactions and fill atomic voids in protein interaction interfaces. Void-X was trained using 8.7 million spherical clusters of atoms from experimental structures in the Protein Data Bank. In each cluster, ~70% of the atoms are used as context (or prompt), and ~30% are masked for information recovery (or answer). By training the model with 172 million parameters, Void-X achieves an overall accuracy of 78.3% and 68.2% for intra- and interchain spherical clusters, respectively. Furthermore, we find that information entropy is a reliable indicator of the prediction accuracy for Void-X. This level of performance allows de novo generation of molecular interactions at the atomic level, offering an alternative approach of protein design complementary to the existing ones.
Association between menstrual-related disorders and sexually transmitted infections: A nationwide cross-sectional study in Japan
Background To investigate the association between menstrual-related disorders and sexually transmitted infections (STI) among young women in Japan, and to examine differences according to disorder type and hormonal therapy use. Methods This cross-sectional study used the Japan Medical Data Center Claims Database and included women younger than 40 years who had at least one healthcare visit in 2023. Menstrual-related disorders were defined as endometriosis or dysmenorrhea based on ICD-10 codes. The prevalence of five STIs—gonorrhea, genital chlamydia infection, trichomoniasis, genital herpes, and other sexually transmitted conditions—was compared between women with and without menstrual-related disorders. Subgroup analyses were conducted for endometriosis, dysmenorrhea, and hormonal therapy (low-dose estrogen–progestin combinations or dienogest). Prevalence ratios (PR) and prevalence differences (PD) with 95% confidence intervals (CI) were estimated. Results Among 3,440,929 women, 257,897 (7.5%) had menstrual-related disorders. All STI were substantially more prevalent in this group than in women without menstrual-related disorders, with PRs ranging from 4.31 to 5.29. Endometriosis showed the highest prevalence, particularly for genital chlamydia infection (4.98%; PR 7.44). Dysmenorrhea was also associated with consistently elevated STI prevalence. Among women with menstrual-related disorders, STI prevalence differed only slightly according to hormonal therapy use, with differences generally within one percentage point. Conclusion Menstrual-related disorders were strongly associated with increased diagnosis of STI in Japanese young women. These findings highlight the importance of integrating STI screening and reproductive health education into routine gynecologic care for women with endometriosis or dysmenorrhea. The influence of healthcare-seeking behavior and diagnostic patterns should be considered when interpreting claims-based STI data.
Early and late mortality among patients with T1–T3 head and neck squamous cell carcinoma: a machine learning analysis using a SEER population-based cohort study
RNF126 is a peroxisomal fate switch enabling redifferentiation therapy in hepatocellular carcinoma
Tumor hypoxia promotes dedifferentiation and metabolic reprogramming in hepatocellular carcinoma (HCC), undermining normal liver functions. Here, we identify the E3 ubiquitin ligase RNF126 as a hypoxia-inducible “peroxisomal fate” switch that links the hypoxic microenvironment to loss of hepatocyte differentiation. Under hypoxia, HIF-2α drives RNF126 expression, which in turn ubiquitinates the peroxisomal membrane transporter ABCD3, triggering selective peroxisome autophagy (pexophagy) and depletion of peroxisomes. This organelle loss ablates very-long-chain fatty acid β-oxidation and hydrogen peroxide detoxification, erasing key hepatocyte differentiation features. We show that genetic RNF126 ablation restores peroxisomal functions and impairs hypoxic HCC growth. Leveraging these insights, we developed a small-molecule RNF126 inhibitor, D665-1412, which selectively blocks hypoxia-induced pexophagy. D665-1412 treatment stabilizes peroxisomes, normalizes lipid metabolism, and reactivates hepatocytic differentiation markers, thereby “redifferentiating” HCC cells and suppressing tumor progression in vitro and in vivo. Our findings establish the HIF-2α–RNF126–ABCD3 axis as a driver of HCC dedifferentiation and present organelle-targeted redifferentiation therapy as a promising approach for liver cancer.