Dynamic prediction of future clinical outcomes based on longitudinally measured predictors plays a crucial role in disease management and patient counseling, particularly when conventional static models are inadequate. Joint modeling of longitudinal and time-to-event data provides a useful framework for addressing this challenge. In this paper, we present a comprehensive development of the recently proposed backward joint model (BJM; Shen and Li, 2021), which factorizes the likelihood into the distribution of time-to-event data and the conditional distribution of longitudinal data given the event time. This structure facilitates computation and is well-suited for multivariate longitudinal data. We introduce several novel developments to the BJM, including the extrapolation and two-part specifications, as well as the incorporation of competing risks. We also address an important yet underexplored problem in the literature: predicting future longitudinal trajectories conditional on predicted event times. Additionally, we explore the connection between BJM and existing joint modeling approaches. All these extensions preserve the computational advantages of the basic BJM formulation, including one-dimensional numerical integration, convex optimization via the EM algorithm, and a quick procedure for consistent estimation using standard software. We evaluate the method's performance through simulation studies and illustrate its utility in a chronic kidney disease application.

Dynamic benzyl-hydrazone crosslinks are widely used in covalent adaptable hydrogels due to their hydrolytic stability and tunable exchange kinetics. This reversibility enables competitive inhibition strategies in which small-molecule competitors modulate network dynamics by replacing crosslinking sites. Here, we demonstrate that adding molecules to compete with crosslinks can unintentionally perturb hydrogel mechanics through environmental effects, including changes in pH and ion concentration, in addition to direct bond disruption. In benzyl-hydrazone hydrogels, methyl hydrazine competitors unexpectedly increased the average relaxation time rather than accelerating network exchange. To decouple environmental effects from competitive inhibition, we systematically investigate how pH, ion concentration, and buffer composition influence hydrogel mechanics. We find that increasing ion concentration enhances the storage modulus, consistent with salt-mediated stabilization. Comparison across biologically relevant media further reveals that relaxation dynamics vary significantly with buffer identity, even when elastic moduli remain similar. Notably, more basic environments lead to markedly slower network relaxation, even in the presence of competitors to the crosslink. These findings demonstrate that, in competitively inhibited benzyl-hydrazone hydrogels, pH, ion concentration, and buffer identity can influence network mechanics in ways that differ from the expected effects of competitor addition alone, highlighting the need for careful interpretation of competitive inhibition experiments.

Radiation therapy for rectal cancer often causes long-term bowel dysfunction. We investigated radiation-associated motility changes in human rectal smooth muscle, focusing on the role of platelet-derived growth factor receptor alpha-positive (PDGFRα[+]) cells and interstitial cells of Cajal (ICC). Human rectal tissues were obtained from patients undergoing surgery with (n=61) or without (n=51) preoperative concurrent chemoradiotherapy (CCRT). Isometric tension recordings were used to assess myogenic responses to potassium chloride (KCl), acetylcholine (ACh), sodium nitroprusside (SNP), and adenosine triphosphate (ATP). Neurogenic components were assessed using electrical field stimulation. Intracellular microelectrode recordings measured slow wave activity. Expression of interstitial cells, neuronal cells and smooth muscle cells was assessed by immunohistochemistry and quantitative PCR. ATP-induced relaxation and ATP-associated suppression of slow wave activity were significantly attenuated in irradiated rectal tissue, while responses to KCl, ACh, and SNP were preserved. PDGFRα and Kit expression levels were markedly decreased in irradiated tissue (P < 0.001), whereas NOS1, VAChT, and MYH11 expression levels remained unchanged. Immunostaining confirmed reduced PDGFRα[+] cells and ICC in irradiated tissue. Pelvic irradiation delivered in the context of preoperative CCRT was associated with reduced PDGFRα[+] cells and ICC, with associated attenuation of ATP-mediated inhibitory responses, which may contribute to rectal dysmotility. These results suggest that preserving purinergic signaling may offer a potential therapeutic approach to improve long-term bowel function after pelvic radiotherapy.

Papain and Fucoidan are extracted enzymes that have gained recognition across food industry, pharmaceutical and digestive applications, but their comparative effects on Biliary flow rate and electrolytes are not known. Hence, this study compared the effects of papain and fucoidan on Biliary flow rate and electrolytes. Twenty (20) male albino Wistar rats weighing between 100g and 150g were divided into 4 groups of 5 animals each as follows: Group I (Control group) were administered normal saline and had access to food and water ad libitum. Group II (Papain group) were administered with 800mg/kg body weight of the stock solution of papain and were allowed free access to food and water. Group III (Fucoidan group) was given 800mg/kg body weight of the stock solution of fucoidan plus food and water. Group IV (Metoclopramide group) was administered with 30mg/kg body weight of Metoclopramide stock solution plus food and water ad libitum. The administration lasted for a duration of 28 days. Bile was collected from the liver (hepatic duct) and was analyzed for bile flow rate and its composition. The results showed that papain significantly increased biliary sodium and chloride, reduced bicarbonate levels, and had no significant effect on bile flow rate compared to the control group. Fucoidan significant effect on Biliary sodium, chloride and bile flow rate when compared to the control group. These results conclude that the two compounds have regulatory, but not stimulatory effects on biliary secretion, which proves their hepatoprotective and stabilising effects. Keywords: fucoidan, Papain, bile flow rate, biliary electrolyte. Short running title: Modulation of Fucoidan and Papain on Biliary Parameter.

β-Glucosidases are in high demand for industrial processes such as lignocellulosic saccharification and high-salt food fermentation. However, conventional enzymes often lose activity under high-salt and alkaline conditions, which constrains their broader applicability. In this study, a glycoside hydrolase family 3 (GH3) β-glucosidase (designated PlGH3) was cloned from Pontixanthobacter luteolus SW-109, and was heterologously expressed in Escherichia coli, followed by systematic characterization of its enzymatic properties and structural simulation. PlGH3 showed an optimal pH of 9.0 and optimal temperature of 50 °C, the kinetic parameters of PlGH3 toward p-nitrophenyl-β-D-glucopyranoside (pNPG) were determined as Km = 0.63 mM and Vmax = 3.00 U/mg. PlGH3 still maintained 40%-70% activity in alkaline environment for 24 h. Ca[2+], Mg[2+], and Mn[2+] improved its activity by 120%-140%. Notably, high salt strongly enhanced PlGH3's activity, 4 M NaCl increased enzyme activity by ~ 2.5-fold. It also exhibited ≥ 80% stability in most organic solvents and detergents. Local enrichment of acidic residues on the PlGH3 surface could generate a negative electrostatic potential, which enables adaptation to high-salt and alkaline environments, thereby sustaining the enzyme's catalytic activity under such extreme conditions. Our study enriches marine extremophilic β-glucosidase resources and provides a promising candidate for high-salt/alkaline processes.

High-nickel layered oxides are the leading commercial cathode candidates for lithium-ion batteries, yet their widespread deployment remains constrained by limited cycling stability. Niobium (Nb) coating/doping has emerged as an effective mitigation strategy, but current approaches typically rely on wet-chemical or gas-phase routes that are difficult to scale. Herein, we report a dry process that achieves homogeneous Nb[5+] doping into Li1Ni0.83Mn0.05Co0.12O2 by treating the precursor with ultrafine Nb2O5 nanoparticles synthesized via flame spray pyrolysis. With only 0.5 mol.% Nb[5+], the doped material exhibits improved lattice ordering and refined particle architecture, delivering high capacity up to 211 mAh g[-1], exceptional capacity retention 97% after 100 cycles in half cell, and markedly improved rate capability (170 mAh g[-1] at 5C) and long-term cyclability (83% over 500 cycles at 1C) in full cells. Multiscale structural and chemical analyses reveal the crucial role of ultrafine Nb[5+] addition at the precursor stage in modifying the grain morphology, which ends in homogeneous doping providing mitigation of intergranular cracking and suppression of surface rock-salt reconstruction, thereby preserving coherent grain boundaries under extended cycling. This work highlights the mechanistic effectiveness of homogeneous Nb[5+] doping via dry process in microstructural control and stabilization of high-nickel cathodes.

Traditional microbiology education is fundamentally constrained by the requirement for sterile laboratory conditions, which limits the implementation of practical activities in school settings. This limitation can be overcome by using Halobacterium salinarum, a halophilic archaeon that grows readily on media containing up to 5 mol·l[-1] (290 g·l[-1]) sodium chloride, effectively preventing contamination. Moreover, this micro-organism is non-pathogenic and well suited for educational use. This article presents two simple hands-on activities that can be easily carried out in a standard school science laboratory using common consumer products with the aim of reducing operational costs. The first activity introduces basic microbiological techniques by highlighting characteristic features of H. salinarum colonies, including their pink pigmentation and violet fluorescence under UV light. The second activity involves microscopic observation of cells stained with crystal violet, using microscope slides prepared according to a protocol adapted for halophilic microorganisms. Well-stained, flexible rod-shaped cells are observed, reflecting the absence of a rigid cell wall. Following these activities, a short questionnaire is proposed to encourage reflection on the experimental work performed. Instructors are also invited to discuss with students the role of extremophiles in the evolution of life forms.

Salinity stress poses a significant challenge to the productivity of maize, adversely affecting crop growth and development. The present study was conducted to elucidate the potential protective role of phenylalanine against salinity stress by modulating morphological traits, antioxidant defense mechanisms, and ionic balance. The study comprises two factors, including (i) salinity stress: NS = No salinity (control) SS = Salinity stress at 100 mM (sodium chloride), and phenylalanine foliar applications: NS = No spray, DWS = Distilled water spray, PAN10 = 10 mM, PAN20 = 20 mM, PAN30 = 30 mM, and PAN40 = 40 mM spray of phenylalanine. The results revealed that salinity stress caused a significant reduction in the morphological attributes (SFW by 47% and RFW by 39%) and photosynthetic pigments (chlorophyll a by 14% and chlorophyll b by 8%), while the foliar-applied PAN40 ameliorated the stress induce toxicity and improved these morphological attributes by 49% and 43% and photosynthetic pigments by 32% and 47%, respectively as compared to control conditions. Salinity stress increased the production of stress indicators such as MDA by 10% and H2O2 by 19%, while foliar application of PAN40 improved the activities of enzymatic and non-enzymatic antioxidants such as POD by 38%, CAT by 36%, and AsA by 38% and reduced the production of MDA by 10% and H2O2 by 19% under salinity stress. In crux, the foliar-applied PNA (40 mM) showed better performance under stress by improving the morphological and biochemical attributes to cope with the toxic effects of stress. The application of PAN may serve as a scalable, sustainable strategy to impart salinity stress tolerance in maize, improving both agronomic and biochemical resilience.

Wolbachia-based mosquito population replacement is a promising biocontrol strategy to reduce arboviral disease transmission by introducing Wolbachia-infected mosquitoes into wild populations. The success of this approach depends on the strain-specific characteristics of the Wolbachia symbiont and the mosquito host. This study presents a mathematical modelling framework to evaluate how Wolbachia strains and mosquito hosts influence the success of population replacement. The model incorporates key biological factors, including incomplete cytoplasmic incompatibility (CI), imperfect maternal transmission (MT), fitness costs, immigration, and potential loss of Wolbachia from mosquitoes. Analytical and numerical simulations demonstrate that strain-specific differences significantly impact the establishment, spread, and long-term persistence of Wolbachia in mosquito populations. Results indicate that high CI and MT levels, combined with low fitness costs and minimal immigration, facilitate successful Wolbachia establishment. To account for environmental stress, the model is extended to a stochastic framework incorporating environmental noise. Analysis reveals that stochasticity can shift invasion thresholds, destabilize equilibria, and induce noise-driven transitions between coexistence states. Numerical simulations show that low noise levels allow deterministic thresholds to remain predictive, whereas stronger fluctuations can undermine replacement success despite favourable deterministic conditions. A stochastic optimal control formulation further indicates that higher and more prolonged releases are necessary in noisy environments to ensure replacement. Collectively, these findings highlight how both strain traits and environmental stress shape the deterministic and stochastic thresholds governing the success of Wolbachia-based mosquito population replacement.

The adaptable nature of Escherichia coli, shifting from benign to virulent forms, poses a major healthcare challenge due to rising multidrug resistance and hypervirulence. In this study, using an in silico reverse vaccinology approach, we designed a multiepitope mRNA vaccine candidate targeting the Shiga toxin 1 (Stx1) of Shiga toxin-producing E. coli (STEC). Two cytotoxic T-Lymphocyte (CTL), three Helper T-Lymphocyte (HTL), and two Linear B-Lymphocyte (LBL) epitopes were identified and selected through stringent computational filtering based on high antigenicity, non-allergenicity, and non-toxicity. These epitopes were joined using optimized linkers (EAAK, AAY, GPGPG, KK) and the adjuvant PefE to form a stable 184-residue multi-epitope construct. Physicochemical profiling predicted a molecular weight of 19969.45 Da, an antigenicity score of 0.9278 (VaxiJen v.2.0), a basic isoelectric point (pI) of 10.31, and structural stability. Structural analysis revealed 21.74% alpha-helical content. Molecular docking exhibited strong binding with human Toll-like receptor 2 TLR2 and TLR4, with weighted energy scores of - 1096.2 and - 1110.5 kcal/mol, respectively, mediated by extensive hydrogen-bonding and salt-bridge networks. In silico immune simulation projected a strong clonal expansion of B-cells, active T-helper and cytotoxic T-cells, and higher cytokine production (IFN-γ, IL-10). Codon Adaptation Index (CAI) of 0.87 and a stable mRNA secondary structure were predicted with a minimum free energy (MFE) of - 204.10 kcal/mol. While these computational findings provide immunogenic potential, they represent a predictive hypothesis. Subsequent in vitro synthesis and in vivo testing in animal models are essential to validate its safety, immunogenicity, and protective efficacy.

Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke's R[2], and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.