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Mussel-inspired cross-linking mechanisms enhance gelation and adhesion of multifunctional mucin-derived hydrogels
Mucus supports human health by hydrating, lubricating, and preventing infection of wet epithelial surfaces. The beneficial material properties and bioactivity of mucus stem from glycoproteins called mucins, motivating the development of mucin-derived hydrogels for wound dressings and antifouling coatings. However, these applications require robust gelation and adhesion to a wide range of substrates. Inspired by the chemical cross-linking and water-tolerant adhesion of marine mussel adhesive structures, we use catechol–thiol bonding to drive gelation of native mucin proteins and synthetic mucin-inspired polymers, forming soft, adhesive hydrogels that can be coated onto diverse surfaces. The gelation dynamics and adhesive properties can be systematically tuned by varying the hydrogel composition, polymer architecture, and thiol availability, with gelation timescales adjustable from seconds to hours, and values of elastic modulus, failure stress, and debonding work spanning orders of magnitude. We demonstrate the functionality of these gels in two applications: as tissue adhesives, using porcine skin as a proxy for human skin, and as bioactive surface coatings to prevent bacterial colonization. The results highlight the potential of catechol–thiol cross-linking as a versatile platform for engineering multifunctional glycoprotein hydrogels with applications in wound repair and antimicrobial surface engineering.
Prediction models show differences in highly pathogenic avian influenza outbreaks in Japan and South Korea compared to Europe
Druggable genome screens identify SPP as an antiviral host target for multiple flaviviruses
Mosquito-borne flaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus, and yellow fever virus, pose significant public health threats globally. Extensive efforts have led to the development of promising highly active compounds against DENV targeting viral non-structural protein 4B (NS4B) protein. However, due to the cocirculation of flaviviruses and to prepare for emerging flaviviruses, there is a need for more broadly acting antivirals. Host-directed therapy where one targets a host factor required for viral replication may be active against multiple viruses that use similar replication strategies. Here, we used a CRISPR-Cas9 library that we designed to target the druggable genome and identified signal peptide peptidase (SPP, encoded by Histocompatibility Minor 13, HM13), as a critical host factor in DENV infection. Genetic knockout or introducing mutations that disrupt the proteolytic activity of SPP markedly reduced the replication of multiple flaviviruses. Although their substrates differ, SPP has structural homology with γ-secretase, which has been pursued as a pharmacological target for Alzheimer’s disease. Notably, SPP-targeting compounds exhibited potent anti-DENV activity at low nanomolar concentrations across multiple primary and disease-relevant cell types, acting specifically through SPP inhibition rather than γ-secretase inhibition. Importantly, SPP inhibitors were active at low nanomolar concentrations against flaviviruses other than DENV including ZIKV while DENV NS4B inhibitors lost activity. This study emphasizes the strong potential of SPP as a pan-flaviviral target and provides a framework for identifying host druggable targets to screen for broad-spectrum antivirals.
Retraction Note: Pre-activation of mesenchymal stem cells with TNF-α, IL-1β and nitric oxide enhances its paracrine effects on radiation-induced intestinal injury
Biophysical modeling of membrane curvature generation and curvature sensing by the glycocalyx
Generation of membrane curvature is fundamental to cellular function. Recent studies have established that the glycocalyx, a sugar-rich polymer layer at the cell surface, can generate membrane curvature. While there have been some theoretical efforts to understand the interplay between the glycocalyx and membrane bending, there remain open questions about how the properties of the glycocalyx affect membrane bending. For example, the relationship between membrane curvature and the density of glycosylated proteins on its surface remains unclear. In this work, we use polymer brush theory to develop a detailed biophysical model of the energetic interactions of the glycocalyx with the membrane. Using this model, we identify the conditions under which the glycocalyx can both generate and sense curvature. Our model predicts that the extent of membrane curvature generated depends on the grafting density of the glycocalyx and the backbone length of the polymers constituting the glycocalyx. Furthermore, when coupled with the intrinsic membrane properties such as spontaneous curvature and a line tension along the membrane, the curvature generation properties of the glycocalyx are enhanced. These predictions were tested experimentally by examining the propensity of glycosylated transmembrane proteins to drive the assembly of highly curved filopodial protrusions at the plasma membrane of adherent mammalian cells. Our model also predicts that the glycocalyx has curvature-sensing capabilities, in agreement with the results of our experiments. Thus, our study develops a quantitative framework for mapping the properties of the glycocalyx to the curvature generation capability of the membrane.
Predicting 90-day risk of urinary tract infections following urostomy in bladder cancer patients using machine learning and explainability
Cryo-EM of native membranes reveals an intimate connection between the Krebs cycle and aerobic respiration in mycobacteria
To investigate the structure of the mycobacterial oxidative phosphorylation machinery, we prepared inverted membrane vesicles from Mycobacterium smegmatis , enriched for vesicles containing complexes of interest, and imaged the vesicles with electron cryomicroscopy. We show that this analysis allows determination of the structure of both mycobacterial ATP synthase and the supercomplex of respiratory complexes III and IV in their native membrane. The latter structure reveals that the enzyme malate:quinone oxidoreductase (Mqo) physically associates with the respiratory supercomplex, an interaction that is lost on extraction of the proteins from the lipid bilayer. Mqo catalyzes an essential reaction in the Krebs cycle, and in vivo survival of mycobacterial pathogens is compromised when its activity is absent. We show with high-speed spectroscopy that the Mqo:supercomplex interaction enables rapid electron transfer from malate to the supercomplex. Further, the respiratory supercomplex is necessary for malate-driven, but not NADH-driven, electron transport chain activity and oxygen consumption. Together, these findings indicate a connection between the Krebs cycle and aerobic respiration that directs electrons along a single branch of the mycobacterial electron transport chain.
Characterization of a mock up nuclear waste package using energy resolved MeV neutron analysis
Abstract Reliable radiographic methods for characterizing nuclear waste packages non-destructively (without the need to open containers) have the potential to significantly contribute to safe handling and future disposal options, particularly for legacy waste of unknown content. Due to required shielding of waste containers and the need to characterize materials consisting of light elements, X-ray methods are not suitable. Here, energy-resolved MeV neutron radiography is demonstrated as a first-of-its-kind application for non-destructive and remote examination of mock up nuclear waste packages from a safe position using time-of-flight techniques enabled by a novel event-mode imaging detector system. Energy-resolved neutron transmission spectra were measured spatially, permitting the detection of analogue materials to actual nuclear waste such as water, melamine, and ion exchange resin within a 2.54 cm wall thickness steel pipe. The results demonstrate the capability to locate the materials through this wall thickness by radiography and tomographic reconstruction, revealing detailed 3D distributions and structural anomalies. The method effectively detects residual water in ion exchange resin, highlighting its sensitivity to moisture content, a crucial parameter for nuclear waste characterization. Monte Carlo simulations are in agreement with the experimental findings, providing a pathway to simulate waste forms more difficult to tackle experimentally. This work paves the way to apply sub-nanosecond intense MeV neutron sources, such as laser-driven neutron sources under development, to nuclear waste characterization.
Profile of Mark Kirkpatrick
Comparative assessment of vegetable yield with and without biochar derived from locally sourced apricot shells
Nongenetic adaptation by collective migration
Cell populations must adjust their phenotypic composition to adapt to changing environments. One adaptation strategy is to maintain distinct phenotypic subsets within the population and to modulate their relative abundances via gene regulation. Another strategy involves genetic mutations, which can be augmented by stress-response pathways. Here, we studied how a migrating bacterial population regulates its phenotypic distribution to traverse diverse environments. We generated isogenic Escherichia coli populations with varying distributions of swimming behaviors and observed their phenotype distributions during migration in liquid and porous environments. We found that the migrating populations became enriched with high-performing swimming phenotypes in each environment, allowing the populations to adapt without requiring mutations or gene regulation. This adaptation is dynamic and rapid, reversing in a few doubling times when migration ceases. By measuring the chemoreceptor abundance distributions during migration toward different attractants, we demonstrated that adaptation acts on multiple chemotaxis-related traits simultaneously. These measurements are consistent with a general mechanism in which adaptation results from a balance between cell growth generating diversity and collective migration eliminating underperforming phenotypes. Thus, collective migration enables cell populations with continuous, multidimensional phenotypes to flexibly and rapidly adapt their phenotypic composition to diverse environmental conditions.
Development and validation of a deep reinforcement learning algorithm for auto-delineation of organs at risk in cervical cancer radiotherapy
Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis
Loss-of-function (LOF) pathogenic variants in KCNQ1 encoding a cardiac potassium channel predispose to sudden cardiac death in type 1 congenital long QT syndrome (LQT1). To determine the spectrum of molecular mechanisms responsible for this life-threatening condition, we used an integrative approach to determine the biophysical, functional, and trafficking properties of 61 KCNQ1 variants distributed throughout all domains of the channel. Impaired trafficking to the plasma membrane was the most common cause of LOF across all channel domains, often but not always coinciding with protein instability. However, many LOF variants, particularly in transmembrane domains, trafficked normally, but when coexpressed with KCNE1 exhibited impaired conductance, altered voltage dependence, or abnormal gating kinetics, highlighting diverse pathogenic mechanisms. This indicates a need for personalized treatment approaches for LQT1. Use of our data to benchmark variant pathogenicity prediction methods demonstrated that prediction accuracy depends on the exact mechanism of pathogenicity associated with a given variant.
The relationship between expression level and gene polymorphism of inflammatory factors and sepsis risk
A binary trait model reveals the fitness effects of HIV-1 escape from T cell responses
Natural selection often acts on multiple traits simultaneously. For example, the virus HIV-1 faces pressure to evade host immunity while also preserving replicative fitness. While past work has studied selection during HIV-1 evolution, as in other examples where selection acts on multiple traits, it is challenging to quantitatively separate different contributions to fitness. This task is made more difficult because a single mutation can affect both immune escape and replication. Here, we develop an evolutionary model that disentangles the effects of escaping CD8 + T cell–mediated immunity, which we model as a binary trait, from other contributions to fitness. After validation in simulations, we applied this model to study within-host HIV-1 evolution in a clinical dataset. We observed strong selection for immune escape, sometimes greatly exceeding past estimates, especially early in infection. Conservative estimates suggest that roughly half of HIV-1 fitness gains during the first months to years of infection can be attributed to T cell escape. Our approach is not limited to HIV-1 or viruses and could be adapted to study the evolution of quantitative traits in other contexts.
CDK4/6 inhibitors upregulate cIAP1/2, and Smac mimetic LCL161 enhances their antitumor effects in cholangiocarcinoma cells
Cell-based glycoengineering for production of homogeneous and specific glycoform-enriched antibodies with improved effector functions
Glycosylation of humanized antibody at Fc-Asn297 significantly affects the Fc-mediated killing of target cells through effector functions, especially antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent vaccinal effect (ADVE). Previous studies showed that therapeutic immunoglobulin G (IgG) antibodies with α2,6-sialyl complex type (SCT) glycan attached to Fc-Asn297 exhibited optimal binding to the Fc receptors on effector cells associated with ADCC, ADCP, and ADVE. However, the production of antibodies with homogeneous Fc-SCT glycan requires multiple in vitro enzymatic and purification steps. In this study, we report two cell-based methods to produce Fc-GlcNAc antibody and Fc-SCT-enriched antibodies with improved effector functions. First, we expressed endoglycosidase S2 in Expi293F GnT1- cells to trim all N-glycans to Fc-GlcNAc antibody for in vitro transglycosylation to generate homogeneous antibodies with well-defined Fc glycan. Second, we engineered the glycosylation pathway of HEK293T cells through knock-out of undesired glycosyltransferases and knock-in of desired glycosyltransferases to produce Fc-SCT-enriched antibodies and evaluated their binding to Fc receptors, and we found that the Fc-SCT-enriched antibody is like or better than the homogeneous Fc-SCT antibody in binding to the Fc receptors associated with ADCC, ADCP, and ADVE.
Acute effects of high-intensity interval training and moderate-intensity continuous training on executive functions in healthy older adults
Abstract Numerous studies have demonstrated that executive functions benefit from high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). However, the immediate effects of HIIT and MICT on these functions in older adults have not been compared. This study aimed to examine the acute impact of HIIT and MICT on executive function components in this demographic. Twenty-five healthy community-dwelling older adults (15 females; average age 67.1 ± 4.5 years) participated. The study involved three sessions: an initial session with cognitive assessments (Stroop Task: Naming, Inhibition, and Switching) and a maximal continuous graded exercise test, followed by two sessions involving HIIT (15s at 100% peak power output, 15s rest, 2 × 20 min) or MICT (34 min at 60% peak power output) training protocols in random order. Cognitive tests were administered immediately after and 45 min post-training. The results showed a significant difference in Switching reaction times between MICT and HIIT, with HIIT showing a greater reduction in Switching times after 45 min (p = 0.019). In conclusion, our study indicates that HIIT’s beneficial effects on executive functions demonstrated a larger effect size than those of MICT. This suggests that brief, high-intensity exercise could be more effective in enhancing executive functions among older adults.
Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic
Axon degeneration, driven by the NAD + hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following nerve injury. However, the precise molecular mechanism underlying SARM1 activation remains to be fully elucidated. In this study, we report the identification of a potent proactivator of SARM1, G10, which is converted into a direct activator (M1) by the enzyme nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures of SARM1 bound to M1, as well as to M1 and a nonhydrolyzable NAD + analog (1AD), captured two intermediate activation states and the fully active state, revealing a stepwise mechanism of SARM1 activation. Further, introducing a disulfide bond to prevent conformational transitions between the two intermediate states mediated by M1 stabilized SARM1 in its inactive form and blocked M1-induced cell death. Together, these findings propose a sequential, stepwise activation model for SARM1 and offer a framework for developing potential SARM1 inhibitors for the treatment of neurodegenerative diseases.