Integration of Immune Cell-Target Cell Conjugate Dynamics Changes the Time Scale of Immune Control of Cancer.

The human immune system can recognize, attack, and eliminate cancer cells, but cancers can escape this immune surveillance. Variants of ecological predator-prey models can capture the dynamics of such cancer control mechanisms by adaptive immune system cells. These dynamical systems describe, e.

SNP rs6543176 is associated with extreme human longevity but increased risk for cancer.

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk.

Basic Science and Pathogenesis.

Background: Progressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy in patients, underscoring the need to interrogate additional targets with novel therapeutic modalities to expand the potential therapeutic arsenal. To diversify the therapeutic avenues for PSP and related tauopathies (e.

Integrated Analysis of Methylome and Transcriptome Responses to Exercise Training in Children with Overweight/Obesity.

We examined the effects of a 20-week exercise intervention on whole-blood genome-wide DNA methylation signature and its association with the exercise-induced changes in gene expression profiles in boys and girls with overweight/obesity (OW/OB). Twenty-three children (10.05 ± 1.

Basic Science and Pathogenesis.

Background: Microglial processing and recycling of debris is implicated in AD. AD GWAS loci are enriched for genes in efferocytosis, phagocytosis, endosomal trafficking and cholesterol efflux. Acting as a buffer, lipid droplets increase as a consequence of an imbalance between lipid debris influx and efflux rates.

Kinetics and Optimality of Influenza A Virus Locomotion.

Influenza A viruses (IAVs) must navigate through a dense extracellular mucus to infect airway epithelial cells. The mucous layer, composed of glycosylated biopolymers (mucins), presents sialic acid that binds to ligands on the viral envelope and can be irreversibly cleaved by viral enzymes. It was recently discovered that filamentous IAVs exhibit directed persistent motion along their long axis on sialic acid-coated surfaces.

Versatile Stimuli-Responsive Controlled Release of Pinanediol-Caged Boronic Esters for Spatiotemporal and Nitroreductase-Selective Glucose Bioimaging.

Boronic acids have been widely applied in various biological fields, particularly achieving significant practical progress in boronic acid-based glucose sensing. However, boronic acids exhibit nonspecific binding to other nucleophiles, and the inherent lability of boronic esters in biological systems limits their further applications. Herein, we developed a stimuli-responsive controllable caging strategy to achieve photoresponsive spatiotemporally and nitroreductase-responsive cancer cell-selective glucose sensing.

pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma.

The blood-brain barrier (BBB) remains a major obstacle for effective delivery of therapeutics to treat central nervous system (CNS) disorders. Although transferrin receptor (TfR)-mediated transcytosis is widely employed for brain drug delivery, the inefficient release of therapeutic payload hinders their efficacy from crossing the BBB. Here, we developed a pH-responsive anti-polyethylene glycol (PEG) × anti-TfR bispecific antibody (pH-PEG engager) that can complex with PEGylated nanomedicine at physiological pH to trigger TfR-mediated transcytosis in the brain microvascular endothelial cells, while rapidly dissociating from PEGylated nanomedicine at acidic endosomes for efficient release of PEGylated nanomedicine to cross the BBB.

Competing Hexagonal and Square Lattices on a Spherical Surface.

The structural properties of packed soft-core particles provide a platform to understand the cross-pollinated physical concepts in solid-state and soft-matter physics. Confined on a spherical surface, the traditional differential geometry also dictates the overall defect properties in otherwise regular crystal lattices. Using molecular dynamics simulation of the Hertzian model as a tool, we report here the emergence of new types of disclination patterns: domain and counter-domain defects, when hexagonal and square patterns coexist.

GPSD: a hybrid learning framework for the prediction of phosphatase-specific dephosphorylation sites.

Protein phosphorylation is dynamically and reversibly regulated by protein kinases and protein phosphatases, and plays an essential role in orchestrating a wide range of biological processes. Although a number of tools have been developed for predicting kinase-specific phosphorylation sites (p-sites), computational prediction of phosphatase-specific dephosphorylation sites remains to be a great challenge. In this study, we manually curated 4393 experimentally identified site-specific phosphatase-substrate relationships for 3463 dephosphorylation sites occurring on phosphoserine, phosphothreonine, and/or phosphotyrosine residues, from the literature and public databases.

MVA-based SARS-CoV-2 vaccine candidates encoding different spike protein conformations induce distinct early transcriptional responses which may impact subsequent adaptive immunity.

Introduction: Vaccine platforms such as viral vectors and mRNA can accelerate vaccine development in response to newly emerging pathogens, as demonstrated during the COVID-19 pandemic. However, the differential effects of platform and antigen insert on vaccine immunogenicity remain incompletely understood. Innate immune responses induced by viral vector vaccines are suggested to have an adjuvant effect for subsequent adaptive immunity.

Genetic manipulation of bacteriophage T4 utilizing the CRISPR-Cas13b system.

CRISPR-Cas type II and type V systems are inefficient in modifying bacteriophage T4 genome, due to hypermodification of its DNA. Here, we present a genome editing technique for bacteriophage T4 using the type VI CRISPR-Cas system. Using BzCas13b targeting of T4 phage, we were able to individually delete both T4 glucosyl transferase genes, and .

The African Initiative for Bioinformatics Online Training in Neurodegenerative Diseases (AI-BOND): Investing in the next generation of African neuroscientists.

Unlabelled: Neurodegenerative disorders, including Alzheimer's disease and AD-related dementias (AD/ADRD), pose significant challenges to health care systems globally, particularly in Africa. With the advances in medical technology and research capabilities, especially in next-generation sequencing and imaging, vast amounts of data have been generated from AD/ADRD research. Given that the greatest increase in AD/ADRD prevalence is expected to occur in Africa, it is critical to establish comprehensive bioinformatics training programs to help African scientists leverage existing data and collect additional information to untangle AD/ADRD heterogeneity in African populations.

A Low-Cost, Open-Source 3D Printer for Multimaterial and High-Throughput Direct Ink Writing of Soft and Living Materials.

Direct ink writing is a 3D printing method that is compatible with a wide range of structural, elastomeric, electronic, and living materials, and it continues to expand its uses into physics, engineering, and biology laboratories. However, the large footprint, closed hardware and software ecosystems, and expense of commercial systems often hamper widespread adoption. This work introduces a compact, low-cost, multimaterial, and high-throughput direct ink writing 3D printer platform with detailed assembly files and instructions provided freely online.

ABC transporter activity is affected by the size of lipid nanodiscs.

Lipid nanodiscs have become a widely used approach for studying membrane proteins thanks to several advantages they offer. They have been especially useful for studying ABC transporters, despite the growing concern about the possible restriction of the conformational changes of the transporters due to the small size of the discs. Here, we performed a systematic study to determine the effect of the nanodisc size on the ATPase activity of model ABC transporters from human, plant, and bacteria.

Thrushes in Love: Extensive Gene Flow, With Differential Resistance and Selection, Obscures and Reveals the Evolutionary History of a Songbird Clade.

The application of high-throughput sequencing to phylogenetic analyses is allowing authors to reconstruct the true evolutionary history of species. This work can illuminate specific mechanisms underlying divergence when combined with analyses of gene flow, recombination and selection. We conducted a phylogenomic analysis of Catharus, a songbird genus with considerable potential for gene flow, variation in migratory behaviour and genomic resources.

PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD).

Background: Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have shown remarkable clinical efficacy, they can also induce a paradoxical cancer acceleration, known as hyperprogressive disease (HPD), whose causative mechanisms are still unclear.

Methods: This study investigated the mechanisms of ICI resistance in an HPD-NSCLC model.

Mutant Fam20c knock-in mice recapitulate both lethal and non-lethal human Raine Syndrome.

Background: Inactivation or mutations of FAM20C causes human Raine Syndrome, which manifests as lethal osteosclerosis bone dysplasia or non-lethal hypophosphatemia rickets. However, it is only hypophosphatemia rickets that was reported in the mice with Fam20c deletion or mutations. To further investigate the local and global impacts of Fam20c mutation, we constructed a knock-in allele carrying Fam20c mutation (D446N) found in the non-lethal Raine Syndrome.

The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities.

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon.

Genome-scale evolution in local populations of wild chimpanzees.

Analysis of genome-scale evolution has been difficult in large, endangered animals because opportunities to collect high-quality genetic samples are limited. There is a need for novel field-friendly, cost-effective genetic techniques. This study conducted an exome-wide analysis of a total of 42 chimpanzees (Pan troglodytes) across six African regions, providing insights into population discrimination techniques.

Multi-omic biomarker panel in pancreatic cyst fluid and serum predicts patients at a high risk of pancreatic cancer development.

Integration of multi-omic data for the purposes of biomarker discovery can provide novel and robust panels across multiple biological compartments. Appropriate analytical methods are key to ensuring accurate and meaningful outputs in the multi-omic setting. Here, we extensively profile the proteome and transcriptome of patient pancreatic cyst fluid (PCF) (n = 32) and serum (n = 68), before integrating matched omic and biofluid data, to identify biomarkers of pancreatic cancer risk.

The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure.

A sedimentary ancient DNA perspective on human and carnivore persistence through the Late Pleistocene in El Mirón Cave, Spain.

Caves are primary sites for studying human and animal subsistence patterns and genetic ancestry throughout the Palaeolithic. Iberia served as a critical human and animal refugium in Europe during the Last Glacial Maximum (LGM), 26.5 to 19 thousand years before the present (cal kya).

Programming scheduled self-assembly of circadian materials.

Active biological molecules present a powerful, yet largely untapped, opportunity to impart autonomous regulation of materials. Because these systems can function robustly to regulate when and where chemical reactions occur, they have the ability to bring complex, life-like behavior to synthetic materials. Here, we achieve this design feat by using functionalized circadian clock proteins, KaiB and KaiC, to engineer time-dependent crosslinking of colloids.

Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy.

Dystrophy-associated fer-1-like protein (dysferlin) conducts plasma membrane repair. Mutations in the DYSF gene cause a panoply of genetic muscular dystrophies. We targeted a frequent loss-of-function, DYSF exon 44, founder frameshift mutation with mRNA-mediated delivery of SpCas9 in combination with a mutation-specific sgRNA to primary muscle stem cells from two homozygous patients.