Browse Articles

FcγRIIIa is a noncanonical costimulatory molecule for CD8 T cells

A critical component of the function of IgG antibodies is their capacity to engage specialized cellular receptors, Fcγ receptors (FcγRs), expressed on effector leukocytes. Highlighting the importance of FcγR-mediated signaling in the regulation of the fate, activation, and differentiation status of leukocytes, FcγRs are ubiquitously expressed by nearly all leukocyte populations. Here, we report that while at steady state, T cells are negative for all classes of FcγRs, CD8 T cells specifically induce the expression of the activating FcγR, FcγRIIIa, in response to viral infection in cohorts of COVID-19 and dengue patients, as well as in virus infection models using FcγR humanized mouse strains. In in vivo mechanistic studies, we demonstrate that induction of FcγRIIIa expression on effector CD8 T cells follows a well-defined trajectory that closely tracks the course and magnitude of the immune response, while immune resolution is characterized by receptor downregulation. Uniquely to these CD8 T cells, FcγRIIIa crosslinking alone is paradoxically insufficient to elicit T cell activation and cytotoxicity. However, when coupled with T cell receptor (TCR) stimulation, it results in synergistic cellular activation and, compensates for the downregulation of canonical costimulatory molecules on terminal effector CD8 T cells. These results reveal a previously unappreciated role for FcγRIIIa as a unique costimulatory molecule that synergizes with TCR signaling to lower the effective threshold required for CD8 T cell activation, highlighting the role of virally induced antibodies in modulating CD8 effector cell responses.

Sustainable concrete: investigating the synergistic effects of coconut fiber, wheat straw ash, and silica fume on RAC strength and durability

Abstract As concrete production accounts for a large percentage of worldwide CO2 emissions, there is a need for alternative sustainable construction materials. Simultaneously, the increasing generation of construction and demolition waste has led to the growing interest in using recycled aggregates (RA) in concrete. However, recycling aggregate (RAC) tends to demonstrate poor mechanical and durability performance because of relatively high porosity and weak interfacial transition zone existing in RA. This study explores the synergistic effects of coconut fiber (CF), wheat straw ash (WSA) and silica fume (SF) in its enhancement of RAC performance. Mechanical (compressive and tensile strengths) and durability (water absorption and acid resistance) characteristics of RA (50%, 75%, and 100%) incorporated with various proportions of WSA (5%, 10%, and 15%) have been studied. Additionally, CF (1.5%) and SF (7%) were also added in all mixtures. The findings show that the optimum mix (10% WSA and 50% RA) achieves a compressive strength of 30.7 MPa at 90 days. The tensile strength was also improved, with the 10% WSA mix offering the highest tensile strength of 3.89 MPa at 90 days. Durability tests showed that water absorption decreased, and acid resistance improved with the addition of WSA, especially with 10% WSA, which had the lowest water absorption of 4.8%. Microstructural Analysis of the concrete matrix showed, particularly for mixes with increased WSA content, indicate lower porosity and better bonding. The present work establishes base evidence for the use of CF, WSA and SF in improving the performance and sustainability of RAC and is a viable option for construction applications, particularly in the presence of the high construction and demolition waste regions.

Retraction for Ruby and Novick, Plasmid interactions in <i>Staphylococcus aureus</i> : Nonadditivity of compatible plasmid DNA pools

Robust Bi-CBMSegNet framework for advancing breast mass segmentation in mammography with a dual module encoder-decoder approach

Correction for Napora et al., Subfossil bald cypress trees suggest localized, enduring effects of major climatic episodes on the Southeast Atlantic Coast of the United States

Anti-IgD nanobodies as novel tools for studying human IgD biology

Abstract IgD is the least well characterized of mammalian antibody isotypes and its biology remains poorly understood. Nanobodies are a useful and versatile tool for research and diagnostics, including for protein purification, capture and detection applications. Here we report the characterization of four anti-human IgD nanobodies, specific to the Fc region of IgD. The four nanobodies bound to human IgD with low nanomolar affinity, showing different binding kinetics and interaction stoichiometries, as well as recognizing four distinct epitopes. We found one of these anti-IgD nanobodies, aδNb408, to be an excellent purification tool for IgD, with efficient capture and elution at pH 3.5. To aid the analysis of IgD interactions using surface plasmon resonance, we identified two nanobodies that provided good capture of IgD. Assembling bispecific and bivalent nanobody pairs increased the avidity of the anti-IgD nanobodies, with the bispecific nanobody pair aδNb408-aδNb107 showing robust detection of IgD on Namalwa B cells. The anti-IgD nanobody tools described here can be used for diverse applications that have the potential to further our understanding of IgD biology.

Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia

Macrophages often pervade solid tumors, and clusters of macrophages sometimes associate with longer survival of patients. However, clustering mechanisms and impacts on key functions such as phagocytosis remain obscure. Here, under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term “intrudopodia.” Cluster formation over hours on low-adhesion substrates occurs after macrophage induction to a state colloquially referred to as M1 after exposure to interferons and T cell–derived cytokines. Clusters prove fluid on timescales of minutes and also sort from interleukin-4-treated, so-called M2 macrophages that tend to disperse. M1 macrophages upregulate specific cell–cell adhesion receptors but suppress actomyosin contractility, with both pathways contributing to cluster formation. Decreased cortical tension was not only reflected in a low level of nuclear lamin-A that downregulates cytoskeletal targets of serum response factor and tends to soften the nucleus but was also predicted to unleash pseudopodia. Macrophage neighbors in tumor spheroids indeed coextend intrudopodia between cancer cell junctions—at least when phagocytosis conditions are maximized. Intrudopodia from neighbors help detach and individualize cancer cells for rapid engulfment. Juxtaposition of a macrophage cluster with tumor cell nests defines a broad interface that minimizes cancer cell nearest neighbor interactions and maximizes coordination of macrophage intrudopodia. Cooperative phagocytosis thus overcomes solid tumor cohesion—and might explain why the macrophage clustering factor ITGAL associates with patient survival.

Evolutionary adaptations of cyanobacterial polyhydroxybutyrate (PHB) biosynthesis and metabolic pathways in Spirulina, Arthrospira, and Limnospira spp

Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through autoinhibition

The endosomal–lysosomal network is a hub of organelles that orchestrate the dynamic sorting of hundreds of integral membrane proteins to maintain cellular homeostasis. VPS29 is a central conductor of this network through its assembly into Retromer, Retriever, and Commander endosomal sorting complexes, and its role in regulating RAB GTPase activity. Two VPS29 isoforms have been described, VPS29A and VPS29B, that differ solely in their amino-terminal sequences. Here, we identify a third VPS29 isoform, which we term VPS29C, that harbors an extended amino-terminal sequence compared to VPS29A and VPS29B. Through a combination of AlphaFold predictive modeling, in vitro complex reconstitution, mass spectrometry, and molecular cell biology, we find that the amino-terminal VPS29C extension constitutes an autoinhibitory sequence that limits access to a hydrophobic groove necessary for effector protein recruitment to Retromer, and association with Retriever and Commander. VPS29C is therefore unique in its ability to uncouple Retromer-dependent cargo sorting from the broader roles of VPS29A and VPS29B in regulating the endosomal–lysosomal network through accessory protein recruitment. Our identification and characterization of VPS29C points to additional complexity in the differential subunit assembly of Retromer, an important consideration given the increasing interest in Retromer as a potential therapeutic target in neurodegenerative diseases.

Failure mode identification and effects analysis of mobile X-ray machine using selected MADM techniques

The cultural construction of “executive function”

In cognitive science, the term “executive function” (EF) refers to universal features of the mind. Yet, almost all results described as measuring EF may actually reflect culturally specific cognitive capacities. After all, typical EF measures require forms of decontextualized/arbitrary processing which decades of cross-cultural work indicate develop primarily in “schooled worlds”–industrialized societies with universal schooling. Here, we report comparisons of performance on typical EF tasks by children inside, and wholly outside schooled worlds. Namely, children ages 5 to 18 from a postindustrial context with universal schooling (UK) and their peers in a rural, nonindustrialized context with no exposure to schooling (Kunene region, Namibia/Angola), as well as two samples with intermediate exposure to schooled worlds. In line with extensive previous work on decontextualized/arbitrary processing across such groups, we find skills measured by typical EF tasks do not develop universally: Children from rural groups with limited or no formal schooling show profound, sometimes qualitative, differences in performance compared to their schooled peers and, especially, compared to a “typical” schooled-world sample. In sum, some form of latent cognitive control capacities are obviously crucial in all cultural contexts. However, typical EF tasks almost certainly reflect culturally specific forms of cognitive development. This suggests we must decide between using the term EF to describe 1) universal capacities or 2) the culturally specific skill set reflected in performance on typical tasks. Either option warrants revisiting how we understand what has been measured as EF to date, and what we wish to measure going forward.

Exploring the role of two polypeptide nanofiber gels derived from RADA16-I self-assembly in accelerating burn wound healing

Axonal pathology differentially affects human Purkinje cell subpopulations in the essential tremor cerebellum

The cerebellar cortex is organized into discrete regions populated by molecularly distinct Purkinje cells (PCs), the sole cortical output neurons. While studies in animal models have shown that PC subtypes differ in their vulnerability to disease, our understanding of human PC subtype and vulnerability remains limited. Here, we demonstrate that human cerebellar regions specialized for motor vs. cognitive functions (lobule HV vs. Crus I) contain distinct PC populations characterized by specific molecular and anatomical features, which show selective vulnerability in essential tremor (ET), a cerebellar degenerative disorder. Using a known PC subtype marker, neurofilament heavy chain (NEFH), we found that motor lobule HV contains PCs with high NEFH expression, while cognitive lobule Crus I contains PCs with low NEFH expression in postmortem samples from healthy controls. In the same cerebella, PC axons in lobule HV were 2.2-fold thicker than those in Crus I. Across lobules, axon caliber positively correlated with NEFH expression. In ET cerebella, we identified motor lobule-specific PC axon pathology with a 1.5-fold reduction in caliber and increased axon variability in lobule HV, while Crus I axons were unaffected. Tremor severity and duration in ET correlated with axon diameter variability selectively in lobule HV PCs. Given that axonal caliber is a major determinant of neural signaling capacity, our results 1) suggest that disrupted cerebellar corticonuclear signaling is occurring in ET, and 2) provide evidence of region-specific PC populations in the human cerebellum and offer insight into how different PC subpopulations may contribute to the pathophysiology of cerebellar degeneration.

A branching bivariate weibull distribution model for evaluating exosomes in androgen-deprived agency in the presence of prostate cancer

Patchy harmonic functional connectivity of the mouse auditory cortex

Analyzing the functional connectivity of the brain is an enormous challenge, as deciphering functional connectivity requires knowledge of functional responses and connections. One promising strategy is analyzing the spatial pattern of activity correlations across cell populations. In the primary auditory cortex (A1), cells respond to different sound features. On the large scale, there exists a tonotopic map, which is fractured at the small scale, raising the question of whether functional connections are spatially ordered or disordered. To test whether functional connectivity on a local and a global scale is also disordered, we first designed a robust statistical model to estimate parameters and test for the significance of the estimated correlation maps. We developed an inference method that allows efficient model fitting and statistical testing to project the correlation maps to 2D space. We then performed in vivo two-photon calcium imaging in layer 2/3 of A1 with pure tones (PT) or a combination of two tones (TT; harmonically related or not). We found that the spatial patterns of signal correlations (SCs) depend on the type of sound stimuli that were presented. The functional 2D maps of PT-driven SCs are more restricted to local neurons than TT signal correlations which showed more global textures. 2D SC patterns for harmonic stimuli showed spatially distinct relationships. TT SCs revealed spatially precise functional connectivity between harmonically related neurons. Thus, even though the frequency preference of neighboring neurons in A1 is functionally diverse, the functional connection pattern of these neurons is functionally precise and harmonically related.

An enhanced deep learning approach for speaker diarization using TitaNet, MarbelNet and time delay network

Preservation bias obscures gradual Ordovician reef evolution

The fossil record often creates an illusion of sudden evolutionary bursts, which may reflect preservation biases rather than actual biological events. The Great Ordovician Biodiversification Event (GOBE) appears to mark the abrupt rise of diverse reef-building metazoans during the late Darriwilian (~460 Ma), seemingly contradicting gradual evolutionary models. Here, we demonstrate this apparent burst is largely an artifact of a global sea-level fall (~475 to 460 Ma) that produced widespread unconformities. Integrated stratigraphic and fossil occurrence data reveal early reef-builders likely appeared earlier than the late Middle Ordovician, but their record was erased by sea-level-driven erosion. During the peak of this sea-level fall (Dapingian Stage, 471 to 469 Ma), both carbonate deposition and fossil occurrences were minimal, with significant correlation between carbonate preservation and reef-builder occurrences. The subsequent transgression enabled these already-diversified organisms to recolonize shallow-water environments simultaneously across multiple regions, generating a misleading impression of sudden diversification. This “Sppil–Rongis effect” biased our understanding of the GOBE in reef ecosystems, illustrating how stratigraphic incompleteness can distort evolutionary patterns. Rather than a discrete evolutionary event, the GOBE reflects a continuous trajectory, interrupted and reshaped by sea-level fluctuations.

A novel model for expanding horizons in sign Language recognition

Abstract The American Sign Language Recognition Dataset is a pivotal resource for research in visual-gestural languages for American Sign Language and Sign-Language MNIST Dataset. The dataset contains over 64,000 images meticulously labeled with the corresponding ASL gesture or letter to recognize and classify ASL signs. Recent computer vision and deep learning advances have enabled various ASL recognition techniques. However, further improvements in accuracy and robustness are still needed. This study comprehensively evaluates different ASL recognition methods and introduces a novel architecture called Sign Nevestro Densenet Attention (SNDA). All methods are evaluated on the ASL Recognition Dataset to ensure a representative evaluation. SNDA employs the Nadam optimizer for faster convergence during training. Accurate ASL classification has practical implications for improving communication accessibility. SNDA achieves state-of-the-art performance with 99.76% accuracy, perfect sensitivity, and high specificity and precision. These results validate the effectiveness of SNDA for ASL gesture recognition and highlight its potential to promote inclusivity for deaf and hard-of-hearing communities. The fused attention mechanism demonstrates how deep learning models can be enhanced for specific application domains.

SpbR controls lipoteichoic acid length by directly inhibiting signal peptidase SpsB in <i>Staphylococcus aureus</i>

Staphylococcus aureus is a Gram-positive pathogen that causes life-threatening infections. Its cell envelope contains anionic polymers called teichoic acids that are required for cell viability. Teichoic acids come in two forms and are made by different biosynthetic pathways. One form, lipoteichoic acid (LTA), is anchored in the cell membrane; the other form, wall teichoic acid (WTA), is covalently linked to the peptidoglycan cell wall. Although the LTA and WTA biosynthetic pathways have been characterized, regulation of teichoic acid production is not well understood. Here, we identified SpbR ( SAOUHSC_00965 ), a polytopic membrane protein similar to a eukaryotic CAAX protease, as a factor that controls LTA levels in S. aureus cells. We show that loss of SpbR results in short LTAs and a synthetically sick phenotype when WTA biosynthesis is prevented, whereas overexpressing SpbR results in elongated LTAs. Mechanistically, we find that SpbR physically associates with the type I signal peptidase SpsB, which cleaves LtaS, the polymerase that assembles LTA on the extracellular side of the membrane, and we show that this physical interaction inhibits SpsB cleavage of LtaS both in vivo and in vitro. Although the phenotypes investigated here are dominated by SpbR’s effects on LtaS, it also inhibits cleavage of other SpsB substrates. Based on its role in regulating the activity of SpsB, we named this factor SpbR ( S ignal p eptidase b R egulator).

Virtual reality-augmented differentiable simulations for digital twin applications in surgical planning