Communications Biology最新文献

Predicting how residue variations affect protein stability is crucial for rational protein design and for assessing the impact of disease-related mutations. Recent advances in protein language models have revolutionized computational protein analysis, enabling more accurate predictions of mutational effects. However, balancing predictive accuracy with the fundamental laws of thermodynamics remains a challenge for sequence-based models. Here we show JanusDDG, a physics-informed neural network that leverages embeddings from protein language models and a bidirectional cross-attention transformer architecture to predict stability changes for both single and multiple residue mutations. By adopting a physics-informed paradigm, the model is explicitly constrained to satisfy fundamental thermodynamic principles, such as antisymmetry and transitivity, while maintaining high predictive performance. Instead of conventional self-attention, JanusDDG employs a cross-interleaved attention mechanism that computes the relationship between wild-type and mutant embeddings to capture mutation-induced perturbations while preserving essential contextual information. Our results demonstrate that JanusDDG achieves state-of-the-art performance in predicting stability changes from sequence alone, matching or exceeding the accuracy of structure-based methods for both single and multiple mutations.

Liver fibrosis is a major global health burden with limited treatment options. Transforming growth factor-beta-induced protein (TGFBI) is crucial in fibrotic diseases and tumors, however, its precise mechanism in liver fibrosis remains unclear. Here we show that TGFBI promotes liver fibrosis in male C57BL/6 mice. TGFBI is upregulated in fibrotic livers and derived from non-parenchymal cells. Genetic TGFBI deficiency alleviates liver fibrosis in both CCl₄ (carbon tetrachloride) injection and bile duct ligation (BDL) models. Mechanistically, PDGFRβ is identified via RNA sequencing as a key downstream molecule upregulated by TGFBI in hepatic stellate cells (HSCs) via the integrin αvβ3-FAK-STAT3 pathway, promoting HSC proliferation and activation. Meanwhile, TGFBI increases PDGF-B expression in macrophages through the integrin αvβ3-AKT-ERK pathway, driving their proliferation, migration and differentiation into the profibrotic TREM2⁺CD9⁺ subpopulation. Elevated PDGF-B reversely stimulates TGFBI production in macrophages, which creates a positive feedback loop. This TGFBI-mediated interaction between HSCs and macrophages remodels the profibrotic microenvironment to promote liver fibrosis, identifying a potential therapeutic target.

Many physicochemical properties in the cellular milieu are important for cell function and survival. However, the polarity of different subcellular compartments and its role in protein condensate and aggregate formation within cells are less characterized. Here, we develop a method to compare the polarity in different subcellular compartments using the same polarity-sensitive solvatochromic fluorescent probe. Unexpectedly, the endoplasmic reticulum (ER) lumen displays a higher polarity and a more crowded environment than the cytosol in human cells. Polarity-decreasing and crowding-increasing hypertonic conditions induce condensate or aggregate formation of two intrinsically disordered proteins, with-no-lysine kinase 1 and Huntingtin gene (Htt) exon1 with an expanded polyQ stretch (Htt-polyQ), in the cytosol. However, targeting Htt-polyQ to the ER prevents its aggregation, suggesting that polarity but not crowding is more relevant to protein aggregation. Our results reveal the heterogeneity in subcellular polarity and crowding, and uncover previously unrecognized high-polarity in the ER lumen, which provides a unique environment for maintaining robust proteostasis.

Time-restricted feeding (TRF) may modulate metabolic homeostasis through circadian rhythms, but its effects on male fertility remain unclear. This study investigates how different TRF schedules influence testicular homeostasis and spermatogenesis, focusing on the gut-testis axis. Mice are subjected to daytime (DRF) or nighttime (NRF) restricted feeding, compared with ad libitum controls. The results show that NRF reduces testicular index and sperm quality, while DRF shows no adverse effects. Histological analysis confirms decreased numbers of spermatocytes and spermatozoa in the NRF group. 16S rRNA sequencing reveals altered gut microbiota composition in NRF mice, and metabolomics identify elevated levels of kynurenic acid (KYNA), a tryptophan metabolite. KYNA administration inhibits spermatogenesis in a dose-dependent manner, mimicking the NRF phenotype. These findings suggest that feeding timing influences male reproductive health, with gut-derived metabolites like KYNA potentially mediating TRF effects, offering new targets for fertility interventions.

Antibodies are widely used in life sciences and medical therapy. Broadly applicable methods to determine epitope heterogeneity in immunostaining systems are missing. Here, we present a simple-to-use approach to characterize and quantify antibody binding properties that constitute the staining directly in the system of choice. We determine an epitope heterogeneity on the basis of a computational analysis of antibody-dilution immunofluorescence stainings. This allows us to choose signal-specificity maximizing dilutions and to improve signal quantification. Furthermore, the computational analysis provides approaches to obtain a single-channel antibody multiplexing. Our approach could help improving immunostainings in many laboratories by guiding the choice of antibody dilution, by increasing the possibility of antibody-multiplexing in the same color-channel and by allowing for the analysis of binding targets of multi-specific antibodies.

Anti-major histocompatibility complex class I (MHC-I) mAbs can stimulate immune responses to tumors and infections by blocking suppressive signals delivered via various immune inhibitory receptors. To understand such functions, we determined the structure of a highly cross-reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA-B*44:05 by both cryo-electron microscopy (cryo-EM) and X-ray crystallography. Structural models determined by the two methods were essentially identical revealing that B1.23.2 binds a conserved region on the α2₁ helix that overlaps the killer immunoglobulin-like receptor (KIR) binding site. Structural comparison to KIR/HLA complexes reveals a mechanism by which B1.23.2 blocks inhibitory receptor interactions, leading to natural killer (NK) cell activation. B1.23.2 treatment of the human KLM-1 pancreatic cancer model in humanized (NSG-IL15) mice provides evidence of suppression of tumor growth. Such anti-MHC-I mAb that block inhibitory KIR/HLA interactions may prove useful for tumor immunotherapy.

Cholecystectomy is associated with an increased risk of metabolic syndrome (MetS); however, the underlying mechanism remains unknown. The gallbladder acts as a storage organ for hepatic bile and regulates the feeding/fasting cycles of bile acid (BA) flow in the enterohepatic circulation (EHC). In this study, we aimed to use C57BL/6 mice to investigate the effects of cholecystectomy in the regulation of glucose homeostasis and bile acid metabolism with metabolomics and quantitative RT-PCR. The results show that cholecystectomy increases fasting hepatic BA levels by enhancing EHC. Livers from cholecystectomized (XGB) mice displayed suppression of genes involved in fatty acid oxidation (FAO), abnormal lipid accumulation, and marked remodeling of their metabolomic profiles, particularly a reduction in FAO intermediate acylcarnitines. Many FAO genes were transcriptional targets of the peroxisome proliferator-activated receptor α (PPARα), and BA inhibited PPARα, resulting in impeded FAO. Consistent with this, blocking intestinal BA uptake using an apical sodium-BA transporter inhibitor enhanced fasting hepatic FAO levels and ameliorated metabolic disorders in XGB mice. These findings suggest that cholecystectomy could inhibit fasting hepatic FAO by disturbing the EHC of BA, and reveal the role of the gallbladder in coordinating PPARα-regulated FAO in the liver.

Emotional prosody (EP) processing is vital for social communication. Seed-based functional connectivity has been widely used to probe its neural basis, yet most studies rely on part of predefined regions, introducing uncertainty and bias. Furthermore, although gender and task type modulate its activation pattern, their network-level impact remains unclear. Using activation network mapping (a network-level analogue of meta-analysis), we identified a unified EP network and delineated its modulation by gender and task types (explicit or implicit). Results showed broader activation networks in females compared to males, regardless of the task type. Moreover, explicit tasks recruited additional frontal and sensorimotor regions beyond implicit tasks, supporting hierarchical processing. We also identified associations with specific receptors and diseases like autism and Alzheimer's. These findings underscore the importance of considering gender and task type effects on emotional processing research and provide a network-level neural mechanism underlying emotional prosody.

Mixed-species plantations have been increasingly promoted as a strategy to enhance ecosystem functioning and related ecosystem processes; however, their global impacts on biomass production and nutrient cycling remain uncertain. Here we present a comprehensive meta-analysis based on a random-effects model of 8,450 paired observations from 328 studies spanning diverse climatic zones, stand structures, and silvicultural systems. We demonstrate that species mixing significantly enhances plant biomass and nutrient content compared to monocultures, with positive responses observed across trees, shrubs, litterfall, and both above- and belowground compartments. Mixed-species plantations also increase soil organic carbon, total nitrogen, phosphorus availability, microbial biomass, and leaf nutrient content while maintaining stable soil stoichiometric ratios, collectively reflecting more efficient stand-level nutrient cycling. Importantly, the magnitude of these effects was shaped by climatic and structural contexts, with stronger positive outcomes under warmer and wetter climates, increasing with species richness, and showing unimodal responses to elevation, stand age, and stand density. By synthesizing multi-scale evidence from diverse ecosystems, we reveal that species mixing promotes biomass accumulation, improves nutrient retention, and strengthens biodiversity-nutrient cycling linkages. This study highlights the potential of mixed-species plantations to enhance ecological function, advance forest restoration, and guide plantation management across diverse environmental conditions.

The neuropeptide oxytocin (OT) plays a crucial role in regulating homeostatic responses and complex behaviors, including social interaction. OT can be released from somatodendritic regions, enabling communication through retrograde, autocrine, and volume transmission. However, the mechanisms governing somatodendritic OT dynamics and their impact on neuronal function and behavior are not yet fully understood. Our study identifies SNAP-47, a member of the SNAP-25 protein family highly expressed in the soma of peptidergic neurons in the mouse hypothalamus, where it exhibits a close interaction with OT-containing compartments localized at the plasma membrane. Knocking down SNAP-47 diminishes the recruitment of OT to the plasma membrane in the cell body under both basal conditions and following neuronal stimulation. Reducing endogenous SNAP-47 expression in vivo results in altered spontaneous synaptic transmission in oxytocinergic neurons of the paraventricular nucleus (PVN) and decreases sociability, likely due to disrupted somatic trafficking. These findings provide new insights into the molecular mechanisms governing somatic OT dynamics, its influence on hypothalamic neuromodulation, and its role in OT-dependent behaviors such as social interaction.