Communications Biology最新文献

Lung ischemia-reperfusion injury (LIRI) is a serious complication in critical clinical situations. Despite its importance, the specific role of type II natural killer T (NKT) cells in LIRI remains unclear. In this study, we establish a LIRI mouse model and demonstrate that sulfatide-reactive type II NKT cells promote M2 polarization of alveolar macrophages (AMs) and alleviate LIRI through AMs-mediated mechanisms. This protective effect is absent in Jα18^-/- mice, indicating the essential role of invariant NKT (iNKT) cells. Further analysis shows that interleukin-10 (IL-10) secreted by iNKT cells upregulates AT-rich interaction domain 3 A (Arid3a) in macrophages, which then promotes the transcription of DNA damage inducible transcript 4 (DDIT4). This cascade enhances M2 polarization of macrophages, potentially contributing to lung protection and alleviating LIRI. These findings suggest that NKT cells may offer a therapeutic target for LIRI in the future.

Sepioids are an evolutionarily successful group of modern ten-armed cephalopods (Decabrachia) of high biodiversity, providing a large amount of biomass in present-day oceans. They include the internally shelled order Sepiida (cuttlefish) and the soft-bodied order Sepiolida (bobtail squid). The phylogenetic position and evolutionary history of these orders are, however, so far poorly understood due to the patchy fossil record of the Decabrachia. Here we report Uluciala rotundata gen. et sp. nov. from the upper Campanian to upper Maastrichtian (~74-67 Ma, Upper Cretaceous), South Dakota, which shows an intermediate morphology between Sepiida and Sepiolida. This discovery was facilitated by a new approach in palaeontology, the Digital fossil-mining method incorporating a zero-shot learning AI model. Uluciala rotundata demonstrates a close relationship between the two sepioid orders, which has previously been interpreted controversially. Our findings indicate that sepioids experienced an early phase of radiation in the later part of the Late Cretaceous.

Pancreatic cancer remains a highly lethal disease, underscoring the continued importance of chemotherapy. The first-line chemotherapeutic agent Gemcitabine (GEM) exerts its effect by inducing tumor cell apoptosis, a process which can subsequently convert to pyroptosis via GSDME expression. Nevertheless, the emergence of drug resistance has prompted extensive research to identify novel therapeutic targets. p21-activated kinase 4 (PAK4) plays important roles in various tumors, including the inhibition of tumor cell apoptosis. Here, we show that PAK4 inhibits pyroptosis in pancreatic cancer through the NAcht leucinerich-repeat protein-1 (NLRP1)/caspase-9/caspase-3/GSDME axis. PAK4 phosphorylates the E3 ubiquitin ligase mouse double minute 2 homolog (Mdm2) to promote the degradation of NLRP1, thereby inhibiting pyroptosis. Furthermore, inhibition of PAK4 kinase activity promotes GEM-induced suppression of pancreatic cancer growth both in vitro and in vivo. Our study suggests that targeting PAK4 to promote GEM-induced pyroptosis may provide a new therapeutic approach for the treatment of pancreatic cancer.

Unlike humans, small mammals dedicate considerable energy expenditure (EE) to maintaining core body temperature (Tb). We investigate the influence of ambient temperature (Ta) on energy homeostasis in single housed male mice and rats studied by indirect calorimetry and continuous Tb measurement at Ta ranging from 22 °C to 35 °C. With Tb increases at higher Ta, food intake and body weight decrease, demonstrating that the higher Tb signifies heat stress and not a benign adaptive response. Rats at 30 °C were at the edge of their thermal tolerance. Neither rats nor mice have a broad thermoneutral zone (TNZ). Rather, both have thermoneutral points (TNP), below which EE increases and above which Tb increases. In mice, the EE increase above the TNP is due to the higher Tb (van't Hoff Q₁₀ effect) and increased physical activity. Interestingly, the remaining EE is lower, demonstrating acute thermal adaptation with a reduced basal metabolic rate. In conclusion, rats are less cold-sensitive and more prone to overheating than mice. Despite their larger size, rats, like mice, have a TNP and not a broad TNZ. Studying rats and mice at a Ta of 28-29 °C is a sensible compromise that safely minimizes cold-induced thermogenesis while reducing the risk of heat stress.

Converging evidence suggests that understanding the human brain requires more than just examining pairwise functional brain interactions. The human brain is a complex, nonlinear system, and focusing solely on linear pairwise functional connectivity often overlooks important nonlinear and higher-order interactions. Infancy is a critical period marked by significant brain development that could contribute to future learning, health, and life success. Exploring higher-order functional relationships in the brain can provide insight into brain function and development. To the best of our knowledge, there is no existing research on multiway, multiscale brain network interactions in infants. In this study, we comprehensively investigate the interactions among brain intrinsic connectivity networks (ICNs), including both pairwise (pair-FNC) and triple relationships (tri-FNC). We focused on a dataset of typically developing infants scanned during the first six months of life-a critical period for brain maturation. In total, 71 infants (aged 4-179 days) contributed 126 scans (76 from 41 males, 50 from 30 females). Our results revealed significant hierarchical, multiway, multiscale brain functional network interactions in the infant brain. These findings suggest that tri-FNC provide additional insights beyond what pairwise interactions reveal during early brain development. The tri-FNC predominantly involve the default mode, sensorimotor, visual, limbic, language, salience, and central executive domains. Notably, these triplet networks align with the classical triple network model of the human brain, which includes the default mode network, the salience network, and the central executive network. This suggests that the brain network system might already be initially established during the first six months of infancy. We also found that pair-FNC were less effective at detecting these networks. The present study suggests that exploring tri-FNC can offer additional insights beyond pair-FNC by capturing higher-order nonlinear interactions, potentially yielding more reliable biomarkers to characterize developmental trajectories.

G protein-coupled receptor (GPCR) signaling is regulated by four ubiquitously expressed GPCR kinase isoforms (GRKs), namely GRK2, GRK3, GRK5, and GRK6. Overexpression of individual GRKs occurs in diseases like cancer and heart failure, prompting a search for potent GRK inhibitors. While various in silico and in vitro approaches exist, few methods assess inhibitor efficacy in cellular systems. To address this, we used HEK293 cell lines co-expressing the β2 adrenergic receptor (β2) and one GRK isoform on a quadruple GRK2/3/5/6 knockout background (ΔQ-GRK). We evaluated the inhibition of isoproterenol (ISO)-induced T360/S364-β2 phosphorylation using the 7TM phosphorylation assay. This combination allowed comprehensive evaluation of commercially available GRK inhibitors. We conclude that compound 8h (GRK2/3 inhibitor) and compound 18 (GRK5/6 inhibitor) are highly recommendable tools for the study of GPCR phosphorylation and function in cellular systems. Together, these cell-based GRK inhibitor assays can facilitate medium- to high-throughput screening of future GRK-targeted drug candidates.

Multidisciplinary evidence indicates that the Austroasiatic (AA) language family is the earliest known language in Mainland Southeast Asia (MSEA), dating back to the Neolithic. Yet, the genomic formation and structure of MSEA AA groups remain understudied. Here, we generate genome-wide data for seven AA-speaking and two Sino-Tibetan-speaking populations from Thailand/Laos/Myanmar, which together with published data comprises the largest AA genome-wide dataset to date. We find substantial genetic heterogeneity across both geographic regions and linguistic branches, with the greatest observed in Northern Mon-Khmer highland groups. Analyses with ancient DNA data indicate that northern AA groups exhibit higher East Asian ancestry linking to Iron Age northern Thailand/Cambodia, whereas southern AA groups display additional South Asian ancestry and affinities with Neolithic Laos/Vietnam. Notably, the South Asian-related ancestry is detectable in Neolithic MSEA. Overall, both isolation and contact have together shaped the pronounced genetic heterogeneity observed across linguistic branches of MSEA AA groups.

Cortical folding begins in utero as sulci emerge and continues postnatally as sulci deepen. However, the timeline and mechanisms of postnatal sulcal development remain poorly understood. Using structural and quantitative magnetic resonance imaging from 79 infant sessions spanning birth to one year, we longitudinally examined macroanatomical parameters and microstructural tissue density (longitudinal relaxation rate, [R₁]) across sulci that emerge in utero between 16-31 gestational weeks. Here we show that early emerging sulci are deeper at birth and deepen more slowly postnatally than later emerging sulci. Across the first year, sulci become wider (42%), thicker (21%), denser with tissue (33%), and less concave (14%). Mean depth is predicted by a weighted combination of sulcal span, thickness, curvature, and microstructure, with differential weights across sulci. Fine-grained analyses of local depth along the sulcus further reveal that sulcal fundi differ from sulcal walls: deeper portions show higher curvature and greater tissue density. These data show that postnatal sulcal deepening is nonuniform and reflect coordinated anatomical and microstructural processes anchored to the timing of sulcal emergence in utero. By establishing normative trajectories of postnatal sulcal development, our findings inform theories of cortical folding and offer a framework for characterizing deviations from typical development.

A complete telomere-to-telomere (T2T) pig genome serves as a high-precision reference for functional genomics and structural variation studies due to its high level of completeness and minimal error rate. Here we present a comprehensive framework for genomic research aimed at the effective utilization of Neijiang pig genetic resources. The highly repetitive centromeric regions of the Neijiang pig are identified, and their characteristic centromeric landscapes are constructed using chromosomal landmark identification combined with centromeric repeat monomer localization strategies. Genome-wide association studies (GWAS) based on the T2T reference genome identify key genetic loci associated with reproductive traits, offering potential molecular targets for genetic improvement. Gene family analysis and genetic investigation into head morphology in Neijiang pigs reveal selection signals within olfactory receptor (OR) genes that are associated with head shape differentiation, highlighting the potential role of environmental adaptation in the phenotypic domestication of Chinese indigenous pig breeds. The Neijiang pig T2T genome (NJP-T2T) assembly provides a critical reference resource and foundational dataset for genetic improvement and functional genomic studies in indigenous pig breeds.

Pheochromocytomas and paragangliomas (PPGLs) with SDHB mutations frequently develop metastases, but the molecular mechanisms driving this progression remain unclear. Here we show that SDHB-mutant metastatic PPGLs display an amplified hypermethylation signature, particularly in genes involved in neuronal differentiation, building on previous findings in SDHx-mutated tumors. This epigenetic shift is already detectable in benign SDHB-mutant tumors, suggesting early priming toward a less differentiated state. In parallel, we identify hypomethylation of genes linked to carbohydrate metabolism, notably the fructose transporter SLC2A5. Functional assays reveal that SDHB loss, hypoxia, exogenous succinate, and fructose availability promote tumor cell growth and induce cell-type-restricted, SDHB-dependent, induction of SLC2A5 expression. These findings highlight the dual role of SDHB mutations in driving epigenetic reprogramming and metabolic adaptation, promoting tumor cell plasticity and survival under metabolic stress. By uncovering a fructose-driven metabolic vulnerability, our study provides insights into the molecular mechanisms underlying metastatic PPGLs and identifies potential therapeutic targets at the intersection of epigenetic and metabolic regulation.