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CD28 signaling motifs are sequestered within the membrane via interactions with phospholipids. TCR activation increases the local Ca 2+ concentration, which disrupts CD28-lipid interactions. CD28 provides an essential costimulatory signal for T cell activation, and its function is critical in antitumor immunity. However, the molecular mechanism of CD28 transmembrane signaling remains elusive. Here we show that the conformation and signaling of CD28 are regulated by two counteractive charged factors, acidic phospholipids and Ca 2+ ions. NMR spectroscopy analyses showed that acidic phospholipids can sequester CD28 signaling motifs within the membrane, thereby limiting CD28 basal signaling. T cell receptor (TCR) activation induced an increase in the local Ca 2+ concentration around CD28, and Ca 2+ directly disrupted CD28-lipid interaction, leading to opening and signaling of CD28. We observed that the TCR, Ca 2+ , and CD28 together form a dual-positive-feedback circuit that substantially amplifies T cell signaling and thus increases antigen sensitivity. This work unravels a new regulatory mechanism for CD28 signaling and thus contributes to the understanding of the dependence of costimulation signaling on TCR signaling and the high sensitivity of T cells.

B cells that express the isotype-switched IgG-B cell receptor (IgG-BCR) are one of the driving forces for antibody memory. To allow for a rapid memory IgG antibody response, IgG-BCR evolved into a highly effective signalling machine. Here, we report that the positively charged cytoplasmic domain of mIgG (mIgG-tail) specifically interacts with negatively charged acidic phospholipids. The key immunoglobulin tail tyrosine (ITT) in mIgG-tail is thus sequestered in the membrane hydrophobic core in quiescent B cells. Pre-disruption of such interaction leads to excessive recruitment of BCRs and inflated BCR signalling upon antigen stimulation, resulting in hyperproliferation of primary B cells. Physiologically, membrane-sequestered mIgG-tail can be released by antigen engagement or Ca 2+ mobilization in the initiation of B cell activation. Our studies suggest a novel regulatory mechanism for how dynamic association of mIgG-tail with acidic phospholipids governs the enhanced activation of IgG-BCR. Adaptive immunity is the memory of previously experienced pathogens, where B cells establish a rapid antibody response upon IgG-B cell receptor activation. Here, Chen et al . show that sequestration of the cytoplasmic domain of mIgG by plasma membrane phospholipids prevents inappropriate activation of IgG-BCR signalling.

T-cell receptor-CD3 complex （TCR） is a versatile signaling machine that can initiate antigen-specific immune re- sponses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3ε cytoplasmic domain （CD3εCD）. At the single-molecule level, we found that CD3εCD could have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3εCD had heterogeneous lipid-binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3εCD at different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR.

As a kind of binding protein, the type 1 Na + /H + exchanger (NHE1) is a receptor for the highly pathogenic Avian leukosis viruses-J subgroup (ALV-J) in chicken. In order to investigate the potential effect of chicken NHE1 gene on leukosis, we compared its expression between ALV-J-affected and -unaffected chicken, screened variations across the whole gene, and then performed association analysis with ALV-J affected/unaffected trait in three un-related chicken populations. We found that the NHE1 gene expressed in four immune tissues including spleen, bursa fabricius, liver, and thymus, and its expression was significantly up-regulated in liver and thymus of ALV-J-affected chickens (with leukosis phenotype) compared to -unaffected ones (ALV-J-negative controls). Thirty-six single nucleotide polymorphisms (SNP) were identified in a 6,105 bp region of the chicken NHE1 gene, giving rise to every 170 bp per SNP. Two SNP of g.4405A>G and g.5886C>G were genotyped with PCR-RFLP method. Results showed that g.4405A>G was significantly associated ( P  < 0.05) with ALV-J infection in all of the three chicken populations, including White Recessive Rock (WRR), Dwarf Yellow (DY) and Shiki Yellow (SY), while g.5886C>G was significantly associated ( P  < 0.05) with ALV-J infection in SY. These results indicated that the NHE1 gene was related to ALV-J infection in chicken.

Mitochondria have various cellular functions, including ATP synthesis, calcium homeostasis, cell senescence, and death. Mitochondrial dysfunction has been identified in a variety of disorders correlated with human health. Among the many underlying mechanisms of mitochondrial dysfunction, the opening up of the mitochondrial permeability transition pore (mPTP) is one that has drawn increasing interest in recent years. It plays an important role in apoptosis and necrosis; however, the molecular structure and function of the mPTP have still not been fully elucidated. In recent years, the abnormal opening up of the mPTP has been implicated in the development and pathogenesis of diverse diseases including ischemia/reperfusion injury (IRI), neurodegenerative disorders, tumors, and chronic obstructive pulmonary disease (COPD). This review provides a systematic introduction to the possible molecular makeup of the mPTP and summarizes the mitochondrial dysfunction-correlated diseases and highlights possible underlying mechanisms. Since the mPTP is an important target in mitochondrial dysfunction, this review also summarizes potential treatments, which may be used to inhibit pore opening up via the molecules composing mPTP complexes, thus suppressing the progression of mitochondrial dysfunction-related diseases.

In marine ecosystems, viruses exert control on the composition and metabolism of microbial communities, influencing overall biogeochemical cycling. Deep sea sediments associated with cold seeps are known to host taxonomically diverse microbial communities, but little is known about viruses infecting these microorganisms. Here, we probed metagenomes from seven geographically diverse cold seeps across global oceans to assess viral diversity, virus–host interaction, and virus-encoded auxiliary metabolic genes (AMGs). Gene-sharing network comparisons with viruses inhabiting other ecosystems reveal that cold seep sediments harbour considerable unexplored viral diversity. Most cold seep viruses display high degrees of endemism with seep fluid flux being one of the main drivers of viral community composition. In silico predictions linked 14.2% of the viruses to microbial host populations with many belonging to poorly understood candidate bacterial and archaeal phyla. Lysis was predicted to be a predominant viral lifestyle based on lineage-specific virus/host abundance ratios. Metabolic predictions of prokaryotic host genomes and viral AMGs suggest that viruses influence microbial hydrocarbon biodegradation at cold seeps, as well as other carbon, sulfur and nitrogen cycling via virus-induced mortality and/or metabolic augmentation. Overall, these findings reveal the global diversity and biogeography of cold seep viruses and indicate how viruses may manipulate seep microbial ecology and biogeochemistry.

Utilization of digital technologies for cataract screening in primary care is a potential solution for addressing the dilemma between the growing aging population and unequally distributed resources. Here, we propose a digital technology-driven hierarchical screening (DH screening) pattern implemented in China to promote the equity and accessibility of healthcare. It consists of home-based mobile artificial intelligence (AI) screening, community-based AI diagnosis, and referral to hospitals. We utilize decision-analytic Markov models to evaluate the cost-effectiveness and cost-utility of different cataract screening strategies (no screening, telescreening, AI screening and DH screening). A simulated cohort of 100,000 individuals from age 50 is built through a total of 30 1-year Markov cycles. The primary outcomes are incremental cost-effectiveness ratio and incremental cost-utility ratio. The results show that DH screening dominates no screening, telescreening and AI screening in urban and rural China. Annual DH screening emerges as the most economically effective strategy with 341 (338 to 344) and 1326 (1312 to 1340) years of blindness avoided compared with telescreening, and 37 (35 to 39) and 140 (131 to 148) years compared with AI screening in urban and rural settings, respectively. The findings remain robust across all sensitivity analyses conducted. Here, we report that DH screening is cost-effective in urban and rural China, and the annual screening proves to be the most cost-effective option, providing an economic rationale for policymakers promoting public eye health in low- and middle-income countries. Economic evaluation of utilization of digital technologies for cataract screening remains unknown. Here the authors show that digital hierarchical screening is cost-effective in China and annual screening proved to be the most cost-effective option.

ObjectivesTo investigate the value of radiomics based on CT imaging in predicting invasive adenocarcinoma manifesting as pure ground-glass nodules (pGGNs).MethodsThis study enrolled 395 pGGNs with histopathology-confirmed benign nodules or adenocarcinoma. A total of 396 radiomic features were extracted from each labeled nodule. A Rad-score was constructed with the least absolute shrinkage and selection operator (LASSO) in the training set. Multivariate logistic regression analysis was conducted to establish the radiographic model and the combined radiographic–radiomics model. The predictive performance was validated by receiver operating characteristic (ROC) curve. Based on the multivariate logistic regression analysis, an individual prediction nomogram was developed and the clinical utility was assessed.ResultsFive radiomic features and four radiographic features were selected for predicting the invasive lesions. The combined radiographic–radiomics model (AUC 0.77; 95% CI, 0.69–0.86) performed better than the radiographic model (AUC 0.71; 95% CI, 0.62–0.81) and Rad-score (AUC 0.72; 95% CI, 0.63–0.81) in the validation set. The clinical utility of the individualized prediction nomogram developed using the Rad-score, margin, spiculation, and size was confirmed in the validation set. The decision curve analysis (DCA) indicated that using a model with Rad-score to predict the invasive lesion would be more beneficial than that without Rad-score and the clinical model.ConclusionsThe proposed radiomics-based nomogram that incorporated the Rad-score, margin, spiculation, and size may be utilized as a noninvasive biomarker for the assessment of invasive prediction in patients with pGGNs.Key Points• CT-based radiomics analysis helps invasive prediction manifested as pGGNs.• The combined radiographic–radiomics model may be utilized as a noninvasive biomarker for predicting invasive lesion for pGGNs.• Radiomics-based individual nomogram may serve as a vital decision support tool to identify invasive pGGNs, obviating further workup and blind follow-up.

Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder caused by mutations in the Translocase of Inner Mitochondrial Membrane 8A (TIMM8A) gene, which encodes TIMM8a, a protein localized to the mitochondrial intermembrane space (IMS). The pathophysiology of MTS remains poorly understood. To investigate the molecular mechanisms underlying MTS, we established induced pluripotent stem cells (iPSCs) from a male MTS patient carrying a novel TIMM8A mutation (c.225-229del, p.Q75fs95*), referred to as MTS-iPSCs. To generate an isogenic control, we introduced the same mutation into healthy control iPSCs (CTRL-iPSCs) using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9), resulting in mutant iPSCs (MUT-iPSCs). We differentiated the three iPSC lines into neurons and evaluated their mitochondrial function and neuronal development. Both MTS- and MUT-iPSCs exhibited impaired neuronal differentiation, characterized by smaller somata, fewer branches, and shorter neurites in iPSC-derived neurons. Additionally, these neurons showed increased susceptibility to apoptosis under stress conditions, as indicated by elevated levels of cytochrome c and cleaved caspase-3. Mitochondrial function analysis revealed reduced protein levels and activity of complex IV, diminished ATP synthesis, and increased reactive oxygen species (ROS) generation in MTS- and MUT-neurons. Furthermore, transmission electron microscopy revealed mitochondrial fragmentation in MTS-neurons. RNA sequencing identified differentially expressed genes (DEGs) involved in axonogenesis, synaptic activity, and apoptosis-related pathways. Among these DEGs, coiled-coil-helix-coiled-coil-helix domain-containing 2 ( CHCHD2 ), which encodes a mitochondrial IMS protein essential for mitochondrial homeostasis, was significantly downregulated in MTS-neurons. Western blot analysis confirmed decreased CHCHD2 protein levels in both MTS- and MUT-neurons. Overexpression of CHCHD2 rescued mitochondrial dysfunction and promoted neurite elongation in MTS-neurons, suggesting that CHCHD2 acts as a downstream effector of TIMM8a in the pathogenesis of MTS. In summary, loss-of-function of TIMM8a leads to a downstream reduction in CHCHD2 levels, collectively impairing neurogenesis by disrupting mitochondrial homeostasis. TIMM8a mutation (p.Q75fs95*) leads to mitochondrial dysfunction and neuronal defects in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome, which are rescued by overexpression of CHCHD2. TIMM8a translocase of inner mitochondrial membrane 8a, CHCHD2 coiled-coil-helix-coiled-coil-helix domain-containing protein 2, MTS Mohr–Tranebjaerg syndrome, I mitochondrial complex I, II mitochondrial complex II, III mitochondrial complex III, IV mitochondrial complex IV, Q coenzyme Q10, Cyt c cytochrome c.

Dynamic biomaterials excel at recapitulating the reversible interlocking and remoldable structure of the extracellular matrix (ECM), particularly in manipulating cell behaviors and adapting to tissue morphogenesis. While strategies based on dynamic chemistries have been extensively studied for ECM-mimicking dynamic biomaterials, biocompatible molecular means with biogenicity are still rare. Here, we report a nature-derived strategy for fabrication of dynamic biointerface as well as a three-dimensional (3D) hydrogel structure based on reversible receptor–ligand interaction between the glycopeptide antibiotic vancomycin and dipeptide D-Ala-D-Ala. We demonstrate the reversible regulation of multiple cell types with the dynamic biointerface and successfully implement the dynamic hydrogel as a functional antibacterial 3D scaffold to treat tissue repair. In view of the biogenicity and high applicability, this nature-derived reversible molecular strategy will bring opportunities for malleable biomaterial design with great potential in biomedicine.