Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.

Monosynaptic viral tracers are essential tools for dissecting neuronal connectomes and for targeted delivery of molecular sensors and effectors. Viral toxicity and complex multi-injection protocols are major limiting application barriers. To overcome these barriers, we developed an anterograde monosynaptic H129Amp tracer system based on HSV-1 strain H129. The H129Amp tracer system consists of two components: an H129-dTK-T2-pacFlox helper which assists H129Amp tracer's propagation and transneuronal monosynaptic transmission. The shared viral features of tracer/helper allow for simultaneous single-injection and subsequent high expression efficiency from multiple-copy of expression cassettes in H129Amp tracer. These improvements of H129Amp tracer system shorten experiment duration from 28-day to 5-day for fast-bright monosynaptic tracing. The lack of toxic viral genes in the H129Amp tracer minimizes toxicity in postsynaptic neurons, thus offering the potential for functional anterograde mapping and long-term tracer delivery of genetic payloads. The H129Amp tracer system is a powerful tracing tool for revealing neuronal connectomes.

Placental dysfunction, including senescent changes, is associated with the pathogenesis of missed miscarriage, although the underlying mechanism is unclear. Increasing evidence indicates that placenta-specific miRNAs are packaged in extracellular vesicles (EVs) from placental syncytiotrophoblasts and are released into the maternal circulation. Aberrant cargos including miRNAs in placental EVs have been reported to be associated with the pathogenesis of complicated pregnancies. In this study, we compared the miRNA profiles in EVs derived from missed miscarriage and healthy placentae and investigated possible biological pathways which may be involved in senescence, one cause of missed miscarriage. The total concentration of RNA in placental EVs was not different between the two groups. However, there were 54 and 94 differentially expressed miRNAs in placental large and small EVs from missed miscarriage compared to EVs from healthy controls. The aberrantly expressed miRNAs seen in placental EVs were also observed in missed miscarriage placentae. Gene enrichment analysis showed that some of those differentially expressed miRNAs are involved in cellular senescence, endocytosis, cell cycle and endocrine resistance. Furthermore, transfection of trophoblasts by a single senescence-associated miRNA that was differentially expressed in placental EVs derived from missed miscarriage did not cause trophoblast dysfunction. In contrast, EVs derived from missed miscarriage placenta induced senescent changes in the healthy placenta. Our data suggested that a complex of placental EVs, rather than a few differentially expressed miRNAs in placental EVs derived from missed miscarriage placentae could contribute in an autocrine manner to placental senescence, one of the causes of missed miscarriage.

Inflammatory stress in anesthesia management and surgical process has been reported to induce long-term cognitive dysfunction in vulnerable aged brain, while few studies focused on the network mechanism. The default mode network (DMN) plays a significant role in spontaneous cognitive function. Changes in topology structure and functional connectivity (FC) of DMN in vulnerable aged brain following inflammatory stress-induced long-term cognitive dysfunction are rarely studied. Eighty-eight aged male rats received intraperitoneal injection of lipopolysaccharide (LPS) as treatment or equal amount of normal saline (NS) as control. Morris Water Maze (MWM) was performed to assess short- (<7 days) and long-term (>30 days) learning and spatial working memory. Enzyme-linked immunosorbent assay (ELISA) was used to measure systemic and hippocampus inflammatory cytokines. Real-time polymerase chain reaction (RT-PCR) was used to measure the changes in gene level. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to exam brain function prior to MWM on days 3, 7, and 31 after LPS exposure. Graph theory analysis was used to analyze FC and topology structures in aged rat DMN. Aged rats treated with LPS showed short- and long-term impairment in learning and spatial working memory in MWM test. Graph theory analysis showed temporary DMN intrinsic connectivity increased on day 3 followed with subsequent DMN intrinsic connectivity significantly altered on day 7 and day 31 in LPS-exposed rats as compared with controls. Short- and long-term alterations were observed in FC, while alterations in topology structures were only observed on day 3. Rats with inflammatory stress exposure may cause short- and long-term alterations in intrinsic connectivity in aged rat's DMN while the changes in topology structures only lasted for 3 days. Inflammatory stress has prolonged effects on FC, but not topology structures in venerable aged brain.

Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication.

Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis. Proteogenomic characterization and integrative proteomic analysis provide a functional context to annotate genomic abnormalities with prognostic value.

Colon adenocarcinoma (COAD) is a common digestive system malignancy with high mortality and poor prognosis. Accumulating evidence indicates that choline metabolism is closely related to tumorigenesis and development. However, the efficacy of choline metabolism-related signature in predicting patient prognosis, immune microenvironment and chemotherapy response has not been fully clarified.

Interactive display devices integrating multiple functions have become a development trend of display technology. The excellent luminescence properties of perovskite quantum dots (PQDs) make it an ideal luminescent material for the next generation of wide-color gamut displays. Here we design and fabricate dual-function light-sensing/displaying light-emitting devices based on PQDs. The devices can display information as an output port, and simultaneously sense outside light signals as an input port and modulate the display information in a non-contact mode. The dual functions were attributed to the device designs: (1) the hole transport layer in the devices also acts as the light-sensing layer to absorb outside light signals; (2) the introduced hole trapping layer interface can trap holes originating from the light-sensing layer, and thus tune the charge transport properties and the light-emitting intensities. The sensing and display behavior of the device can be further modulated by light signals with different time and space information. This fusion of sensing and display functions has broad prospects in non-contact interactive screens and communication ports.

To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds.

The neurobiological basis of suicidal behaviors among female adolescents with major depressive disorder (MDD) remains largely unclear.

It has long been evident that physical exercise reduces the risk of cancer and improves treatment efficacy in tumor patients, particularly in lung cancer (LC). Several molecular mechanisms have been reported, but the mechanisms related to microRNAs (miRNAs) are not well understood. MiRNAs modulated various basic biological processes by negatively regulating gene expression and can be transmitted between cells as signaling molecules. Recent studies have shown that miRNAs are actively released into the circulation during exercise, and are deeply involved in cancer pathology. Hence, the role of exercise intervention in LC treatment may be further understood by identifying miRNAs associated with LC and physical activity. Here, miRNAs expression datasets related to LC and exercise were collected to screen altered miRNAs. Further bioinformatic approaches were performed to analyze the value of the selected miRNAs. The results identified 42 marker miRNAs in LC, of which three core-miRNAs (has-miR-195, has-miR-26b, and has-miR-126) were co-regulated by exercise and cancer, mainly involved in cell cycle and immunity. Our study supports the idea that using exercise intervention as adjuvant therapy for LC patients. These core-miRNAs, which are down-regulated in cancer but elevated by exercise, may act as suppressors in LC and serve as non-invasive biomarkers for cancer prevention.

Necroptosis is considered to be a new form of programmed necrotic cell death, which is associated with metastasis, progression and prognosis of various types of tumors. However, the potential role of necroptosis-related genes (NRGs) in the triple negative breast cancer (TNBC) is unclear.

Endothelial dysfunction is an early pathological event in diabetic angiopathy which is the most common complication of diabetes. This study aims to investigate individual and combined actions of Curcumin (Cur) and Baicalein (Bai) in protecting vascular function. The cellular protective effects of Cur, Bai and Cur+Bai (1:1, w/w) were tested in H2O2 (2.5 mM) impaired EA. hy926 cells. Wistar rats were treated with vehicle control as the control group, Goto-Kakizaki rats (n=5 each group) were treated with vehicle control (model group), Cur (150 mg/kg), Bai (150 mg/kg), or Cur+Bai (75 mg/kg Cur + 75 mg/kg Bai, OG) for 4 weeks after a four-week high-fat diet to investigate the changes on blood vessel against diabetic angiopathy. Our results showed that Cur+Bai synergistically restored the endothelial cell survival and exhibited greater effects on lowering the fasting blood glucose and blood lipids in rats comparing to individual compounds. Cur+Bai repaired the blood vessel structure in the aortic arch and mid thoracic aorta. The network pharmacology analysis showed that Nrf2 and MAPK/JNK kinase were highly relevant to the multi-targeted action of Cur+Bai which has been confirmed in the in vitro and in vivo studies. In conclusion, Cur+Bai demonstrated an enhanced activity in attenuating endothelial dysfunction against oxidative damage and effectively protected vascular function in diabetic angiopathy rats.

Vascular aging is associated with metabolic remodeling, and most studies focused on fatty acid and glucose metabolism. Based on our metabolomic data, leucine was significantly reduced in the aortas of aged mice. Whether leucine supplementation can reverse aging-induced vascular remodeling remains unknown. To investigate the effectiveness of leucine, male mice at 15 or 18 months were supplemented with leucine (1.5%) for 3 months. All the aged mice, with or without leucine, were sacrificed at 21 months. Blood pressure and vascular relaxation were measured. H&E, Masson's trichrome, and Elastica van Gieson staining were used to assess aortic morphology. Vascular inflammation, reactive oxidative stress (ROS), and vascular smooth muscle cell (VSMC) phenotype were also measured in mouse aortas. Compared with the 21-month-old mice without leucine, leucine supplementation from 15 months significantly improved vascular relaxation, maintained the contractile phenotype of VSMCs, and repressed vascular inflammation and ROS levels. These benefits were not observed in the mice supplemented with leucine starting from 18 months, which was likely due to the reduction in leucine transporters Slc3a2 or Slc7a5 at 18 months. Furthermore, we found benefits from leucine via activating the Sirt1-induced Foxo1 deacetylation. Our findings indicated that leucine supplementation in middle-aged mice improved aging-induced vascular remodeling and dysfunction.

Okadaic acid (OA) is a marine biotoxin associated with diarrhetic shellfish poisoning (DSP), posing some threat to human beings. The oral toxicity of OA is complex, and the mechanism of toxicity is not clear. The interaction between OA and gut microbiota may provide a reasonable explanation for the complex toxicity of OA. Due to the complex environment in vivo, an in vitro study may be better for the interactions between OA and gut microbiome. Here, we conducted an in vitro fermentation experiment of gut bacteria in the presence of 0-1000 nM OA. The remolding ability of OA on bacterial composition was investigated by 16S rDNA sequencing, and differential metabolites in fermentation system with different concentration of OA was detected by LC-MS/MS. We found that OA inhibited some specific bacterial genera but promoted others. In addition, eight possible metabolites of OA, including dinophysistoxin-2 (DTX-2), were detected in the fermentation system. The abundance of Faecalitalea was strongly correlated with the possible metabolites of OA, suggesting that Faecalitalea may be involved in the metabolism of OA in vitro. Our findings confirmed the direct interaction between OA and gut bacteria, which helps to reveal the metabolic process of OA and provide valuable evidence for elucidating the complex toxicity of OA.

One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) shows increased antigen-binding and virus-neutralizing activities against multiple SARS-CoV-2 variants as well as increased breadth of neutralizing activity compared to the cocktail. X-ray crystallography and cryo-EM reveal distinct binding models for individual cocktail antibodies, and computational simulations suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and multiple variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.

Platycodon grandiflorus (Jacq.) A. DC. (PG) root is one of the most commonly used medicine-food materials for respiratory discomfort in Asia, usually in the form of a decoction or leaching solution. As everyone knows, both of decoction and leaching solution is a polyphase dispersion system, containing low-molecular-weight water-soluble active ingredients and hydrophilic macromolecules. This study aimed to discuss the synergistic effect of Platycodon grandiflorus polysaccharide (PGP) and platycodin D (PD) in PG decoction against chronic bronchitis (CB) and the mechanism underlying. A series of PGP, PD, and PGD + PD suspensions were administrated to CB model rats, on the levels of whole animal and in situ intestinal segment with or without mesenteric lymphatic vessels ligation. It exhibited that PGP exhibited synergistic effects with PD, on improving the histopathological abnormity, mucus secretion excess, and immunological imbalance in lung of CB model rat, closely associated with its modulations on the mucosal immunity status in small intestine. The polysaccharide macromolecules in PG decoction or leaching solution should be responsible for the modulation of pulmonary immune state, possibly through the common mucosal immune between small intestine and lung. These results might be a new perspective that illustrates the classical theory of "the lung and intestine are related" in traditional Chinese medicine.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic reaction. Pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Aberrant up-regulation of periostin expression has been reported in activated PSCs. In this study, we investigated the role of periostin and the mechanisms underlying its aberrant upregulation in PDAC. We used lentiviral shRNA and human recombinant periostin protein to down and up regulate periostin expression in vitro. Specific oncogenic signaling pathways such as EGFR-Akt and EGFR-Erk-c-Myc were assessed in vitro and in vivo. Tissue microarray immunohistochemical assays including 80 pancreatic cancer tissues and paired normal tissues were used to understand the function relationship between periostin expression and PDAC pathologic stage and overall survival. We found that periostin was strongly expressed in PSCs and the stroma of PDAC tumors. We also observed a significant decrease in proliferation, metastasis, and clonality of pancreatic cancer cells when co-cultured with supernatant of periostin shRNA-transfected PSCs. Specifically, the biological behavior of periostin correlated with EGFR-Akt and EGER-Erk-c-Myc signaling pathways. Moreover, increased periostin expression significantly associated with advanced disease stage and decreased survival rate in PDAC patients. Together, our findings provide novel insights into the role of microenvironmental periostin in pancreatic cancer progression, and periostin may serve as a prognostic biomarker for PDAC.

IgA nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. It has been considered that the deposited IgA is synthesized by B cells, although recent reports have suggested the implication of other cell types. Therefore, the present study investigated whether glomerular mesangial cells could produce IgA by themselves. Semi‑quantitative reverse transcription-polymerase chain reaction, and immunostaining analysis revealed that the IgA protein and gene transcripts were expressed in primary human renal mesangial cells (HRMCs). Furthermore, the IgA heavy chain (α1 and α2) and the light chain (κ and λ) were localized in the cytoplasm or were located on the cell membranes of human mesangial cells (HMCs). Mass spectrometry results indicated that Ig α1 and Ig α2 were secreted in the culture media of HMCs. The transcripts of Ig α, Ig κ and Ig λ constant regions were detected. The predominant rearrangement pattern of the variable region of Ig κ, was Vκ3‑20*01/Jκ1*01 in HMCs and Vκ1‑12*01/Jκ4*01 in HRMCs. In addition, knockdown of Ig α1 expression by small interfering RNA (siRNA) inhibited cell adhesion and promoted apoptosis. Our findings demonstrate that HMCs can express IgA, and that this expression is associated with cell functions, which may contribute to the deposition of IgA in patients with IgAN.