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Background Visual deprivation can lead to abnormal and plastic changes in the brain's visual system and other systems. Although the secondary changes of gray matter in patients have been well studied, the study of white matter is rare. In fact, subtle changes in white matter may be revealed by diffusion tensor imaging, and tract‐based spatial statistics can be used to analyze DTI image data. Purpose In the present study, diffusion tensor imaging (DTI) and tract‐based spatial statistics (TBSS) were used to investigate abnormal structural changes in the white matter (WM) of patients with monocular blindness (MB). Methods We recruited 16 healthy controls (HC) (fourteen males and two females) and 16 patients (fifteen males and one female) with right‐eye blindness (without differences in left‐eye vision). All patients were of similar age. Data acquisition was performed using magnetic resonance imaging (MRI) and DTI. Voxel‐based whole brain comparisons of fractional anisotropy (FA) and radial diffusivity (RD) of WM fibers in patients and HC were performed using the TBSS method. The mean FA and RD values for altered brain regions in MB patients were analyzed via the receiver operating characteristic (ROC) curve. Correlation analysis was performed to investigate the relationships between the average FA (RD) value of the whole brain and anxiety score, depression score, and visual function questionnaire score in MB patients. Results In MB patients, the mean FA of the whole brain was decreased versus HC. Moreover, the FA values of the corpus callosum, the corona radiata, the posterior thalamic radiation, and the right retrolenticular part of internal capsule were significantly decreased. In addition, the average RD value of the whole brain in MB patients was higher than that observed in HC. The mean FA and RD values of brain regions were analyzed using the ROC curve, and the results showed that the area under the ROC curve was more accurate. Furthermore, the average FA and RD values of the whole brain were significantly correlated with anxiety score, depression score, and visual function‐related quality of life score. Conclusion DTI and TBSS may be useful in examining abnormal spontaneous alterations in the WM of MB patients. The observed changes in FA and RD values may imply the larvaceous neurological mechanism involved in MB. Diffusion tensor imaging and tract‐based spatial statistics may be useful in examining abnormal spontaneous alterations in the white matter of monocular blindness patients. The observed changes in fractional anisotropy and radial diffusivity values may imply the larvaceous neurological mechanism involved in patients with monocular blindness.

Radiotherapy (RT) is a cornerstone of cancer therapy that exerts cytotoxic effects while also modulating anti-tumor immunity. RT-induced DNA damage can, under specific biological conditions, activate the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream stimulator of interferon genes (STING) pathway, eliciting type I interferon (IFN-I) responses and dendritic cell-mediated T-cell priming. This signaling is tightly regulated by TREX1-mediated DNA degradation, apoptotic caspases, and chromatin-bound nuclear DNA, resulting in heterogeneous immune outcomes. Notably, tumors with mismatch repair deficiency, such as MLH1 loss, exhibit pre-existing cGAS-STING activity, in which RT primarily amplifies innate sensing. However, even in this context, excessive or sustained STING activation may paradoxically induce immune tolerance, and the clinical application of STING agonists remains constrained by dose-limiting toxicities and delivery challenges. Here, we review the context-dependent interplay between RT and the cGAS-STING axis, highlighting mechanistic regulation, tumor genetics, and the tumor microenvironment. We propose strategies for precision calibration of RT and STING agonist delivery to enhance anti-tumor immunity, enable cold-to-hot tumor transformation, and guide rational combination with immunotherapy.

Background After the scale-up of antiretroviral therapy (ART) for HIV infected people, increasing numbers of patients have pretreatment drug resistance (PDR). In this study, the prevalence of PDR was evaluated in adults initiating antiretroviral therapy in China. Methods Blood samples were obtained from 1943 patients who initiated antiretroviral therapy (ART) in 2017 from 13 provinces or cities in China. Pol sequences were used to analyze drug resistance and construct transmission networks. Logistic regression model was used to estimate the potential factors associated with PDR. Results In total, 1711 eligible patients (76.0% male; 87.8% aged ≥ 25 years) were included, of which 117 (6.8%) had PDR. The highest rates of PDR were 12.2% in Liangshan Prefecture of Sichuan and 9.3 and 8.9% in Dehong and Lincang Prefecture of Yunnan. A multivariate logistic regression analysis revealed that PDR was significantly higher among intravenous drug users (adjusted Odds Ratio (a OR ) = 2.64, 95% CI : 1.57–4.44) and individuals from Liangshan, Dehong, and Lincang (a OR  = 2.04, 95% CI : 1.26–3.30). In total, 754 sequences were used to generate 164 transmission networks. Five transmission networks had two or three sequences containing the same mutations, two networks contained subjects from Liangshan, and one network contained subjects from Dehong. Conclusions Overall, the PDR prevalence was moderate, with a particularly high prevalence in areas with severe HIV epidemics. These results indicate the importance of continuous PDR monitoring in patients initiating antiretroviral therapy.

Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.

The purpose of this study was to examine the sedimentary facies characteristics of lower Cambrian Niutitang Formation (∈1n) in South China, to reveal the mechanism of organic matter enrichment, and to guide exploration of shale gas. Macro investigation and experimental analyses were used to assess the lithology in detail, total organic matter mass fraction w(TOC), mineral composition, and trace element characteristics of ∈1n. The influencing factors of organic matter enrichment were discussed extensively, and a sedimentary facies mode was suggested. In the early stage of ∈1n, the locations of Well E’yangye 1, Well Ciye 1, Well Changye 1, and Well Anye 1 respectively develop, platform inner sag, outer shelf, Jiangnan slope belt, and South China detention basin. In the late stage of ∈1n, the sedimentary facies evolve with decreasing sea level. The study area presents a complete three-step basin in the Early Cambrian. In the early stage of ∈1n, the first step is the Yangtze carbonate platform, the second step is the outer shelf and slope, and the third step is the deep-water basin. From the Yangtze carbonate platform to the deep-water basin, w(TOC) and the mass fraction of quartz gradually increase, the mass fraction of carbonate mineral decreases, and the mass fraction of clay mineral is higher in the second step. The sea level fluctuation results in a higher w(TOC) vertically in the lower ∈1n shale, and the paleogeographic (provenance) conditions lead to better horizontal development of organic matter in the outer shelf, slope and detention basin. Trace elements are abundant in the lower ∈1n, and w(TOC) is correlated positively with many trace elements. In the outer shelf, slope, and adjacent areas, hydrothermal activity and upwelling current bring nutrient-rich material and promote organic matter enrichment under a strong reducing condition. Deep-shelf, slope and deep-water basin are the best facies for the formation and preservation of organic matter, especially deep-water basin facies. It remains necessary to strengthen the exploration of shale gas in the deep-water basin of ∈1n in central Hunan, China.

Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis.

Calcium (Ca2+), a second messenger, plays a crucial role in plant growth and development as well as in responding to biotic and abiotic stresses. In this work, we explored the role of exogenous calcium in alleviating cold stress and examined the relationship between calcium chloride (CaCl2) and calcium channel blockers, lanthanum chloride (LaCl3), in tea plants under cold stress at the physiological and transcriptional levels. Exogenous Ca2+ partially offsets the negative impacts of cold stress which increased the tolerance of tea plants by significantly raising the photochemical efficiency of PSII, protective enzyme activities, and the ABA content, which reduced the relative electrical conductivity (REC) level and the malondialdehyde (MDA) concentration. At the transcriptome level, exogenous Ca2+ significantly enhanced the expression of key genes involved in cold response pathways. Nevertheless, LaCl3 treatment not only significantly inhibited the activities of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), but also increased cold damage. This study aims to provide essential insight into the role of exogenous Ca2+ in tea plants responding to cold stress, and to better understand the molecular mechanisms that facilitate Ca-mediated cold tolerance.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.

Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals. Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is emerging as a regulator of immunometabolism in inflammation and infection. Upregulation of ACOD1 expression occurs in activated immune cells (e.g., macrophages and monocytes) in response to pathogen infection (e.g., bacteria and viruses), pathogen-associated molecular pattern molecules (e.g., LPS), cytokines (e.g., TNF and IFNs), and damage-associated molecular patterns (e.g., monosodium urate). Mechanistically, several immune receptors (e.g., TLRs and IFNAR), adapter proteins (e.g., MYD88), ubiquitin ligases (e.g., A20), and transcription factors (e.g., NF-κB, IRFs, and STATs) form complex signal transduction networks to control ACOD1 expression in a context-dependent manner. Functionally, ACOD1 mediates itaconate production, oxidative stress, and antigen processing and plays dual roles in immunity and diseases. On the one hand, activation of the ACOD1 pathway may limit pathogen infection and promote embryo implantation. On the other hand, abnormal ACOD1 expression can lead to tumor progression, neurodegenerative disease, and immune paralysis. Further understanding of the function and regulation of ACOD1 is important for the application of ACOD1-based therapeutic strategies in disease.

ObjectiveAdaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).DesignWe screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-induced IDO1 and CD274 expression in 24 human and mouse cancer cell lines as well as in primary cancer cells from patients with PDAC or ovarian carcinoma. We tested the effects of dinaciclib on IFNG-induced signal transducer and activator of transcription 1 activation and immunological cell death, and investigated the potential utility of dinaciclib in combination with IFNG for pancreatic cancer therapy in vivo, and compared gene expression levels between human cancer tissues with patient survival times using the Cancer Genome Atlas datasets.ResultsPharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically ‘cold’ tumour microenvironment into a ‘hot’ one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC.ConclusionCDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.