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Rock types with similar lithological components and pore structures form the basic units of porous limestone reservoirs; this influences the reservoir evaluation efficiency and water injection development. As the main oil and gas pay zone in central Iraq, the Cretaceous Khasib Formation reservoirs are influenced by deposition, dissolution, and cementation. There is strong vertical heterogeneity in the most important zone of the Kh2 layer, with diverse rock types and complex pore structures. Based on core observation and casting thin-section identification, the Kh2 layer in the study area was divided into eight lithofacies types as argillaceous bioclastic wackestone, planktic foraminiferium wackestone, lamellar bioclastic wackestone, intraclastic–bioclastic packstone, patchy green algae packstone, green algae and pelletoid packstone, benthic foraminiferium–bioclastic packstone, and intraclastic grainstone. Along with the reservoir void space types of the lithofacies, capillary pressure curves are used to quantitatively analyze the throat and pore features of the different lithofacies. From the porosity–permeability cross-plot characteristics and distribution of pore types, 14 petrophysical facies are obtained. Finally, based on the differences between the lithofacies and petrophysical facies, the Kh2 member is divided into 13 rock types with different geological origins and petrophysical characteristics. Among these, the rock type RT1-8-14 has the best and rock type RT1-1-1 has the worst physical properties among the reservoir rock types. This study provides an optimization method for carbonate reservoir evaluation and is expected to be beneficial for efficient development of similar carbonate reservoirs.

Reservoir heterogeneity is one of the key factors affecting the exploration and development of oil and gas reservoirs. The Kh2 layer in the A field of Central Iraq is a major pay zone with strong longitudinal and lateral heterogeneity. The heterogeneity, controlled by geological factors, has not yet been confirmed, which seriously restricts the development of this pay zone. This study aims to establish a geological pattern for the reservoir heterogeneity of bioclastic limestone, providing a geological basis for heterogeneity evaluation. Based on the core observation, thin-section identification, and physical property analysis, the microfacies are classified, and the diagenetic sequences and the pore structure of the Kh2 layer are analyzed. Seven types of microfacies are developed in the Kh2 layer, namely, planktic foraminiferal wackestone (MFT1), lamellar bioclastic wackestone (MFT2), intraclastic–bioclastic packstone (MFT3), green algal packstone (MFT4), green alga–pelletoid packstone (MFT5), bioclastic–intraclastic packstone (MFT6), and intraclastic grainstone (MFT7). The heterogeneity of the different microfacies and heterogeneity within the same microfacies were evaluated using the variation coefficient of permeability tested from cores collected from wells and calculated by well-logging at different intervals. The highest heterogeneity was observed in the lamellar bioclastic wackestone (MFT2), with an average variation coefficient of 0.72. The lowest heterogeneity was observed in the green algal packstone (MFT4), with an average variation coefficient of 0.11. The vertical heterogeneity of the permeability is mainly controlled by sedimentation, while the lateral heterogeneity is mainly influenced by cementation, bioturbation, and the distribution of green algae. Finally, a micro-scale geological pattern for determining the reservoir heterogeneity of bioclastic limestone reservoirs is established. This study can guide the current injection development and remaining oil prediction in oilfields with similar backgrounds.

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level.Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing.Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit.Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics.

Dietary fibers (DFs) and their metabolites attract significant attention in research on health and disease, attributing to their effects on regulating metabolism, proliferation, inflammation, and immunity. When fermented by gut microbiota, DFs mainly produce short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, and butyric acid. As the essential nutrients for intestinal epithelial cells, SCFAs maintain intestinal homeostasis and play essential roles in a wide range of biological functions. SCFAs have been found to inhibit histone deacetylase, activate G protein-coupled receptors, and modulate the immune response, which impacts cancer and anti-cancer treatment. Notably, while extensive studies have illuminated the roles of SCFAs in colorectal cancer development, progression, and treatment outcomes, limited evidence is available for other types of cancers. This restricts our understanding of the complex mechanisms and clinical applications of SCFAs in tumors outside the intestinal tract. In this study, we provide a comprehensive summary of the latest evidence on the roles and mechanisms of SCFAs, with a focus on butyric acid and propionic acid, derived from microbial fermentation of DFs in cancer. Additionally, we recapitulate the clinical applications of SCFAs in cancer treatments and offer our perspectives on the challenges, limitations, and prospects of utilizing SCFAs in cancer research and therapy.

Epstein-Barr virus (human herpesvirus 4, EBV) is a linear double-stranded DNA virus that infects over 90% of the population worldwide. However, our understanding of EBV’s contribution to tumorigenesis of EBV-associated GC (EBVaGC) remains incomplete. Recent advancements in EBVaGC research have highlighted that EBV-encoded microRNAs (miRNAs) play prominent roles in critical cellular processes such as migration, cell cycle, apoptosis, cell proliferation, immune response, and autophagy. Notably, the largest group of EBV-encoded miRNAs, known as BamHI-A rightward transcripts (BARTs), exhibit bidirectional effects in EBVaGC. For instance, they present both anti-apoptotic and pro-apoptotic functions and enhance chemosensitivity while also conferring resistance to 5-fluorouracil. Despite these findings, the comprehensive mechanisms through which miRNAs contribute to EBVaGC are yet to be fully elucidated. In this work, we summarize the current evidence of the roles of miRNA in EBVaGC, particularly with the application of multi-omic techniques. Additionally, we discuss the application of miRNA in EBVaGC in retrospective analyses and provide novel perspectives on the use of miRNA in EBVaGC in translational medicine.

Substantial improvement in prognosis among metastatic renal cell carcinoma (mRCC) patients has been achieved, owing to the rapid development and utilization of immunotherapy. In particular, immune checkpoint inhibitors (ICIs) have been considered the backbone of systemic therapy for patients with mRCC alongside multi-targeted tyrosine kinase inhibitors (TKIs) in the latest clinical practice guidelines. However, controversies and challenges in optimal individualized treatment regarding immunotherapy remains still About 2/3 of the patients presented non-response or acquired resistance to ICIs. Besides, immune-related toxicities, namely immune-related adverse events, are still elusive and life-threatening. Thus, reliable biomarkers to predict immunotherapeutic outcomes for mRCC patients are needed urgently. Tumor microenvironment (TME), consisting of immune cells, vasculature, signaling molecules, and extracellular matrix and regulates tumor immune surveillance and immunological evasion through complex interplay, plays a critical role in tumor immune escape and consequently manipulates the efficacy of immunotherapy. Various studied have identified the different TME components are significantly associated with the outcome of mRCC patients receiving immunotherapy, making them potential valuable biomarkers in therapeutic guidance. The present review aims to summarize the latest evidence on the associations between the components of TME including immune cells, cytokines and extracellular matrix, and the therapeutic responses among mRCC patients with ICI-based treatment. We further discuss the feasibility and limitation of these components as biomarkers.

Bacterial infection is a major challenge that could threaten the patient’s life in repairing bone defects with implant materials. Developing functional scaffolds with an intelligent antibacterial function that can be used for bone repair is very important. We constructed a drug delivery (HA@TA-CS/SA) scaffold with curcumin-loaded dendritic mesoporous organic silica nanoparticles (DMON@Cur) via 3D printing for antibacterial bone repair. Inspired by the adhesion mechanism of mussels, the HA@TA-CS/SA scaffold of hydroxyapatite (HA) and chitosan (CS) is bridged by tannic acid (TA), which in turn binds sodium alginate (SA) using electrostatic interactions. The results showed that the HA@TA-CS/SA composite scaffold had better mechanical properties compared with recent literature data, reaching 68.09 MPa. It displayed excellent degradation and mineralization capabilities with strong biocompatibility in vitro. Furthermore, the antibacterial test results indicated that the curcumin-loaded scaffold inhibited S.aureus and E.coli with 99.99% and 96.56% effectiveness, respectively. These findings show that 3D printed curcumin-loaded HA@TA-CS/SA scaffold has considerable promise for bone tissue engineering.

Enterobactin is an archetypical catecholate siderophore that plays a key role in the acquisition of ferric iron by microorganisms. Catechol moieties have been shown to be promising siderophore cores. Variants of the conserved 2,3-dihydroxybenzoate (DHB) moiety with structural modifications expand the bioactivity. Streptomyces are characterized by metabolites with diverse structures. The genomic sequence of Streptomyces varsoviensis indicated that it possessed a biosynthetic gene cluster for DHB containing siderophores and metabolic profiling revealed metabolites correlated with catechol-type natural products. Here, we report the discovery of a series of catecholate siderophores produced by S. varsoviensis and a scale-up fermentation was performed to purify these compounds for structural elucidation. A biosynthetic route for the catecholate siderophores is also proposed. These new structural features enrich the structural diversity of the enterobactin family compounds. One of the new linear enterobactin congeners shows moderate activity against a food-borne pathogen Listeria monocytogenes. This work demonstrated that changing culture conditions is still a promising approach to explore unexplored chemical diversity. The availability of the biosynthetic machinery will enrich the genetic toolbox of catechol siderophores and facilitate such engineering efforts.

BackgroundMore than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics.MethodsThis cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort.ResultsHigh-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts.ConclusionsOur results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.

Endorsement of implicit age stereotypes was assessed with the propositional evaluation paradigm (PEP) in a high-powered, preregistered study, comprising samples of young (n = 89) and older (n = 125) adults. To investigate whether implicit age stereotypes shape the behavior via self-stereotyping (“embodiment”), we examined whether implicit endorsement of the belief of older (young) people being cautious (reckless) predicts older (young) individuals’ spontaneous behavior in a speeded response time task. In both age groups, we found significant implicit endorsement effects of age stereotypical beliefs. However, implicit endorsement effects of the cautiousness-related age stereotypes were unrelated to our indicators of spontaneous cautious/reckless behavior in the speeded RT task (as assessed with the parameter a of a diffusion model analysis) for both age groups. The same pattern of results (endorsement of age stereotypic beliefs but no relation with behavioral indicators) was found for explicit measures of age stereotypes. Replicating previous findings, implicit and explicit measures of cautiousness-related age stereotypes were uncorrelated. In sum, our findings provide evidence for the implicit and explicit endorsement of cautiousness-related stereotypical beliefs about old and young people; individual differences in belief endorsement, however, did not predict differences in spontaneous cautiousness-related behavior in a speeded RT task.

To evaluate the performance of expanded non-invasive prenatal testing (expanded noninvasive prenatal testing, NIPT-Plus) in screening for fetal chromosomal abnormalities includes aneuploidies and copy number variations, a total of 23,116 pregnant women with a singleton pregnancy were recruited for NIPT-Plus. Screening positive results were verified by karyotype analysis and chromosomal microarray analysis after amniocentesis. A total of 264 pregnancies (1.14%) were positive results as predicted by NIPT-Plus, including 233 aneuploidies and 31 copy number variations. Following genetic counseling, 233 (88.26%) pregnant women underwent invasive prenatal diagnosis and 136 were verified as true positives, comprising 72 common trisomies (T21, T18, T13), 47 sex chromosomal abnormalities two rare autosomal aneuploidies (RATs) and 15 copy number variations The positive predictive value for common trisomies, SCAs, RATs and CNVs were 68.57%, 68.12%, 6.67% and 51.72%, respectively. Pregnant women with screen-positive results for common trisomies have higher rates of invasive prenatal diagnosis and pregnancy termination than those with positive results for SCAs, RATs, and CNVs. NIPT-Plus showed a good performance in detecting common trisomies, SCAs and also contributed to detecting pathogenic CNVs, but higher accuracy was required in the detection of RATs. In summary, this study provides a reference for the clinical application of NIPT-Plus for screening fetal chromosomal abnormalities in this region. Therefore, we suggest that NIPT-Plus could be widely used in clinical screening for fetal chromosomal abnormalities in combination with prenatal diagnosis and genetic counseling.

As China becomes an aging society, the impacts of the aging population on the social meso domain, namely, the community level, have received increasing attention in recent years. However, relevant studies are limited. With the assumption that regular community participation positively influences well-being, this study investigated the mediating role of community participation between the sense of community and the general well-being of Chinese older adults and the moderating role of social support. A questionnaire survey was conducted with a valid sample size of 566 participants aged 60 and above in the urban communities of Chongqing, Chengdu, and Zunyi in southwest China. Moderated mediation models were constructed to explore factors related to the well-being of older adults, finding that encouraging community participation can improve the general well-being of older adults and build a better society in Chinese cities. The main findings of this study are as follows: (1) a sense of community significantly and positively relates to community participation and general well-being; (2) community participation partially mediates the relationship between sense of community and general well-being; and (3) each pathway through which sense of community influences older adults’ general well-being is moderated by social support.

The underlying surface parameters in the Budyko framework (such as parameter n in the Choudhury–Yang equation) are crucial for studying the relationship between precipitation, evapotranspiration, and runoff. It is important to accurately quantify the influence of climate and human activities on the evolution of underlying surface characteristic parameters. However, due to the spatiotemporal heterogeneity of underlying surface parameters, it is often difficult to accurately quantify these relationships. In this study, taking the Kuye River Basin located in the northern Loess Plateau as the research object, we first used trend analysis and non-linear regression methods to estimate the evolution characteristics of runoff and underlying surface parameter n. We then determined the contribution of runoff changes by using the elasticity coefficient method under the 9-year moving average window. The results showed that: 1) the Kuye River Basin runoff underwent a sudden change in 1997, and the complex human activities are the main reasons for the sharp runoff decrease. 2) In addition to precipitation and potential evapotranspiration, temperature changes will alter the basin’s underlying surface parameters, ultimately changing the runoff. Moreover, climate change first inhibited and then promoted the runoff reduction trend. 3) Human activities, represented by changes in vegetation coverage and coal mining, considerably influenced runoff evolution in Kuye River Basin. More importantly, the change of runoff in the Kuye River Basin caused by coal mining is approximately four times that of the normalized vegetation index. This study can improve the applicability of the Budyko framework in the Loess Plateau sub-basin and provide scientific guidance for water resource management.

BackgroundThe F-box and WD repeat domain containing (FBXW) family of SCF E3 complexes has 10 members that are responsible for ubiquitination and degradation of substrate proteins involved in cell cycle regulation and tumorigenesis. Among them, FBXW1 (also called b-TrCP1/BTRC) and FBXW7 are the central proteins in this category. However, there is still a lack of elaborate exploration of the contribution of FBXW family members, especially FBXW1 and FBXW7, in various tumor types.MethodsIn this present study, we preliminarily analyzed the genetic structure characteristics of the FBXW family, and systematically investigated their expression patterns and clinical correlations based on the TCGA pan-cancer data. Survival analysis of FBXWs was also conducted through the Kaplan-Meier method. In addition, we assessed their immune infiltration level through immune-related algorithms like Timer and xCell.ResultsThere were obvious genetic heterogeneity and different clinical traits in FBXW family members. Moreover, we found that FBXW family genes may be useful in predicting prognosis and therapeutic efficacy using survival analysis. In addition, the immune infiltration of FBXW family was also clearly illustrated in this study. The results showed these genes were closely involved in immune components such as immune score, immune subtypes, tumor-infiltrating lymphocytes and immune checkpoints. Notedly, FBXW1 as an oncogene and FBXW7 as a tumor suppressor gene also show opposite relationships on immune cells.ConclusionOur results provided valuable strategies to guide the therapeutic orientation concerning the role of FBXW family genes in cancer.

IntroductionBreast cancer (BC) has been ranking first in incidence and the leading cause of death among female cancers worldwide based on the latest report. Regulated cell death (RCD) plays a significant role in tumor initiation and provides an important target of cancer treatment. Cuproptosis, a novel form of RCD, is ignited by mitochondrial stress, particularly the lipoylated mitochondrial enzymes aggregation. However, the role of cuproptosis-related genes (CRGs) in tumor generation and progression remains unclear.MethodsIn this study, the mRNA expression data of CRGs in BC and normal breast tissue were extracted from TCGA database, and protein expression patterns of these CRGs were analyzed using UALCAN. The prognostic values of CRGs in BC were explored by using KaplanMeier plotter and Cox regression analysis. Genetic mutations profiles were evaluated using the cBioPortal database. Meanwhile, we utilized CIBERSORT and TIMER 2.0 database to perform the correlation analysis between CRGs and immune cell infiltration.ResultsOur results indicated that CRGs expression is significantly different in BC and normal breast tissues. Then we found that upregulated PDHA1 expression was associated with worse endpoint of BC. Moreover, we also performed immune infiltration analysis of CRGs, and demonstrated that PDHA1 expression was closely related to the infiltration levels of CD4+ memory T cell, macrophage M0 and M1 cell and mast cell in BC.ConclusionsOur results demonstrated the prognostic and immunogenetic values of PDHA1 in BC. Therefore, PDHA1 can be an independent prognostic biomarker and potential target for immunotherapy of BC.

Sepsis is a disease with a high morbidity and mortality rate. At present, there is a lack of ideal biomarker prognostic models for sepsis and promising studies using prognostic models to predict and guide the clinical use of medications. In this study, 71 differentially expressed genes (DEGs) were obtained by analyzing single-cell RNA sequencing (scRNA-seq) and transcriptome RNA-seq data, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses were performed on these genes. Then, a prognosis model with CCL5, HBD, IFR2BP2, LTB, and WFDC1 as prognostic signatures was successfully constructed after univariate LASSO regression analysis and multivariate Cox regression analysis. Kaplan–Meier (K-M) survival analysis, receiver operating characteristic (ROC) time curve analysis, internal validation, and principal component analysis (PCA) further validated the model for its high stability and predictive power. Furthermore, based on a risk prediction model, gene set enrichment analysis (GSEA) showed that multiple cellular functions and immune function signaling pathways were significantly different between the high- and low-risk groups. In-depth analysis of the distribution of immune cells in healthy individuals and sepsis patients using scRNA-seq data revealed immunosuppression in sepsis patients and differences in the abundance of immune cells between the high- and low-risk groups. Finally, the genetic targets of immunosuppression-related drugs were used to accurately predict the potential use of clinical agents in high-risk patients with sepsis.

BackgroundThe SCF (Skp1-cullin-F-box proteins) complex is the largest family of E3 ubiquitin ligases that mediate multiple specific substrate proteins degradation. Two ring-finger family members RBX1/ROC1 and RBX2/RNF7/SAG are small molecular proteins necessary for ubiquitin ligation activity of the multimeric SCF complex. Accumulating evidence indicated the involvement of RBX proteins in the pathogenesis and development of cancers, but no research using pan-cancer analysis for evaluating their difference has been directed previously.MethodsWe investigated RBX1/2 expression patterns and the association with clinicopathological features, and survivals of cancer patients obtained from the TCGA pan-cancer data. The binding energies of RBX1/2-CUL1 complexes were preliminarily calculated by using molecular dynamics simulations. Meanwhile, we assessed their immune infiltration level across numerous databases, including TISIDB and Timer database.ResultsHigh expression levels of RBX1/2 were observed in most cancer types and correlated with poor prognosis of patients analyzed. Nonetheless, exceptions were observed: RBX2 expression in KICH was higher than normal renal tissues and played a detrimental role in KICH. The expression of RBX1 was not associated with the prognostic risk of KICH. Moreover, the combination of RBX1 and CUL1 expression is more stable than that of RBX2 and CUL1. RBX1/2 expression showed their own specific characteristics in tumor pathological stages and grades, copy number variation and immune components.ConclusionsThese findings not only indicated that the difference of RBX1/2 might result in varying degrees of tumor progression, but also suggested that they might serve as biomarkers for immune infiltration in cancers, shedding new light on therapeutics of cancers.

ObjectiveThis study aimed to clarify the change in Cytomegalovirus (CMV) loads in breast milk (BM) of very/extremely premature infants (VPI/EPI) with birth weight < 1,500 g after birth, and to compare the effectiveness of pasteurization and freeze–thawing methods in reducing the CMV load of BM.MethodsBreast milk samples were collected and tested every 2 weeks by fluorescence quantitative polymerase chain reaction (FQ-PCR). We determined CMV load in BM before and after pasteurizing, and freeze-thawing.ResultsCytomegalovirus DNA can already be detected in colostrum. The viral load gradually increased in the first 4 weeks, peaked in the 4th to 6th weeks, and gradually decreased thereafter. The viral load gradually returned to the initial level approximately 10–12 weeks postpartum. During the peak period of the CMV load in BM, the viral load was higher in the EPI than the VPI (P < 0.05). The average CMV load (logarithmic [LG]) in the pasteurization group was significantly lower than that in the raw BM group. The average CMV load in the freeze-thawed BM group was significantly lower than that in the raw BM group. The mean CMV load in the pasteurized BM group was lower than that in the freeze–thawed BM group, but the difference was not statistically significant. The CMV-DNA clearance rate in pasteurized was higher than in freeze–thawed (P < 0.05).ConclusionThe CMV detoxification rate in BM is high and the peak load period is mainly between 4 and 6 weeks. The CMV load values detected are higher than the threshold values (7 × 103 copy number/mL) of CMV infection that are reported in the literature as a concern. Both the freeze-thaw and pasteurization techniques can effectively reduce the CMV load.

The immune system is essential in the process of nerve repair after injury. Successful modulation of the immune response is regarded as an effective approach to improving treatment outcomes. T cells play an important role in the immune response of the nervous system, and their beneficial roles in promoting regeneration have been increasingly recognized. However, the diversity of T-cell subsets also delivers both neuroprotective and neurodegenerative functions. Therefore, this review mainly discusses the beneficial impact of T-cell subsets in the repair of both peripheral nervous system and central nervous system injuries and introduces studies on various therapies based on T-cell regulation. Further discoveries in T-cell mechanisms and multifunctional biomaterials will provide novel strategies for nerve regeneration.

With the rapid process of urbanization and global warming, many metropolises are vulnerable to high temperatures in summer, threatening the health of residents. However, green spaces can generate a cooling effect to mitigate the urban heat island effect in big cities. They can also help to improve the living quality and wellbeing of surrounding residents. In this paper, we utilized the radiative transfer equation algorithm, k-means clustering algorithm, big data crawling, and spatial analysis to quantify and map the spatial distribution, cooling capacity, and cooling contribution for surrounding communities of 1,157 green spaces within Beijing Fifth Ring Road, a typical metropolitan area. The findings showed that (1) the area proportion of the heat island in the study area is larger than that of the cooling island. Accounting for only about 30% area in the study area, the green spaces reduce the average land surface temperature by 1.32°C. (2) The spatial features of green space, such as area and shape complexity, have a significant influence on its cooling effect. (3) Four clusters of green spaces with specific spatial features and cooling capacity were identified. And there were differences among these clusters in green space cooling contribution for the surrounding communities. (4) The differences in green space cooling contribution also existed in different urban zones. Specifically, the middle zone performed significantly better than the inner and outer zones. (5) We furthered in finding that some green spaces with medium and high cooling contributions need to improve their cooling capacity soon, and some green spaces with low cooling contributions or no contributions have a good potential for constructing new communities in the future. Our study could help planners and government understand the current cooling condition of green spaces, to improve their cooling capacity, mitigate the urban heat island effect, and create a comfortable and healthy thermal environment in summer.

Myocardial ischemia/reperfusion injury (MI/RI) is a serious pathophysiological process relating to cardiovascular disease. Oroxin A (OA) is a natural flavonoid glycoside with various biological activities. However, its effect on the pathophysiological process of MI/RI has not yet been reported. The aim of this study was to determine whether OA could alleviate MI/RI induced inflammation and pyroptosis in vivo and in vitro, providing a novel therapeutic regimen for the treatment of MI/RI. A high-throughput drug screening strategy was employed to test 2,661 natural compound libraries that can alleviate MI/RI in vivo and in vitro. The rat model of MI/RI was established by ligating the left anterior descending (LAD) coronary artery. H9c2 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate MI/RI. The results show that OA is able to significantly inhibit apoptosis, pyroptosis and the inflammation response (TNF-α, IL-6, IL-8, IL-10, IL-1β, IL-18) in vivo and in vitro, and reduce the release of myocardial enzymes (cTnI, cTnT, CK-MB, LDH, AST). In the rat MI/RI model, OA can not only improve cardiac function and reduce inflammatory cell infiltration but also reduce myocardial infarct size. The results revealed that OA is an effective remedy against MI/RI as it reduces the inflammatory response and inhibits pyroptosis. This may provide a new therapeutic target for the clinical treatment of MI/RI.

Oropharyngeal squamous cell carcinoma (OPSCC) is an uncommon malignancy worldwide. Remarkably, the rising incidence of OPSCC has been observed in many developed countries over the past few decades. On top of tobacco smoking and alcohol consumption, human papillomavirus (HPV) infection has become a major etiologic factor for OPSCC. The radiotherapy-based or surgery-based systemic therapies are recommended equally as first-line treatment, while chemotherapy-based strategy is applied to advanced diseases. Immunotherapy in head and neck squamous cell carcinoma (HNSCC) is currently under the spotlight, especially for patients with advanced diseases. Numerous researches on programmed death-1/programmed death-ligand 1 checkpoint inhibitors have proven beneficial to patients with metastatic HNSCC. In 2016, nivolumab and pembrolizumab were approved as the second-line treatment for advanced metastatic HNSCC by the USA Food and Drug Administration. Soon after, in 2019, the USA Food and Drug Administration approved pembrolizumab as the first-line treatment for patients with unresectable, recurrent, and metastatic HNSCC. It has been reported that HPV-positive HNSCC patients were associated with increased programmed death-ligand 1 expression; however, whether HPV status indicates different treatment outcomes among HNSCC patients treated with immunotherapy has contradicted. Notably, HPV-positive OPSCC exhibits a significantly better clinical response to primary treatment (i.e., radiotherapy, surgery, and chemotherapy) and a more desirable prognosis compared to the HPV-negative OPSCC. This review summarizes the current publications on immunotherapy in HNSCC/OPSCC patients and discusses the impact of HPV infection in immunotherapeutic efficacy, providing an update on the immune landscape and future perspectives in OPSCC.

BackgroundThe human microbiome has been reported to mediate the response to anticancer therapies. However, research about the influence of the oral microbiome on nasopharyngeal carcinoma (NPC) survival is lacking. We aimed to explore the effect of oral microbiota on NPC prognosis.MethodsFour hundred eighty-two population-based NPC cases in southern China between 2010 and 2013 were followed for survival, and their saliva samples were profiled using 16s rRNA sequencing. We analyzed associations of the oral microbiome diversity with mortality from all causes and NPC.ResultsWithin- and between-community diversities of saliva were associated with mortality with an average of 5.29 years follow-up. Lower Faith’s phylogenetic diversity was related to higher all-cause mortality [adjusted hazard ratio (aHR), 1.52 (95% confidence interval (CI), 1.06–2.17)] and NPC-specific mortality [aHR, 1.57 (95% CI, 1.07–2.29)], compared with medium diversity, but higher phylogenetic diversity was not protective. The third principal coordinate (PC3) identified from principal coordinates analysis (PCoA) on Bray–Curtis distance was marginally associated with reduced all-cause mortality [aHR, 0.85 (95% CI, 0.73–1.00)], as was the first principal coordinate (PC1) from PCoA on weighted UniFrac [aHR, 0.86 (95% CI, 0.74–1.00)], but neither was associated with NPC-specific mortality. PC3 from robust principal components analysis was associated with lower all-cause and NPC-specific mortalities, with HRs of 0.72 (95% CI, 0.61–0.85) and 0.71 (95% CI, 0.60–0.85), respectively.ConclusionsOral microbiome may be an explanatory factor for NPC prognosis. Lower within-community diversity was associated with higher mortality, and certain measures of between-community diversity were related to mortality. Specifically, candidate bacteria were not related to mortality, suggesting that observed associations may be due to global patterns rather than particular pathogens.

In this study, we investigated explicit and implicit endorsement of prescriptive age stereotypes. To achieve that, we captured endorsement of a wide range of prescriptive expectations targeting both younger (younger adults are expected to be ambitious, eager to learn, unconventional, respectful) and older (older adults are expected to stay active, to be generous, dignified, and wise) people. Younger (n = 58, 50% female, Mage = 26.07 years, SD = 3.01) and older adults (n = 75, 44% female, Mage = 66.69 years, SD = 4.63) participated in the study. We assessed implicit endorsement of prescriptive age stereotypes with the Propositional Evaluation Paradigm (PEP) and used a direct measure to assess explicit endorsement. In general, we found strong support for age-specificity in both explicit and implicit endorsement of prescriptive age stereotypes: Sentences ascribing expectations for young/old to the respective age group (e.g., “young should be ambitious”; “old should be wise”) were endorsed much more strongly than sentences in which expectations for young/old were ascribed to the other age group (e.g., “old should be ambitious”; “young should be wise”). Age group differences in the endorsement of prescriptive age stereotypes were found. Compared to younger participants, older participants showed stronger endorsement for prescriptive beliefs targeting both younger and older targets. Explicit and implicit endorsement of prescriptive age stereotypes did not correlate with one another, thus revealing they might assess independent belief systems with different predictive potential.

Significant advances have been made in recent years for the utilization of natural enzymes with antioxidant properties to treat acute kidney injury (AKI). However, these enzymes have been of limited clinical utility because of their limited cellular uptake, poor pharmacokinetic properties, and suboptimal stability. We employed a novel biomimetic mineralization approach to encapsulate catalase (CAT) and superoxide dismutase (SOD) in a zeolitic imidazolate framework-8 (ZIF-8). Next, this SOD@CAT@ZIF-8 complex was anchored with MPEG2000-COOH to yield an MPEG2000-SOD@CAT@ZIF-8 (PSCZ) composite. The composite was then used as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI, remarkably improved intracellular enzyme delivery. This dual-enzyme-embedded metal-organic framework could effectively scavenge reactive oxygen species. In conclusion, the ZIF-8-based “armor plating” represents an effective means of shielding enzymes with improved therapeutic utility to guide the precision medicine-based treatment of AKI.

Successful control of massive hemorrhage in deep wounds with irregular shape and low elasticity still remains great challenges in the clinic. As the wound sites are usually at risk of bacterial infection, it is necessary to design an ideal hemostatic agent with rapid hemostasis and excellent antibacterial activity. In this study, we developed a light responsive hemostatic film for effective handling of liver bleeding with promising photodynamic therapy against S. aureus onnear infrared (NIR) irradiation. Based on silk fibroin, the film exhibited desirable biocompatibility and mechanical property as a hemostat tape. Significantly, the film tape achieved excellent tissue adhesion and hemostasis in vivo within 2 min of UV exposure, which would have a great potential as a multifunctional biomedical material in the field of tissue repair such as wound healing, bone repair, and nerve regeneration.

BackgroundAplastic anemia (AA), megaloblastic anemia (MA), and myelodysplastic syndrome (MDS) were common anemic diseases. Sometimes it was difficult to distinguish patients with these diseases.MethodsIn this article, we proposed one measurement method for the area of red blood cells (RBCs) from microscopic images based on image processing technology and analyzed the differences of the area in 25 patients with AA, 64 patients with MA, and 68 patients with MDS.ResultsThe area of RBCs was 44.19 ± 3.88, 42.09 ± 5.35, 52.87 ± 7.68, and 45.75 ± 8.07 μm2 in normal subjects, patients with AA, MA, and MDS, respectively. The coefficients of variation were 8.78%, 10.05%, 14.53%, and 14.00%, respectively, in these groups. The area of RBCs in patients with MA was significantly higher than normal subjects (p < 0.001). Compared with patients with AA and MDS, the area of RBCs in patients with MA was also significantly higher (p < 0.001). The results of correlation analysis between the area of RBCs and mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), and red cell distribution width showed no significant correlations (p > 0.05). The area under the curve (AUC) results of the Receiver Operating Characteristic (ROC) curves of RBCs area were 0.421, 0.580, and 0.850, respectively, in patients with AA (p = 0.337), MDS (p = 0.237), and MA (p < 0.001).ConclusionIdentifying the area of RBCs in peripheral blood smears based on the image processing technology could achieve rapid and efficient diagnostic support for patients with MDS and MA, especially for patients with MA and in combination with MCV. However, a larger sample study is needed to find the cutoff area values.

BackgroundBilateral cerebral palsy (BCP) is the most common type of CP in children and is often accompanied by different degrees of communication impairment. Several studies have attempted to identify children at high risk for communication impairment. However, most prediction factors are qualitative and subjective and may be influenced by rater bias. Individualized objective diagnostic and/or prediction methods are still lacking, and an effective method is urgently needed to guide clinical diagnosis and treatment. The aim of this study is to develop and validate an objective, individual-based model for the prediction of communication impairment in children with BCP by the time they enter school.MethodsA multicenter prospective cohort study will be conducted in four Chinese hospitals. A total of 178 children with BCP will undergo advanced brain magnetic resonance imaging (MRI) at baseline (corrected age, before the age of 2 years). At school entry, communication performance will be assessed by a communication function classification system (CFCS). Three-quarters of children with BCP will be allocated as a training cohort, whereas the remaining children will be allocated as a test cohort. Multivariate lesion- and connectome-based approaches, which have shown good predictive ability of language performance in stroke patients, will be applied to extract features from MR images for each child with BCP. Multiple machine learning models using extracted features to predict communication impairment for each child with BCP will be constructed using data from the training cohort and externally validated using data from the test cohort. Prediction accuracy across models in the test cohort will be statistically compared.DiscussionThe findings of the study may lead to the development of several translational tools that can individually predict communication impairment in children newly diagnosed with BCP to ensure that these children receive early, targeted therapeutic intervention before they begin school.Trial registrationThe study has been registered with the Chinese Clinical Trial Registry (ChiCTR2100049497).

Cervical cancer is one of the most severe and prevalent female malignancies and a global health issue. The molecular mechanisms underlying cervical cancer development are poorly investigated. As a type of extracellular membrane vesicles, EVs from cancer cells are involved in cancer progression by delivering regulatory factors, such as proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). In this study, we identified an innovative function of extracellular vesicle (EV) lncRNA AGAP2-AS1 in regulating cervical cancer cell proliferation. The EVs were isolated from the cervical cancer cells and were observed by transmission electron microscopy (TEM) and were confirmed by analyzing exosome markers. The depletion of AGAP2-AS1 by siRNA significantly reduced its expression in the exosomes from cervical cancer and in the cervical cancer treated with AGAP2-AS1-knockdown exosomes. The expression of AGAP2-AS1 was elevated in the clinical cervical cancer tissues compared with the adjacent normal tissues. The depletion of EV AGAP2-AS1 reduced cell viabilities and Edu-positive cervical cancer cells, while it enhanced cervical cancer cell apoptosis. Tumorigenicity analysis in nude mice showed that the silencing of EV AGAP2-AS1 attenuated cervical cancer cell growth in vivo. Regarding the mechanism, we identified that AGAP2-AS1 increased SIRT1 expression by sponging miR-3064-5p in cervical cancer cells. The overexpression of SIRT1 or the inhibition of miR-3064-5p reversed EV AGAP2-AS1 depletion-inhibited cancer cell proliferation in vitro. Consequently, we concluded that EV lncRNA AGAP2-AS1 contributed to cervical cancer cell proliferation through regulating the miR-3064-5p/SIRT1 axis. The clinical values of EV lncRNA AGAP2-AS1 and miR-3064-5p deserve to be explored in cervical cancer diagnosis and treatments.

Stroke remains the leading cause of long-term disability worldwide with significant long-term sequelae. However, there is no highly effective treatment to enhance post-stroke recovery despite extensive efforts in exploring rehabilitative therapies. Neurorehabilitation is recognized as the cornerstone of functional restoration therapy in stroke, where treatments are focused on neuroplastic regulation to reverse neural structural disruption and improve neurofunctional networks. Post-stroke neuroplasticity changes begin within hours of symptom onset and reaches a plateau by 3 to 4 weeks within the global brain in animal studies. It plays a determining role in spontaneous stroke recovery. Microglia are immediately activated following cerebral ischemia, which has been found both proximal to the primary ischemic injury and at the remote brain regions which have functional connections to the primary injury area. Microglia exhibit different activation profiles based on the microenvironment and adaptively switch their phenotypes in a spatiotemporal manner in response to brain injuries. Microglial activation coincides with neuroplasticity after stroke, which provides the fundamental base for the microglia-mediated inflammatory responses involved in the entire neural network rewiring and brain repair. Microglial activation exerts important effects on spontaneous recovery after stroke, including structural and functional reestablishment of neurovascular networks, neurogenesis, axonal remodeling, and blood vessel regeneration. In this review, we focus on the crosstalk between microglial activation and endogenous neuroplasticity, with a special focus on the plastic alterations in the whole brain network and their implications for structural and functional restoration after stroke. We then summarize recent advances in the impacts of microglial phenotype polarization on brain plasticity, trying to discuss the potential efficacy of microglia-based extrinsic restorative interventions in promoting post-stroke recovery.

Background: Dexamethasone (DEX) is widely adopted to reduce tumor-associated edema in glioblastoma (GBM) patients despite its side effects. However, the benefits of using DEX in GBM patients remains elusive.Methods: In this study, we performed a comprehensive meta-analysis to address this concern. We searched the relevant studies from PubMed, Web of Science, and EMBASE databases, and then applied random or fixed-effects models to generate estimated summary hazard radios (HRs) and the 95% confidence intervals (CIs). Moreover, subgroup and sensitivity analysis were conducted and publication bias were further evaluated.Results: Ten articles with a total of 2,230 GBM patients were eligible according to the inclusion criteria. In the assessment of overall survival (OS), meta-analysis data revealed that DEX was significantly associated with the poor prognosis of GBM patients (HR=1.44, 95% CI=1.32−1.57). In the progression-free survival (PFS), the pooled results indicated that the use of DEX can increase 48% death risk for GBM patients (HR=1.48, 95% CI=1.11−1.98). Subgroup analyses revealed that DEX was associated with poorer outcome of GBM in subgroup of newly diagnosed patients and GBM patients treated with ≥ 2mg/day. Sensitivity analyses showed that no study changed the pooled results materially for both OS and PFS analyses. The funnel plot had no obvious asymmetry.Conclusion: Our findings partly confirmed that use of DEX was associated with poor treatment outcome in GBM patients. To reach a definitive conclusion, large samples from multi-centers are urgent to address this concern.

Objective: 1q44 microdeletion syndrome is difficult to diagnose due to the wide phenotypic spectrum and strong genetic heterogeneity. We explore the correlation between the chromosome microdeletions and phenotype in a child with 1q44 microdeletion syndrome, we collected the clinical features of the patient and combined them with adjacent copy number variation (CNV) regions previously reported.Methods: We collected the full medical history of the patient and summarized her clinical symptoms. Whole-exome sequencing (WES) and CapCNV analysis were performed with DNA extracted from both the patient's and her parents' peripheral blood samples. Fluorescent quantitative PCR (q-PCR) was performed for the use of verification to the CNV regions.Results: A 28.7 KB microdeletion was detected in the 1q44 region by whole-exome sequencing and low-depth whole-genome sequencing. The deleted region included the genes COX20 and HNRNPU. As verification, karyotype analysis showed no abnormality, and the results of qPCR were consistent with that of whole-exome sequencing and CapCNV analysis.Conclusion: The patient was diagnosed with 1q44 microdeletion syndrome with clinical and genetic analysis. Analyzing both whole-exome sequencing and CapCNV analysis can not only improve the diagnostic rate of clinically suspected syndromes that present with intellectual disability (ID) and multiple malformations but also support further study of the correlation between CNVs and clinical phenotypes. This study lays the foundation for the further study of the pathogenesis of complex diseases.

Pelvic intensity-modulated radiation therapy (IMRT) combined with concurrent chemotherapy is an effective treatment for cervical cancer; however, radiation resistance impairs its clinical benefit. The vaginal microbiome plays an important but poorly understood role in cancer radiochemotherapy. In this study, we investigated the effects of treatment on the overall composition and alteration of the vaginal microbiome in patients receiving pelvic IMRT with concurrent cisplatin-based chemotherapy. We collected samples from twenty patients with cervical cancer and six healthy controls and performed 16S rRNA sequencing. Vaginal microbial composition analysis revealed significant differences between the two groups, but no significant differences between radiation treatment time points. However, the relative abundances of Gammaproteobacteria, Gemmatimonadetes, Gemmatimonadales, Pseudomonadales, Gemmatimonadaceae, Rikenellaceae, Acinetobacter, Desulfovibrio, Prevotella 9, Rikenellaceae RC9 gut group, Turicibacter, and the metagenome increased with time. The results encourage further study into the effects of the vaginal microbiome on cervical cancer treatment strategies, especially radiochemotherapy. Better understanding of these effects could inform new therapeutic approaches to enhance the efficacy of radiochemotherapy.

Objective: Brain imaging is important in diagnosing children with cerebral palsy (CP) and in identifying its etiology. To provide study navigation in this field, a bibliometric analysis was conducted by analyzing the most highly cited articles.Methods: The Web of Science All Databases were used for literature search in this study. All original articles on imaging in children with CP were searched. Two reviewers screened the search results independently and eliminated articles based on exclusion criteria such as participants over 20 years old, topics referring to images outside of the brain, or trauma. According to descending order of yearly citation counts, the top 25% of all included articles were considered as highly cited articles. Information such as yearly citations, research purposes, imaging modalities, CP types, and study designs were recorded and analyzed.Results: A total of 50 highly cited articles ranked by yearly citations (from 23.85 to 3.33, 1991–2018) were included in this study. Considering different research purposes, these studies were classified into three categories: diagnosis studies (n = 25; 1991–2017, median: 2011), mechanism studies (n = 15; 1999–2018; median: 2014), and prognosis and therapeutic effect studies (n = 10; 2008–2017; median: 2014.5). First, for diagnosis studies, 22 studies used single modality and three used multi-modalities; the majority of these studies focused on diagnostic value evaluation (n = 10) and image performance (n = 12) of a single type of CP (n = 15) by using descriptive (n = 14) or cross-sectional approaches (n = 10). Second, for mechanism studies, the ratio between single and multi-modality was 8:7; most of these studies concentrated on a single subtype of spastic CP (hemiplegia = 10, quadriplegia = 2) with a cross-sectional study design (n = 10). Third, regarding the prognosis and therapeutic effect studies, the single vs. multi-modality ratio was 5:5, and these studies were dedicated to the efficiency of constraint-induced movement therapy in children with hemiplegia; paired design trials (n = 6) and randomized controlled trials (n = 2) were used more frequently.Conclusion: Studies using multi-modality and high-level evidence-based design to provide information regarding mechanism, prognosis, and therapeutic efficacy may be the potential future research direction in the field of CP research.

Acute ischemic stroke (AIS) is common in patients with cancer, and mounting clinical evidence suggests that it may shorten the survival of cancer patients. But how stroke affects the progression of cancer remains unclear. We inoculated B16 tumor cells (2 × 105) subcutaneously before distal middle cerebral artery occlusion (dMCAO) or sham surgery in C57BL/6 mice and found that compared to sham operated mice, dMCAO mice developed significantly increased tumor volume and were accompanied by lower survival rate. To explore the underlying mechanism, we performed RNA-sequencing analysis of the tumor tissue from mice with or without stroke and found prominent upregulation of lipocalin 2 (LCN2) in the tumor from stroke mice compared to those from sham mice. Using quantitative reverse transcription-PCR, we confirmed increased mRNA expression of LCN2 as well as anti-inflammatory cytokines-Arg1, IL-10, and decreased mRNA level of pro-inflammatory cytokines-IL-6, IL-23 in the tumor of cancer-bearing stroke mice. Both immunofluorescence staining and flow cytometry analysis revealed that increased expression of LCN2 was mainly derived from the polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) in the tumor. We also found that stroke reduced the PMN-MDSCs in the peripheral blood, but increased PMN-MDSCs in the tumor of the cancer-bearing mice after stroke. In conclusion, cerebral ischemic stroke may exacerbate cancer progression by increasing LCN2 expression in PMN-MDSCs, which turns out to be a promising therapeutic target to suppress cancer progression after ischemic stroke.

The mechanism of bipolar disorder is unclear. Growing evidence indicates that gut microbiota plays a pivotal role in mental disorders. This study aimed to find out changes in the gut microbiota in bipolar depression (BD) subjects following treatment with quetiapine and evaluate their correlations with the brain and immune function. Totally 36 subjects with BD and 27 healthy controls (HCs) were recruited. The severity of depression was evaluated with the Montgomery-Asberg depression rating scale (MADRS). At baseline, fecal samples were collected and analyzed by quantitative polymerase chain reaction (qPCR). T lymphocyte subsets were measured to examine immune function. Near-infrared spectroscopy (NIRS) was used to assess brain function. All BD subjects received quetiapine treatment (300 mg/d) for four weeks, following which the fecal microbiota and immune profiles were reexamined. Here, we first put forward the new concept of brain-gut coefficient of balance (B-GCB), which referred to the ratio of [oxygenated hemoglobin]/(Bifidobacteria to Enterobacteriaceae ratio), to analyze the linkage between the gut microbiota and brain function. At baseline, the CD3+ T cell proportion was positively correlated with log10 Enterobacter spp count, whereas the correlativity between the other bacteria and immune profiles were negative. Log10 B-GCB was positively correlated with CD3+ T cell proportion. In subjects with BD, counts of Faecalibacterium prausnitzii, Bacteroides–Prevotella group, Atopobium Cluster, Enterobacter spp, and Clostridium Cluster IV were higher, whereas the log10 (B/E) were lower than HCs (B/E refers to Bifidobacteria to Enterobacteriaceae ratio and represents microbial colonization resistance). After treatment, MADRS scores were reduced, whereas the levels of Eubacterium rectale, Bifidobacteria, and B/E increased. The composition of the gut microbiota and its relationship to brain function were altered in BD subjects. Quetiapine treatment was effective for depression and influenced the composition of gut microbiota in patients.Clinical Trial Registration:http://www.chictr.org.cn/index.aspx, identifier ChiCTR-COC-17011401, URL: http://www.chictr.org.cn/listbycreater.aspx.

Progressive neurological deterioration poses enormous burden on the aging population with ischemic stroke and neurodegenerative disease patients, such as Alzheimers’ disease and Parkinson’s disease. The past two decades have witnessed remarkable advances in the research of neurovascular unit dysfunction, which is emerging as an important pathological feature that underlies these neurological disorders. Dysfunction of the unit allows penetration of blood-derived toxic proteins or leukocytes into the brain and contributes to white matter injury, disturbed neurovascular coupling and neuroinflammation, which all eventually lead to cognitive dysfunction. Recent evidences suggest that aging-related oxidative stress, accumulated DNA damage and impaired DNA repair capacities compromises the genome integrity not only in neurons, but also in other cell types of the neurovascular unit, such as endothelial cells, astrocytes and pericytes. Combating DNA damage or enhancing DNA repair capacities in the neurovascular unit represents a promising therapeutic strategy for vascular and neurodegenerative disorders. In this review, we focus on aging related mechanisms that underlie DNA damage and repair in the neurovascular unit and introduce several novel strategies that target the genome integrity in the neurovascular unit to combat the vascular and neurodegenerative disorders in the aging brain.

Neurological deficits and cognitive dysfunctions caused by acute ischemic stroke pose enormous burden to the stroke families and the communities. Restoration of the normal function of the neurovascular unit following ischemic stroke is critical for improving neurological recovery and cognitive functions after stroke. Recent evidence suggests that the myeloid cells including both the resident microglia and infiltrating monocytes/macrophages and neutrophils are highly plastic in response to the environmental cues. They intimately interact with multiple components of the neurovascular unit in response to the alarmins, danger associated pattern molecules (DAMPs) and other signals released from the ischemic brain. The aim of this review is to discuss the reciprocal interactions between the myeloid cells and the ischemic neurovascular unit during the late repair phase of cerebral ischemic stroke. We also summarize potential immunotherapeutic targets on myeloid cells and new therapeutic approaches targeting myeloid cells, such as cell transplantation, mitochondrial dynamic and extracellular vesicles-based therapy et al to enhance neurovascular repair for better stroke recovery.

Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF), characterized by an acute deterioration of liver function in the patients with chronic hepatitis B (CHB), is lack of predicting biomarkers for prognosis. Plasma is an ideal sample for biomarker discovery due to inexpensive and minimally invasive sampling and good reproducibility. In this study, immuno-depletion of high-abundance plasma proteins followed by iTRAQ-based quantitative proteomic approach was employed to analyze plasma samples from 20 healthy control people, 20 CHB patients and 20 HBV-ACLF patients, respectively. As a result, a total of 427 proteins were identified from these samples, and 42 proteins were differentially expressed in HBV-ACLF patients as compared to both CHB patients and healthy controls. According to bioinformatics analysis results, 6 proteins related to immune response (MMR), inflammatory response (OPN, HPX), blood coagulation (ATIII) and lipid metabolism (APO-CII, GP73) were selected as biomarker candidates. Further ELISA analysis confirmed the significant up-regulation of GP73, MMR, OPN and down-regulation of ATIII, HPX, APO-CII in HBV-ACLF plasma samples (p < 0.01). Moreover, receiver operating characteristic (ROC) curve analysis revealed high diagnostic value of these candidates in assessing HBV-ACLF. In conclusion, present quantitative proteomic study identified 6 novel HBV-ACLF biomarker candidates and might provide fundamental information for development of HBV-ACLF biomarker.

Ubiquitination-mediated protein degradation plays a crucial role in the turnover of immune proteins through rapid alteration of protein levels. Specifically, the over-accumulation of immune proteins and consequent activation of immune responses in uninfected cells is prevented through degradation. Protein post-translational modifications can influence and affect ubiquitination. There is accumulating evidence that suggests sumoylation, phosphorylation, and acetylation differentially affect the stability of immune-related proteins, so that control over the accumulation or degradation of proteins is fine-tuned. In this paper, we review the function and mechanism of sumoylation, phosphorylation, acetylation, and ubiquitination in plant disease resistance responses, focusing on how ubiquitination reacts with sumoylation, phosphorylation, and acetylation to regulate plant disease resistance signaling pathways. Future research directions are suggested in order to provide ideas for signaling pathway studies, and to advance the implementation of disease resistance proteins in economically important crops.