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PARP inhibitors (PARPi) are a kind of cancer therapy that targets poly (ADP-ribose) polymerase. PARPi is the first clinically approved drug to exert synthetic lethality by obstructing the DNA single-strand break repair process. Despite the significant therapeutic effect in patients with homologous recombination (HR) repair deficiency, innate and acquired resistance to PARPi is a main challenge in the clinic. In this review, we mainly discussed the underlying mechanisms of PARPi resistance and summarized the promising solutions to overcome PARPi resistance, aiming at extending PARPi application and improving patient outcomes.

Fire can significantly affect the structure and function of forest soil microorganisms. Therefore, it is important to study the effects of different fire intensities on soil microbial carbon source utilization capacity in cold-temperate larch forests to protect and utilize forest ecosystems. In this study, we investigated the effects of different burning intensities on the carbon utilization capacity of soil microorganisms in fire sites from 2010 and 2000 using Biolog-Eco technology. Our findings revealed that (1) fire significantly increased soil pH, AN (available nitrogen), and AK (available potassium) (p < 0.05); (2) fire significantly increased the average color change rate (AWCD) of soil microorganisms (p < 0.05); (3) the Shannon index of soil microorganisms increased significantly, whereas the Simpson index and the McIntosh index decreased significantly after the fire—however, the McIntosh index in the 10M site was not altered; (4) the metabolic functions of soil microbial communities differed significantly among different fire intensities—MC (moisture content), TN (total nitrogen), and AK were the most influential soil environmental factors in the soil microbial community; and (5) mid-term fire restoration significantly increased microbial responses to carbohydrates, amino acids, esters, alcohols, amines, and acids, while late-fire burn sites significantly increased the microbial utilization intensity of amino acids, esters, and acids. In conclusion, fire significantly altered the functional diversity of soil microorganisms and microbial activities related to carbon source substrate utilization. Additionally, the ability of microorganisms to utilize a single carbon source substrate was also altered.

Abstract Multiple studies have shown that extracellular vesicles (EVs) play a key role in the process of information transfer and material transport between cells. EVs are classified into different types according to their sizes, which includes the class of exosomes. In comparison to normal EVs, tumor-derived EVs (TDEs) have both altered components and quantities of contents. TDEs have been shown to help facilitate an environment conducive to the occurrence and development of tumor by regulation of glucose, lipids and amino acids. Furthermore, TDEs can also affect the host metabolism and immune system. EVs have been shown to have multiple clinically useful properties, including the use of TDEs as biomarkers for the early diagnosis of diseases and using the transport properties of exosomes for drug delivery. Targeting the key bioactive cargoes of exosomes could be applied to provide new strategies for the treatment of tumors. In this review, we summarize the finding of studies focused on measuring the effects of TDE on tumor-related microenvironment and systemic metabolism. Video Abstract

Ecosystems are frequently disturbed by fires that have an important impact on the soil environment and the composition of soil organisms. In order to provide a baseline for the current research and identify trends on the effects of wildland fire on soil environment and biological changes, the available literature was identified from the Web of Science database, covering the period from 1998/1998/1999 (the year of the earliest publication in this field) to 2023. A bibliometric analysis was performed and the data were visually displayed for the number of publications, countries, authors, research institutions, and keywords representing research hotspots. Specifically, the effects of wildland fire on the soil environment, on soil microorganisms and on soil fauna were analyzed. The results show that the annual number of publications describing effects of wildland fire on the soil environment and on soil microorganisms are increasing over time, while those describing effects on soil fauna are fewer and their number remains constant. The largest number of papers originate from the United States, with the United States Department of Agriculture as the research institution with the largest output. The three authors with the largest number of publications are Stefan H. Doerr, Manuel Esteban Lucas-Borja and Jan Jacob Keizer. The research hotspots, as identified by keywords, are highly concentrated on wildfire, fire, organic matter, and biodiversity, amongst others. This study comprehensively analyzes the current situation of the research on the effects of wildland fire on changes in the soil environment and organisms, and provides reference for relevant scientific researchers in this trend and future research hotspots.

In this paper, we empirically examine the impact of venture capital investment on the dividend policy of the invested companies using a sample of list companies from China’s ChiNext market during the period 2014 to 2019. Our empirical results show that different types of VC investments have different impacts on the dividend policies of the invested companies. To be specific, we found independent venture capital companies (IVCs) promote the company’s dividend payment and increase the level of dividend payments while corporate venture capital (CVC) inhibits the company’s dividend payment. The joint participation of multiple types of venture capital investment (syndication) also increases the company’s dividend distribution. Our main contributions are two-fold. First, we provide a comprehensive analysis in the field of VC and dividend policy; second, we differentiate VC from the perspective of investment objectives and examine its different impacts on the dividend policies of the invested companies.

Abstract Background . Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear. Methods . Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG–producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro. Results . Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro. Conclusion . Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.

The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder treatment. However, the mechanisms by which DBS produces its therapeutic effects remain enigmatic. Here, we define a behavioral cutoff criterion to distinguish depressive-like behaviors and non-depressive-like behaviors in mice after morphine withdrawal. We identified a basolateral amygdala (BLA) to NAc D1 medium spiny neuron (MSN) pathway that controls depressive-like behaviors after morphine withdrawal. Furthermore, the paraventricular nucleus of thalamus (PVT) to NAc D2 MSN pathway controls naloxone-induced acute withdrawal symptoms. Optogenetically induced long-term potentiation with κ-opioid receptor (KOR) antagonism enhanced BLA to NAc D1 MSN signaling and also altered the excitation/inhibition balance of NAc D2 MSN signaling. We also verified that a new 50 Hz DBS protocol reversed morphine withdrawal–evoked abnormal plasticity in NAc. Importantly, this refined DBS treatment effectively alleviated naloxone-induced withdrawal symptoms and depressive-like behaviors and prevented stress-induced reinstatement. Taken together, the results demonstrated that input- and cell type–specific synaptic plasticity underlies morphine withdrawal, which may lead to novel targets for the treatment of opioid use disorder.

Specific emitter identification (SEI) is a powerful technique that identifies different emitters utilizing the features generated from hardware imperfections. The features, also known as radio frequency fingerprints (RFFs), can be extracted via model-based methods or data-based methods. In this paper, we analyze the identification accuracy of SEI system and provide criteria for evaluating different SEI schemes. We use in-phase/quadrature (I/Q) imbalance as an example to examine the identification performance by analyzing the Euclidean distance between radio frequency (RF) signals of different emitters. This derivation can also be generalized to different modulation schemes and distortion models.

Significant progress has been made in the functions of auxin efflux transporter PIN-FORMED (PIN) genes for the regulation of growth and development in rice. However, knowledge on the roles of OsPIN genes in abiotic stresses is limited. We previously reported that the mutation of OsPIN1b alters rice architecture and root gravitropism, while the role of OsPIN1b in the regulation of rice abiotic stress adaptations is still largely elusive. In the present study, two homozygous ospin1b mutants (C1b-1 and C1b-2) were employed to investigate the roles of OsPIN1b in regulating abiotic stress adaptations. Low temperature gradually suppressed OsPIN1b expression, while osmotic stress treatment firstly induced and then inhibited OsPIN1b expression. Most OsPIN genes and auxin biosynthesis key genes OsYUC were up-regulated in ospin1b leaves, implying that auxin homeostasis is probably disturbed in ospin1b mutants. The loss of function of OsPIN1b significantly decreased rice chilling tolerance, which was evidenced by decreased survival rate, increased death cells and ion leakage under chilling conditions. Compared with the wild-type (WT), ospin1b mutants accumulated more hydrogen peroxide (H2O2) and less superoxide anion radicals (O2−) after chilling treatment, indicating that reactive oxygen species (ROS) homeostasis is disrupted in ospin1b mutants. Consistently, C-repeat binding factor (CBF)/dehydration-responsive element binding factor (DREB) genes were downregulated in ospin1b mutants, implying that OsDREB genes are implicated in OsPIN1b-mediated chilling impairment. Additionally, the mutation of OsPIN1b led to decreased sensitivity to abscisic acid (ABA) treatment in seed germination, impaired drought tolerance in the seedlings and changed expression of ABA-associated genes in rice roots. Taken together, our investigations revealed that OsPIN1b is implicated in chilling and drought tolerance in rice and provide new insight for improving abiotic stress tolerance in rice.

Abstract Background Preterm birth is serious public health worldwide, and early prediction of preterm birth in pregnant women may provide assistance for timely intervention and reduction of preterm birth. This study aimed to develop a preterm birth prediction model that is readily available and convenient for clinical application. Methods Data used in this case-control study were extracted from the National Vital Statistics System (NVSS) database between 2018 and 2019. Univariate and multivariate logistic regression analyses were utilized to find factors associated with preterm birth. Odds ratio (OR) and 95% confidence interval (CI) were used as effect measures. The area under the curve (AUC), accuracy, sensitivity, and specificity were utilized as model performance evaluation metrics. Results Data from 3,006,989 pregnant women in 2019 and 3,039,922 pregnant women in 2018 were used for the model establishment and external validation, respectively. Of these 3,006,989 pregnant women, 324,700 (10.8%) had a preterm birth. Higher education level of pregnant women [bachelor (OR = 0.82; 95%CI, 0.81–0.84); master or above (OR = 0.82; 95%CI, 0.81–0.83)], pre-pregnancy overweight (OR = 0.96; 95%CI, 0.95–0.98) and obesity (OR = 0.94; 95%CI, 0.93–0.96), and prenatal care (OR = 0.48; 95%CI, 0.47–0.50) were associated with a reduced risk of preterm birth, while age ≥ 35 years (OR = 1.27; 95%CI, 1.26–1.29), black race (OR = 1.26; 95%CI, 1.23–1.29), pre-pregnancy underweight (OR = 1.26; 95%CI, 1.22–1.30), pregnancy smoking (OR = 1.27; 95%CI, 1.24–1.30), pre-pregnancy diabetes (OR = 2.08; 95%CI, 1.99–2.16), pre-pregnancy hypertension (OR = 2.22; 95%CI, 2.16–2.29), previous preterm birth (OR = 2.95; 95%CI, 2.88–3.01), and plurality (OR = 12.99; 95%CI, 12.73–13.24) were related to an increased risk of preterm birth. The AUC and accuracy of the prediction model in the testing set were 0.688 (95%CI, 0.686–0.689) and 0.762 (95%CI, 0.762–0.763), respectively. In addition, a nomogram based on information on pregnant women and their spouses was established to predict the risk of preterm birth in pregnant women. Conclusions The nomogram for predicting the risk of preterm birth in pregnant women had a good performance and the relevant predictors are readily available clinically, which may provide a simple tool for the prediction of preterm birth.

IntroductionWe explored latent classes of helicopter parenting among Korean and Chinese college students. In addition, we examined whether these latent classes of helicopter parenting are related to Korean and Chinese students’ game and social media addictive behaviors.MethodsA three-step latent class analysis was conducted using 452 students from six universities in South Korea and 372 students from four universities in China.Results and discussionWe identified four distinct helicopter parenting latent classes among the parents of Korean and Chinese students: weak, strong, academic management, and academic and schedule management. We also found that Korean students in the strong class reported significantly higher levels of game and social media addictive behaviors than those in the other three classes, but this did not hold for Chinese students. This finding indicates that the association between helicopter parenting and college students’ game and social media addictive behaviors can be differentiated within Asian cultural contexts.

N deposition is a key factor affecting the composition and function of soil microbial communities in wetland ecosystems. Previous studies mainly focused on the effects of N deposition in the soil during the growing season (summer and autumn). Here, we focused on the response of the soil microbial community structure and function in winter. Soil from the Sanjiang Plain wetland, China, that had been treated for the past 11 years by using artificial N deposition at three levels (no intervention in N0, N deposition with 4 g N m−2 yr−1 in N1, and with 8 g N m−2 yr−1 in N2). Soil characteristics were determined and the bacterial composition and function was characterized using high-throughput sequence technology. The N deposition significantly reduced the soil bacterial diversity detected in winter compared with the control N0, and it significantly changed the composition of the bacterial community. At the phylum level, the high N deposition (N2) increased the relative abundance of Acidobacteria and decreased that of Myxococcota and Gemmatimonadota compared with N0. In soil from N2, the relative abundance of the general Candidatus_Solibacter and Bryobacter was significantly increased compared with N0. Soil pH, soil organic carbon (SOC), and total nitrogen (TN) were the key factors affecting the soil bacterial diversity and composition in winter. Soil pH was correlated with soil carbon cycling, probably due to its significant correlation with aerobic_chemoheterotrophy. The results show that a long-term N deposition reduces soil nutrients in winter wetlands and decreases soil bacterial diversity, resulting in a negative impact on the Sanjiang plain wetland. This study contributes to a better understanding of the winter responses of soil microbial community composition and function to the N deposition in temperate wetland ecosystems.

Background: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. Methods: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1’s role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1’s regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. Results: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. Conclusions: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.

The tumor-adipose microenvironment (TAME) is a universal microecosystem, that is characterized by the dysfunction of lipid metabolism, such as excessive free fatty acids (FFAs). Macrophages are the most abundant immune cell type within TAME, although their diversity in the TAME is not clear. We first reveal that infiltration of M2-like macrophages in the TAME is associated with poor survival in breast cancer. To explore lipid-associated alterations in the TAME, we also detected the levels of FFAs transporters including fatty acid binding proteins (FABPs) and fatty acid transport protein 1 (FATP1). The results indicated that expression of fatty acid transporters in the TAME is tightly linked to the function of macrophages and predicts survival in breast cancer. To explore the impact of FFAs transporters on the function of macrophages, we performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Consequently, we identified a special subpopulation of macrophages defined as lipid-associated macrophages (LAMs), highly expressed macrophage markers (CD163, SPP1 and C1QC), genes involved in lipid metabolism (FABP3, FABP4, FABP5, LPL and LIPA) and some lipid receptors (LGALS3 and TREM2). Functionally, LAMs were characterized by a canonical functional signature of M2-like macrophages, lipid accumulation and enhancing phagocytosis, and they were mostly distributed in tumor-adipose junctional regions. Finally, the allograft cancer mouse models confirmed that LAMs depletion in the TAME synergizes the antitumorigenic effects of anti-PD1 therapy. In summary, we defined a novel subtype of macrophages in the TAME, that has unique features and clinical outcomes.

BackgroundGiven the rapid innovation of wearable technology, additional physical indicators can be detected, and blood pressure (BP) has become the focus of many emerging medical-device manufacturers. This study aimed to validate the accuracy of the newly developed HUAWEI WATCH in BP monitoring, according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO 81060-2:2018) guidelines.Materials and methodsThe same arm sequential BP measurement was applied. One validation included four reference BP measurements taken simultaneously by two independent observers using a mercury sphygmomanometer, alternating with three test-watch measurements. Each test-watch measurement was compared against the average of the previous and subsequent reference BP readings. Two criteria were required for validation: (1) a mean BP difference of 5 mm Hg or less, with a standard deviation (SD) of 8 mm Hg or less for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the 255 pairs of measurements, and (2) an SD for the of 85 averaged BP differences within the threshold defined by the mean test-reference BP difference listed in the ANSI/AAMI/ISO 81060-2:2018 guidelines.ResultsThe mean age of the 85 participants was 48 ± 18 years (range: 21–85), and 53 (62.4%) were male. The mean differences between the test and reference BPs were -0.25 ± 5.62 mm Hg and -1.33 ± 6.81 mm Hg for SBP and DBP, respectively (according to Criterion 1). The mean differences between the test BPs and reference BPs were -0.25 ± 5.00 mm Hg and -1.33 ± 6.31 mm Hg for SBP and DBP, respectively, according to Criterion 2.ConclusionBlood pressure measurement using the HUAWEI WATCH showed excellent consistency with reference BPs, and fulfilled both validation criteria of the guidelines, show its promise as a wearable device for BP self-monitoring.

ABSTRACT Baculovirus is a powerful tool for biological control in agriculture and foreign gene expression and delivery in insect and mammalian cells. Baculovirus enters host cells by multiple endocytic pathways; however, the current understanding of the Bombyx mori nucleopolyhedrovirus (BmNPV) entry mechanism remains limited. Previous studies have identified NPC1 and NPC2 as important host factors for viral infection in insect cells, although their exact role in viral infection has not yet been determined. In this study, we demonstrate that the BmNPC1 protein is an important intracellular factor for BmNPV escape from the endosomal compartment, and the expression of BmNPC1 in Sf9 cells confers the virus the ability to enter into the nucleus of Sf9 cells. Additionally, the second luminal domain of BmNPC1 (BmNPC1-C) binds to the viral glycoprotein gp64, and preincubation of BmNPV with purified BmNPC1-C inhibits virus infection. Furthermore, knockout of the BmNPC2 protein results in reduced efficiency of viral fusion with the endosomal membrane, and BmNPC2 protein interacts directly with both viral envelope glycoprotein gp64 and the host BmNPC1 protein. BmNPC2 was found to be incorporated into progeny viral particles. Taken together, our results suggest that NPC2 protein incorporated into viral particles may facilitate viral infection through promoting the interaction of BmNPV and NPC1 in the endosome, thus enhancing viral fusion and escape from endosomes. These results, combined with those from previous studies, support that BmNPV hijacks two important cholesterol receptor members (NPC1 and NCP2) in the cholesterol intracellular transport pathway for viral entry into host cells. IMPORTANCE Baculovirus is an important biological factor for controlling insect populations and represents a powerful biological tool for gene delivery and expression. However, the host receptor of baculovirus is still unknown. In this study, we demonstrate that BmNPC1 protein is an important intracellular factor for BmNPV escape from the endosomal compartment, and the expression of BmNPC1 confers the ability of virus to enter into the host cell nucleus in nonpermissive Sf9 cells. BmNPC2 can bind to the virus and promote progeny virion infection through the NPC1-NPC2 endosome cholesterol transport pathway. We believe that our study on the BmNPV entry mechanism will further facilitate the application of baculovirus systems in eukaryotic gene delivery. Not only can the cholesterol transport pathway NPC1 protein be used by a variety of enveloped viruses, but the NPC2 protein can also be used by viruses to infect host cells. This will provide new insights into the study of enveloped virus infection mechanisms.

Background Although hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, there is a lack of effective diagnostic measures. Circular RNAs (circRNAs) can be used as biomarkers for monitoring the occurrence and development of HCC. However, a convenient and reliable serum circRNA biomarker is not currently available. Materials & Methods CircRNA expression profiles were explored using high-throughput sequencing technology, and targeted circRNAs and mRNAs were validated by quantitative reverse transcription PCR (RT-qPCR). The biological functions of circRNAs were investigated using Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Downstream miRNAs and mRNAs of dysregulated circRNAs were predicted using TargetScan, miRanda, and miRDB; then circRNA-miRNA-mRNA interaction networks were constructed based on sequencing data and the Cancer Genome Atlas (TCGA). Results A total of 50,327 circRNAs were identified, with 1,187 circRNAs significantly differentially expressed between hepatitis B virus (HBV)-related HCC and HBV asymptomatic carriers. Among these circRNAs, four (circRNA1002, circRNA7941, circRNA 39338, and circRNA44142) were validated by RT-qPCR as being statistically different either in HCC tissue or serum samples. circRNA1002 was significantly down-regulated in both HCC serum and tissue, indicating its reliability. Bioinformatics analysis showed that circRNA1002-associated genes were enriched in GO terms relating to hormone pathway and cell-cell interaction processes, which are involved in the progression of HCC. Conclusion Our circRNA analysis of HCC patients and HBV asymptomatic carriers showed that circRNA1002 may be a reliable serum biomarker for HCC. These results could provide an improved assay for the early detection of HCC.

Schizophrenia (SZ) and obsessive-compulsive disorder (OCD) share several epidemiological and clinical features, but the neurobiological substrates shared by these two diseases remain unclear. This study aimed to explore the similarities and differences in brain function between them using near-infrared spectroscopy (NIRS). Eventually, 130 SZ patients, 70 OCD and 75 normal controls (NCs) were enrolled. A 52-channel NIRS instrument was used to detect the concentration changes in oxygenated hemoglobin ([oxy-Hb]) during the verbal fluency task. Ten regions of interests (ROIs) were defined: the bilateral dorsolateral prefrontal cortex (DLPFC), frontopolar cortex (FPC), orbitofrontal cortex (OFC), inferior prefrontal gyrus (IFG) and temporal gyrus (TG). Through two different analysis strategies based on channels or ROIs, we compared the [oxy-Hb] changes in three groups by one-way analysis of variance (ANOVA) and post-hoc tests. Across 52 channels, compared to the NC group, both SZ and OCD groups exhibited reduced activity in 17 channels, including left FPC, left DLPFC, bilateral OFC, IFG, middle TG, supplementary motor cortex and Broca’s area, while SZ showed lower activity in channel 35 (right OFC) than OCD patients. Across all ROIs, compared to the NC group, both SZ and OCD groups showed reduced activity in 7 ROIs, including left FPC, bilateral OFC, IFG and TG, while SZ showed lower activity in the right OFC than OCD group, which were almost consistent with the results based on channels. This study suggests SZ and OCD present with some similar neuropathological changes, while SZ shows more severe impairment in the right OFC than OCD.

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene, which is mainly involved in the repair of DNA damage, cell cycle regulation, maintenance of genome stability, and other important physiological processes. Mutations or defects in the BRCA1 gene significantly increase the risk of breast, ovarian, prostate, and other cancers in carriers. In this review, we summarized the molecular functions and regulation of BRCA1 and discussed recent insights into the detection and treatment of BRCA1 mutated breast cancer.

Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.

Cardiac ischemia–reperfusion (I/R) injury represents a key threat to human health. This study reveals that the long noncoding RNA lncRNA-CIRBIL is protective against I/R injury by inhibiting the nuclear translocation of Bclaf1.

In this study, the influence mechanism of rare earth elements Ce and Nd on the corrosion behavior of Mg alloy was studied by combining experimental characterization with the first-principles calculation. The changes of work function and surface energy of the rare Earth phase and matrix phase in binary rare Earth Mg alloys Mg-0.3%Ce and Mg-0.3%Nd. In addition, the electronic properties of the second rare Earth phase and matrix phase, and the correlation between the interface energy of the second rare Earth phase and matrix and the corrosion behavior of Mg alloys were investigated. The experimental results show that Mg _12 Ce and Mg _12 Nd as the second phases of Mg-0.3%Ce and Mg-0.3%Nd, respectively, have not obvious roles in the galvanic corrosion of the alloys. The corrosion morphology of the two alloys is similar, the matrix undergoes filamentary corrosion through the grain to a large area. The results of the first-principles calculation show that the binding energy of the rare Earth phase is higher than that of the matrix phase, this implied the addition of light rare Earth elements Ce and Nd can improve the stability of the second phase. The work function of different surfaces of the second phase is similar to that of the matrix phase, so limited effect of the rare Earth phase on corrosion behavior has been found. In addition, the addition of rare Earth Ce and Nd will decrease the surface stability of Mg matrix, this result reaffirms the higher corrosion rates of Mg-0.3%Ce and Mg-0.3%Nd over that of the pure Mg.

ABSTRACT The mechanisms of persistent central nervous system (CNS) inflammation in people with HIV (PWH) despite effective antiretroviral therapy (ART) are not fully understood. We have recently shown that plasma anti-CD4 IgGs contribute to poor CD4+ T cell recovery during suppressive ART via antibody-mediated cytotoxicity (ADCC) against CD4+ T cells, and that plasma anti-CD4 IgG levels are associated with worse cognitive performance and specific brain area atrophy. However, the role of anti-CD4 IgGs in neuroinflammation remains unclear. In the current study, plasma and cerebrospinal fluid (CSF) samples from 31 ART-naive and 26 treated, virologically suppressed PWH, along with 16 HIV-seronegative controls, were evaluated for CSF levels of anti-CD4 IgG, white blood cell (WBC) counts, soluble biomarkers of neuroinflammation, and neurofilament light chain (NfL). We found that 37% of the PWH exhibited elevated CSF anti-CD4 IgG levels, but few or none of the PWH were observed with elevated CSF anti-CD4 IgM, anti-CD8 IgG, or anti-double-strand DNA IgG. CSF anti-CD4 IgG levels in PWH were directly correlated with neuroinflammation (WBC counts, neopterin, and markers of myeloid cell activation), but not with CSF NfL levels. Using cells from one immune nonresponder to ART, we generated a pathogenic anti-CD4 monoclonal IgG (JF19) presenting with ADCC activity; JF19 induced the production of soluble CD14 (sCD14) and interleukin-8 (IL-8) in human primary monocyte-derived macrophages via CD4 binding in vitro. This study demonstrates for the first time that elevated CSF anti-CD4 IgG levels present in a subgroup of PWH which may play a role in neuroinflammation in HIV. IMPORTANCE This study reports that an autoantibody presents in the CNS of HIV patients and that its levels in the CSF correlate with some markers of neuroinflammation.

Fuzzy logical control is a robust and effective control method in industrial fields, which renders it applicable to the attitude control of a solar sail. However, it is hard to apply in black-box and time-varying problem as real solar sail attitude control. Considering the lack of a priori knowledge and the unacceptable manual workload in the design of the fuzzy logical controller (FLC), an intelligent FLC designer (IFLCD) is developed by introducing neural network modelling and automatic design method. Besides, IFLCD also supports self-adaption for better control accuracy. By applying the proposed IFLCD in the attitude stabilization of a solar sail with individually controllable elements (SSICE), an effective solution of unmanned, time-varying, and complex system control method is offered without any mathematical model, which also overcomes the difficulties in FLC design Considering the performance degradation, accident, and distance problems faced by spacecraft, IFLCD can help with more practical problems that are hard be solved by traditional control theory.

Background: Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Methods: In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. Findings: We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased β-amyloid 42 protein production in the mouse brains. Interpretation: This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.

Abstract Background Hepatitis B virus (HBV) remains a major cause of chronic hepatitis and hepatocellular carcinoma, and miRNAs play important roles in HBV pathogenesis. Our previous study has shown that miR-328-3p is upregulated in HBV-infected patients and serves as a potent predictor for the prognosis of HBV-related liver failure. Methods Here, the role of miR-328-3p in modulating cell injury in HBV-infected liver cells THLE-2 was investigated in detail. MiR-328-3p expression was examined using qRT-PCR. The levels of pro-inflammatory cytokines were measured using ELISA. HBV RNA and HBV DNA levels were quantified. The interactions between STAT3 and miR-328-3p promoter as well as miR-328-3p and FOXO4 were analyzed using chromatin immunoprecipitation (CHIP) assay and luciferase reporter assay, respectively. THLE-2 cell injury was evaluated by examining cell viability and apoptosis. Results HBV promoted expression of miR-328-3p through the STAT3 signal pathway and that increasingly expressed miR-328-3p downregulated its target FOXO4, leading to the promotion of cell injury in HBV-infected liver cells THLE-2. Conclusion These data demonstrate that HBV-STAT3-miR-328-3p-FOXO4 regulation pathway may play an important role in the pathogenesis of HBV infection.

The transient of the DFIG engages a lot of non-smooth elements such as switches of controllers and saturation of limiters, thus, the simplified non-smooth model of DFIG for electromechanical transient analysis is needed. This paper proposes a non-smooth simplified model of DFIG for electromechanical transient analysis, with the viewpoint of the transient response and energy accumulation. First, the general non-smooth dynamic behavior of DFIG during fault-on and post-fault periods are presented and the model is divided into four smooth stages. Then, the detailed model for the transient stage, according to without/with the trigger of the crowbar is presented. Furthermore, the simplified model of DFIG in the steady state is introduced according to without/with the trigger of the crowbar and saturation of limiters, determined by the stator voltage. Moreover, the transient model with/without the crowbar protection are simplified according to the principle of constant energy accumulation. Thus, the overall non-smooth simplified models of DFIG is obtained. Finally, the effectiveness of the proposed non-smooth simplified model is verified with the simulations.

The genomic signature of dog domestication reveals adaptation to a starch-rich diet compared with their ancestor wolves. Diet is a key element to shape gut microbial populations in a direct way as well as through coevolution with the host. We investigated the dynamics in the gut microbiota of dogs when shifting from a starch-rich, processed kibble diet to a nature-like raw meat diet, using wolves as a wild reference. Six healthy wolves from a local zoo and six healthy American Staffordshire Terriers were included. Dogs were fed the same commercial kibble diet for at least 3 months before sampling at day 0 (DC), and then switched to a raw meat diet (the same diet as the wolves) for 28 days. Samples from the dogs were collected at day 1 (DR1), week 1 (DR7), 2 (DR14), 3 (DR21), and 4 (DR28). The data showed that the microbial population of dogs switched from kibble diet to raw diet shifts the gut microbiota closer to that of wolves, yet still showing distinct differences. At phylum level, raw meat consumption increased the relative abundance of Fusobacteria and Bacteroidetes at DR1, DR7, DR14, and DR21 (q < 0.05) compared with DC, whereas no differences in these two phyla were observed between DC and DR28. At genus level, Faecalibacterium, Catenibacterium, Allisonella, and Megamonas were significantly lower in dogs consuming the raw diet from the first week onward and in wolves compared with dogs on the kibble diet. Linear discriminant analysis effect size (LEfSe) showed a higher abundance of Stenotrophomonas, Faecalibacterium, Megamonas, and Lactobacillus in dogs fed kibble diet compared with dogs fed raw diet for 28 days and wolves. In addition, wolves had greater unidentified Lachnospiraceae compared with dogs irrespective of the diets. These results suggested that carbohydrate-fermenting bacteria give way to protein fermenters when the diet is shifted from kibble to raw diet. In conclusion, some microbial phyla, families, and genera in dogs showed only temporary change upon dietary shift, whereas some microbial groups moved toward the microbial profile of wolves. These findings open the discussion on the extent of coevolution of the core microbiota of dogs throughout domestication.

Numerous genes involved in male reproduction regulate testis development and spermatogenesis. In this study, the testis tissue transcriptome was used to identify candidate genes and key pathways associated with fecundity in sheep. Histological analysis of testis tissue using hematoxylin–eosin (HE) routine staining was performed for two sheep breeds. Overall, 466 differentially expressed genes (DEGs) were identified between Hu sheep (HS) and Tibetan sheep (TS) through RNA sequencing technology (RNA-Seq), including 226 upregulated and 240 downregulated genes. Functional analysis showed that several terms and pathways, such as “protein digestion and absorption”, “cAMP signaling pathway”, “focal adhesion”, and “p53 signaling pathway” were closely related to testis development and spermatogenesis. Several genes (including COL1A1, COL1A2, COL3A1, SOX9, BCL2, HDC, and GGT5) were significantly enriched in these terms and pathways and might affect the reproduction of sheep by regulating the migration of spermatogenic cells, apoptosis of spermatogenic cells, and secretion of sterol hormones via testicular interstitial cells. Our results provide a theoretical basis for better understanding the molecular mechanisms of reproduction in sheep.

Background: Alternative polyadenylation (APA) events may be modulated by single nucleotide polymorphisms (SNPs). Therefore, this study aims to evaluate the association between APA quantitative trait loci (apaQTLs)-related SNPs (apaQTL-SNPs) and non-small-cell lung cancer (NSCLC) risk. Methods: APA-related genes associated with NSCLC (LUAD and LUSC) were first identified, and the respective apaQTL-SNPs of those genes were selected. Then, a two-phase case-control study was performed to evaluate the association between candidate apaQTL-SNPs and NSCLC risk. Results: A total of 7 LUAD- and 21 LUSC-associated apaQTL-SNPs were selected. In the first phase, the apaQTL-SNP rs10138506 was significantly associated with LUAD risk (p < 0.05), whereas the other two apaQTL-SNPs (rs1130698 and rs1130719) were significantly associated with LUSC risk (p < 0.05). In the second phase, the variant G allele of rs10138506 was still significantly associated with an increased risk of LUAD (OR = 1.42, 95%CI = 1.02–1.98, p = 0.038). Functional annotation indicated that the variant G allele of rs10138506 was significantly associated with a higher PDUI value of CHURC1. Meanwhile, 3′RACE experiments verified the presence of two poly(A) sites (proximal and distal) in CHURC1, while qRT-PCR results indicated that different genotypes of rs1127968 which, in perfect LD with rs10138506, can mediate changes in the lengths of the 3′UTR of CHURC1 isoforms. Conclusion: The variant G allele of rs10138506 in CHURC1 was correlated with a longer 3′UTR of CHURC1 mRNA and an increased LUAD risk. Further studies should evaluate the interaction between rs10138506 and different 3′UTR lengths of CHURC1 that regulate LUAD development.

Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity.

With the interconnection of large-scale wind power, the sub-synchronous oscillation (SSO) which is mainly analyzed by the local small-signal method occurs in many power grids. This paper presents the phenomenon of the sub-synchronous band oscillation (SSBO) of the doubly-fed induction generator (DFIG) system due to limits, which belongs to global dynamics, and analyzes its relationship with certain limits from the viewpoint of non-smooth bifurcation, which can serve as one of the mathematical foundations of the SSBO. Specifically, the concept of non-smooth bifurcation, a power system interconnected with the DFIG and the related current limit (CL) of d-axis and q-axis in the outer power control loop (OPCL) of the DFIG's rotor side converter (RSC) are introduced first. Secondly, the SSBO phenomenon induced by the CL of d-axis and q-axis is presented. And then, the influence of one parameter on the SSBO is analyzed, such as the short circuit capacity, the fault grounding resistance and the PI parameters of the OPCL, which reveals the non-smooth bifurcation with respect to relative one parameter. Finally, on the plane, the non-smooth bifurcation characteristics of PI controller parameters in the OPCL are given, showing that the non-smooth bifurcation/SSBO may be associated with saturation of different limits.

Depression is a common affective disorder characterized by significant and persistent low mood. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to have a rapid and durable antidepressant effect, but the mechanisms are unclear. Protein phosphorylation is a post-translational modification that plays a crucial role in cell signaling. Thus, we present a phosphoproteomics approach to investigate the mechanisms underlying stress-induced depression and the rapid antidepressant effect of ketamine in mice. We analyzed the phosphoprotein changes induced by chronic unpredictable mild stress (CUMS) and ketamine treatment in two known mood control centers, the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). We initially obtained >8,000 phosphorylation sites. Quantitation revealed 3,988 sites from the mPFC and 3,196 sites from the NAc. Further analysis revealed that changes in synaptic transmission-related signaling are a common feature. Notably, CUMS-induced changes were reversed by ketamine treatment, as shown by the analysis of commonly altered sites. Ketamine also induced specific changes, such as alterations in synapse organization, synaptic transmission, and enzyme binding. Collectively, our findings establish a signaling framework for stress-induced depression and the rapid antidepressant effect of ketamine.

Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.

Increasing evidence supports the significance of long non-coding RNA in cancer development. Several recent studies suggest the oncogenic activity of long non-coding RNA metastasis–associated lung adenocarcinoma transcript 1 (MALAT1) in hepatocellular carcinoma. In this study, we explored the molecular mechanisms by which MALAT1 modulates hepatocellular carcinoma biological behaviors. We found that microRNA-204 was significantly downregulated in sh-MALAT1 HepG2 cell and 15 hepatocellular carcinoma tissues by quantitative real-time polymerase chain reaction analysis. Through bioinformatic screening, luciferase reporter assay, RNA-binding protein immunoprecipitation, and RNA pull-down assay, we identified microRNA-204 as a potential interacting partner for MALAT1. Functionally, wound-healing and transwell assays revealed that microRNA-204 significantly inhibited the migration and invasion of hepatocellular carcinoma cells. Notably, sirtuin 1 was recognized as a direct downstream target of microRNA-204 in HepG2 cells. Moreover, si-SIRT1 significantly inhibited cell invasion and migration process. These data elucidated, by sponging and competitive binding to microRNA-204, MALAT1 releases the suppression on sirtuin 1, which in turn promotes hepatocellular carcinoma migration and invasion. This study reveals a novel mechanism by which MALAT1 stimulates hepatocellular carcinoma progression and justifies targeting metastasis–associated lung adenocarcinoma transcript 1 as a potential therapy for hepatocellular carcinoma.

Hepatitis B virus X protein (HBx) is recognized as an oncogene in hepatocellular carcinoma (HCC). HBx regulates microRNA expression, including down-regulating miR-338-3p in LO2 cells. Here, we investigated miR-338-3p function in HBx-mediated hepatocarcinogenesis. In 23 HBV-infected HCC clinical patient tumor and adjacent non-tumor control tissues, 17 and 19 tumors expressed HBx mRNA and protein, respectively. When considered as a group, HBV-infected HCC tumors had lower miR-338-3p expression than controls; however, miR-338-3p was only significantly down-regulated in HBx-positive tumors, indicating that HBx inversely correlated with miR-338-3p. Functional characterization of miR-338-3p indicated that miR-338-3p mimics inhibited cell proliferation by inducing cell cycle arrest at the G1/S phase as assessed by EdU and cell cycle assays in HBx-expressing LO2 cells. CyclinD1, containing two putative miR-338-3p targets, was confirmed as a direct target using 3′-UTR luciferase reporter assays from cells transfected with mutated binding sites. Mutating the 2397–2403 nt binding site conferred the greatest resistance to miR-338-3p suppression of CyclinD1, indicating that miR-338-3p suppresses CyclinD1 at this site. Overall, this study demonstrates that miR-338-3p inhibits proliferation by regulating CyclinD1, and HBx down-regulates miR-338-3p in HCC. This newly identified miR-338-3p/CyclinD1 interaction provides novel insights into HBx-mediated hepatocarcinogenesis and may facilitate therapeutic development against HCC.

Hepatitis B Virus (HBV) DNA integration and HBV X (HBx) deletion mutation occurs in HBV-positive liver cancer patients, and C-terminal deletion in HBx gene mutants are highly associated with hepatocarcinogenesis. Our previous study found that the HBx-d382 deletion mutant (deleted at nt 382-400) can down-regulate miR-338-3p expression in HBx-expressing cells. The aim of the present study is to examine the role of miR-338-3p in the HBx-d382-mediated liver-cell proliferation.We established HBx-expressing LO2 cells by Lipofectamine 2000 transfection. A miR-338-3p mimics or inhibitor was transfected into LO2/HBx-d382 and LO2/HBx cells using miR-NC as a control miRNA. In silico analysis of potential miR-338-3p targets revealed that miR-338-3p could target the cell cycle regulatory protein CyclinD1. To confirm that CyclinD1 is negatively regulated by miR-338-3p, we constructed luciferase reporters with wild-type and mutated CyclinD1-3'UTR target sites for miR-338-3p binding. We examined the CyclinD1 expression by real-time PCR and western blot, and proliferation activity by flow cytometric cell cycle analysis, Edu incorporation, and soft agar colony.HBx-d382 exhibited enhanced proliferation and CyclinD1 expression in LO2 cells. miR-338-3p expression inhibited cell proliferation in LO2/HBx-d382 cells (and LO2/HBx cells), and also negatively regulated CyclinD1 protein expression. Of the two putative miR-338-3p binding sites in the CyclinD1-3'UTR region, the effect of miR-338-3p on the second binding site (nt 2397-2403) was required for the inhibition.miR-338-3p can directly regulate CyclinD1 expression through binding to the CyclinD1-3'UTR region, mainly at nt 2397-2403. Down-regulation of miR-338-3p expression is required for liver cell proliferation in both LO2/HBx and LO2/HBx-d382 mutant cells, although the effect is more pronounced in LO2/HBx-d382 cells. Our study elucidated a novel mechanism, from a new miRNA-regulation perspective, underlying the propensity of HBx deletion mutants to induce hepatocarcinogenesis at a faster rate than HBx.