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Aspergillus fumigatus, a prevalent saprophytic fungus in the atmosphere, is known to rapidly induce severe invasive aspergillosis (IA) upon inhalation of its conidia by humans or animals. The mortality rate associated with IA exceeds 50%. The misuse of antifungal agents has contributed to the emergence of numerous highly pathogenic drug-resistant strains of A. fumigatus. Our study found that the combination of domiphen and itraconazole had sound synergistic antimicrobial effects against wild-type and itraconazole-resistant A. fumigatus in vivo and in vitro through MIC, FIC, plate inoculation, growth curve experiments, and Galleria mellonella infection model. Drug cytotoxicity and pharmacological tests for acute toxicity assays demonstrated that both itraconazole and domiphen showed minimal cytotoxicity and good biocompatibility. The transcriptome sequencing experiment demonstrated that domiphen exerted a suppressive effect on the expression of various genes, including those involved in drug efflux, redox regulation, and cellular membrane and cell wall remodeling. The present investigation explores the synergistic antimicrobial mechanisms of domiphen and itraconazole, encompassing three key aspects: (i) domiphen inhibited the efflux of itraconazole by reducing the expression of drug efflux-related genes, (ii) the combination has good ability to disrupt the cell membrane and cell wall, (iii) the combination also can remove biofilm more effectively. In summary, the utilization of domiphen as a synergist of itraconazole exhibited disruptive effects on the biofilm, cell wall, and cell membrane of A. fumigatus. This subsequently led to a modified distribution of itraconazole within the fungal organism, ultimately resulting in enhanced antifungal efficacy. The results of this study may provide a new therapeutic strategy for the treatment of IA caused by drug-resistant A. fumigatus.

Aim: Pay-as-you-throw (PAYT) is a recognized waste-charging method commonly used in developed countries to reduce waste effectively and improve resource utilization efficiency. China is currently transitioning from a traditional fixed-fee model to a PAYT model.Method: In this study, a sample of 1,346 urban residents in China is analyzed empirically to investigate their willingness to accept this change and the waste fees they are willing to pay for it.Results: The results indicate that, 1) at present, the proportion of urban residents willing to accept the PAYT charging model is low, accounting for only 54.53%. 2) The average annual cost for residents’ households willing to pay for PAYT is 58.616 RMB, which is relatively low. 3) The main reasons for the residents’ low acceptance of PAYT are behavioral attitudes, social norms, and perceived behavioral control factors. 4) Income and education levels mainly explain the low level of expenses paid by residents.Conclusion: Therefore, we suggest that, in the short term, publicity and education should be used to encourage residents to establish a correct environmental concept and a sense of environmental governance ownership, increase their knowledge of waste recycling and disposal and their awareness of waste charging rules, and thus improve their willingness to accept the PAYT charging model. In the long term, the PAYT charging model should be compatible with the levels of economic development and family education, and residents’ waste charges for PAYT should increase steadily.

Human activities and climate change have significantly impacted the quantity and sustainable utilization of medicinal plants. Gentiana manshurica Kitagawa, a high-quality original species of Gentianae Radix et Rhizoma, has significant medicinal value. However, wild resources have experienced a sharp decline due to human excavation, habitat destruction, and other factors. Consequently, it has been classified as an Endangered (EN) species on the IUCN Red List and is considered a third-level national key-protected medicinal material in China. The effects of climate change on G. manshurica are not yet known in the context of the severe negative impacts of climate change on most species. In this study, an optimized MaxEnt model was used to predict the current and future potential distribution of G. manshurica. In addition, land use data in 1980, 2000, and 2020 were used to calculate habitat quality by InVEST model and landscape fragmentation by the Fragstats model. Finally, using the above-calculated results, the priority protection areas and wild tending areas of G. manshurica were planned in ZONATION software. The results show that the suitable area is mainly distributed in the central part of the Songnen Plain. Bio15, bio03, bio01, and clay content are the environmental variables affecting the distribution. In general, the future potential distribution is expected to show an increasing trend. However, the species is expected to become threatened as carbon emission scenarios and years increase gradually. At worst, the high suitability area is expected to disappear completely under SSP585-2090s. Combined with the t-test, this could be due to pressure from bio01. The migration trends of climate niche centroid are inconsistent and do not all move to higher latitudes under different carbon emission scenarios. Over the past 40 years, habitat quality in the current potential distribution has declined yearly, and natural habitat has gradually fragmented. Existing reserves protect only 9.52% of G. manshurica’s priority conservation area. To avoid extinction risk and increase the practicality of the results, we clarified the hotspot counties of priority protection area gaps and wild tending areas. These results can provide an essential reference and decision basis for effectively protecting G. manshurica under climate change.

Carbapenem-resistant Klebsiella pneumoniae (CRKP), particularly those with high virulence, cause invasive disease in clinical settings. An epidemiological investigation was conducted on the evolution, virulence, and antimicrobial resistance of CRKP isolates in two tertiary teaching hospitals in Jiangsu, China from November 2020 to December 2021. There were 31 different CRKP strains discovered. We performed whole genome sequencing (WGS) on 13 SHV, cmlv, and FosA6-producing CRKP to reveal molecular characteristics. Five ST15/ST11 isolates had CRISPR-Cas systems. By conjugation tests, KPC-2 can be transmitted horizontally to E. coil. A conjugative pHN7A8-related multi-resistance plasmid (KPC-2, blaCTX-M-65, blaTEM-1, fosA3, catII, and rmtB) was first discovered in CRKP clinical isolates. Using bacteriological testing, a serum killing assay, and an infection model with Galleria mellonella, three ST11-K64 KPC-2 generating carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) were identified. These strains harbored a virulent plasmid and an IncFII-family pKPC/pHN7A8 conjugative plasmid, which led to hypervirulence and resistance. One of these CR-hvKPs, which co-harbored KPC-2, NDM-6, SHV-182, SHV-64, and blaCTX-M-122 genes, was first discovered. Importantly, this CR-hvKP strain also produced biofilm and had non-inferior fitness. The widespread use of ceftazidime/avibactam might provide this CR-hvKP with a selective advantage; hence, immediate action is required to stop its dissemination. Another important finding is the novel ST6136 in K. pneumoniae. Finally, the sterilization efficiency rates of Fe2C nanoparticles in CRKP were more than 98%. Furthermore, our novel antibacterial Fe2C nanoparticles may also provide a therapeutic strategy for infections.

Soybean is an important grain and oil crop cultivated worldwide. Mepiquat chloride (DPC), a plant growth regulator, is widely used in cotton planting; however, its application in soybean remains rarely studied. Herein, we explored DPC regulation in soybeans using morphology, physiology, and proteomics analyses. Morphological and physiological analyses showed that DPC significantly reduced the plant height and shoot dry weight, promoted the growth of lateral roots in a specific concentration range, increased the activities of the leaf protective enzymes (superoxide dismutase and catalase), and decreased and increased malondialdehyde and total flavonoid contents, respectively. Proteomic analysis of leaves treated with 100 mg/L DPC revealed that multiple proteins related to plant growth and stress resistance were regulated after treatment. The key proteins involved in photosynthesis and cell wall elongation in the two varieties of soybean were significantly downregulated and those related to promoting lateral root growth and stress resistance were significantly upregulated. Overall, DPC inhibited shoot growth and photosynthesis in soybean but promoted lateral root growth, enhanced protective enzyme activity, and improved the ability of plants to resist abiotic stress. This study preliminarily determined the suitable DPC concentration for soybean spraying and provided a theoretical basis for its rational application.

IntroductionSoybean is the world’s most important cultivated crop, and drought can affect their growth and, eventually, yields. Foliar application of mepiquat chloride (MC) can potentially alleviate the damage caused by drought stress in plants; however, the mechanism of MC regulation of soybean drought response has not been studied.MethodsThis study investigated the mechanism of soybean drought response regulation by mepiquat chloride in two varieties of soybean, sensitive Heinong 65 (HN65) and drought-tolerant Heinong44 (HN44), under three treatment scenarios, normal, drought stress, and drought stress + MC conditions.Results and discussionMC promoted dry matter accumulation under drought stress, reduced plant height, decreased antioxidant enzyme activity, and significantly decreased malondialdehyde content. The light capture processes, photosystems I and II, were inhibited; however, accumulation and upregulation of several amino acids and flavonoids by MC was observed. Multi-omics joint analysis indicated 2-oxocarboxylic acid metabolism and isoflavone biosynthetic pathways to be the core pathways by which MC regulated soybean drought response. Candidate genes such as LOC100816177, SOMT-2, LOC100784120, LOC100797504, LOC100794610, and LOC100819853 were identified to be crucial for the drought resistance of soybeans. Finally, a model was constructed to systematically describe the regulatory mechanism of MC application in soybean under drought stress. This study fills the research gap of MC in the field of soybean resistance.

BackgroundNitrous oxide (N2O) is an increasingly popular recreational drug. N2O irreversibly disturbs the metabolism of vitamin B12, resulting in a functional deficiency. Vitamin B12 is vital for myelin synthesis and its deficiency primarily produces neurological complications. Inhaling N2O is more common and neurological complications are more evident than before.Case presentationWe report a young man who developed progressive limb numbness and unsteady walking after N2O abuse. The dominant diagnosis was subacute combined degeneration of the spinal cord (SCD). The patient was admitted to the hospital and given adenosylcobalamin treatment, but his symptoms progressed significantly from before and he developed acute cognitive impairment. After methylprednisolone combined with vitamin B12 treatment, symptoms significantly improved.ConclusionClinicians need to understand the presentation and treatment of SCD caused by N2O abuse. When symptoms progress despite conventional vitamin B12 therapy, the combination of methylprednisolone and vitamin B12 may be considered.

BackgroundPostherpetic neuralgia (PHN) is a common, complex, and refractory type of neuropathic pain. Several systematic reviews support the efficacy of acupuncture and related treatments for PHN. Nevertheless, the efficacy of various acupuncture-related treatments for PHN remains debatable.ObjectiveWe aimed to assess the efficacy and safety of acupuncture-related treatments for PHN, identify the most effective acupuncture-related treatments, and expound on the current inadequacies and prospects in the applications of acupuncture-related therapies.MethodsWe searched PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Google Scholar, four Chinese databases (China National Knowledge Infrastructure, China Biomedical, Chongqing VIP, and Wan Fang databases), clinical research registration platform (World Health Organization International Clinical Trial Registration platform, China Clinical Trial Registration Center) for relevant studies. We also examined previous meta-analyses; gray literature; and reference lists of the selected studies. We then evaluated the risk of bias in the included studies and performed a Bayesian multiple network meta-analysis.ResultsWe included 29 randomized controlled trials comprising 1,973 patients, of which five studies showed a high risk of bias. The pairwise meta-analysis results revealed that the efficacy of all acupuncture-related treatments for pain relief related to PHN was significantly better than antiepileptics. The network meta-analysis results showed that pricking and cupping plus antiepileptics were the most effective treatment, followed by electroacupuncture (EA) plus antiepileptics for pain relief in patients with PHN. EA plus antiepileptics ranked the best regarding reduced Pittsburgh Sleep Quality Index (PSQI) and Self-Rating Depression Scale (SDS) scores in patients with PHN. No results were found regarding the total response rate or quality of life in this study. Acupuncture-related treatments showed a lower incidence of adverse events than that of antiepileptics.ConclusionAcupuncture-related therapies are potential treatment options for PHN and are safe. Pricking and cupping plus antiepileptics, are the most effective acupuncture-related techniques for pain relief, while EA plus antiepileptics is the best acupuncture-related technique for improving PHN-related insomnia and depression symptoms. However, owing to the limitations of this study, these conclusions should be cautiously interpreted, and future high-quality studies are needed.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021226422, identifier CRD42021226422.

Colletotrichum fructicola is a pathogenic fungus causing leaf black spot and fruit rot disease in a wide variety of crops. Some mycoviruses that cause detrimental effects on fungal hosts could be useful in studying the pathogenesis of fungal hosts. In this study, we reported two mycoviruses, Colletotrichum fructicola ourmia-like virus 1- Colletotrichum gloeosporioides ourmia-like virus 1 (CfOLV1-CgOLV1) and Colletotrichum fructicola ourmia-like virus 2 (CfOLV2), from a C. fructicola fungus. The complete genome sequences of CfOLV1-CgOLV1 and CfOLV2 contain 2,516 bp and 2,048 bp, respectively. Both of these viruses contain only one open reading frame (ORF), which encodes an RNA-dependent RNA polymerase (RdRp). CfOLV1-CgOLV1 was identical as the previously reported virus CgOLV1. Phylogenetic analysis showed that CfOLV2 is closely related to Scleroulivirus and Magoulivirus in the family Botourmiaviridae. Virus elimination and horizontal transmission experiments proved that the associated mycoviruses could reduce the pathogenicity of the host C. fructicola. In addition, we found that the virus-containing strains showed a much higher percentage of appressorium formation and more melanin production compared to isogenic virus-free strain, and the presence of the virus is detrimental to the growth of host fungi and regulates the integrity of the cell wall. Transcriptomic analysis showed that mycovirus infection caused various abnormal genes expression in C. fructicola. To the best of our knowledge, this is the first report of a hypovirulence-associated ourmia-like mycovirus in C. fructicola.

BackgroundThe neurobiological basis of suicidal behaviors among female adolescents with major depressive disorder (MDD) remains largely unclear.Materials and methodsFifty-eight drug-naïve, first-episode female adolescent MDD [including 31 patients with suicidal attempt (SA group) and 27 patients without SA (non-SA group)], and 36 matched healthy controls (HCs) participated in the present study. Resting-state functional magnetic resonance imaging (MRI) was performed on each subject. The metrics of the amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) were compared among the three groups. Then seed-based functional connectivity (FC) was conducted based on the ALFF/fALFF and ReHo results, which were then correlated to clinical variables.ResultsCompared with the non-SA group, the SA group exhibited increased fALFF in the bilateral insula and right precentral gyrus, and enhanced ReHo in the left superior temporal gyrus, left middle cingulate cortex, right insula, and right precentral gyrus. Relative to the HCs, the SA group demonstrated additionally reduced fALFF and ReHo in the left middle frontal gyrus. Moreover, the SA group showed increased FC between the right precentral gyrus and the left middle frontal gyrus and left insula, and between the right insula and anterior/middle cingulate cortex compared to the non-SA and HC groups. In addition, the fALFF in the left middle frontal gyrus was positively correlated with the 17-item Hamilton Depression Rating Scale scores, and the values in the fALFF/ReHo in the right insula were positively correlated with the duration of MDD within the patient group.ConclusionThese findings highlight the multiple abnormalities of the frontolimbic circuit, which may enhance our understanding of the neurobiological basis underlying female MDD with SA during adolescence.

Background and objectivesHematopoietic stem cell transplantation (HCT) is a treatment for hematopoietic diseases. However, most cured female patients may suffer from premature ovarian insufficiency (POI) after HCT, which is mainly caused by the pre-HCT conditioning regimen. Hence, this study aims to explore the impact of HCT treatment on reproductive and ovarian functions in female survivors.MethodsA total of 55 female participants under the age of 40, who underwent HCT and met the inclusion criteria were enrolled. Data related to blood disease, menstruation, and fertility in the 3 years following HCT were collected.ResultsThe involved patients received transplantation at different age stages, ranging from 8 to 37. All patients, except those with aplastic anemia (AA; 5/55), received a myeloablative conditioning regimen, usually modified total body irradiation/cyclophosphamide (TBI/Cy; 25/55) or modified Busulfan/cyclophosphamide (Bu/Cy; 23/55). Among women (42/55) who menstruated before HCT, 16.67% (7/42) had a spontaneous menstrual relapse and 83.3% (35/42) had amenorrhea after HCT. 72.7% (40/55) could be regarded as having POI. This proportion included 100% (25/25) of women aged 21–40 at the time of HCT, 62.5% (15/24) of those aged 11–20, and 0% (0/6) of those ≤10 years old. Patients with AML were more likely to have POI (95.7%). Patients aged ≤10 years (0%) or 11–20 years (16.7%) at the time of HCT were less likely to have moderate to severe menopause than those 21–40 years old (44%).ConclusionThe prevalence of POI following HCT was high and POI was associated with age, conditioning regimen, and type of blood disease.

Although it is generally very difficult to supplement flow energy into the tight oil reservoir, there is still good prospect for enhanced oil and gas recovery in this area due to its large proportion of hydrocarbon reserves. However, due to the sensitivity of tight oil reservoir to formation pressure, the porosity and permeability of the reservoir will change greatly with the change of formation pressure in the process oil development, which has a complex impact on dynamic analysis, productivity evaluation and later adjustment of potential stimulation measures. This study mainly focus on the characterization of tight formation rock in the Northwest part of China. In order to get a visual impression of the reservoir core, some routine tests were firstly carried out. After that, porosity and permeability are tested under overburden pressure conditions. Studies show that overburden porosity and permeability will decrease but total decrease percentage will increase with the increase of net effective overburden pressure. The decrease percentage of permeability is much higher compared with that of porosity decrease percentage under overburden pressures. When the net effective overburden pressure is larger than 10 MPa, the decrease of overburden porosity will become relatively small. At the same time, when the net effective overburden pressure is larger than 15 MPa, the decrease of overburden permeability will become relatively small. Taking the pressure-increasing process and the pressure-decreasing process as a whole: the permeability cannot recover to the initial level when overburden pressure is the same as previous round because certain permeability is permanently damaged in the process. At the same time, when the net effective overburden pressure increased to a higher level, the permeability damaged will become relatively smaller. These experiments compose of a comprehensive characterization of formation rock and are of great significance to accurately understand the reservoir damage in the process of tight oil development and reasonably evaluate the productivity of oil producers.

BackgroundChildren and adolescents are at a high risk of major depressive disorder (MDD) with known sex differences in epidemiology. However, there are currently no objective laboratory-based sex-specific biomarkers available to support the diagnoses of male and female patients with MDD.MethodsHere, a male set of 42 cases and 27 healthy controls (HCs) and a female set of 42 cases and 22 HCs were recruited. This study investigated the sex differences of plasma metabolite biomarkers in young patients with MDD by the application of ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry.ResultsThe metabolic profiles showed clear separations in both male and female sets. In total, this study identified 57 male-related and 53 female-related differential metabolites. Compared with HCs, both male and female subjects with MDD displayed four significantly altered pathways. Notably, biliverdin was selected as an independent diagnostic male-specific biomarker with an area under the receiver operating characteristic curve of 0.966, and phosphatidylcholine (10:0/14:1) was selected as a female-specific biomarker, achieving an area under the curve (AUC) of 0.957.ConclusionThis metabolomics study may aid in the development of a plasma-based test for the diagnosis of male and female children and adolescents with MDD, as well as give new insight into the pathophysiology of sex differences in children and adolescents with MDD.

RationaleWhile reactive oxygen species (ROS) has been recognized as one of the main causes of cardiac injury following myocardial infarction, the clinical application of antioxidants has shown limited effects on protecting hearts against ischemia–reperfusion (I/R) injury. Thus, the precise role of ROS following cardiac injury remains to be fully elucidated.ObjectiveWe investigated the role of mitsugumin 53 (MG53) in regulating necroptosis following I/R injury to the hearts and the involvement of ROS in MG53-mediated cardioprotection.Methods and ResultsAntioxidants were used to test the role of ROS in MG53-mediated cardioprotection in the mouse model of I/R injury and induced human pluripotent stem cells (hiPSCs)-derived cardiomyocytes subjected to hypoxia or re-oxygenation (H/R) injury. Western blotting and co-immunoprecipitation were used to identify potential cell death pathways that MG53 was involved in. CRISPR/Cas 9-mediated genome editing and mutagenesis assays were performed to further identify specific interaction amino acids between MG53 and its ubiquitin E3 ligase substrate. We found that MG53 could protect myocardial injury via inhibiting the necroptosis pathway. Upon injury, the generation of ROS in the infarct zone of the hearts promoted interaction between MG53 and receptor-interacting protein kinase 1 (RIPK1). As an E3 ubiquitin ligase, MG53 added multiple ubiquitin chains to RIPK1 at the sites of K316, K604, and K627 for proteasome-mediated RIPK1 degradation and inhibited necroptosis. The application of N-acetyl cysteine (NAC) disrupted the interaction between MG53 and RIPK1 and abolished MG53-mediated cardioprotective effects.ConclusionsTaken together, this study provided a molecular mechanism of a potential beneficial role of ROS following acute myocardial infarction. Thus, fine-tuning ROS levels might be critical for cardioprotection.

The fatty acid dehydrogenase fat-1 gene, derived from Caenorhabditis elegans, encodes n-3 polyunsaturated fatty acid dehydrogenase (Δ15 desaturase) and catalyzes the 18–20-carbon n-6 polyunsaturated fatty acids (n-6 PUFA) to generate corresponding n-3 polyunsaturated fatty acids (n-3 PUFA). Subsequently, fat-1 can influence the n-6: n-3 PUFA ratio in fat-1 transgenic cells. This study aimed to explore which processes of energy metabolism are affected exogenous fat-1 transgene and the relationship between these effects and DNA methylation. Compared with the wild-type group, the n-3 PUFA content in fat-1 transgenic bovine fetal fibroblasts was significantly increased, and the n-6 PUFA content and the n-6: n-3 PUFA ratio decreased. In the context of energy metabolism, the increase of exogenous fat-1 transgene decreased ATP synthesis by 39% and reduced the activity and expression of key rate-limiting enzymes in glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation, thus weakening the cells’ capacity for ATP production. DNA methylation sequencing indicated that this inhibition of gene expression may be due to altered DNA methylation that regulates cell energy metabolism. Exogenous fat-1 transgenic cells showed changes in the degree of methylation in the promoter region of genes related to energy metabolism rate-limiting enzymes. We suggest that alters the balance of n-6/n-3 PUFA could regulate altered DNA methylation that affect mitochondrial energy metabolism.

The operational uncertainty of the power system is significantly increased by the high penetration of renewable energy and diversification of load behavior, which have aroused the novel research on stochastic steady-state security assessment (SSSA) urgently when the operational condition gets worse and contingency happens more frequently. First of all, a novel contingency analysis model has been proposed based on chance constrained optimal power flow (CCOPF) in this work, which is able to give a comprehensive consideration on conventional generator outage, uncertainty of system operation and load shedding of interruptible loads (ILs). Moreover, the proposed model is very practical and can be solved much efficiently by an iteration method so that the purpose of secure system operation after contingency can be better realized. Second, to further enhance the steady-state security of the system, a novel pricing method for ILs has been developed here. In addition, a composite contingency ranking index has been also established to reflect the severity of generator outage more accurately. Finally, extensive study results based on a modified IEEE-39 test system have demonstrated the validity of the proposed model, which can hold a good balance amongst security, economy, controllability, and maneuverability.

Myostatin (MSTN), a major negative regulator of skeletal muscle mass and an endocrine factor, can regulate the metabolism of various organisms. Inhibition of the MSTN gene can improve meat production from livestock. Rumen microorganisms are associated with production and health traits of cattle, but changes in the microbial composition and metabolome in the four stomach compartments of MSTN gene–edited cattle have not previously been studied. Our results indicated that microbial diversity and dominant bacteria in the four stomach compartments were very similar between MSTN gene–edited and wild-type (WT) cattle. The microbiota composition was significantly different between MSTN gene–edited and WT cattle. Our results show that the relative abundance of the phylum Proteobacteria in the reticulum of MSTN gene–edited cattle was lower than that of WT cattle, whereas the relative abundance of the genus Prevotella in the omasum of MSTN gene–edited cattle was significantly higher than that of WT cattle. Metabolomics analysis revealed that the intensity of L-proline and acetic acid was significantly different in the rumen, reticulum, and abomasum between the two types of cattle. Meanwhile, pathway topology analysis indicated that the differential metabolites were predominantly involved in arginine biosynthesis and glutamate metabolism in the rumen, reticulum, and omasum but were mainly involved in pyruvate metabolism and glycolysis/gluconeogenesis in the abomasum. Spearman correlation network analysis further demonstrated that there was a significant correlation between microflora composition and metabolic pathways. These findings provide clues for studying nutrient digestion and absorption ability of MSTN gene–edited cattle.

We aimed to elucidate the mechanism by which hepatitis B virus X (HBx) mutations increase the occurrence of hepatocellular carcinoma (HCC) and identify novel putative therapeutic targets. Wild-type HBx (WT-HBx) and four HBx mutants (M1, A1762T/G1764A; M2, T1674G+T1753C+A1762T/G1764A; M3, C1653T+T1674G+A1762T/G1764A; and Ct-HBx, carboxylic acid-terminal truncated HBx) were delivered into Sleeping Beauty (SB) mouse models. The HCC incidence was higher in the M3-HBx- and Ct-HBx-injected SB mice. M3-HBx had a stronger capacity of upregulating inflammatory cytokines than other HBx variants. Ectopic expression of M3-HBx and Ct-HBx significantly increased proliferation and S phase proportion of HepG2 and HeLa cells, compared to WT-HBx. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors by cDNA microarray analysis. M3-HBx and Ct-HBx significantly upregulated the expression of PAI1 and CDC20 in HepG2 and HeLa cells as well as the livers of SB mice. Silencing PAI1 attenuated the effects of M3-HBx and Ct-HBx on the growth of HepG2 and HeLa cells. PAI1, an important player bridging the HBx mutants and HCC, should be a promising candidate as a prognostic biomarker and therapeutic target in HBV-related HCC.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype independent of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. It has a poor prognosis and high recurrence. Due to its limited treatment options in the clinic, novel therapies are urgently needed. Single treatment with the death receptor ligand TRAIL was shown to be poorly effective. Recently, we have shown that artemisinin derivatives enhance TRAIL-induced apoptosis in colon cancer cells. Here, we utilized transferrin (TF) to enhance the effectiveness of dihydroartemisinin (DHA) in inducing cell death in TNBC cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468 and BT549). We found that the combination of DHA-TF and the death receptor 5-specific TRAIL variant DHER leads to an increase in DR5 expression in all four TNBC cell lines, while higher cytotoxicity was observed in MDA-MB-231, and MDA-MB-436. All the data point to the finding that DHA-TF stimulates cell death in TNBC cells, while the combination of DHA-TF with TRAIL variants will trigger more cell death in TRAIL-sensitive cells. Overall, DHA-TF in combination with TRAIL variants represents a potential novel combination therapy for triple-negative breast cancer.

Myostatin (MSTN) is a primary negative regulator of skeletal muscle mass and causes multiple metabolic changes. However, whether MSTN mutation affects heart morphology and physiology remains unclear. Myostatin mutation (MT) had no effect on cattle cardiac muscle in histological examination, but in biochemical assays, glycolysis increased in cattle hearts with MT. Compared with wild-type cattle, there were no differences in mRNA and protein levels of rate-limiting enzymes, but phosphofructokinase (PFK) phosphorylation increased in cattle hearts with MT. Transcriptome analysis showed that phosphodiesterase-5A (PDE5A), a target for inhibiting cGMP-PKG signaling, was downregulated. For the mechanism, chromatin immunoprecipitation qPCR showed that the SMAD2/SMAD3 complex in the canonical downstream pathway for MSTN combined with the promoter of PDE5A. The cGMP-PKG pathway was activated, and PKG increased phosphorylation of PFK in cattle hearts with MT. In addition, activation of PKG and the increase in PFK phosphorylation promoted glycolysis. Knockdown of PKG resulted in the opposite phenomena. The results indicated that MT potentiated PFK phosphorylation via the PDE5A-cGMP-PKG pathway and thereby promoted glycolysis in the heart.

The hippocampus is one of the most phylogenetically preserved structures in the mammalian brain. Engaged in a host of diverse cognitive processes, there has been increasing interest in understanding how the hippocampus dynamically supports these functions. One of the lingering questions is how to reconcile the seemingly disparate cytoarchitectonic organization, which favors a dorsal-ventral layering, with the neurofunctional topography, which has strong support for longitudinal axis (anterior-posterior) and medial-lateral orientation. More recently, meta-analytically driven (e.g., big data) approaches have been employed, however, the question remains whether they are sensitive to important task-specific features such as context, cognitive processes recruited, or the type of stimulus being presented. Here, we used hierarchical clustering on functional magnetic resonance imaging (fMRI) data acquired from healthy individuals at 7T using a battery of tasks that engage the hippocampus to determine whether stimulus or task features influence cluster profiles in the left and right hippocampus. Our data suggest that resting state clustering appears to favor the cytoarchitectonic organization, while task-based clustering favors the neurofunctional clustering. Furthermore, encoding tasks were more sensitive to stimulus type than were recognition tasks. Interestingly, a face-name paired associate task had nearly identical clustering profiles for both the encoding and recognition conditions of the task, which were qualitatively morphometrically different than simple encoding of words or faces. Finally, corroborating previous research, the left hippocampus had more stable cluster profiles compared to the right hippocampus. Together, our data suggest that task-based and resting state cluster profiles are different and may account for the disparity or inconsistency in results across studies.

Streptococcus agalactiae, also known as group B streptococcus (GBS), can cause pneumonia, meningitis, and bacteremia, making it a pathogen that can increase the risk of death in newborns and immunodeficient individuals. Neutrophils are the first barrier to a host’s innate immune defense against these infections. Fpr2(Formyl peptide receptor 2) is an important chemotactic receptor of neutrophils, though its activation would cause pro- and anti-inflammatory effects. In this study, we found that mice without Fpr2 receptor were highly susceptible to GBS infections. These mice demonstrated decreased chemotaxis to neutrophils, decreased bactericidal ability of neutrophils, and high mortality. RNA-seq and Luminex assay indicated that Fpr2 activates key signal molecules downstream and produces chemokines CXCL1/2 to chemotaxis neutrophils. Like Fpr2-/-, CXCL1/2 or neutrophil depletion impairs host’s ability to defend against GBS infection. Altogether, these data indicate that Fpr2 contributes to a host’s ability to control GBS infection and that a lack of Fpr2 was associated with selective impairment during the production of chemokines CXCL1 and CXCL2 as well as neutrophil recruitment. Here, We clarified that Fpr2, as a chemotactic receptor, could not only directly chemotactic neutrophils, but also regulate the production of chemokines to control infection by chemotactic neutrophils.

Background: Anxiety disorder is the most prevalent mental disorder in children and adolescents. However, evidence for efficacy and acceptability between individual cognitive behavior therapy (I-CBT) and group cognitive behavior therapy (G-CBT) in anxiety disorders in children and adolescents remains unclear.Methods: Eight electronic databases (PubMed, Embase, Cochrane, Web of Science, CINAHL, PsycINFO, ProQuest, and LILACS) were searched from inception to October 2019. Randomized controlled trials comparing I-CBT with G-CBT for anxiety disorders in children and adolescents were included. The primary outcomes were efficacy (mean change in anxiety symptom scores) at post-treatment and acceptability (all-cause discontinuation). The secondary outcome was remission at post-treatment. Subgroup analyses were also conducted to examine whether the result would be influenced by age, number of treatment sessions, parental involvement, male/female sex, and number of participants.Results: Nine studies were selected in this meta-analysis. The pooled analyses indicated no significant difference between I-CBT and G-CBT for efficacy at post-treatment [standardized mean difference (SMD), −0.14; 95% confidence interval (CI), −0.37 to 0.09], acceptability [odds ratio (OR), 1.30; 95% CI, 0.61–2.77], and remission at post-treatment (OR, 1.15; 95% CI, 0.79–1.66). In the subgroup analysis of age, I-CBT was significantly more effective than G-CBT in adolescents at post-treatment (SMD, −0.77; 95% CI, −1.51 to −0.02), but not in children (SMD, 0.00; 95% CI, −0.02 to 0.20). However, the findings were not materially different from those of the efficacy subgroup analysis of number of treatment sessions, parental involvement, male/female sex, and number of participants.Conclusions: Based on those current evidence, I-CBT was shown to be more beneficial than G-CBT for anxiety disorders in adolescents, but not in children. However, further well-designed clinical studies should be performed to confirm these findings.Systematic Review Registration:http://osf.io/xrjkp, identifier: 10.17605/OSF.IO/XRJKP.

Current antidepressants do not confer a clear advantage in children and adolescents with major depressive disorder (MDD). Accumulating evidence highlights the potential antidepressant-like effects of inosine on adult MDD, and gut microbiomes are significantly associated with MDD via the microbiota-gut-brain axis. However, few studies have investigated possible associations between inosine and gut microbiota in adolescents with MDD. The current study investigated the potential antidepressant effects of inosine in adolescent male C57BL/6 mice. After 4 weeks of chronic unpredictable mild stress (CUMS) stimulation, the mice were assessed by body weight, the sucrose preference test (SPT), open field test, and the elevated plus maze (EPM). The microbiota compositions of feces were determined by 16S rRNA gene sequencing. Inosine significantly improved CUMS-induced depressive and anxiety-like behaviors in adolescent mice including SPT and EPM results. Fecal microbial composition differed in the CON+saline, CUMS+saline, and CUMS+inosine groups, which were characterized by 126 discriminative amplicon sequence variants belonging to Bacteroidetes and Firmicute at the phylum level and Muribaculaceae and Lachnospiraceae at the family level. Muribaculaceae was positively associated with depressive and anxiety-like behaviors. KEGG functional analysis suggested that inosine might affect gut microbiota through carbohydrate metabolism and lipid metabolism pathways. The results of the study indicated that inosine improved depressive and anxiety-like behaviors in adolescent mice, in conjunction with the alteration of fecal microbial composition. Our findings may provide a novel perspective on the antidepressant effects of inosine in children and adolescents.

ObjectiveThe aim of this study was to investigate the relationship between blood pressure variability (BPV) and poststroke cognitive impairment (PSCI).MethodsSeven-hundred ninety-six patients with acute ischemic stroke were included in this study. Midterm BPV was evaluated by calculating the SD and coefficient of variation (CV, 100 × SD/mean) of systolic blood pressure (SBP) and diastolic blood pressure during the 7 days after stroke onset. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) at admission and at all follow-up visits. Patients with MoCA scores