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Helicobacter pylori causes globally prevalent infections that are highly related to chronic gastritis and even development of gastric carcinomas. With the increase of antibiotic resistance, scientists have begun to search for better vaccine design strategies to eradicate H. pylori colonization. However, while current strategies prefer to formulate vaccines with a single H. pylori antigen, their potential has not yet been fully realized. Outer membrane vesicles (OMVs) are a potential platform since they could deliver multiple antigens. In this study, we engineered three crucial H. pylori antigen proteins (UreB, CagA, and VacA) onto the surface of OMVs derived from Salmonella enterica serovar Typhimurium (S. Typhimurium) mutant strains using the hemoglobin protease (Hbp) autotransporter system. In various knockout strategies, we found that OMVs isolated from the ΔrfbP ΔfliC ΔfljB ΔompA mutants could cause distinct increases in immunoglobulin G (IgG) and A (IgA) levels and effectively trigger T helper 1- and 17-biased cellular immune responses, which perform a vital role in protecting against H. pylori. Next, OMVs derived from ΔrfbP ΔfliC ΔfljB ΔompA mutants were used as a vector to deliver different combinations of H. pylori antigens. The antibody and cytokine levels and challenge experiments in mice model indicated that co-delivering UreB and CagA could protect against H. pylori and antigen-specific T cell responses. In summary, OMVs derived from the S. Typhimurium ΔrfbP ΔfliC ΔfljB ΔompA mutant strain as the vector while importing H. pylori UreB and CagA as antigenic proteins using the Hbp autotransporter system would greatly benefit controlling H. pylori infection.

BackgroundObservational studies have reported associations between Barrett's esophagus (BE) and obstructive sleep apnea syndrome (OSAS), but the causal relationship remained unclear due to potential confounding biases. Our study aimed to elucidate this causal relationship by deploying a two-sample Mendelian randomization (MR) methodology.MethodsInstrumental variables (IVs) for Barrett's esophagus were obtained from a public database that comprised 13,358 cases and 43,071 controls. To investigate OSAS, we utilized summary statistics from a comprehensive genome-wide association study (GWAS) encompassing 38,998 cases of OSAS and 336,659 controls. Our MR analyses adopted multiple techniques, including inverse variance weighted (IVW), weighted median, weighted mode, MR-Egger, and simple mode.ResultsThe IVW analysis established a causal relationship between Barrett's esophagus and OSAS, with an odds ratio (OR) of 1.19 and a 95% confidence interval (CI) of 1.11–1.28 (p = 8.88E-07). Furthermore, OSAS was identified as a contributing factor to the onset of Barrett's esophagus, with an OR of 1.44 and a 95% CI of 1.33–1.57 (p = 7.74E-19). Notably, the MR–Egger intercept test found no evidence of directional pleiotropy (p > 0.05).ConclusionThis study identifies a potential association between BE and an increased occurrence of OSAS, as well as the reverse relationship. These insights could influence future screening protocols and prevention strategies for both conditions.

Hemophagocytic lymphohistiocytosis (HLH) is a rare histiocytic disorder characterized by reactive hyperplasia of the mononuclear phagocytic system, which is primarily caused by dysfunction of cytotoxic killer cells and natural killer cells, leading to antigen clearance barriers and the overactivation of the mononuclear phagocytic system due to continuous antigen stimulation. HLH encompasses a group of clinical syndromes marked by the overproduction of inflammatory cytokines. A 68-year-old Chinese man presented with persistent fever, chills, nausea, and vomiting; the patient had no history of any underlying conditions. Laboratory investigations revealed decreased levels of red blood cells, white blood cells, and platelets, along with reduced natural killer cell activity, increased CD25, hyperferritinemia, and the detection of Rickettsia DNA in his blood, meeting the diagnostic criteria of the Histiocyte Society HLH-2004 guidelines. The patient was treated with antibiotics, improving anemia, glucocorticoid therapy, and continuous renal replacement therapy (CRRT), temporarily improving his condition. However, the patient died after 2 years from chronic renal failure caused by septic shock.

Abstract The explosive growth of digital communication promotes advanced memory and computing devices in Big Data and artificial intelligence era. In particular, memristors hold great promise for in‐memory computing and artificial synapses, expected to break through restrictions on hardware computational power and storage capacity caused by the von Neumann bottleneck and declining Moore's Law. The memristance controllability is vital to memristors, in which functional layer materials are key. As novel functional layer materials, carbon dots (CDs) are expected to overtake silicon‐based materials due to their satisfactory modulation effects on memristance and distinguished memristive performances. The combination of CDs and matrix materials may carry out multimode sensation memristors for interactive intelligent systems. This review first gives a brief introduction to memristors and their functional layer materials, especially different CDs and their relations with memristance. Then the modulation effects of CDs on memristance are highlighted, mainly including the local electric field enhancement effect, the electron trapping and detrapping effect, and the photosensitization effect, accompanied by applications of CDs‐based memristors (CDMs). Lastly, challenges and perspectives of CDMs are pointed out. This work is rewarding to understand the role of CDs in memristors, to guide relevant research about CDMs, and to promote implementation for intelligent memory and computing.

BackgroundCandida albicans is a commensal yeast that may cause life-threatening infections. Studies have shown that the cytochrome b-c1 complex subunit 7 gene (QCR7) of C. albicans encodes a protein that forms a component of the mitochondrial electron transport chain complex III, making it an important target for studying the virulence of this yeast. However, to the best of our knowledge, the functions of QCR7 have not yet been characterized.MethodsA QCR7 knockout strain was constructed using SN152, and BALb/c mice were used as model animals to determine the role of QCR7 in the virulence of C. albicans. Subsequently, the effects of QCR7 on mitochondrial functions and use of carbon sources were investigated. Next, its mutant biofilm formation and hyphal growth maintenance were compared with those of the wild type. Furthermore, the transcriptome of the qcr7Δ/Δ mutant was compared with that of the WT strain to explore pathogenic mechanisms.ResultsDefective QCR7 reduced recruitment of inflammatory cells and attenuated the virulence of C. albicans infection in vivo. Furthermore, the mutant influenced the use of multiple alternative carbon sources that exist in several host niches (GlcNAc, lactic acid, and amino acid, etc.). Moreover, it led to mitochondrial dysfunction. Furthermore, the QCR7 knockout strain showed defects in biofilm formation or the maintenance of filamentous growth. The overexpression of cell-surface-associated genes (HWP1, YWP1, XOG1, and SAP6) can restore defective virulence phenotypes and the carbon-source utilization of qcr7Δ/Δ.ConclusionThis study provides new insights into the mitochondria-based metabolism of C. albicans, accounting for its virulence and the use of variable carbon sources that promote C. albicans to colonize host niches.

Resistance to thyroid hormone beta (RTHβ) is an autosomal dominant hereditary disorder that is difficult to diagnose because of its rarity and variable clinical features, which are caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies have indicated a close association between THRB mutations and human cancers, but the mechanistic role of THRB mutations in carcinogenesis is unknown. Herein, we report two cases of RTHβ coexisting with papillary thyroid carcinoma (PTC) and their follow-up results. Two female patients presented with elevated serum thyroid hormone levels and nonsuppressed thyrotropin (TSH). Genetic analysis showed that each patient had a THRB gene mutation (p.P453T and p. R320H). Based on the results of ultrasound-guided fine-needle aspiration biopsy, the thyroid nodules were suspected to be PTC. Intraoperative pathology confirmed that the two patients had PTC with multifocal carcinoma of both lobes. One patient underwent total thyroidectomy and central lymph node dissection, and the other underwent total thyroidectomy alone. Following surgery, large doses of levothyroxine were administered to suppress TSH levels and prevent recurrent or persistent disease. However, it is difficult to continually suppress TSH levels below the upper limit of the normal range. To date, the two patients have experienced no recurrence of PTC on ultrasound.

BackgroundHand-foot-mouth disease (HFMD) is caused by a group of enteroviruses (EVs) and has a high incidence in children; some subtypes had high mortalities in children. The subtypes of HFMD had a different incidence across seasons. Thereby, we suspect that the infection of HFMD is varied by meteorological factors. However, studies examining serotype-specific associations between meteorological factors and HFMD incidence were rare.MethodsWe obtained all HFMD cases that occurred from 1 January 2010 to 31 December 2018 in Zhejiang province from the China Information System for Disease Control and Prevention (CISDCP). Daily meteorological data for Zhejiang province were provided by the China Methodological Data Sharing Service System and linked to HFMD cases based on residential addresses and dates of onset. The associations between meteorological factors and HFMDs were examined using distributed lag non-linear models (DLNMs) for each serotype.ResultsOverall, the incidences of all HFMD cases were increasing in study years, while the number of severe and fatality cases were decreasing. The dominant serotypes varied by study year. The association between temperature and incidence of both CVA16 and EV71 serotypes showed an inverted U shape. The risk ratio for CVA16 was increasing when temperature is 11–25°C, reaching the maximum RR at 18°C and humidity above 77% can promote the occurrence with CVA16, and temperature between 11 and 32°C with the maximum RR at 21°C and relative humidity above 77% are risk conditions of the occurrence of HFMD associated with EV71. For other enteroviruses causing HFMD, temperature above 11°C and humidity above 76% have a risk effect. CVA16, EV71, and all enteroviruses of HFMD have a maximum effect on lag day 0, and temperature is 35, 34, and 33°C respectively, while the enteroviruses of HFMD other than EV71 and CVA16 has a maximum effect when the temperature is 33°C and the lag time is 7 days.ConclusionThis study shows that meteorological factors have an effect on the occurrence of different HFMD serotypes. Local control strategies for public health should be taken in time to prevent and reduce the risk of HFMD while the weather is getting warmer and wetter.

ABSTRACT The saprophytic filamentous fungus Trichoderma reesei represents one of the most prolific cellulase producers isolated from nature. T. reesei also produces a typical yellow pigment identified as sorbicillinoids during cultivation. Here, we identified an evolutionarily conserved histone remodeling factor, ISW1, in T. reesei that simultaneously participates in regulating cellulase and the yellow pigment biosynthesis. Trisw1 deletion almost abolished vegetable growth, asexual spore formation, and cellulase gene expression. However, its absence significantly enhanced the production of the yellow pigment. The observed dual regulatory role of TrISW1 was dependent on its ATPase activity. We demonstrated that Trisw1 disruption elevated the transcription of ypr1 coding for the transcriptional activator of sor genes encoding the polyketide synthases catalyzing the biosynthesis of sorbicillinoids but compromised that of xyr1 encoding the key transcriptional activator of cellulase genes. Discrete T. reesei homologous ISW1 accessory factors were also found to exert differential effects on the expression of these two types of genes. Further analyses showed that TrISW1 was recruited to cellulase gene promoters, and its absence interfered with loss of histone H4 at the cbh1 and eg1 promoters upon cellulose induction. To the contrary, Trisw1 deletion facilitated loss of H4 at the sor locus. These data indicate that TrISW1 represents an important chromatin remodeler with a dual role in coordinating the cellulolytic response and biosynthesis of the major secondary metabolite in T. reesei. IMPORTANCE Microorganisms, including Trichoderma reesei, constantly face the challenge to outcompete other species to ensure efficient colonization in their natural habitat. They achieve this usually by adopting two alternative strategies by either maintaining fast growth on limited nutrient resources or producing a versatile array of secondary metabolites to fight against competitors. These two strategies, however, have to be subtly controlled to balance the assignment of and thus make the best use of cellular resources. Here, we identified a chromatin remodeling factor, TrISW1, with a dual role in coordinating the cellulolytic response and biosynthesis of the major secondary metabolite in T. reesei. The data also provide a novel insight into how T. reesei takes advantage of a chromatin remodeler to exquisitely balance two different adaptive strategies to ensure an efficient allocation of cellular resources to achieve efficient colonization in a specific environment.

Desert ecosystem CO2 exchange may play an important role in global carbon cycling. However, it is still not clear how the CO2 fluxes of shrub-dominated desert ecosystems respond to precipitation changes. We performed a 10-year long-term rain addition experiment in a Nitraria tangutorum desert ecosystem in northwestern China. In the growing seasons of 2016 and 2017, with three rain addition treatments (natural precipitation +0%, +50%, and +100% of annual average precipitation), gross ecosystem photosynthesis (GEP), ecosystem respiration (ER), and net ecosystem CO2 exchange (NEE) were measured. The GEP responded nonlinearly and the ER linearly to rain addition. The NEE presented a nonlinear response along the rain addition gradient, with a saturation threshold by rain addition between +50% and +100%. The growing season mean NEE ranged from −2.25 to −5.38 μmol CO2 m−2 s−1, showing net CO2 uptake effect, with significant enhancement (more negative) under the rain addition treatments. Although natural rainfall fluctuated greatly in the growing seasons of 2016 and 2017, reaching 134.8% and 44.0% of the historical average, the NEE values remained stable. Our findings highlight that growing season CO2 sequestration in desert ecosystems will increase against the background of increasing precipitation levels. The different responses of GEP and ER of desert ecosystems under changing precipitation regimes should be considered in global change models.

Galangin, a naturally available flavonoid, induces a variety of pharmacological activities and biological effects via several mechanisms. However, in vivo metabolism of galangin has not been fully explored, which means knowledge of its pharmacodynamics and application potential is limited. The objective of this study was to establish an ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry method for the rapid profiling and identification of galangin metabolites in vitro and in vivo using unique online information-dependent acquisition with multiple mass defect filtering combined with dynamic background subtraction in positive ion mode. A total of 27 metabolites were detected and characterized, among which eight metabolites in liver microsomes and four metabolites in intestinal microflora were characterized, and 27 metabolites from rat plasma, bile, urine, feces, and a number of different tissue samples were characterized. Thirteen major metabolic pathways including hydrogenation, hydroxylation, glycosylation, methylation, acetylation, glucuronidation, and sulfation were observed to be attributable to the biotransformation of the metabolites. This study provides evidence for the presence of in vitro and in vivo metabolites and the pharmacokinetic mechanism of galangin. Moreover, the study promotes the further development and utilization of galangin and the plant from which it is derived, Alpinia officinarum Hance.

Proteus mirabilis, an opportunistic pathogen, is found to be an emerging threat to both animals and humans for a variety of infections. However, the characteristics of P. mirabilis infections from foxes, raccoons and minks remain unclear. In this context, we identified the antibiotic resistance genes and virulence genes of P. mirabilis isolates from foxes, raccoons and minks in China. Most isolates showed resistance to florfenicol (90.57%), trimethoprim-sulfamethoxazole (73.58%), and imipenem (71.70%). A total of 73.58% of isolates were resistant to antibiotics from at least three or more classes, and were categorized as multi-drug resistant. A total of 33.33% of the isolates were resistant to antibiotics from seven classes. The most prevalent resistant were sul1 (94.34%), followed by floR, blaTEM, aac(6’)Ib-cr and blaOXA-1 with the detection rate of 88.68%, 83.02%, 71.70% and 60.38%, respectively. Among the 51 P. mirabilis isolates that were resistant to beta-lactam antibiotics, all isolates carried at least one beta-lactam gene. In addition, blaNDM and blaOXA-24 genes were firstly reported in carbapenem-resistant P. mirabilis isolates from foxes, raccoons and minks. All isolates exhibited the virulence genes ureC, zapA, pmfA, atfA and mrpA. P. mirabilis isolates carrying all detected 10 virulence genes from different animal species showed different lethal abilities in a G. mellonella larvae model. More importantly, the profiles of antibiotic resistance genes of isolates from fur animals and the environment were generally similar, and phylogenetic analysis showed that the P. mirabilis isolates from farm environment samples may have close relatedness with that from animals.

Event detection is a key task in the field of natural language processing, aiming to identify event trigger words and correctly classify their event types. Sentence-level event detection methods fail to effectively utilize intra-sentence and inter-sentence event relevance information, facing numerous challenges such as polysemy and event co-occurrence. Additionally, neural network-based event detection models require a large amount of text data for training, but the scarcity of corpus data severely affects the accuracy of results and the stability of the model. To address these issues, this paper proposes a document-level event detection method based on information aggregation and data augmentation, called LGIA (local and global information aggregation). This method adopts an encoder-decoder framework, designing a sentence-level local information extraction module based on dilated convolutional networks and a document-level global information extraction module based on conditional layer normalization, to deeply explore the contextual semantic information and the event correlations of the entire document. Meanwhile, this paper employs a data augmentation strategy of synonym replacement to effectively expand the data samples, thereby alleviating the impact of data scarcity. Experimental results validate that the proposed LGIA method achieves good results on the ACE2005 dataset and significantly improves performance on the augmented TAC-KBP2017 dataset, with F1 scores reaching 77.6% and 65.3%, respectively, demonstrating superior performance compared with existing baseline methods.

Coxsackievirus group B3 (CVB3) belongs to the genus Enteroviruses of the family Picornaviridae and is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, and then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for treating this disease. IMPORTANCE Viral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3, and discovered the therapeutic potential of citrulline for VMC. [ABSTRACT FROM AUTHOR]