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Abstract Mitogen‐activated protein kinase (MAPK) cascade is the center of plant signal transduction system that amplify immune signals into cellular responses by phosphorylating diverse substrates. The MAPK cascade consisting of MAPK kinase kinases (MAPKKKs), MAPK kinases (MAPKKs), and MAPKs is well characterized in plants, in which Raf‐like kinases are generally regarded as MAPKKKs. However, it is rarely reported that Raf‐like MAPKKKs function as middle regulators to link MAPK and its downstream transcription factors in plant immunity. Verticillium wilt, caused by the soil‐borne vascular fungus Verticillium dahliae, is a serious disease in many plants, including cotton. The previous studies showed that GhMPK9 (a MAPK) is involved in the response to Verticillium wilt. Here, the Raf‐like kinase GhRAF39_1 is reported as helper regulates the phosphorylation of WRKY transcription factor GhWRKY40a by GhMPK9. The phosphorylated GhWRKY40a can further activate the transcription of GhERF1b to up‐regulate defense‐related genes while inhibit the transcription of GhABF2 to regulate the stomatal opening, thus improving the resistance to Verticillium wilt in cotton. This study reveals a new signaling module of GhMPK9‐GhRAF39_1‐GhWRKY40a to regulate GhERF1b‐ and GhABF2‐mediated defense responses, which triggers plant defense against Verticillium wilt.

Abstract Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer’s disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of β-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN–GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.

Summary: Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3-mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in humans and mice. We unexpectedly discover an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts are altered in Shank3-mutant mice and postmortem brain tissues from individuals with autism spectrum disorder. The enhanced SHANK3 transcriptome significantly improves the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest that both deterministic and stochastic transcription of the genome is associated with SHANK family genes.

Background A retrospective study was performed to evaluate the patterns of cytogenomic findings detected from a case series of products of conception (POC) in recurrent pregnancy loss (RPL) over a 16-year period from 2007 to 2023.

Nephrolithiasis is a major public health concern associated with high morbidity and recurrence. Despite decades of research, the pathogenesis of nephrolithiasis remains incompletely understood, and effective prevention is lacking. An increasing body of evidence suggests that non-coding RNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a role in stone formation and stone-related kidney injury. MiRNAs have been studied quite extensively in nephrolithiasis, and a plethora of specific miRNAs have been implicated in the pathogenesis of nephrolithiasis, involving remarkable changes in calcium metabolism, oxalate metabolism, oxidative stress, cell–crystal adhesion, cellular autophagy, apoptosis, and macrophage (Mp) polarization and metabolism. Emerging evidence suggests a potential for miRNAs as novel diagnostic biomarkers of nephrolithiasis. LncRNAs act as competing endogenous RNAs (ceRNAs) to bind miRNAs, thereby modulating mRNA expression to participate in the regulation of physiological mechanisms in kidney stones. Small interfering RNAs (siRNAs) may provide a novel approach to kidney stone prevention and treatment by treating related metabolic conditions that cause kidney stones. Further investigation into these non-coding RNAs will generate novel insights into the mechanisms of renal stone formation and stone-related renal injury and might lead to new strategies for diagnosing and treating this disease.

The role of mitochondrial activity in angiogenesis is not entirely understood. Here, the authors show that mitochondria as a signaling hub and their dysfunction causes augmented TGFβ signaling to induce retinal sprouting retardation and vascular malformations.

Designing efficient ORR/OER bifunctional electrocatalysts is very significant for reducing energy consumption and environmental protection. Hence, we studied the ORR/OER bifunctional catalytic activity of iron polyphthalocyanine (FePPc) coordinated by a series of axial ligands which has different electronegative coordination atom (FePPc-L) (L = -CN, -SH, -SCH3, -SC2H5, -I, -Br, -NH2, -Cl, -OCH3, -OH, and -F) in alkaline medium by DFT calculations. Among all FePPc-L, FePPc-CN, FePPc-SH, FePPc-SCH3, and FePPc-SC2H5 exhibit excellent ORR/OER bifunctional catalytic activities. Their ORR/OER overpotential is 0.256 V/0.234 V, 0.278 V/0.256 V, 0.280 V/0.329 V, and 0.290 V/0.316 V, respectively, which are much lower than that of the FePPc (0.483 V/0.834 V). The analysis of the electronic structure of the above catalysts shows that the electronegativity of the coordination atoms in the axial ligand is small, resulting in less distribution of dz2, dyz, and dxz orbitals near Ef, weak orbital polarization, small charge and magnetic moment of the central Fe atom, and weak adsorption strength for *OH. All these prove that the introduction of axial ligands with appropriate electronegativity coordinating atoms can adjust the adsorption of catalyst to intermediates and modify the ORR/OER bifunctional catalytic activities. This is an effective strategy for designing efficient ORR/OER bifunctional electrocatalysts.

Despite effective vaccines against SARS-CoV-2, therapeutic options such as anti-virals and neutralizing antibodies are critical in treating disease, especially given the breakthrough infections of emerging VOCs. Here, Peng et al. generate two potent monoclonal antibodies and a bispecific antibody with two antigenrecognition variable regions targeting SARS-CoV-2 spike, provide CryoEM structures and show in vitro and in vivo efficacy of a humanized antibody against wildtype virus and delta variant.

SARS-CoV-2 infection can lead to progressive pathology in patients with COVID-19, but information for this disease progression is sparse. Here the authors use multi-omics approach to profile the immune responses of patients, assessing immune repertoire and effects of tocilizumab treatments, to find a dyssynchrony between innate and adaptive immunity in progressive COVID-19.

IntroductionImmune checkpoint inhibitors (ICIs) have shown promising results for the treatment of multiple cancers. ICIs and related therapies may also be useful for the treatment of thyroid cancer (TC). In TC, Myc binding protein 2 (MYCBP2) is correlated with inflammatory cell infiltration and cancer prognosis. However, the relationship between MYCBP2 expression and ICI efficacy in TC patients is unclear.MethodsWe downloaded data from two TC cohorts, including transcriptomic data and clinical prognosis data. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict the efficacy of ICIs in TC patients. MCPcounter, xCell, and quanTIseq were used to calculate immune cell infiltration scores. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to evaluate signaling pathway scores. Immunohistochemical (IHC) analysis and clinical follow up was used to identify the MYCBP2 protein expression status in patients and associated with clinical outcome.ResultsA higher proportion of MYCBP2-high TC patients were predicted ICI responders than MYCBP2-low patients. MYCBP2-high patients also had significantly increased infiltration of CD8+ T cells, cytotoxic lymphocytes (CTLs), B cells, natural killer (NK) cells and dendritic cells (DC)s. Compared with MYCBP2-low patients, MYCBP2-high patients had higher expression of genes associated with B cells, CD8+ T cells, macrophages, plasmacytoid dendritic cells (pDCs), antigen processing and presentation, inflammatory stimulation, and interferon (IFN) responses. GSEA and ssGSEA also showed that MYCBP2-high patients had significantly increased activity of inflammatory factors and signaling pathways associated with immune responses.In addiation, Patients in our local cohort with high MYCBP2 expression always had a better prognosis and greater sensitivity to therapy while compared to patients with low MYCBP2 expression after six months clinic follow up.ConclusionsIn this study, we found that MYCBP2 may be a predictive biomarker for ICI efficacy in TC patients. High MYCBP2 expression was associated with significantly enriched immune cell infiltration. MYCBP2 may also be involved in the regulation of signaling pathways associated with anti-tumor immune responses or the production of inflammatory factors.

To provide an overview of the current situation, challenges, and trends in online medical services from the perspective of andrology and promote the development of online medical services. Users of the Learning Alliance of Urology, who mainly worked in central regions of China, were invited to complete the questionnaire that included information on the participants and their institutions and their involvement in and concerns for online medical services. We received 875 complete responses. The percentage of online andrology patients at most institutions was less than 30%. The most common services were online appointment registration (92.7%) and online payment (81.8%). Online chat consultation (77.7%) was the most common form of consultation. Only 1 in 5 of the institutions had constructed their Internet hospital. Factors related to the percentage of online andrology patients included specialized andrology clinics and wards, sufficient time for doctors to provide online services, more diversified services, and online clinic training. The biggest challenge for online medical services was diagnosis and treatment safety. It is essential to raise awareness of online medical services for hospitals and patients and strengthen standardized management and training of online medical services, especially applicable to central regions of China. However, online medical services cannot wholly replace offline services due to insufficient diagnosis and treatment.

Machine learning (ML) algorithms were used to identify a novel biological target for breast cancer and explored its relationship with the tumor microenvironment (TME) and patient prognosis. The edgR package identified hub genes associated with overall survival (OS) and prognosis, which were validated using public datasets. Of 149 up-regulated genes identified in tumor tissues, three ML algorithms identified COL11A1 as a hub gene. COL11A1was highly expressed in breast cancer samples and associated with a poor prognosis, and positively correlated with a stromal score (r=0.49, p

ObjectiveTo evaluate the clinical features, treatment, and outcomes of pulmonary embolism (PE) after urological non-oncological surgery in a tertiary hospital of China.MethodsA total of eight patients who suffered from PE after urological non-oncological surgery from 2016 to 2019 were recruited to the study. Clinical data such as symptoms, vital signs, electrocardiogram, echocardiography, and computed tomographic pulmonary arteriography (CTPA) were reviewed. In addition, the management and long-term follow-up outcome of PE were reported. Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire was applied for five patients to evaluate health-related quality of life after PE.ResultsAll patients survived during their hospitalization, and five patients were contacted during follow-up. Five of the eight patients were anticoagulated regularly until the re-examination results of CTPA and lower extremities ultrasound were normal. The period of anticoagulant sustained at least one month for each patient. The long-term follow-up outcomes showed that PE had little impact on the patients' quality of life.ConclusionsThe study demonstrated that the prognosis of PE patients was not as terrible as feared when treated immediately in the ward. Early diagnosis and treatment of PE is vital for prognosis. However, further verifications based on the results of large studies are still needed.

People with HIV (PWH) on antiretroviral therapy (ART) experience elevated rates of neurological impairment, despite controlling for demographic factors and comorbidities, suggesting viral or neuroimmune etiologies for these deficits. Here, we apply multimodal and cross-compartmental single-cell analyses of paired cerebrospinal fluid (CSF) and peripheral blood in PWH and uninfected controls. We demonstrate that a subset of central memory CD4+ T cells in the CSF produced HIV-1 RNA, despite apparent systemic viral suppression, and that HIV-1–infected cells were more frequently found in the CSF than in the blood. Using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we show that the cell surface marker CD204 is a reliable marker for rare microglia-like cells in the CSF, which have been implicated in HIV neuropathogenesis, but which we did not find to contain HIV transcripts. Through a feature selection method for supervised deep learning of single-cell transcriptomes, we find that abnormal CD8+ T cell activation, rather than CD4+ T cell abnormalities, predominated in the CSF of PWH compared with controls. Overall, these findings suggest ongoing CNS viral persistence and compartmentalized CNS neuroimmune effects of HIV infection during ART and demonstrate the power of single-cell studies of CSF to better understand the CNS reservoir during HIV infection.

Abstract Background The OncoScan microarray assay (OMA) using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP) loci enabled the detection of cytogenomic abnormalities of chromosomal imbalances and pathogenic copy number variants (pCNV). The small size of molecular inversion probes is optimal for SNP genotyping of fragmented DNA from fixed tissues. This retrospective study evaluated the clinical utility of OMA as a uniform platform to detect cytogenomic abnormalities for pregnancy loss from fresh and fixed tissues of products of conception (POC). Results Fresh specimens of POC were routinely subjected to cell culture and then analyzed by karyotyping. POC specimens with a normal karyotype (NK) or culture failure (CF) and from formalin-fixed paraffin-embedded (FFPE) tissues were subjected to DNA extraction for OMA. The abnormality detection rate (ADR) by OMA on 94 cases of POC-NK, 38 cases of POC-CF, and 35 cases of POC-FFPE tissues were 2% (2/94), 26% (10/38), and 57% (20/35), respectively. The detected cytogenomic abnormalities of aneuploidies, triploidies and pCNV accounted for 50%, 40% and 10% in POC-CF and 85%, 10% and 5% in POC-FFPE, respectively. False negative result from cultured maternal cells and maternal cell contamination were each detected in one case. OMA on two cases with unbalanced structural chromosome abnormalities further defined genomic imbalances and breakpoints. Conclusion OMA on POC-CF and POC-FFPE showed a high diagnostic yield of cytogenomic abnormalities. This approach circumvented the obstacles of CF from fresh specimens and fragmented DNA from fixed tissues and provided a reliable and effective platform for detecting cytogenomic abnormalities and monitoring true fetal result from maternal cell contamination.

Against the background of low global carbonization, blast furnace ironmaking technology with coking puts huge amounts of pressure on the global steel industry to save energy and reduce emissions due to its high pollution levels and high energy consumption. Bath smelting reduction technology is globally favored and studied by metallurgists as a non-blast furnace ironmaking technology that directly reduces iron ore into liquid metal without using coke as the raw material. The smelting reduction reaction of iron ore, which is the core reaction of the process, is greatly significant to its productivity and energy saving. Therefore, this paper focuses on the behavior and mechanism of iron ore’s smelting reduction. This work focuses on three key aspects of smelting reduction, namely, the thermal decomposition characteristics of iron ore during the smelting reduction, the smelting reduction mechanism of iron-ore particles, and the smelting reduction mechanism of FeO-bearing slag. The experimental study methods, reaction mechanisms, influencing factors, and kinetic behavior of the three are highlighted. In this work, the reaction mechanism of thermal iron-ore decomposition, iron-ore particle smelting reduction, and FeO-bearing slag smelting reduction on the three reactions were observed, providing a theoretical basis for how to select and optimize raw materials for the bath smelting reduction process. Moreover, the kinetic study clarifies the limiting steps of the reactions and provides guidance for an improvement in the reaction rate. However, certain blank points in previous studies need to be further explored, such as the differences in the research results of same factor, the large variation in reaction activation energy, and the coupling mechanism and inter-relatedness of the three key aspects’ reactions with each other.

The phenomenon of cracking and deterioration of iron ore particles is a widespread scientific problem in the field of mineral processing and metallurgy. In this paper, the thermal decomposition properties of iron ore were investigated by a non-isothermal method using thermogravimetric equipment, and the crack evolution behavior of iron ore within Fe-C melt was investigated experimentally, by scanning electron microscopy and Micro-CT. The results show that the start decomposition temperature of #2 iron ore is 292.7 °C, which is 37.3 °C higher compared to that of #1 iron ore, because of its smaller pores and the difficulty of water vapor diffusion. The initial decomposition of iron ore is the decomposition goethite to form water vapor, and as heat transfer continues, hematite particles break into smaller particles and decompose to form Fe3O4. During the smelting reduction process, the Crack index (CI) of #1 iron ore was 5.50% at 4 s, and the CI index increased to 23.54% when time was extended to 16 s, and the internal evolved from locally interconnected holes to cracked structure. The iron ore maintains a relatively intact form during reduction within the Fe-C melt, and interfacial reduction reaction is dominant in the later stage.

ObjectiveVenous thromboembolism (VTE) in patients following transurethral resection of the prostate (TURP) has been overlooked for many years. This research was aimed to investigate the incidence and risk factors of VTE in patients after TURP.MethodsA total of 451 patients who underwent TURP between January 2017 and December 2020 were retrospectively analyzed. Clinical data of the patients were collected, such as basic demographic data, prostate volume, creatinine values, hemoglobin values, surgery duration, Caprini score, international prostate symptom score (IPSS), quality of life (QOL) score, plasma D-dimer levels, and so on. Univariate analysis and multivariate logistic regression were performed to identify the potential risk factors of VTE. Venous ultrasonography of lower extremities was performed routinely to detect VTE for patients after TURP.ResultsIn total, 36 (8%) out of the 451 patients suffered from VTE. A total of 12 (2.7%) patients were confirmed with deep venous thrombosis (DVT). Two patients (0.4%) were identified with pulmonary embolism (PE). Twenty-two (4.9%) patients were suffered from superficial venous thrombosis. Furthermore, according to the results of multivariate stepwise logistic regression analysis, having a history of VTE (adjusted odds ratio [aOR] = 10.980, 95% CI = 2.265–53.223), complicated with postoperative bladder hematoma (aOR = 6.302, 95% CI = 2.265–17.532), D-dimer >1.25 mg/L (aOR = 4.402, 95% CI = 1.798–10.774), and age >65 (aOR = 3.106, 95% CI = 1.084–8.893) were independent risk factors of VTE after TURP. In addition, the nomogram prediction model is a useful auxiliary prevention tool of VTE.ConclusionThe incidence of VTE is severely underestimated in patients following TURP. A lot of asymptomatic VTEs have been overlooked. Early detection and diagnosis of VTE are essential. Nevertheless, further verifications based on the results of large-scaled studies are still needed.

Summary: Electric-field (E-field) control of magnetic switching provides an energy-efficient means to toggle the magnetic states in spintronic devices. The angular tunneling magnetoresistance (TMR) of an magnetic tunnel junction (MTJ)/PMN-PT magnetoelectronic hybrid indicates that the angle-dependent switching fields of the free layer can decrease significantly subject to the application of an E-field. In particular, the switching field along the major axis is reduced by 59% from 28.0 to 11.5 Oe as the E-field increases from 0 to 6 kV/cm, while the TMR ratio remains intact. The switching boundary angle decreases (increases) for the parallel (antiparallel) to antiparallel (parallel) state switch, resulting in a shrunk switching window size. The non-volatile and reversible 180° magnetization switching is demonstrated by using E-fields with a smaller magnetic field bias as low as 11.5 Oe. The angular magnetic switching originates from competition among the E-field-induced magnetoelastic anisotropy, magnetic shape anisotropy, and Zeeman energy, which is confirmed by micromagnetic simulations.

There are currently limited Food and Drug Administration (FDA)-approved drugs and vaccines for the treatment or prevention of Coronavirus Disease 2019 (COVID-19). Enhanced understanding of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and pathogenesis is critical for the development of therapeutics. To provide insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2, we performed single-cell (sc) RNA sequencing (RNA-seq) of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface (ALI) cultures over a time course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target at the onset of infection, which we confirmed by electron and immunofluorescence microscopy. Over the course of infection, the cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III interferons (IFNs) and interleukin (IL)-6 but not IL-1. This results in expression of interferon-stimulated genes (ISGs) in both infected and bystander cells. This provides a detailed characterization of genes, cell types, and cell state changes associated with SARS-CoV-2 infection in the human airway.

In this paper, a low-concentration photovoltaic/thermal (LCPV/T) coupled with air-source heat pump (AHP) system is proposed which fully utilizes the heat generated by LCPV/T and improves the performance of the AHP. The system is built and investigated in the Transient System Simulation Program (TRNSYS) and an experimental room model is established to verify the feasibility of the system. The performance of the system is researched from the perspective of energy and exergy, and the system performance with LCPV/T and without LCPV/T is compared. Finally, the influence of the variation of key parameters of the system is studied. The results indicated that on the coldest day, the electrical efficiency of LCPV/T reached 10% which was equal to the electrical exergy efficiency. The maximum thermal efficiency was 31.88% while thermal exergy efficiency was 2.7%. The maximum coefficient of performance (COP) of AHP was 3.3, and the thermal exergy efficiency was 47%. The indoor temperature was maintained at about 20 °C in the heating season. When LCPV/T was adopted, the COP and thermal exergy efficiency of the AHP was generally higher than those without LCPV/T. In conclusion, the utilization of LCPV/T has a positive impact on the performance of the AHP.

Crop domestication from wild ancestors has resulted in the wide adaptation coupled with improved yield and quality traits. However, the genetic basis of many domesticated characteristics remains to be explored. Upland cotton (Gossypium hirsutum) is the most important tetraploid cotton species, accounting for about 90% of world cotton commerce. Here, we reveal the effects of domestication on fiber and stress traits through comprehensive analyses of semi-domesticated races and cultivated cotton accessions. A total of 416 cotton accessions were genotyped, and a decrease in genetic diversity from races to landraces and modern cultivars was detected. Furthermore, 71 domestication selective sweeps (DSS) and 14 improvement selective sweeps (ISS) were identified, with the Dt sub-genome experiencing stronger selection than the At sub-genome during the both selection types. The more expressed genes and a delay in the expression peak of genes related to secondary cell wall (SCW) development in modern cultivars compared to semi-domesticated cotton races, may have contributed to long fibers in these plants. However, down-regulation of genes related to stress response was responsible for decreasing stress tolerance in modern cultivars. We further experimentally confirmed that silencing of PR1 and WRKY20, genes that showed higher expression in the semi-domesticated races, drastically compromised cotton resistance to V. dahliae. Our results reveal fiber improvement and decreased stress tolerance as a result of the domestication of modern upland cotton cultivars.

The extracellular matrix (ECM) not only provides essential physical scaffolding for cellular constituents but also initiates crucial biochemical and biomechanical cues that are required for tissue morphogenesis. In this study, we utilized wheat germ agglutinin (WGA) staining to characterize the ECM architecture in ascidian embryos and larvae. The results showed three distinct populations of ECM presenting in Ciona embryogenesis: the outer layer localized at the surface of embryo, an inner layer of notochord sheath and the apical ECM secreted by the notochord. To further elucidate the precise structure of Ciona embryonic ECM, we employed scanning and transmission electron microscopy, and found that the outer membrane was relatively thick with short fibres, whereas the ECM layer in notochord sheath was not as thick as the outer membrane but more regular arranged; the lumen between notochord cells was hydrostatic and sticky. Then, we used the RNA sequencing data from the embryos and larvae of Ciona savignyi to identify ECM genes and acquire their expression patterns. We identified 115 unigenes as 67 ECM genes, and 77 unigenes showed dynamic expression changes between different stages. Our results reveal the architecture, molecular composition and dynamic expression profile of ECM in ascidian embryogenesis, and may increase understanding of the function of the ECM in chordate development.

Abstract Background Lysin motif (LysM)-containing proteins are important pattern recognition receptors (PRRs) in plants, which function in the perception of microbe-associated molecular patterns (MAMPs) and in the defense against pathogenic attack. To date, the LysM genes have not been systematically analyzed in cotton or effectively utilized for disease resistance. Results Here, we identified 29, 30, 60, and 56 LysM genes in the four sequenced cotton species, diploid Gossypium raimondii, diploid G. arboreum, tetraploid G. hirsutum acc. TM-1, and G. barbadense acc. 3–79, respectively. These LysM genes were classified into four groups with different structural characteristics and a variety of expression patterns in different organs and tissues when induced by chitin or Verticillium dahliae. We further characterized three genes, Lyp1, Lyk7 and LysMe3, which showed significant increase in expression in response to chitin signals, V. dahliae challenge and several stress-related signaling compounds. Lyp1, Lyk7 and LysMe3 proteins were localized to the plasma membrane, and silencing of their expression in cotton drastically impaired salicylic acid, jasmonic acid, and reactive oxygen species generation, impaired defense gene activation, and compromised resistance to V. dahliae. Conclusion Our results indicate that Lyp1, Lyk7, and LysMe3 are important PRRs that function in the recognition of chitin signals to activate the downstream defense processes and induce cotton defense mechanisms against V. dahliae.

Graphene–metal substrates have received widespread attention due to their superior surface-enhanced Raman scattering (SERS) performance. The strong coupling between graphene and metal particles can greatly improve the SERS performance and thus broaden the application fields. The way in which to make full use of the synergistic effect of the hybrid is still a key issue to improve SERS activity and stability. Here, we used graphene as a chemical mechanism (CM) layer and Ag nanoparticles (AgNPs) as an electromagnetic mechanism (EM) layer, forming a CM–EM unit and constructing a multi-layer hybrid structure as a SERS substrate. The improved SERS performance of the multilayer nanostructure was investigated experimentally and in theory. We demonstrated that the Raman enhancement effect increased as the number of CM–EM units increased, remaining nearly unchanged when the CM–EM unit was more than four. The limit of detection was down to 10−14 M for rhodamine 6G (R6G) and 10−12 M for crystal violet (CV), which confirmed the ultrahigh sensitivity of the multilayer SERS substrate. Furthermore, we investigated the reproducibility and thermal stability of the proposed multilayer SERS substrate. On the basis of these promising results, the development of new materials and novel methods for high performance sensing and biosensing applications will be promoted.

Background: Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD. Methods: Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed. Findings: Serum PGRN levels were significantly lower in GD patients (96.65 ± 53.45 ng/ml) than those in healthy controls of the general population (164.99 ± 43.16 ng/ml, p

Pulsed power technology, whereas the electrical energy stored in a relative long period is released in much shorter timescale, is an efficient method to create high energy density physics (HEDP) conditions in laboratory. Around the beginning of this century, China Academy of Engineering Physics (CAEP) began to build some experimental facilities for HEDP investigations, among which the Primary Test Stand (PTS), a multi-module pulsed power facility with a nominal current of 10 MA and a current rising time ∼90 ns, is an important achievement on the roadmap of the electro-magnetically driven inertial confinement fusion (ICF) researches. PTS is the first pulsed power facility beyond 10 TW in China. Therefore, all the technologies have to be demonstrated, and all the engineering issues have to be overcome. In this article, the research outline, key technologies and the preliminary HEDP experiments are reviewed. Prospects on HEDP research on PTS and pulsed power development for the next step are also discussed.

The accuracy of the bottom curve of a PC track beam is strongly related to the production quality of the entire beam. Many factors may affect the parameters of the bottom curve, such as the superelevation of the curve and the deformation of a PC track beam. At present, no effective method has been developed to determine the bottom curve of a PC track beam; therefore, a new technique is presented in this paper to deduce the parameters of such a curve and to control the accuracy of the computation results. First, the domain of the bottom curve of a PC track beam is assumed to be a spindle plane. Then, the corresponding supposed top curve domain is determined based on a geometrical relationship that is the opposite of that identified by the conventional method. Second, several optimal points are selected from the supposed top curve domain according to the dichotomy algorithm; the supposed top curve is thus generated by connecting these points. Finally, one rigorous criterion is established in the fractal dimension to assess the accuracy of the assumed top curve deduced in the previous step. If this supposed curve coincides completely with the known top curve, then the assumed bottom curve corresponding to the assumed top curve is considered to be the real bottom curve. This technique of determining the bottom curve of a PC track beam is thus proven to be efficient and accurate.

Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present study is to investigate the possible effects of chronic administration of myricetin on depressant-like behaviors in mice subjected to repeated restraint (4 h/day) for 21 days. Our results showed that myricetin administration specifically reduced the immobility time in mice exposed to chronic stress, as tested in both forced swimming test and tail suspension test. Myricetin treatment improved activities of glutathione peroxidase (GSH-PX) in the hippocampus of stressed mice. In addition, myricetin treatment decreased plasma corticosterone levels of those mice subjected to repeated restraint stress. The effects of myricetin on the brain-derived neurotrophic factor (BDNF) levels in hippocampus were also investigated. The results revealed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provided more evidence that chronic administration of myricetin improves helpless behaviors. The protective effects of myricetin might be partially mediated by an influence on BDNF levels and might be attributed to myricetin-mediated anti-oxidative stress in the hippocampus.

De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways.

The sea potato (Acaudina molpadioides) is a species of sea cucumber of the family Holothuroidea under Phylum Echinodermata. In this study, we firstly sequenced and annotated the complete mitochondrial genome of A. molpadioides, which was 16,028 bps in size and contained 13 protein-coding genes, 2 rRNAs, 19 tRNA genes, and 1 putative control region. The overall A + T content (65.47%) was higher than G + C content (34.53%), showing the AT bias, consistently with other invertebrate mitochondrial genomes. Phylogenetic analyses showed that the mitochondrial DNAs of A. molpadioides were closely related to other species of Holothuroidea.

Researchers have shown significantly pervasive interest in English Foreign Language (EFL) vocabulary performance through blended learning in both K-12 and tertiary education. This study is a systematic literature review (SLR) of quantitative studies related to vocabulary performance through blended learning approach in EFL context aiming at exploring the trend of this research topic and the effectiveness of this teaching approach on learners' vocabulary performance, EFL skills (except vocabulary performance), emotions and behaviors. We systematically searched articles on the related topic in four major databases, namely, Education Resource Information Center (ERIC), Web of Science, Scopus and Google Scholar from 2017 to 2021 and the reviewers independently performed the quality assessment by using PICOS principle. 45 out of 2894 studies with 3557 participants were included in this SLR article with which employed blended learning in experimental or quasi-experimental research designs mainly cultivating learners' vocabulary. Results showed that blended learning approach was frequently associated with statistically positive significance and displayed better academic performance and imposed positive effect on learners' EFL socio- psychological factors including skills, emotions and behaviors. This study quantifies an objective evaluation and precise estimation of the effects from blended learning studies that could further encourage researchers to bridge learning gaps and to know the research trend of this topic more comprehensively.

DNA methylation is an important epigenetic mechanism for phenotypic diversification in all forms of life. We previously described remarkable cell-to-cell heterogeneity in epigenetic pattern within a clonal population of Streptococcus pneumoniae, a leading human pathogen. We here report that the epigenetic diversity is caused by extensive DNA inversions among hsdSA, hsdSB, and hsdSC, three methyltransferase hsdS genes in the Spn556II type-I restriction modification (R-M) locus. Because hsdSA encodes the sequence recognition subunit of this type-I R-M DNA methyltransferase, these site-specific recombinations generate pneumococcal cells with variable HsdSA alleles and thereby diverse genome methylation patterns. Most importantly, the DNA methylation pattern specified by the HsdSA1 allele leads to the formation of opaque colonies, whereas the pneumococci lacking HsdSA1 produce transparent colonies. Furthermore, this HsdSA1-dependent phase variation requires intact DNA methylase activity encoded by hsdM in the Spn556II (renamed colony opacity determinant or cod) locus. Thus, the DNA inversion-driven ON/OFF switch of the hsdSA1 allele in the cod locus and resulting epigenetic switch dictate the phase variation between the opaque and transparent phenotypes. Phase variation has been well documented for its importance in pneumococcal carriage and invasive infection, but its molecular basis remains unclear. Our work has discovered a novel epigenetic cause for this significant pathobiology phenomenon in S. pneumoniae. Lastly, our findings broadly represents a significant advancement in our understanding of bacterial R-M systems and their potential in shaping epigenetic and phenotypic diversity of the prokaryotic organisms because similar site-specific recombination systems widely exist in many archaeal and bacterial species.

The Gram-negative bacterium Neisseria meningitidis features extensive genetic variability. To present, proposed virulence genotypes are also detected in isolates from asymptomatic carriers, indicating more complex mechanisms underlying variable colonization modes of N. meningitidis. We applied the Single Molecule, Real-Time (SMRT) sequencing method from Pacific Biosciences to assess the genome-wide DNA modification profiles of two genetically related N. meningitidis strains, both of serogroup A. The resulting DNA methylomes revealed clear divergences, represented by the detection of shared and of strain-specific DNA methylation target motifs. The positional distribution of these methylated target sites within the genomic sequences displayed clear biases, which suggest a functional role of DNA methylation related to the regulation of genes. DNA methylation in N. meningitidis has a likely underestimated potential for variability, as evidenced by a careful analysis of the ORF status of a panel of confirmed and predicted DNA methyltransferase genes in an extended collection of N. meningitidis strains of serogroup A. Based on high coverage short sequence reads, we find phase variability as a major contributor to the variability in DNA methylation. Taking into account the phase variable loci, the inferred functional status of DNA methyltransferase genes matched the observed methylation profiles. Towards an elucidation of presently incompletely characterized functional consequences of DNA methylation in N. meningitidis, we reveal a prominent colocalization of methylated bases with Single Nucleotide Polymorphisms (SNPs) detected within our genomic sequence collection. As a novel observation we report increased mutability also at 6mA methylated nucleotides, complementing mutational hotspots previously described at 5mC methylated nucleotides. These findings suggest a more diverse role of DNA methylation and Restriction-Modification (RM) systems in the evolution of prokaryotic genomes.

While Caenorhabditis elegans specifically responds to infection by the up-regulation of certain genes, distinct pathogens trigger the expression of a common set of genes. We applied new methods to conduct a comprehensive and comparative study of the transcriptional response of C. elegans to bacterial and fungal infection. Using tiling arrays and/or RNA-sequencing, we have characterized the genome-wide transcriptional changes that underlie the host's response to infection by three bacterial (Serratia marcescens, Enterococcus faecalis and otorhabdus luminescens) and two fungal pathogens (Drechmeria coniospora and Harposporium sp.). We developed a flexible tool, the WormBase Converter (available at http://wormbasemanager.sourceforge.net/), to allow cross-study comparisons. The new data sets provided more extensive lists of differentially regulated genes than previous studies. Annotation analysis confirmed that genes commonly up-regulated by bacterial infections are related to stress responses. We found substantial overlaps between the genes regulated upon intestinal infection by the bacterial pathogens and Harposporium, and between those regulated by Harposporium and D. coniospora, which infects the epidermis. Among the fungus-regulated genes, there was a significant bias towards genes that are evolving rapidly and potentially encode small proteins. The results obtained using new methods reveal that the response to infection in C. elegans is determined by the nature of the pathogen, the site of infection and the physiological imbalance provoked by infection. They form the basis for future functional dissection of innate immune signaling. Finally, we also propose alternative methods to identify differentially regulated genes that take into account the greater variability in lowly expressed genes.

BackgroundArcobacter butzleri is a member of the epsilon subdivision of the Proteobacteria and a close taxonomic relative of established pathogens, such as Campylobacter jejuni and Helicobacter pylori. Here we present the complete genome sequence of the human clinical isolate, A. butzleri strain RM4018.Methodology/principal findingsArcobacter butzleri is a member of the Campylobacteraceae, but the majority of its proteome is most similar to those of Sulfuromonas denitrificans and Wolinella succinogenes, both members of the Helicobacteraceae, and those of the deep-sea vent Epsilonproteobacteria Sulfurovum and Nitratiruptor. In addition, many of the genes and pathways described here, e.g. those involved in signal transduction and sulfur metabolism, have been identified previously within the epsilon subdivision only in S. denitrificans, W. succinogenes, Sulfurovum, and/or Nitratiruptor, or are unique to the subdivision. In addition, the analyses indicated also that a substantial proportion of the A. butzleri genome is devoted to growth and survival under diverse environmental conditions, with a large number of respiration-associated proteins, signal transduction and chemotaxis proteins and proteins involved in DNA repair and adaptation. To investigate the genomic diversity of A. butzleri strains, we constructed an A. butzleri DNA microarray comprising 2238 genes from strain RM4018. Comparative genomic indexing analysis of 12 additional A. butzleri strains identified both the core genes of A. butzleri and intraspecies hypervariable regions, where Conclusion/significanceThe presence of pathways and loci associated often with non-host-associated organisms, as well as genes associated with virulence, suggests that A. butzleri is a free-living, water-borne organism that might be classified rightfully as an emerging pathogen. The genome sequence and analyses presented in this study are an important first step in understanding the physiology and genetics of this organism, which constitutes a bridge between the environment and mammalian hosts.