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We develop a tool, which we name Protoplanetary Disk Operator Network (PPDONet), that can predict the solution of disk–planet interactions in protoplanetary disks in real time. We base our tool on Deep Operator Networks, a class of neural networks capable of learning nonlinear operators to represent deterministic and stochastic differential equations. With PPDONet we map three scalar parameters in a disk–planet system—the Shakura–Sunyaev viscosity α , the disk aspect ratio h _0 , and the planet–star mass ratio q —to steady-state solutions of the disk surface density, radial velocity, and azimuthal velocity. We demonstrate the accuracy of the PPDONet solutions using a comprehensive set of tests. Our tool is able to predict the outcome of disk–planet interaction for one system in less than a second on a laptop. A public implementation of PPDONet is available at https://github.com/smao-astro/PPDONet.

Neutralizing antibodies (nAbs) are important assets to fight COVID-19, but most existing nAbs lose the activities against Omicron subvariants. Here, we report a human monoclonal antibody (Ab08) isolated from a convalescent patient infected with the prototype strain (Wuhan-Hu-1). Ab08 binds to the receptor-binding domain (RBD) with pico-molar affinity (230 pM), effectively neutralizes SARS-CoV-2 and variants of concern (VOCs) including Alpha, Beta, Gamma, Mu, Omicron BA.1 and BA.2, and to a lesser extent for Delta and Omicron BA.4/BA.5 which bear the L452R mutation. Of medical importance, Ab08 shows therapeutic efficacy in SARS-CoV-2-infected hACE2 mice. X-ray crystallography of the Ab08-RBD complex reveals an antibody footprint largely in the β-strand core and away from the ACE2-binding motif. Negative staining electron-microscopy suggests a neutralizing mechanism through which Ab08 destructs the Spike trimer. Together, our work identifies a nAb with therapeutic potential for COVID-19.

Employees’ perceived overqualification (POQ) is prevalent in organizations and has drawn increasing attention from both researchers and practitioners. Drawing from social cognitive theory, the purpose of this study is to extend existing understanding of the consequences of POQ by examining how and when POQ leads to deviant innovation behavior. This study hypothesizes that employees’ POQ indirectly impacts deviant innovation through enhanced creative self-efficacy (CSE), and that perceived organizational support (POS) strengthens this indirect relationship. Using data collected from 286 employees in China at two time points, this study found support for our hypotheses that POQ is positively related to CSE, and that CSE mediates the relationship between POQ and deviant innovation behavior. In addition, this study found that POS moderates the relationship between POQ and CSE, as well as the indirect effect of POQ on deviant innovation behavior via CSE. The theoretical and practical implications of our findings and future research directions are discussed.

BackgroundConsidering the high incidence of medical privacy disclosure, it is of vital importance to study doctors’ privacy protection behavior and its influencing factors. ObjectiveWe aim to develop a scale for doctors’ protection of patients’ privacy in Chinese public medical institutions, following construction of a theoretical model framework through grounded theory, and subsequently to validate the scale to measure this protection behavior. MethodsCombined with the theoretical paradigm of protection motivation theory (PMT) and semistructured interview data, the grounded theory research method, followed by the Delphi expert and group discussion methods, a theoretical framework and initial scale for doctors in Chinese public medical institutions to protect patients' privacy was formed. The adjusted scale was collected online using a WeChat electronic survey measured using a 5-point Likert scale. Exploratory and confirmatory factor analysis (EFA and CFA) and tests to analyze reliability and validity were performed on the sample data. SPSS 19.0 and Amos 26.0 statistical analysis software were used for EFA and CFA of the sample data, respectively. ResultsAccording to the internal logic of PMT, we developed a novel theoretical framework of a “storyline,” which was a process from being unaware of patients' privacy to having privacy protection behavior, that affected doctors' cognitive intermediary and changed the development of doctors' awareness, finally affecting actual privacy protection behavior in Chinese public medical institutions. Ultimately, we created a scale to measure 18 variables in the theoretical model, comprising 63 measurement items, with a total of 208 doctors participating in the scaling survey, who were predominantly educated to the master’s degree level (n=151, 72.6%). The department distribution was relatively balanced. Prior to EFA, the Kaiser-Meyer-Olkin (KMO) value was 0.702, indicating that the study was suitable for factor analysis. The minimum value of Cronbach α for each study variable was .754, which met the internal consistency requirements of the scale. The standard factor loading value of each potential measurement item in CFA had scores greater than 0.5, which signified that all the items in the scale could effectively converge to the corresponding potential variables. ConclusionsThe theoretical framework and scale to assess doctors' patient protection behavior in public medical institutions in China fills a significant gap in the literature and can be used to further the current knowledge of physicians’ thought processes and adoption decisions.

The calcineurin B-like (CBL)-interacting protein kinases (CIPKs), a type of plant-specific genes in the calcium signaling pathway, function in response to adverse environments. However, few halophyte derived CIPKs have been studied for their role in plant physiological and developmental adaptation during abiotic stresses, which inhibits the potential application of these genes to improve environmental adaptability of glycophytes. In this study, we constructed Nitraria billardieri CIPK25 overexpressing Arabidopsis and analyzed the seedling development under salt treatment. Our results show that Arabidopsis with NbCIPK25 expression exhibits more vigorous growth than wild type plants under salt condition. To gain insight into the molecular mechanisms underlying salt tolerance, we profiled the transcriptome of WT and transgenic plants via RNA-seq. GO and KEGG analyses revealed that upregulated genes in NbCIPK25 overexpressing seedlings under salt stress are enriched in photosynthesis related terms; Calvin-cycle genes including glyceraldehyde-3-phosphate dehydrogenases (GAPDHs) are significantly upregulated in transgenic plants, which is consistent with a decreased level of NADPH (GAPDH substrate) and increased level of NADP+. Accordingly, NbCIPK25 overexpressing plants exhibited more efficient photosynthesis; soluble sugar and proteins, as photosynthesis products, showed a higher accumulation in transgenic plants. These results provide molecular insight into how NbCIPK25 promotes the expression of genes involved in photosynthesis, thereby maintaining plant growth under salt stress. Our finding supports the potential application of halophyte-derived NbCIPK25 in genetic modification for better salt adaptation.

Cholesterol metabolism in the brain plays a crucial role in normal physiological function, and its aberrations are associated with cognitive dysfunction. The present study aimed to determine which cholesterol-related genes play a vital role in cognitive dysfunction and to dissect its underlying molecular mechanisms using a systems genetics approach in the BXD mice family. We first systematically analyzed the association of expression of 280 hippocampal genes related to cholesterol metabolism with cognition-related traits and identified lipoprotein lipase (Lpl) as a critical regulator. This was further confirmed by phenome-wide association studies that indicate Lpl associated with hippocampus volume residuals and anxiety-related traits. By performing expression quantitative trait locus mapping, we demonstrate that Lpl is strongly cis-regulated in the BXD hippocampus. We also identified ∼3,300 genes significantly (p < 0.05) correlated with the Lpl expression. Those genes are mainly involved in the regulation of neuron-related traits through the MAPK signaling pathway, axon guidance, synaptic vesicle cycle, and NF-kappa B signaling pathway. Furthermore, a protein–protein interaction network analysis identified several direct interactors of Lpl, including Rab3a, Akt1, Igf1, Crp, and Lrp1, which indicates that Lpl involves in the regulation of cognitive dysfunction through Rab3a-mediated synaptic vesicle cycle and Akt1/Igf1/Crp/Lrp1-mediated MAPK signaling pathway. Our findings demonstrate the importance of the Lpl, among the cholesterol-related genes, in regulating cognitive dysfunction and highlighting the potential signaling pathways, which may serve as novel therapeutic targets for the treatment of cognitive dysfunction.

Hantaan virus (HTNV) is the etiological pathogen of hemorrhagic fever with renal syndrome in East Asia. There are currently no effective therapeutics approved for HTNV and other hantavirus infections. We found that griffithsin (GRFT), an algae-derived lectin with broad-spectrum antiviral activity against various enveloped viruses, can inhibit the growth and spread of HTNV. In vitro experiments using recombinant vesicular stomatitis virus (rVSV) with HTNV glycoproteins as a model revealed that the GRFT inhibited the entry of rVSV-HTNV-G into host cells. In addition, we demonstrated that GRFT prevented authentic HTNV infection in vitro by binding to the viral N-glycans. In vivo experiments showed that GRFT partially protected the suckling mice from death induced by intracranial exposure to HTNV. These results demonstrated that GRFT can be a promising agent for inhibiting HTNV infection.

BackgroundDepression is a serious risk for cardiovascular disease (CVD). Improving depression can alleviate cardiac symptoms and improve quality of life. Studies have shown that acupuncture has a positive effect on depression and CVD. This systematic review and meta-analysis will evaluate the efficacy and safety of acupuncture in the treatment of depression complicated with CVD.MethodsWe searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and China Biomedical Literature databases. Randomized controlled trials of acupuncture vs. standard care or sham acupuncture or antidepressants were included. The retrieval time is from database construction to 07 April 2022. We used the “risk of bias” tool of Cochrane Collaboration, and the Review Manager (RevMan.) Version 5.4.1 for statistics analysis. Primary outcomes included Hamilton scale for depression (HAMD), self-rating depression scale (SDS), and the effective rate of depression. Secondary outcomes included frequency of angina pectoris and visual analogue scale (VAS) scores for angina pain.ResultsA total of 2,366 studies were screened based on the search strategy. Twelve eligible studies with a total of 1,203 participants have been identified. The result showed that acupuncture reduced the HAMD score [weighted mean difference (WMD): −3.23; 95% confidence interval (CI): −5.38 to −1.09; P = 0.003] and the SDS score (WMD: −1.85; 95% CI: −2.14 to −1.56; P < 0.00001) in patients with depression complicated with CVD. Acupuncture also improved the effective rate of depression (risk ratio: 1.15; 95% CI: 1.03 to 1.29; P = 0.01). The result also showed that acupuncture reduced the attack frequency of angina pectoris (WMD: −4.54; 95% CI: −5.96 to −3.11; P < 0.00001) and the VAS score for angina pain (WMD: −0.72; 95% CI: −1.06 to −0.38; P < 0.0001). This article reviewed the significant advantages of acupuncture for depression and the superiority of acupuncture over no-intervention therapy, antidepressant therapy, and psychotherapy in reducing angina frequency and pain intensity in patients with CVD.ConclusionThis systematic review suggested that acupuncture was a good complementary and alternative therapy for CVD complicated with depression. Considering the limitations of the included research literature, it is still necessary to perform multi-center, large-sample, and double-blind high-quality studies to provide higher-level evidence in the later stage.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022304957].

Objective: To compare the rate of refractive growth (RRG3) of the crystalline lens (“lens”) versus the eye excluding the lens (“globe”) for the fellow, noncataractous eyes of participants in the Infant Aphakia Treatment Study. Design: Retrospective cohort study. Subjects: A total of 114 children who had unilateral cataract surgery as infants were recruited. Biometric and refraction data were obtained from the normal eyes at surgery and at 1, 5, and 10 years. Subjects were included if complete data (axial length [AL], corneal power, and refraction) were available at surgery and at 10 years of age. Methods: At surgery and at 1, 5, and 10 years, AL, corneal power, and cycloplegic refraction were measured in the normal eyes. For each eye, the RRG3 was defined by linear regression of refraction at the intraocular lens (IOL) plane against log10 (age + 0.6 years). The RRG3 for the globe was based on IOL power for emmetropia; the RRG3 for the lens was based on IOL power calculated to give the observed refractions. Intraocular lens powers were calculated with the Holladay 1 formula. The means were compared with a paired 2-tailed t test, and linear regression was used to look for a correlation between RRG3 of the lens globe. Main Outcome Measures: The RRG3 of the lens and globe. Results: Complete data were available for 107 normal eyes. The mean RRG3 of the lenses was −12.0 ± 2.5 diopters (D) and the mean RRG3 of the globes was −14.1 ± 2.7 D (P < 0.001). The RRG3 of the lens correlated with the RRG3 of the globe (R2 = 0.25, P < 0.001). Conclusions: The RRG3 was 2 D more negative in globes compared with lenses in normal eyes. Globes with a greater rate of growth tended to have lenses with a greater rate of growth.

BackgroundTrichinella spiralis is a foodborne parasitic nematode which is a serious risk to meat safety. Development of anti-Trichinella vaccine is needed to control Trichinella infection in food animals. In this study, two novel T. spiralis genes (calreticulin and serine protease 1.1) in combination were used to construct oral DNA vaccines, and their induced protective immunity was evaluated in a murine model.Methodology/principal findingsTsCRT+TsSP1.1, TsCRT and TsSP1.1 DNA were transformed into attenuated Salmonella typhimurium ΔcyaSL1344. Oral vaccination of mice with TsCRT+TsSP1.1, TsCRT and TsSP1.1 DNA vaccines elicited a gut local mucosal sIgA response and systemic Th1/Th2 mixed response. Oral vaccination with TsCRT+TsSP1.1 induced obviously higher level of serum specific antibodies, mucosal sIgA and cellular immune response than either of single TsCRT or TsSP1.1 DNA vaccination. Oral vaccination of mice with TsCRT+TsSP1.1 exhibited a 53.4% reduction of enteral adult worms and a 46.05% reduction of muscle larvae, conferred a higher immune protection than either of individual TsCRT (44.28 and 42.46%) or TsSP1.1 DNA vaccine (35.43 and 29.29%) alone. Oral vaccination with TsCRT+TsSP1.1, TsCRT and TsSP1.1 also obviously ameliorated inflammation of intestinal mucosa and skeletal muscles of vaccinated mice after challenge.ConclusionsTsCRT and TsSP1.1 might be regarded the novel potential targets for anti-Trichinella vaccines. Attenuated Salmonella-delivered DNA vaccine provided a prospective approach to control T. spiralis infection in food animals.

ObjectiveTo investigate the prevalence of depression or anxiety in patient with multiple myeloma (MM) in China during maintenance treatment and its associated influencing factors.MethodsPatients with MM (n = 160) received maintenance therapy, and control subjects (without MM, n = 160) matched on age, sex, and BMI were recruited. Patients completed questionnaires, including the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder 7-item Scale (GAD-7), and the Verbal Pain Rating Scale (VPRS). Data on the Clinical characteristics, biochemical indicators of de novo MM were from the database of the Hematology Department of Beijing Chao-yang Hospital. Multiple linear regression model analysis was used to compare the differences in PHQ-9 and GAD-7 scale scores between the control group and the case group after correction for relevant variables. Multiple logistic regression models were subsequently used to analyze the correlation between the presence or absence of anxiety and depression and clinical indicators in the MM groups.ResultsDepression symptoms was present in 33.33% and anxiety symptoms in 24.68% of first-episode MM in the maintenance phase of treatment, and depression symptoms in the index-corrected MM group was significantly different from that in the control group (t = 2.54, P < 0.05). Analyses of multiple logistic regressions: biochemical indicators and clinical typing were not significantly associated with anxiety and depression. Compared to the pain rating 1, the risk of depressive mood was greater in the case group with the pain rating 2 (OR = 2.38) and the pain rating ≥ 3 (OR = 4.32). The risk of anxiety was greater in the case group with the pain rating ≥ 3 than the pain rating 1 (OR = 2.89).ConclusionDespite being in clinical remission, depressive mood problems in patients with MM remain prominent. Clinicians should enhance mood assessment and management in patients with concomitant pain.

IntroductionTherapeutic strategies aimed at reactivating HBG gene transcription and fetal hemoglobin (HbF) synthesis remain the most effective strategy to ameliorate the clinical symptoms of sickle cell disease (SCD). We previously identified microRNA29B (MIR29B) as a novel HbF inducer via targeting enzymes involved in DNA methylation. We provided further evidence that the introduction of MIR29B into KU812 leukemia cells significantly reduced MYB protein expression. Therefore, the aim of this study was to determine the extent to which MIR29B mediates HbF induction via targeting MYB in KU812 leukemia cells and human primary erythroid progenitors and to investigate the role of MIR29B in HbF induction in vivo in the humanized Townes SCD mouse model.Materials and methodsHuman KU812 were cultured and normal CD34 cells (n = 3) were differentiated using a two-phase erythropoiesis culturing system and transfected with MIR29B (50 and 100 nM) mimic or Scrambled (Scr) control in vitro. A luciferase reporter plasmid overexpressing MYB was transfected into KU812 cells. Luciferase activity was quantified after 48 h. Gene expression was determined by quantitative real-time PCR. In vivo studies were conducted using Townes SCD mice (6 per group) treated with MIR29B (2, 3, and 4 mg/kg/day) or Scr control by 28-day continuous infusion using subcutaneous mini osmotic pumps. Blood samples were collected and processed for complete blood count (CBC) with differential and reticulocytes at weeks 0, 2, and 4. Flow cytometry was used to measure the percentage of HbF-positive cells.ResultsIn silico analysis predicted complementary base-pairing between MIR29B and the 3′-untranslated region (UTR) of MYB. Overexpression of MIR29B significantly reduced MYB mRNA and protein expression in KU812 cells and erythroid progenitors. Using a luciferase reporter vector that contained the full-length MYB 3′-UTR, we observed a significant reduction in luciferase activity among KU812 cells that co-expressed MIR29B and the full-length MYB 3′-UTR as compared to cells that only expressed MYB 3′-UTR. We confirmed the inhibitory effect of a plasmid engineered to overexpress MYB on HBG activation and HbF induction in both KU812 cells and human primary erythroid progenitors. Co-expression of MIR29B and MYB in both cell types further demonstrated the inhibitory effect of MIR29B on MYB expression, resulting in HBG reactivation by real-time PCR, Western blot, and flow cytometry analysis. Finally, we confirmed the ability of MIR29B to reduce sickling and induce HbF by decreasing expression of MYB and DNMT3 gene expression in the humanized Townes sickle cell mouse model.DiscussionOur findings support the ability of MIR29B to induce HbF in vivo in Townes sickle cell mice. This is the first study to provide evidence of the ability of MIR29B to modulate HBG transcription by MYB gene silencing in vivo. Our research highlights a novel MIR-based epigenetic approach to induce HbF supporting the discovery of new drugs to expand treatment options for SCD.

The efficacy of treating solid tumors with chemotherapy is primarily hindered by dose-limiting toxicity due to off-target effects and the heterogeneous drug distribution caused by the dense extracellular matrix. The enhanced permeability and retention (EPR) effect within tumors restricts the circulation and diffusion of drugs. To overcome these obstacles, hydrogels formed in situ at the tumor site have been proposed to promote drug accumulation, retention, and long-lasting release. We developed a thiolated chitosan (CSSH) hydrogel with a gelation point of 37°C. Due to the pH-sensitive characteristics of disulfides, the prepared hydrogel facilitated drug release in the acidic tumor environment. A drug release system composed of hydrophilic doxorubicin (Dox) and hydrophobic liposome-encapsulated curcumin (Cur–Lip) was designed to enhance the long-lasting therapeutic impacts and reduce adverse side effects. These composite gels possess a suitable gelation time of approximately 8–12 min under physiological conditions. The cumulative release ratio was higher at pH = 5.5 than at pH = 7.4 over the first 24 h, during which approximately 10% of the Dox was released, and Cur was released slowly over the following 24–120 h. Cell assays indicated that the Cur–Lip/Dox/CSSH gels effectively inhibited the growth of cancer cells. These in situ-formed Cur–Lip/Dox gels with long-term drug release capabilities have potential applications for tumor suppression and tissue regeneration after surgical tumor resection.

[INLINE:1] Alzheimer’s disease (AD) is affected by genetic factors. Polymorphisms in the glutathione S-transferase omega-1 (Gsto1) gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD. Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to characterize the mechanisms underlying regulation of Gsto1 variation regulation and to identify network members that may contribute to AD risk or progression. Allele-specific assays confirmed that variation in Gsto1 expression is controlled by cis-expression quantitative trait loci. We found that Gsto1 mRNA levels were related to several central nervous system traits, such as glial acidic fibrillary protein levels in the caudate putamen, cortical gray matter volume, and hippocampus mossy fiber pathway volume. We identified 2168 genes whose expression was highly correlated with that of Gsto1. Some genes were enriched for the most common neurodegenerative diseases. Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD, such as APP, Grin2b, Ide, and Psenen. To evaluate the relationships between Gsto1 and candidate network members, we transfected astrocytes with Gsto1 siRNA and assessed the effect on putative downstream effectors. We confirmed that knockdown of Gsto1 had a significant influence on Pa2g4 expression, suggesting that Pa2g4 may be a downstream effector of Gsto1, and that both genes interact with other genes in a network during AD pathogenesis.

Since COVID-19 emerged in 2019, significant levels of suffering and disruption have been caused on a global scale. Although vaccines have become widely used, the virus has shown its potential for evading immunities or acquiring other novel characteristics. Whether current drug treatments are still effective for people infected with Omicron remains unclear. Due to the long development cycles and high expense requirements of de novo drug development, many researchers have turned to consider drug repositioning in the search to find effective treatments for COVID-19. Here, we review such drug repositioning and combination efforts towards providing better handling. For potential drugs under consideration, aspects of both structure and function require attention, with specific categories of sequence, expression, structure, and interaction, the key parameters for investigation. For different data types, we show the corresponding differing drug repositioning methods that have been exploited. As incorporating drug combinations can increase therapeutic efficacy and reduce toxicity, we also review computational strategies to reveal drug combination potential. Taken together, we found that graph theory and neural network were the most used strategy with high potential towards drug repositioning for COVID-19. Integrating different levels of data may further improve the success rate of drug repositioning.

Abstract Background The outbreak of Covid-19 had negative impacts on the mental stress and induced psychological distress among university students worldwide. This study proposed a moderated mediation model, and hypothesized that the Covid-19 pandemic-related stress was positively related to depressive symptoms among international medical students. Methods An online survey on stress and depressive symptoms of international students was conducted in a medical university. Questions on Covid-19 pandemic-related stress, Patient Health Quesionnaire-9, Simplified Coping Style Questionnaire and the Perceived Social Support Scale were used as measurements, and model analyses were conducted using Hayes’ PROCESS macro for SPSS. Results It was found that 9.83%, 3.08% and 2.12% students had mild, moderate and severe depressive symptoms, respectively, and the positive association between Covid-19 pandemic-related stress and depressive symptoms was significant (β = 0.27, t = 6.87, P

Abstract Tumor metastasis is a hallmark of cancer. The communication between cancer-derived exosomes and stroma plays an irreplaceable role in facilitating pre-metastatic niche formation and cancer metastasis. However, the mechanisms underlying exosome-mediated pre-metastatic niche formation during colorectal cancer (CRC) liver metastasis remain incompletely understood. Here we identified HSPC111 was the leading upregulated gene in hepatic stellate cells (HSCs) incubated with CRC cell-derived exosomes. In xenograft mouse model, CRC cell-derived exosomal HSPC111 facilitated pre-metastatic niche formation and CRC liver metastases (CRLM). Consistently, CRC patients with liver metastasis had higher level of HSPC111 in serum exosomes, primary tumors and cancer-associated fibroblasts (CAFs) in liver metastasis than those without. Mechanistically, HSPC111 altered lipid metabolism of CAFs by phosphorylating ATP-citrate lyase (ACLY), which upregulated the level of acetyl-CoA. The accumulation of acetyl-CoA further promoted CXCL5 expression and secretion by increasing H3K27 acetylation in CAFs. Moreover, CXCL5-CXCR2 axis reinforced exosomal HSPC111 excretion from CRC cells and promoted liver metastasis. These results uncovered that CRC cell-derived exosomal HSPC111 promotes pre-metastatic niche formation and CRLM via reprogramming lipid metabolism in CAFs, and implicate HSPC111 may be a potential therapeutic target for preventing CRLM.

Abstract Gland macrophages are primed for gland development and functions through interactions within their niche. However, the phenotype, ontogeny, and function of steady-state salivary gland (SG) macrophages remain unclear. We herein identified CD11c+ and CD11c− subsets among CD64+ macrophages in steady-state murine SGs. CD11c− macrophages were predominant in the SGs of embryonic and newborn mice and decreased with advancing age. CD11c+ macrophages were rarely detected in the embryonic period, but rapidly expanded after birth. CD11c+, but not CD11c−, macrophage numbers decreased in mice treated with a CCR2 antagonist, suggesting that CD11c+ macrophages accumulate from bone marrow-derived progenitors in a CCR2-dependent manner, whereas CD11c− macrophages were derived from embryonic progenitors in SGs. CD11c+ and CD11c− macrophages strongly expressed colony-stimulating factor (CSF)-1 receptor, the injection of an anti-CSF-1 receptor blocking antibody markedly reduced both subsets, and SGs strongly expressed CSF-1, indicating the dependency of SG resident macrophage development on CSF-1. The phagocytic activity of SG macrophages was extremely weak; however, the gene expression profile of SG macrophages indicated that SG macrophages regulate gland development and functions in SGs. These results suggest that SG CD11c+ and CD11c− macrophages are developed and instructed to perform SG-specific functions in steady-state SGs.

Abstract Background Natural variation in protein expression is common in all organisms and contributes to phenotypic differences among individuals. While variation in gene expression at the transcript level has been extensively investigated, the genetic mechanisms underlying variation in protein expression have lagged considerably behind. Here we investigate genetic architecture of protein expression by profiling a deep mouse brain proteome of two inbred strains, C57BL/6 J (B6) and DBA/2 J (D2), and their reciprocal F1 hybrids using two-dimensional liquid chromatography coupled with tandem mass spectrometry (LC/LC-MS/MS) technology. Results By comparing protein expression levels in the four mouse strains, we observed 329 statistically significant differentially expressed proteins between the two parental strains and characterized the genetic basis of protein expression. We further applied a proteogenomic approach to detect variant peptides and define protein allele-specific expression (pASE), identifying 33 variant peptides with cis-effects and 17 variant peptides showing trans-effects. Comparison of regulation at transcript and protein levels show a significant divergence. Conclusions The results provide a comprehensive analysis of genetic architecture of protein expression and the contribution of cis- and trans-acting regulatory differences to protein expression.

Objective To evaluate the outcomes of cervical spondylotic radiculopathy secondary to bony foraminal stenosis treated with anterior cervical discectomy and fusion (ACDF) combined with anterior cervical foraminotomy (ACF) assisted by High‐Definition 3‐Dimensional Exoscope. Methods In this retrospective study, a total of 19 consecutive patients (12 males and seven females, with an average of 49.2 years, range from 40 to 59 years) with spondylotic radiculopathy caused by bony foraminal stenosis underwent ACDF combined with ACF assisted by High‐Definition 3‐Dimensional Exoscope in our hospital between January 2019 and December 2019 were included in this study. All patients signed the consent form before the surgery. The patient baseline information such as gender, age, body mass index (BMI), surgery time, blood loss, hospital stay, lesion segment, side, follow‐up time and postoperative complications were recorded. The Japanese Orthopedic Association (JOA), Neck Disability Index (NDI), and Visual Analogue Scale (VAS) were measured and compared before surgery, 1 months and final follow‐up after surgery. The radiographic outcomes were evaluated using the C2‐C7 angel, disc height, foraminal height, superior diagonal distance, inferior diagonal distance, and foraminal area. Results The involved levels included C4‐C5 (six cases), C5‐C6 (10 cases), C6‐C7 (three cases). The mean duration of the surgery, mean blood loss, mean hospital stay, and mean follow‐up were 100 ± 11.10 min, 19.4 ± 7.05 mL, 7.1 ± 0.99 days, and 12.1 ± 2.25 months, respectively. The average preoperative JOA score was 11.9 ± 1.31, then improved to 15.7 ± 0.73 (t = −13.45, P

Abstract Background Diagnosing seronegative rheumatoid arthritis (RA) can be challenging due to complex diagnostic criteria. We sought to discover diagnostic biomarkers for seronegative RA cases by studying metabolomic and lipidomic changes in RA patient serum. Methods We performed comprehensive metabolomic and lipidomic profiling in serum of 225 RA patients and 100 normal controls. These samples were divided into a discovery set (n = 243) and a validation set (n = 82). A machine-learning-based multivariate classification model was constructed using distinctive metabolites and lipids signals. Results Twenty-six metabolites and lipids were identified from the discovery cohort to construct a RA diagnosis model. The model was subsequently tested on a validation set and achieved accuracy of 90.2%, with sensitivity of 89.7% and specificity of 90.6%. Both seropositive and seronegative patients were identified using this model. A co-occurrence network using serum omics profiles was built and parsed into six modules, showing significant association between the inflammation and immune activity markers and aberrant metabolism of energy metabolism, lipids metabolism and amino acid metabolism. Acyl carnitines (20:3), aspartyl-phenylalanine, pipecolic acid, phosphatidylethanolamine PE (18:1) and lysophosphatidylethanolamine LPE (20:3) were positively correlated with the RA disease activity, while histidine and phosphatidic acid PA (28:0) were negatively correlated with the RA disease activity. Conclusions A panel of 26 serum markers were selected from omics profiles to build a machine-learning-based prediction model that could aid in diagnosing seronegative RA patients. Potential markers were also identified in stratifying RA cases based on disease activity.

Abstract Posterior reversible encephalopathy syndrome (PRES) is a rare clinical disease that refers to the subcortical vasogenic edema involving bilateral parieto-occipital regions, with a usually reversible syndrome when causes are eliminated or controlled. Hypertension or blood pressure fluctuations are most common causes of PRES, but other contributors like chemotherapy and autoimmune disorders have also been reported. PRES has rapid onset of symptoms. Therefore, it is of major importance to determine whether blood pressure management plays an important role in prognosis. We presented two PRES patients who developed non-convulsive seizure but had normal baseline blood pressure at the time of presence of cause. The diagnosis of PRES was made by neurologists. The patients had no history of seizure or hypertension, but during the disease course they presented with temporal elevation of blood pressure with different durations. The second patients without instant blood pressure control developed residual symptoms of seizure at 90- and 120-day follow-up. Although the exact pathophysiology of PRES remains to be fully understood, primary and secondary prolonged blood pressure fluctuations may be associated with the prognosis of this syndrome. Early blood pressure management would be critical to favorable outcome.

Objective The purpose of this study was to explore the application value of digital surgery in the reconstruction of mandibular composite defects with a chimeric deep circumflex iliac artery perforator flap (DCIAPF). Methods Six patients with complex defects within half of the mandible underwent reconstruction using DCIAPF from January 2019 to January 2020 in Shenzhen People’s Hospital. Doppler was used to locate the deep iliac circumflex artery, the range of mandibular osteotomy was designed, and DCIAPF was used to repair the mandibular composite under the guidance of the guide plate during the operation. Twelve months postoperatively, the facial shape, jaw height, and occlusal relationship were evaluated.Results DCIAPF was harvested successfully in 6 patients, and the heights of all alveolar ridges and occlusal function of patients were significantly restored, without pain or snapping in the temporomandibular joint area. Conclusion The blood supply of DCIAPF is rich, and soft-bone tissue is sufficient for the reconstruction of mandibular composite defects. Combined with digital surgery, the accuracy and safety are improved

AIM:To investigate the efficacy and safety of different fillers combined with vitrectomy and internal limiting membrane stripping in the treatment of idiopathic macular hole(IMH).METHODS: This retrospective study included 117 patients(117 eyes)with IMH who were admitted to the department of ophthalmology in the hospital between July 2018 and March 2020. Both groups were treated with vitrectomy combined with internal limiting membrane stripping. Sixty-five patients(65 eyes)receiving air filling were included in the air group, while 52 cases(52 eyes)receiving C3F8 filling were included in the C3F8 group. Re-examination was performed before operation and at 1, 2, and 3mo after operation. The rate of hole closure, closed shape, visual acuity, central macular thickness(CRT), exterior limiting membrane(ELM)defect diameter, ellipsoid band defect diameter, intraocular pressure, and the incidence of postoperative complications at the last follow-up were counted. RESULTS: The postoperative air absorption time of air group and C3F8 group was 8.55±2.17d and 25.74±7.41d, respectively(P0.05). There were no significant differences in the proportions of different shapes of closed holes between the two groups(P>0.05). Visual acuity of the two groups was significantly improved at 3mo after operation(P0.05). The CRT was increased significantly after operation(P0.05). There was no significant difference in intraocular pressure between the two groups before and after treatment(P>0.05). No serious complications were observed in the two groups. CONCLUSION: Vitrectomy and internal limiting membrane stripping combined with air filling and C3F8 filling are effective and safe in the treatment of IMH. Clinically, the operation mode can be selected according to the actual situation.

Abstract The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.

Abstract Background Weifuchun (WFC), a Chinese herbal prescription consisting of Red Ginseng, Isodon amethystoides and Fructus Aurantii, is commonly used in China to treat a variety of chronic stomach disorders. The aim of the paper was to determine the effect of WFC on intestinal microbiota changes in precancerous lesions of gastric cancer (PLGC) patients. Methods PLGC patients of H. pylori negative were randomly divided into two groups and received either WFC tablets for a dose of 1.44 g three times a day or vitacoenzyme (Vit) tablets for a dose of 0.8 g three times a day. All patients were treated for 6 months consecutively. Gastroscopy and histopathology were used to assess the histopathological changes in gastric tissues before and after treatment. 16S rRNA gene sequencing was carried out to assess the effects WFC on intestinal microbiota changes in PLGC patients. Receiver Operating Characteristics (ROC) analysis was used to assess the sensitivity and specificity of different intestinal microbiota in distinguishing between PLGC patients and healthy control group. Results Gastroscopy and histopathological results indicated that WFC could improve the pathological condition of PLGC patients, especially in the case of atrophy or intestinal metaplasia. The results of 16S rRNA gene sequencing indicated that WFC could regulate microbial diversity, microbial composition, and abundance of the intestinal microbiota of PLGC patients. Following WFC treatment, the relative abundance of Parabacteroides decreased in WFC group when compared with the Vit group. ROC analysis found that the Parabacteroides could effectively distinguish PLGC patients from healthy individuals with sensitivity of 0.79 and specificity of 0.8. Conclusions WFC could slow down the progression of PLGC by regulating intestinal microbiota abundance. Trial registration NCT03814629. Name of registry: Randomized Clinical Trial: Weifuchun Treatment on Precancerous Lesions of Gastric Cancer. Registered 3 August 2018-Retrospectively registered, https://register.clinicaltrials.gov/ NCT03814629.

Abstract The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses. Golgi membrane protein 1 (GOLM1) is correlated to hepatocellular carcinoma (HCC) progression and metastasis. However, little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC. In this study, GOLM1 was positively correlated with infiltrating tumor-associated macrophages (TAMs) expressed high levels of programmed death-ligand 1 (PD-L1) and CD8+ T cell suppression in HCC tissues. Both gain- and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression. In the mechanism, GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression. Furthermore, co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages. Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1+ TAMs infiltration and alleviated CD8+ T cell suppression, resulting in tumor growth inhibition in the mouse HCC model. Together, our study unveils a mechanism by which GOLM1 induces CD8+ T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent. Targeting PD-L1+ TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.

SARS-CoV-2 was detected in mink farms in the Netherlands in the first wave of the pandemic with evidence of human-to-mink and mink-to-human transmission. Here, the authors investigate this outbreak using phylodynamic analysis and show that personnel links and spatial proximity are predictors of transmission between farms.

Editor's Note: this Article has been retracted; the Retraction Note is available at https://doi.org/10.1038/s41598-023-32251-x

The phytohormone abscisic acid (ABA) plays important roles in response to abiotic and biotic stresses in plants. Pyrabactin resistance 1-like (PYR/PYL) proteins are well-known as ABA receptors, which are responsible for ABA signal transduction. Nevertheless, the characteristics of PYL genes from Liriodendron chinense, an endangered timber tree, remain unclear in coping with various stresses. In this study, five PYLs were identified from the genome of Liriodendron chinense by sequence alignment and conserved motif analysis, which revealed that these LcPYLs contain a conserved gate and latch motif for ABA binding. The LcPYL promoters possess a series of cis-acting elements involved in response to various hormone and abiotic stresses. Moreover, the transcriptome data of Liriodendron hybrid leaves reveal that LcPYL genes specifically transcript under different abiotic stresses; Lchi11622 transcription was induced by drought and cold treatment, and Lchi01385 and Lchi16997 transcription was upregulated under cold and hot stress, respectively. Meanwhile, the LcPYLs with high expression levels shown in the transcriptomes were also found to be upregulated in whole plants treated with the same stresses tested by qPCR. Moreover, under biotic stress caused by scale insect and whitefly, Liriodendron hybrid leaves exhibited a distinct phenotype including disease spots that are dark green in the middle and yellow on the margin; the qPCR results showed that the relative expression levels of Lchi13641 and Lchi11622 in infected leaves were upregulated by 1.76 and 3.75 folds relative to normal leaves, respectively. The subcellular localizations of these stress-responsive LcPYLs were also identified in protoplasts of Liriodendron hybrid. These results provide a foundation to elucidate the function of PYLs from this elite tree species and assist in understanding the molecular mechanism of Liriodendron hybrid in dealing with abiotic and biotic stresses. In future research, the detailed biological function of LcPYLs and the genetic redundancy between LcPYLs can be explored by gene overexpression and knockout based on this study.

Surface incident solar radiation (Rs) plays an important role in climate change on Earth. Recently, the use of satellite-retrieved datasets to obtain global-scale Rs with high spatial and temporal resolutions has become an indispensable tool for research in related fields. Many studies were carried out for Rs evaluation based on the monthly satellite retrievals; however, few evaluations have been performed on their diurnal variation in Rs. This study used independently widely distributed ground-based data from the Baseline Surface Radiation Network (BSRN) to evaluate hourly Rs from the Clouds and the Earth’s Radiant Energy System Synoptic (CERES) SYN1deg–1Hour product through a detrended standardization process. Furthermore, we explored the influence of cloud cover and aerosols on the diurnal variation in Rs. We found that CERES-retrieved Rs performs better at midday than at 7:00–9:00 and 15:00–17:00. For spatial distribution, CERES-retrieved Rs performs better over the continent than over the island/coast and polar regions. The Bias, MAB and RMSE in CERES-retrieved Rs under clear-sky conditions are rather small, although the correlation coefficients are slightly lower than those under overcast-sky conditions from 9:00 to 15:00. In addition, the range in Rs bias caused by cloud cover is 1.97–5.38%, which is significantly larger than 0.31–2.52% by AOD.

Fencing enclosures play an important role in improving ecological quality. There is a direct impact of implementing fencing enclosures on the change in soil quality. The soil quality index was used to examine the effects of fencing enclosures for different years (7 and 11 years) on soil quality in Biru County of Qinghai–Tibet Plateau, China. The fencing enclosure significantly increased soil water content, non-capillary porosity, soil organic matter, total nitrogen, total phosphorus, and alkali-hydrolyzable nitrogen, and significantly decreased the soil bulk density. The soil quality gradually improved as the fencing enclosure time length increased, probably due to the increase of vegetation coverage and biomass under the fencing enclosure. The minimum data set was composed of soil organic matter, capillary porosity, total potassium, and non-capillary porosity. The minimum data set was significantly correlated with the total data set and could replace the total data set for soil quality evaluation in the fencing enclosure project area. In summary, our study reflects that fencing enclosures significantly improve soil quality, and the implementation of the fencing enclosure project will effectively curb land degradation in Biru County of the Qinghai–Tibet Plateau, China.

We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral activity. Therefore, we designed and synthesized a dePEGylated lipopeptide, EKL1C, by replacing the PEG linker in EK1C4 with a short peptide. Similar to EK1C4, EKL1C displayed potent inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses. In this study, we found that EKL1C also exhibited broad-spectrum fusion inhibitory activity against human immunodeficiency virus type 1 (HIV-1) infection by interacting with the N-terminal heptad repeat 1 (HR1) of viral gp41 to block six-helix bundle (6-HB) formation. These results suggest that HR1 is a common target for the development of broad-spectrum viral fusion inhibitors and EKL1C has potential clinical application as a candidate therapeutic or preventive agent against infection by coronavirus, HIV-1, and possibly other class I enveloped viruses.

Background: Hepatocellular carcinoma (HCC) is a life-threatening human malignancy and the fourth leading cause of cancer-related deaths worldwide. Patients with HCC are often diagnosed at an advanced stage with a poor prognosis. Sorafenib is a multikinase inhibitor used as the first-line treatment for patients with advanced HCC. However, acquired resistance to sorafenib in HCC leads to tumor aggression and limits the drug’s survival benefits; the underlying molecular mechanisms for this resistance remain unclear. Methods: This study aimed to examine the role of the tumor suppressor RBM38 in HCC, and its potential to reverse sorafenib resistance. In addition, the molecular mechanisms underlying the binding of RBM38 and the lncRNA GAS5 were examined. The potential involvement of RBM38 in sorafenib resistance was examined using both in vitro and in vivo models. Functional assays were performed to assess whether RBM38: binds to and promotes the stability of the lncRNA GAS5; reverses the resistance of HCC to sorafenib in vitro; and suppresses the tumorigenicity of sorafenib-resistant HCC cells in vivo. Results: RBM38 expression was lower in HCC cells. The IC50 value of sorafenib was significantly lower in cells with RBM38 overexpression than in control cells. RBM38 overexpression improved sorafenib sensitivity in ectopic transplanted tumors and suppressed the growth rate of tumor cells. RBM38 could bind to and stabilize GAS5 in sorafenib-resistant HCC cells. In addition, functional assays revealed that RBM38 reversed sorafenib resistance both in vivo and in vitro in a GAS5-dependent manner. Conclusions: RBM38 is a novel therapeutic target that can reverse sorafenib resistance in HCC by combining and promoting the lncRNA GAS5.

Nucleotide-binding and oligomerization domain-like receptors (NOD-like receptors, NLRs) can regulate the inflammatory response to eliminate pathogens and maintain the host’s homeostasis. In this study, the head kidney macrophages of Siberian sturgeon were treated with lipopolysaccharide (LPS) to induce inflammation by evaluating the expression of cytokines. The high-throughput sequencing for macrophages after 12 h treatment showed that 1224 differentially expressed genes (DEGs), including 779 upregulated and 445 downregulated, were identified. DEGs mainly focus on pattern recognition receptors (PRRs) and the adaptor proteins, cytokines, and cell adhesion molecules. In the NOD-like receptor signaling pathway, multiple NOD-like receptor family CARD domains containing 3-like (NLRC3-like) were significantly downregulated, and pro-inflammatory cytokines were upregulated. Based on the transcriptome database, 19 NLRs with NACHT structural domains were mined and named in Siberian sturgeon, including 5 NLR-A, 12 NLR-C, and 2 other NLRs. The NLR-C subfamily had the characteristics of expansion of the teleost NLRC3 family and lacked the B30.2 domain compared with other fish. This study revealed the inflammatory response mechanism and NLRs family characterization in Siberian sturgeon by transcriptome and provided basic data for further research on inflammation in teleost.

The high vascularization of glioma highlights the potential value of anti-angiogenic therapeutics for glioma treatment. Previously, we designed a novel vascular-targeting and blood–brain barrier (BBB)-penetrating peptide, TAT-AT7, by attaching the cell-penetrating peptide TAT to a vascular-targeting peptide AT7, and we demonstrated that TAT-AT7 could target binding to the vascular endothelial growth factor receptor 2 (VEGFR-2) and Neuropilin-1 (NRP-1), which are both highly expressed in endothelial cells. TAT-AT7 has been proven to be a good targeting peptide which could effectively deliver the secretory endostatin gene to treat glioma via the TAT-AT7-modified polyethyleneimine (PEI) nanocomplex. In the current study, we further explored the molecular binding mechanisms of TAT-AT7 to VEGFR-2 and NRP-1 and its anti-glioma effects. Accordingly, TAT-AT7 was proven to competitively bind to VEGFR-2 and NRP-1 and prevent VEGF-A165 binding to the receptors by the surface plasmon resonance (SPR) assay. TAT-AT7 inhibited endothelial cells’ proliferation, migration, invasion, and tubule formation, as well as promoted endothelial cells’ apoptosis in vitro. Further research revealed that TAT-AT7 inhibited the phosphorylation of VEGFR-2 and its downstream PLC-γ, ERK1/2, SRC, AKT, and FAK kinases. Additionally, TAT-AT7 significantly inhibited angiogenesis of zebrafish embryo. Moreover, TAT-AT7 had a better penetrating ability and could penetrate the BBB into glioma tissue and target glioma neovascularization in an orthotopic U87-glioma-bearing nude mice model, and exhibited the effect of inhibiting glioma growth and angiogenesis. Taken together, the binding and function mechanisms of TAT-AT7 were firstly revealed, and TAT-AT7 was proven to be an effective and promising peptide for the development of anti-angiogenic drugs for targeted treatment of glioma.

ObjectiveTo investigate whether an acclimatization period should be introduced into the home cage experiment for the detection of metabolic function in mice, and how to judge and set its length.MethodsData from 31 home cage experiments in 2016-2017 were collected, and each experiment was set up with a 3-day (72 hours) acclimatization period. Data such as water consumption, food intake, heat production, and body weight were recorded. The data were analyzed using 24-hour interval analysis to determine the acclimatization effect.ResultsApproximately 12% of the 356 mice drank less than 1 mL at the end of 96 hours. There were significant differences in water consumption, food intake, heat production rate, and body weight between 24-48 hours and 48-72 hours, but no significant differences were detected between 48-72 hours and 72-96 hours, except in food intake. Independent verification of the food intake of each experiment showed that there was a significant correlation between food intake adaptability and weight.ConclusionApproximately 12% of the mice were unable to learn or adapt to the new water bottle after the 72-hour acclimatization period, therefore, researchers should consider increasing the sample size of the experiment to eliminate invalid data. If food intake is not the focus of a study, the 48-hour acclimatization is sufficient to obtain reliable results.

PurposeTo investigate cortical differences, age-related cortical differences, and structural covariance differences between children with intermittent exotropia (IXT) and healthy controls (HCs) using high-resolution magnetic resonance imaging (MRI).MethodsSixteen IXT patients and 16 HCs underwent MRI using a 3-T MR scanner. FreeSurfer software was used to obtain measures of cortical volume, thickness, and surface area. Group differences in cortical thickness, volume and surface area were examined using a general linear model with intracranial volume (ICV), age and sex as covariates. Then, the age-related cortical differences between the two groups and structural covariance in abnormal morphometric changes were examined.ResultsCompared to HCs, IXT patients demonstrated significantly decreased surface area in the left primary visual cortex (PVC), and increased surface area in the left inferior temporal cortex (ITC). We also found increased cortical thickness in the left orbitofrontal cortex (OFC), right middle temporal cortex (MT), and right inferior frontal cortex (IFC). No significant differences were found in cortical volume between the two groups. There were several negative correlations between neuroanatomic measurements and age in the HC group that were not observed in the IXT group. In addition, we identified altered patterns of structural correlations across brain regions in patients with IXT.ConclusionTo our knowledge, this study is the first to characterize the cortical morphometry of the children and adolescents with IXT. Based on our results, children and adolescents with IXT exhibited significant alterations in the PVC and association cortices, different cortical morphometric development patterns, and disrupted structural covariance across brain regions.

Fruit branch angle (FBA), a pivotal component of cotton plant architecture, is vital for field and mechanical harvesting. However, the molecular mechanism of FBA formation is poorly understood in cotton. To uncover the genetic basis for FBA formation in cotton, we performed a genome-wide association study (GWAS) of 163 cotton accessions with re-sequencing data. A total of 55 SNPs and 18 candidate genes were significantly associated with FBA trait. By combining GWAS and transcriptome analysis, four genes underlying FBA were identified. An FBA-associated candidate gene Ghi_A09G08736, which is homologous to SAUR46 in Arabidopsis thaliana, was detected in our study. In addition, transcriptomic evidence was provided to show that gravity and light were implicated in the FBA formation. This study provides new insights into the genetic architecture of FBA that informs architecture breeding in cotton.

Pectobacterium brasiliense (P. brasiliense) is a necrotrophic bacterium that causes the soft rot disease in Brassica rapa. However, the mechanisms underlying plant immune responses against necrotrophic bacterial pathogens with a broad host range are still not well understood. Using a flg22-triggered seedling growth inhibition (SGI) assay with 455 Brassica rapa inbred lines, we selected six B. rapa flagellin-insensitive lines (Brfin2-7) and three B. rapa flagellin-sensitive lines (Brfs1-3). Brfin lines showed compromised flg22-induced immune responses (oxidative burst, mitogen-activated protein kinase (MAPK) activation, and seedling growth inhibition) compared to the control line R-o-18; nevertheless, they were resistant to P. brasiliense. To explain this, we analyzed the phytohormone content and found that most Brfin lines had higher P. brasiliense-induced jasmonic acid (JA) than Brfs lines. Moreover, MeJA pretreatment enhanced the resistance of B. rapa to P. brasiliense. To explain the correlation between the resistance of Brfin lines to P. brasiliense and activated JA signaling, we analyzed pathogen-induced glucosinolate (GS) content in B. rapa. Notably, in Brfin7, the neoglucobrassicin (NGBS) content among indole glucosinolates (IGS) was significantly higher than that in Brfs2 following P. brasiliense inoculation, and genes involved in IGSs biosynthesis were also highly expressed. Furthermore, almost all Brfin lines with high JA levels and resistance to P. brasiliense had higher P. brasiliense-induced NGBS levels than Brfs lines. Thus, our results show that activated JA-mediated signaling attenuates flg22-triggered immunity but enhances resistance to P. brasiliense by inducing indole glucosinolate biosynthesis in Brassica rapa. This study provides novel insights into the role of JA-mediated defense against necrotrophic bacterial pathogens within a broad host range.

Health risks caused by crucial environmental carcinogens N-nitrosamines triggered ubiquitous attention. As the liver exerted vital function through metabolic process, lipid metabolism disorders have been confirmed as potential drivers for toxicological effects, and the mechanisms of lipid regulation related to hepatotoxicity induced by N-nitrosamines remained largely unclear. In this study, we comprehensively explored the disturbance of hepatic lipid homeostasis in mice induced by nitrosamines. The results implied that nitrosamines exposure induced hepatotoxicity accompanied by liver injury, inflammatory infiltration, and hepatic edema. Lipidomics profiling analysis indicated the decreased levels of phosphatidic acids (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), lyso-phosphatidylcholines (LPC), lyso-phosphatidylethanolamines (LPE), diacylglycerols (DAG) and triacylglycerols (TAG), the elevation of ceramides (Cer) and decomposition of free fatty acids (FFA) in high-dose nitrosamines exposure group. Importantly, nitrosamines exposure promoted fatty acid oxidation (FAO) by facilitating fatty acid uptake and decomposition, together with the upregulation of genes associated with FAO accompanied by the activation of inflammatory cytokines TNF-α, IL-1β and NLRP3. Furthermore, fatty acid translocase CD36-mediated fatty acid oxidation was correlated with the enhancement of oxidative stress in the liver caused by nitrosamines exposure. Overall, our results contributed to the new strategies to interpret the early toxic effects of nitrosamines exposure.

The plant-specific module of calcineurin B-like proteins (CBLs) and CBL-interacting protein kinases (CIPKs) play a crucial role in plant adaptation to different biotic and abiotic stresses in various plant species. Despite the importance of the CBL-CIPK module in regulating plant salt tolerance, few halophyte CIPK orthologs have been studied. We identified NbCIPK25 in the halophyte Nitraria billardieri as a salt-responsive gene that may improve salt tolerance in glycophytes. Sequence analyses indicated that NbCIPK25 is a typical CIPK family member with a conserved NAF motif, which contains the amino acids: asparagine, alanine, and phenylalanine. NbCIPK25 overexpression in salt-stressed transgenic Arabidopsis seedlings resulted in enhanced tolerance to salinity, a higher survival rate, longer newly grown roots, more root meristem cells, and less damaged root cells in comparison to wild-type (WT) plants. H2O2 accumulation and malondialdehyde (MDA) content were both deceased in NbCIPK25-transgenic plants under salt treatment. Furthermore, their proline content, an important factor for scavenging reactive oxygen species, accumulated at a significantly higher level. In concordance, the transcription of genes related to proline accumulation was positively regulated in transgenic plants under salt condition. Finally, we observed a stronger auxin response in salt-treated transgenic roots. These results provide evidence for NbCIPK25 improving salt tolerance by mediating scavenging of reactive oxygen species, thereby protecting cells from oxidation and maintaining plant development under salt stress. These findings suggest the potential application of salt-responsive NbCIPK25 for cultivating glycophytes with a higher salt tolerance through genetic engineering.

Colorectal cancer (CRC) is one of the most common malignant carcinomas. CRC is characterized by asymptomatic onset, and most patients are already in the middle and advanced stages of disease when they are diagnosed. Inflammatory bowel disease (IBD) and the inflammatory-cancer transformation of advanced colorectal adenoma are the main causes of CRC. There is an urgent need for effective prevention and intervention strategies for CRC. In recent years, rapid research progress has increased our understanding of gut microbiota. Meanwhile, with the deepening of research on the pathogenesis of colorectal cancer, gut microbiota has been confirmed to play a direct role in the occurrence and treatment of colorectal cancer. Strategies to regulate the gut microbiota have potential value for application in the prevention and treatment of CRC. Regulation of gut microbiota is one of the important ways for natural products to exert pharmacological effects, especially in the treatment of metabolic diseases and tumours. This review summarizes the role of gut microbiota in colorectal tumorigenesis and the mechanism by which natural products reduce tumorigenesis and improve therapeutic response. We point out that the regulation of gut microbiota by natural products may serve as a potential means of treatment and prevention of CRC.

Corona Virus Disease 2019 (COVID-19), an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly worldwide, resulting in a pandemic with a high mortality rate. In clinical practice, we have noted that many critically ill or critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. In addition, it has been demonstrated that severe COVID-19 has some pathological similarities with sepsis, such as cytokine storm, hypercoagulable state after blood balance is disrupted and neutrophil dysfunction. Considering the parallels between COVID-19 and non-SARS-CoV-2 induced sepsis (hereafter referred to as sepsis), the aim of this study was to analyze the underlying molecular mechanisms between these two diseases by bioinformatics and a systems biology approach, providing new insights into the pathogenesis of COVID-19 and the development of new treatments. Specifically, the gene expression profiles of COVID-19 and sepsis patients were obtained from the Gene Expression Omnibus (GEO) database and compared to extract common differentially expressed genes (DEGs). Subsequently, common DEGs were used to investigate the genetic links between COVID-19 and sepsis. Based on enrichment analysis of common DEGs, many pathways closely related to inflammatory response were observed, such as Cytokine-cytokine receptor interaction pathway and NF-kappa B signaling pathway. In addition, protein-protein interaction networks and gene regulatory networks of common DEGs were constructed, and the analysis results showed that ITGAM may be a potential key biomarker base on regulatory analysis. Furthermore, a disease diagnostic model and risk prediction nomogram for COVID-19 were constructed using machine learning methods. Finally, potential therapeutic agents, including progesterone and emetine, were screened through drug-protein interaction networks and molecular docking simulations. We hope to provide new strategies for future research and treatment related to COVID-19 by elucidating the pathogenesis and genetic mechanisms between COVID-19 and sepsis.

In rice, the spikelet is the basic unit of inflorescence, and its development is important for determining the grain yield and quality. We reported a rice spikelet mutant multi-floret spikelet 4 (mfs4) which resulted in the production of extra floral organs or a whole extra floret, and elongated sterile lemmas. The results suggested that the mutation of the MFS4 gene interfered with spikelet meristem determinacy and floral organ identity. In addition, the plant height and the grain length and width in the mfs4 mutant were all less than those in the wild type. Using the bulked segregant analysis method, the MFS4 gene was localized in a 557-kb region on the long arm of chromosome 1. Sequence analysis showed that there was a C-base deletion at the open reading frame of LOC_Os01g67430. Further tests indicated that a wild type copy of LOC_Os01g67430 was able to reverse the mfs4 defects, which indicated that LOC_Os01g67430 was the MFS4 gene. The MFS4 gene encodes a lipase located in the mitochondria and is expressed strongly in the young inflorescence. qRT-PCR results showed that the expression of some genes that were known to regulate spikelet meristem determinacy and grain size were decreased in the mfs4 mutant, which indicated that the MFS4 gene regulates spikelet meristem determinacy and grain size by modulating the expression of these genes.

Abstract Background Haemolymphangioma arising from the small bowel and its mesentery is extremely rare in the clinical setting. To date, only 8 cases of small bowel haemolymphangioma have been reported, and there have been no previously reported cases of haemolymphangioma in the small bowel mesentery (PubMed). The formation of this tumour is mostly congenital, but the exact mechanism is still unclear. As a benign tumour, the presentation of the disease may vary from a simple well-defined cystic lesion to an aggressive ill-defined lesion mimicking malignancy. However, there are no typical symptoms, and preoperative diagnosis is difficult. Case presentation We present two cases of haemolymphangioma in the small bowel mesentery in a 54-year-old man and a 52-year-old woman. Both of them came to the hospital due to an abdominal mass. In the first case, a cystic teratoma in the left abdominal area was considered after abdominal plain computed tomography (CT) and magnetic resonance imaging (MRI) scans. After taking an enhanced CT scan, a lipoma was considered based on the images. In the second case, cystic masses of the left upper and middle abdomen were observed on abdominal ultrasonography. An abdominal plain CT scan showed an irregular low-density mass in the left upper and middle abdomen. With an enhanced CT scan, haemolymphangioma was considered based on the images. After complete surgical removal, the masses were found to originate from the small bowel mesentery and had not invaded into the peripheral lymphatic tissue. In case 1 in this study, the routine pathology diagnosis was lymphangioma, while in case 2, the diagnosis was haemangioma. The final diagnosis was confirmed to be haemolymphangioma by immunohistochemistry in both cases. No recurrence was evident during 4 months of follow-up. We review the previous case reports of haemolymphangioma in the abdominal cavity and discuss their clinical features, diagnosis, treatment and prognosis. Conclusions The clinical manifestations of abdominal haemolymphangiomas can vary for both location and size. Abdominal CT examination has important clinical value for haemolymphangioma in the abdominal cavity. The final diagnosis of haemolymphangioma depends on a postoperative pathological examination. In addition, postoperative regular follow-up is necessary.

Abstract Background Our previous studies have shown that combining the antiviral lectin GRFT and the pan-CoV fusion inhibitory peptide EK1 results in highly potent inhibitory activity against SARS-CoV-2 infection. In this study, we aimed to design and construct a bivalent protein consisting of GRFT and EK1 components and evaluate its inhibitory activity and mechanism of action against infection by SARS-CoV-2 and its mutants, as well as other human coronaviruses (HCoVs). Methods The bivalent proteins were expressed in E. coli and purified with Ni-NTA column. HIV backbone-based pseudovirus (PsV) infection and HCoV S-mediated cell–cell fusion assays were performed to test their inhibitory activity. ELISA and Native-PAGE were conducted to illustrate the mechanism of action of these bivalent proteins. Five-day-old newborn mice were intranasally administrated with a selected bivalent protein before or after HCoV-OC43 challenge, and its protective effect was monitored for 14 days. Results Among the three bivalent proteins purified, GL25E exhibited the most potent inhibitory activity against infection of SARS-CoV-2 PsVs expressing wild-type and mutated S protein. GL25E was significantly more effective than GRFT and EK1 alone in inhibiting HCoV S-mediated cell–cell fusion, as well as infection by SARS-CoV-2 and other HCoVs, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and HCoV-OC43. GL25E could inhibit authentic SASR-CoV-2, HCoV-OC43 and HCoV-229E infection in vitro and prevent newborn mice from authentic HCoV-OC43 infection in vivo. GL25E could bind to glycans in the S1 subunit and HR1 in the S2 subunit in S protein, showing a mechanism of action similar to that of GRFT and EK1 alone. Conclusions Since GL25E showed highly potent and broad-spectrum inhibitory activity against infection of SARS-CoV-2 and its mutants, as well as other HCoVs, it is a promising candidate for further development as a broad-spectrum anti-HCoV therapeutic and prophylactic to treat and prevent COVID-19 and other emerging HCoV diseases.

Abstract Background In rice, panicle apical abortion is a common phenomenon that usually results in a decreased number of branches and grains per panicle, and consequently a reduced grain yield. A better understanding of the molecular mechanism of panicle abortion is thus critical for maintaining and increasing rice production. Results We reported a new rice mutant panicle apical abortion 3 (paa3), which exhibited severe abortion of spikelet development on the upper part of the branches as well as decreased grain size over the whole panicle. Using mapping-based clone, the PAA3 was characterized as the LOC_ Os04g56160 gene, encoding an H+-ATPase. The PAA3 was expressed highly in the stem and panicle, and its protein was localized in the plasma membrane. Our data further showed that PAA3 played an important role in maintaining normal panicle development by participating in the removal of reactive oxygen species (ROS) in rice. Conclusions Our studies suggested that PAA3 might function to remove ROS, the accumulation of which leads to programmed cell death, and ultimately panicle apical abortion and decreased seed size in the paa3 panicle.

Abstract The ongoing coronavirus disease-2019 (COVID-19) pandemic, caused by a novel coronavirus termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that is closely related to SARS-CoV, poses a grave threat to global health and has devastated societies worldwide. One puzzling aspect of COVID-19 is the impressive variation in disease manifestations among infected individuals, from a majority who are asymptomatic or exhibit mild symptoms to a smaller, largely age-dependent fraction who develop life-threatening conditions. Some of these differences are likely the consequence of host genetic factors. Systems genetics using diverse and replicable cohorts of isogenic mice represents a powerful way to dissect those host genetic differences that modulate microbial infections. Here we report that the two founders of the large BXD family of mice—C57BL/6J and DBA/2J, differ substantially in their susceptibility to a mouse-adapted SARS-CoV, MA15. Following intranasal viral challenge, DBA/2J develops a more severe disease than C57BL/6J as evidenced by more pronounced and sustained weight loss. Disease was accompanied by high levels of pulmonary viral replication in both strains early after infection but substantially delayed viral clearance in DBA/2J. Our data reveal that the parents of the BXD family are segregated by clear phenotypic differences during MA15 infection and support the feasibility of using this family to systemically dissect the complex virus-host interactions that modulate disease progression and outcome of infection with SARS-CoV, and provisionally also with SARS-CoV-2.