Whole-genome sequencing reveals host factors underlying critical COVID-19.

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer.

The secreted protein collagen and calcium-binding EGF domain 1 (CCBE1) is critical for embryonic lymphatic development through its role in the proteolytic activation of mature vascular endothelial growth factor C (VEGFC). We previously reported that CCBE1 is overexpressed in colorectal cancer (CRC) and that its transcription is negatively regulated by the TGFß-SMAD pathway, but the transcriptional activation mechanism of CCBE1 in CRC remains unknown. Recent studies have revealed the vital role of the hippo effectors YAP/TAZ in lymphatic development; however, the role of YAP/TAZ in tumor lymphangiogenesis has not been clarified. In this study, we found that high nuclear expression of transcription factor TEAD4 is associated with lymph node metastasis and high lymphatic vessel density in patients with CRC. YAP/TAZ-TEAD4 complexes transcriptionally upregulated the expression of CCBE1 by directly binding to the enhancer region of CCBE1 in both CRC cells and cancer-associated fibroblasts, which resulted in enhanced VEGFC proteolysis and induced tube formation and migration of human lymphatic endothelial cells in vitro and lymphangiogenesis in a CRC cell-derived xenograft model in vivo. In addition, the bromodomain and extraterminal domain (BET) inhibitor JQ1 significantly inhibited the transcription of CCBE1, suppressed VEGFC proteolysis, and inhibited tumor lymphangiogenesis in vitro and in vivo. Collectively, our study reveals a new positive transcriptional regulatory mechanism of CCBE1 via YAP/TAZ-TEAD4-BRD4 complexes in CRC, which exposes the protumor lymphangiogenic role of YAP/TAZ and the potential inhibitory effect of BET inhibitors on tumor lymphangiogenesis.

Genetic and phenotypic links between obesity and extracellular vesicles.

Obesity has a highly complex genetic architecture, making it difficult to understand the genetic mechanisms, despite the large number of discovered loci via genome-wide association studies (GWAS). Omics techniques have provided a better resolution to view this problem. As a proxy of cell-level biology, extracellular vesicles (EVs) are useful for studying cellular regulation of complex phenotypes such as obesity. Here, in a well-established Scottish cohort, we utilized a novel technology to detect surface proteins across millions of single EVs in each individual's plasma sample. Integrating the results with established obesity GWAS, we inferred 78 types of EVs carrying one or two of 12 surface proteins to be associated with adiposity-related traits such as waist circumference. We then verified that particular EVs' abundance is negatively correlated with body adiposity, while no association with lean body mass. We also revealed that genetic variants associated with protein-specific EVs capture 2-4-fold heritability enrichment for blood cholesterol levels. Our findings provide evidence that EVs with specific surface proteins have phenotypic and genetic links to obesity and blood lipids, respectively, guiding future EV biomarker research.

The genetic landscape of histologically transformed marginal zone lymphomas.

BACKGROUND: Marginal zone lymphomas (MZLs) comprise a diverse group of indolent lymphoproliferative disorders; however, some patients develop histologic transformation (HT) with rapid progression to aggressive lymphoma. METHODS: Forty-three MZLs with HT (HT-MZLs), 535 MZLs, and 174 de novo diffuse large B-cell lymphomas (DLBCLs) without rearrangements of MYC, BCL2, and BCL6 were collected. Among these, 22 HT-MZLs, 39 MZLs, and 174 DLBCLs were subjected to 148-gene targeted exome sequencing. The clinicopathologic features of patients who had HT-MZL and their genetic alterations were compared with those of patients who had MZLs and DLBCLs. RESULTS: All 43 HT-MZLs corresponded to DLBCLs. No HT-MZLs harbored BCL2 and MYC and/or BCL6 rearrangements. Bone marrow involvement and higher levels of lactate dehydrogenase were significantly more common in HT-MZLs than in MZLs. Furthermore, upregulated BCL6, MUM1, C-MYC, and Ki-67 expression was observed more frequently in HT-MZLs than in MZLs. TBL1XR1 was the most frequently altered gene (63.6%) in HT-MZLs, followed by CCND3 (31.8%), CARD11, ID3, and TP53 (22.7%). A trend toward worse progression-free survival in patients with TBL1XR1 mutations was observed. Compared with MZLs and non-germinal center B-cell (GCB) type DLBCLs, significantly higher frequencies of TBL1XR1 and ID3 mutations were identified in HT-MZLs. PIM1 mutations frequently occurred in DLBCLs and were significantly associated with TBL1XR1 mutations but were mutated less in HT-MZLs that had TBL1XR1 mutations. CONCLUSIONS: The current findings reveal the clinicopathologic and genetic features of HT-MZLs, suggesting that these tumors might constitute a group distinct from MZL and de novo non-GCB type DLBCL. TBL1XR1 mutations may be considered a predictor of HT in MZL.

Dual-trait genomic analysis in highly stratified Arabidopsis thaliana populations using genome-wide association summary statistics.

Genome-wide association study (GWAS) is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset of Arabidopsis thaliana. We demonstrate the efficiency of dual-phenotype analysis to uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, a common allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate gene AT1G11560 that potentially causes this association. Further analysis indicates that this locus is co-selected with flowering-time-related genes. The discovered pleiotropic genotype-phenotype map provides new insights into understanding the genetic correlation of complex traits.

Effects of intraoperative low-dose esketamine on postoperative pain after vestibular schwannoma resection: A prospective randomized, double-blind, placebo-controlled study.

AIMS: Esketamine may reduce acute postoperative pain in several settings. However, the effects of low-dose esketamine on postoperative pain after vestibular schwannoma (VS) resection with propofol/remifentanil total intravenous anaesthesia (TIVA) are unclear. The aim of this study is to observe the effects of intraoperative low-dose esketamine on postoperative pain after vestibular schwannoma resection. METHODS: This single-centre, randomized, placebo-controlled, double-blind trial included 90 adults undergoing VS resection via the retrosigmoid approach with TIVA. The patients were randomly allocated to two groups: esketamine or control (n = 45 in each group). Patients received low-dose esketamine (0.2 mg/kg) or a similar volume of normal saline after dural closure. The primary outcome was the pain score during movement (gentle head movement) at 24 h postoperatively. Secondary outcomes included recovery time, bispectral index (BIS) values and haemodynamic profiles during the first 30 min after esketamine administration, and adverse effects. RESULTS: Low-dose esketamine did not reduce pain scores at rest (P > .05) or with movement (P > .05) within the first 24 h after surgery. Esketamine moderately increased BIS values for at least 30 min after administration (P < .0001) but did not affect heart rate (P = .992) or mean arterial blood pressure (P = .994). Esketamine prolonged extubation time (P = .042, 95% confidence interval: 0.08 to 4.42) and decreased the effect-site concentration of remifentanil at extubation (P = .001, 95% confidence interval: -0.53 to -0.15) but did not affect the time to resumption of spatial orientation. Postoperative nausea and vomiting rates did not differ between groups, and no hallucinations or excessive sedation was observed. CONCLUSION: Intraoperative low-dose esketamine did not significantly reduce acute pain after VS resection with propofol/remifentanil TIVA. However, BIS values increased for at least 30 min after esketamine administration.

Direct chemical-vapor-deposition growth of alloyed perovskite microcrystals for tunable emissions.

Tunable composition of perovskite micro/nanostructures are perfect candidate for the designing of multifunctional optoelectronic circuits. Especially, integrated polychromatic luminescence based on the perovskite materials along a single substrate or chip is essential to the integrated photonic devices and multicolor displays. Here, we reported a synthesis of composition tunable CsPbI3(1-x)Br3x(X = 0.65-0.9) perovskite microstructures on a single substrate via a magnetic-pulling CVD method. The PL emissions can be changed gradually from green (558 nm, 2.23 eV) to red (610 nm, 2.03 eV) under a focused 375 nm laser illumination. Furthermore, these composition-graded alloyed perovskite microcrystals show stable emissions after six months in air, which may find applications in multicolor display and broad band light sources in the future.

First Report of Diaporthe tectonendophytica Causing Leaf Spot on Dalbergia odorifera in Guangxi, China.

Dalbergia odorifera T. Chen (Family: Fabaceae) is a national level II protected plant in China, with extremely high economic value and medical properties (Zhao et al. 2020). In June 2023, an unknown leaf spot was found in a garden land of Pingxiang city, Guangxi, China, and approximately 80% of the plants covered an area of 500 m2 displayed similar symptoms. The spots were grey to white, 4~6 mm in diameter (n=30) with black pycnida on the spots surface (Fig S1, A-D). Multiple disease spots were observed on a single leaf. The pycnida on the lesion were picked and mashed, to make a conidia suspension using sterile water. The conidial solution was then spread onto a potato dextrose agar (PDA) plate containing streptomycin, with 10 mg of streptomycin per 100 mL, and incubated for 3 days at 28°C with a 12 hour photoperiod. Three isolates (GXPX01, GXPX02 and GXPX03) were obtained by re-culturing the colonies on fresh PDA plates. The colony on PDA were white with aerial mycelia (Fig S1, E-F). Black conidiomata developed at 28°C with a 12 hour photoperiod in 20 days (Fig S1, G-H). Alpha conidia were 4.2~6.4 µm × 1.8~2.6 µm (average =5.1 × 2.3 µm, n = 30), mostly bi-guttulate, hyaline, ellipsoid, apex bluntly rounded, base obtuse to subtruncate, smooth (Fig S1, I). Beta conidia were 15.1~33.5 µm × 1~1.8 µm (average = 24.5 × 1.5 µm, n = 30), filiform, hyaline, curved or hamate, aseptate, base subtruncate (Fig S1, J). Morphological characteristics of the three isolates matched those of Diaporthe spp.(Gomes et al. 2013). The rDNA internal transcribed spacer (ITS) region, the translation elongation factor 1-α (TEF1), the calmodulin (CAL), the histone H3 (HIS) and the ß-tubulin (TUB2) genes of the three isolates were amplified using the primer pairs ITS4/ITS5, EF1-728F/EF1-986R, CAL-228F/CAL2Rd, CYLH3F/H3-1B, and T1 /CYLTUB1R, respectively (Crous et al. 2004, Sun et al. 2021). The sequences were all deposited in GenBank (accession numbers OR437511 to OR437513 for ITS, OR454965 to OR454967 for TEF1, OR454968 to OR454970 for CAL, OR454971 to OR454973 for TUB2, OR454974 to OR454976 for H3). Sequences had 98.36% to 100% homology with the corresponding sequences of known Diaporthe tectonendophytica strains MFLUCC 13-0471 in the NCBI database. Phylogenetic analysis was based on combined ITS, TEF1, TUB2 and CAL sequences data using MEGA 11 software to construct phylogenetic tree with Maximum Likelihood (Doilom et al. 2017). In the phylogenetic tree, the combined sequences attributed the three isolates to the D. tectonendophytica (Fig S2). The pathogenicity was tested on leaves of 1.5-year-old D. odorifera seedlings. Three leaves were wounded with a sterile needle and individually inoculated with a 5 mm mycelial disk of PDA culture from each isolate. Sterile PDA disks inoculated leaves as a control. The test was repeated three times. The inoculated plants were placed in a greenhouse at 25℃ and 90% humidity, with a photoperiod of 12 hours. Five days after inoculation, necrotic lesions appeared on inoculated leaves and symptoms from all three isolates were the same as those form natural infections ( Fig S1, K-N), whereas all the control remained symptomless (Fig S1, P). The pathogen was reisolated from the inoculated leaves and again identified as D. tectonendophytica, with the same methodology used for the initial identification. D. tectonendophytica was reported to cause plant diseases, such as stem gray blight of red-fleshed dragon fruit (Hylocereus polyrhizus) (Rahim et al. 2021), leaf spots disease on Elaeagnus conferta and Pometia pinnata (Sun et al. 2021). To our knowledge, this is the first report of D. ctonendophytica causing leaf spot disease on D. odorifera.

Comparative Genomic Analysis of PEBP Genes in Cucurbits Explores the Interactors of Cucumber CsPEBPs Related to Flowering Time.

The family of phosphatidylethanolamine-binding proteins (PEBPs) participates in various plant biological processes, mainly flowering regulation and seed germination. In cucurbit crops, several PEBP genes have been recognized to be responsible for flowering time. However, the investigation of PEBP family members across the genomes of cucurbit species has not been reported, and their conservation and divergence in structure and function remain largely unclear. Herein, PEBP genes were identified from seven cucurbit crops and were used to perform a comparative genomics analysis. The cucurbit PEBP proteins could be classified into MFT, FT, TFL, and PEBP clades, and further, the TFL clade was divided into BFT-like, CEN-like, and TFL1-like subclades. The MFT-like, FT-like, and TFL-like proteins were clearly distinguished by a critical amino acid residue at the 85th position of the Arabidopsis FT protein. In gene expression analysis, CsaPEBP1 was highly expressed in flowers, and its expression levels in females and males were 70.5 and 89.2 times higher, respectively, than those in leaves. CsaPEBP5, CsaPEBP6, and CsaPEBP7 were specifically expressed in male flowers, with expression levels 58.1, 17.3, and 15.7 times higher, respectively, than those of leaves. At least five CsaPEBP genes exhibited the highest expression during the later stages of corolla opening. Through clustering of time-series-based RNA-seq data, several potential transcription factors (TFs) interacting with four CsaPEBPs were identified during cucumber corolla opening. Because of the tandem repeats of binding sites in promoters, NF-YB (Csa4G037610) and GATA (Csa7G64580) TFs appeared to be better able to regulate the CsaPEBP2 and CsaPEBP5 genes, respectively. This study would provide helpful information for further investigating the roles of PEBP genes and their interacting TFs in growth and development processes, such as flowering time regulation in cucurbit crops.

The miR-182-5p/GPX4 Pathway Contributes to Sevoflurane-Induced Ototoxicity via Ferroptosis.

Our study aimed to investigate the role of ferroptosis in sevoflurane-induced hearing impairment and explore the mechanism of the microRNA-182-5p (miR-182-5p)/Glutathione Peroxidase 4 (GPX4) pathway in sevoflurane-induced ototoxicity. Immunofluorescence staining was performed using myosin 7a and CtBP2. Cell viability was assessed using the CCK-8 kit. Fe2+ concentration was measured using FerroOrange and Mi-to-FerroGreen fluorescent probes. The lipid peroxide level was assessed using BODIPY 581/591 C11 and MitoSOX fluorescent probes. The auditory brainstem response (ABR) test was conducted to evaluate the hearing status. Bioinformatics tools and dual luciferase gene reporter analysis were used to confirm the direct targeting of miR-182-5p on GPX4 mRNA. GPX4 and miR-182-5p expression in cells was assessed by qRT-PCR and Western blot. Ferrostatin-1 (Fer-1) pretreatment significantly improved hearing impairment and damage to ribbon synapses in mice caused by sevoflurane exposure. Immunofluorescence staining revealed that Fer-1 pretreatment reduced intracellular and mitochondrial iron overload, as well as lipid peroxide accumulation. Our findings indicated that miR-182-5p was upregulated in sevoflurane-exposed HEI-OC1 cells, and miR-182-5p regulated GPX4 expression by binding to the 3'UTR of GPX4 mRNA. The inhibition of miR-182-5p attenuated sevoflurane-induced iron overload and lipid peroxide accumulation. Our study elucidated that the miR-182-5p/GPX4 pathway was implicated in sevoflurane-induced ototoxicity by promoting ferroptosis.

Comprehensive analysis of N6-methyladenosine-related RNA methylation in the mouse hippocampus after acquired hearing loss.

BACKGROUND: The mechanism underlying cognitive impairment after hearing loss (HL) remains unclear. N6-methyladenosine (m6A) is involved in many neurodegenerative diseases; however, its role in cognitive impairment after HL has not yet been investigated. Therefore, we aimed to analyze the m6A modification profile of the mouse hippocampus after HL exposure. A mouse model of neomycin-induced HL was established. An auditory brainstem-response test was utilized for detecting hearing threshold. The passive avoidance test was served as the mean for evaluating cognitive function. The m6A-regulated enzyme expression levels were analyzed by using reverse transcription quantitative real-time polymerase chain reaction and western blot analyses. RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq) were performed with the aim of investigating gene expression differences and m6A modification in the mouse hippocampus. RESULTS: Neomycin administration induced severe HL in mice. At four months of age, the mice in the HL group showed poorer cognitive performance than the mice in the control group. METTL14, WTAP, and YTHDF2 mRNA levels were downregulated in the hippocampi of HL mice, whereas ALKBH5 and FTO mRNA levels were significantly upregulated. At the protein level, METTL3 and FTO were significantly upregulated. Methylated RNA immunoprecipitation sequencing analysis revealed 387 and 361 m6A hypermethylation and hypomethylation peaks, respectively. Moreover, combined analysis of mRNA expression levels and m6A peaks revealed eight mRNAs with significantly changed expression levels and methylation. CONCLUSIONS: Our findings revealed the m6A transcriptome-wide profile in the hippocampus of HL mice, which may provide a basis for understanding the association between HL and cognitive impairment from the perspective of epigenetic modifications.

Chromosome diversity in Dasypyrum villosum, an important genetic and trait resource for hexaploid wheat engineering.

BACKGROUND AND AIMS: Dasypyrum villosum (2n = 2x = 14) harbours potentially beneficial genes for hexaploid and tetraploid wheat improvement. Highly diversified chromosome variation exists among and within accessions due to its open-pollination nature. The wheat-D. villosum T6VS·6AL translocation was widely used in breeding mainly because gene Pm21 in the 6VS segment conferred high and lasting powdery mildew resistance. However, the widespread use of this translocation may narrow the genetic base of wheat. A better solution is to utilize diversified D. villosum accessions as the genetic source for wheat breeding. Analysis of cytological and genetic polymorphisms among D. villosum accessions also provides genetic evolution information on the species. Using cytogenetic and molecular tools we analysed genetic polymorphisms among D. villosum accessions and developed consensus karyotypes to assist the introgression of beneficial genes from D. villosum into wheat. METHODS: A multiplex probe of repeats for FISH, GISH and molecular markers were used to detect chromosome polymorphisms among D. villosum accessions. Polymorphic signal block types, chromosome heterogeneity and heterozygosity, and chromosome polymorphic information content were used in genetic diversity analysis. KEY RESULTS: Consensus karyotypes of D. villosum were developed, and the homoeologous statuses of individual D. villosum chromosomes relative to wheat were determined. Tandem repeat probes of pSc119.2, (GAA)10 and the AFA family produced high-resolution signals and not only showed different signal patterns in D. villosum chromosomes but also revealed the varied distribution of tandem repeats among chromosomes and accessions. A total of 106 polymorphic chromosomes were identified from 13 D. villosum accessions and high levels of chromosomal heterozygosity and heterogeneity were observed. A subset of 56 polymorphic chromosomes was transferred into durum wheat through wide crosses, and seven polymorphic chromosomes are described in two newly developed durum-D. villosum amphidiploids. CONCLUSIONS: Consensus karyotypes of D. villosum and oligonucleotide FISH facilitated identification of polymorphic signal blocks and a high level of chromosomal heterozygosity and heterogeneity among D. villosum accessions, seen in newly developed amphiploids. The abundant genetic diversity of D. villosum and range of alleles, exploitable through interploid crosses, backcrosses and recombination (chromosome engineering), allow introduction of biotic and abiotic stress resistances into wheat, translating into increasing yield, end-use quality and crop sustainability.

Constipation is associated with depression of any severity, but not with suicidal ideation: insights from a large cross-sectional study.

OBJECTIVE: The association between constipation and depression or suicidal ideation (SI) has not been adequately studied. This study aims to examine whether constipation is associated with depression or SI in US adults. METHOD: 4,562 adults aged 20 and older were selected from the National Health and Nutrition Examination Survey 2009-2010 for the sample. The Bowel Health Questionnaire provided constipation information. Clinical depression and depression severity were assessed by the validated Patient Health Questionnaide-9 (PHQ-9), and item 9 of the PHQ-9 assessed SI. Adjusted odds ratios (ORs) were calculated using multivariate logistic regression models. Stability of the results was ensured by a subgroup analysis. RESULT: After adjusting for covariates such as demographics, risk behaviors, associated comorbidities, dietary intake, and related medications, the PHQ-9 score and clinical depression were both significantly associated with constipation, with ORs and 95%CIs of 1.13 (1.10-1.16) and 3.76 (2.65-5.34). Depression of all severities was also significantly associated with constipation. The ORs and 95%CIs of constipation with mild depression, moderate depression, and moderately severe to severe depression were 2.21 (1.54-3.16), 3.69 (2.34-5.81) and 6.84 (4.19-11.15), respectively. Subgroup analyses showed no statistically significant interactions (P > 0.05), and the association was stronger in men than in women (OR: 7.81, 95%CI: 3.67-16.61 vs OR: 3.46, 95%CI: 2.31-5.19). The association between constipation and SI was not significant (OR: 1.36, 95%CI: 0.78-2.37). CONCLUSION: In conclusion, constipation was significantly associated with depression of any severity, but not with SI, suggesting that enough attention should be paid to the emotional and psychological status of patients with constipation, especially male patients.

Refractive errors and ocular findings in children and adolescents with mental disorders: a retrospective study.

BACKGROUND: An increasing prevalence of mental disorders (MDs) has been reported among children and adolescents. However, only few studies have conducted ocular examinations, including those on refractive status, in these groups of patients. Thus, the purpose of this study was to evaluate the refractive status and ocular findings in children and adolescents with MDs compared with matched controls with similar socioeconomic backgrounds. METHODS: A total of 178 participants with MDs and 200 controls were recruited between April 2021 and May 2022. All the children and adolescents underwent cycloplegic or noncycloplegic autorefraction and retinoscopy, slit-lamp biomicroscopy, and dilated fundus examinations. Ocular alignment was assessed using Hirschberg, Krimsky, or prism cover tests. The prevalence of refractive errors and ocular findings was the main outcome. RESULTS: Twenty-seven percent of patients with MDs and 8% of controls had ocular findings, the most common of which were conjunctivitis, keratitis, and trichiasis. For refractive status, 70% (124/178) of patients with MDs had myopia ≤-1.00 DS, and 2% (4/178) had hyperopia ≥+2.00 DS. In the control group, 70% (140/200) of patients had myopia ≤-1.00 DS, and 1% (2/200) had hyperopia ≥+2.00 DS. No differences were observed between the MD and control groups. However, the patients in the MD group (14.25±2.69 years) were significantly more susceptible to strabismus (P<0.05) and amblyopia (P<0.01) than those in the control group (13.65±3.04 years). There was a substantial difference between the two groups in the time spent on screen-based devices (P<0.001). Furthermore, mental retardation (OR=3.286, P<0.01), emotional disorders (OR=2.003, P<0.01), and adjustment disorders (OR=2.629, P<0.01) were associated with an increased risk of amblyopia. Depression (OR =1.362, P<0.01) and emotional disorders (OR=2.205, P<0.01) were associated with a higher prevalence of strabismus. CONCLUSION: Ophthalmological examinations should be performed in children and adolescents with MDs because MDs are associated with a high prevalence of refractive errors and ocular diseases. Detection and intervention of ocular and refractive findings in children and adolescents with MDs are necessary and effective in alleviating the economic burden in healthcare and improving individuals' quality of life.

Safety and efficacy of ultrasonography of tension after zone II flexor tendon repair: A randomized controlled trial.

BACKGROUND: Primary flexor tendon repairs of lacerations in zone II of the hand are fraught with problems. Traditionally, exercise (active and passive), orthoses, and physical agents are common interventions for the rehabilitation of patients experiencing these issues. One area of focus in this field is how to safely utilize tension to lengthen gliding distance following zone II injury. Finding effective solutions in this area is a key priority for improving patient outcomes and quality of life. PURPOSE: To identify the optimal immobilization position that meets safety standards for tension and is the most efficient, and consequently, to validate our clinical effectiveness. STUDY DESIGN: A cross-sectional study was adopted for the first part of the research (Research 1). A prospective, parallel, 2-group, randomized trial was conducted with concealed allocation and single blinding in the second part of the research (Research 2). METHODS: A total of 60 healthy adults were recruited to select the best-fit protective immobilization position in Research 1, which was confirmed by tendon tension (via Young's modulus) and excursion (via gliding distance). We then randomly assigned 45 patients after zone II flexor tendon repair into two groups in Research 2 to compare functional outcomes. The control group underwent the conventional modified Duran protocol with early passive motion, while the experimental group received the protocol (optimized by Research 1) with early active motion. Ultrasonography was used to measure the tension and excursion of the flexor tendons. The outcomes measured at 16 weeks post-repair included total active motion, strength, the Disabilities of the Arm, Shoulder and Hand, and Strickland scores. RESULTS: Three participants were unable to participate in Research 2 due to medical issues and poor attendance. The investigation found that the safe tendon threshold was 345.09 ± 87.74 kPa for partial active digital motion among the 60 participants. The optimal immobilization position requires the wrist to be neutral with a flexion angle of 30° at the metacarpophalangeal joint. The grip strengths (p = 0.012), ratio of grip strength (p = 0.015), the Disabilities of the Arm, Shoulder and Hand (p = 0.036), and total active motion (p = 0.023) differed significantly between the two groups. CONCLUSIONS: Protective immobilization of the wrist in a neutral flexion position and with the metacarpophalangeal joint flexed at 30° can secure the repaired flexor tendon safely and efficiently. The effects of an early active motion protocol may improve the grip strength and upper limb mobility of individuals after zone II flexor tendon repair. CLINICAL TRIAL REGISTRATION: ChiCTR2000030592.

Borna disease virus 1 impairs DNA double-strand break repair through the ATR/Chk1 signalling pathway, resulting in learning and memory impairment in rats.

Borna disease virus 1 (BoDV-1) is a highly neurotropic RNA virus that can establish persistent infection in the central nervous system and cause cognitive dysfunction in neonatally infected rats. However, the mechanisms that lead to this cognitive impairment remain unclear. DNA double-strand breaks (DSBs) and their repair are associated with brain development and cognition. If DNA repair in the brain is reduced or delayed and DNA damage accumulates, abnormal cognitive function may result. We generated a rat model of BoDV-1 infection during the neonatal period and assessed behavioural changes using the open field test and Morris water maze. The levels of DSBs were determined by immunofluorescence and comet assays. Western blotting assessed proteins associated with DNA repair pathways. The results showed that BoDV-1 downregulated the ATR/Chk1 signalling pathway in the brain, impairing DNA damage repair and increasing the number of DSBs, which ultimately leads to cognitive dysfunction. Our findings suggest a molecular mechanism by which BoDV-1 interferes with DNA damage repair to cause learning and memory impairment. This provides a theoretical basis for elucidating BoDV-1-induced neurodevelopmental impairment.

miR-505 inhibits replication of Borna disease virus 1 via inhibition of HMGB1-mediated autophagy.

Borna disease virus 1 (BoDV-1) is a highly neurotropic RNA virus which was recently demonstrated to cause deadly human encephalitis. Viruses can modulate microRNA expression, in turn modulating cellular immune responses and regulating viral replication. A previous study indicated that BoDV-1 infection down-regulated the expression of miR-505 in rats. However, the underlying mechanism of miR-505 during BoDV-1 infection remains unknown. In this study, we found that miR-505 can inhibit autophagy activation by down-regulating the expression of its target gene HMGB1, and ultimately inhibit the replication of BoDV-1. Specifically, we found that the expression of miR-505 was significantly down-regulated in rat primary neurons stably infected with BoDV-1. Overexpression of miR-505 can inhibit the replication of BoDV-1 in cells. Bioinformatics analysis and dual luciferase reporter gene detection confirmed that during BoDV-1 infection, the high-mobility group protein B1 (HMGB1) that mediates autophagy is the direct target gene of miR-505. The expression of HMGB1 was up-regulated after BoDV-1 infection, and overexpression of miR-505 could inhibit the expression of HMGB1. Autophagy-related detection found that after infection with BoDV-1, the expression of autophagy-related proteins and autophagy-related marker LC3 in neuronal cells was significantly up-regulated. Autophagy flow experiments and transmission electron microscopy also further confirmed that BoDV-1 infection activated HMGB1-mediated autophagy. Further regulating the expression of miR-505 found that overexpression of miR-505 significantly inhibited HMGB1-mediated autophagy. The discovery of this mechanism may provide new ideas and directions for the prevention and treatment of BoDV-1 infection in the future.

Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis.

BACKGROUND AND AIMS: Insulin receptor (IR) transduces cell surface signal through phosphoinositide 3-kinase (PI3K)-AKT pathways or translocates to the nucleus and binds to the promoters to regulate genes associated with insulin actions, including de novo lipogenesis (DNL). Chronic activation of IR signaling drives malignant transformation, but the underlying mechanisms remain poorly defined. Down-regulation of fructose-1,6-bisphosphate aldolase (ALDO) B in hepatocellular carcinoma (HCC) is correlated with poor prognosis. We aim to study whether and how ALDOB is involved in IR signaling in HCC. APPROACH AND RESULTS: Global or liver-specific ALDOB knockout (L-ALDOB-/- ) mice were used in N-diethylnitrosamine (DEN)-induced HCC models, whereas restoration of ALDOB expression was achieved in L-ALDOB-/- mice by adeno-associated virus (AAV). 13 C6 -glucose was employed in metabolic flux analysis to track the de novo fatty acid synthesis from glucose, and nontargeted lipidomics and targeted fatty acid analysis using mass spectrometry were performed. We found that ALDOB physically interacts with IR and attenuates IR signaling through down-regulating PI3K-AKT pathways and suppressing IR nuclear translocation. ALDOB depletion or disruption of IR/ALDOB interaction in ALDOB mutants promotes DNL and tumorigenesis, which is significantly attenuated with ALDOB restoration in L-ALDOB-/- mice. Notably, attenuated IR/ALDOB interaction in ALDOB-R46A mutant exhibits more significant tumorigenesis than releasing ALDOB/AKT interaction in ALDOB-R43A, whereas knockdown IR sufficiently diminishes tumor-promoting effects in both mutants. Furthermore, inhibiting phosphorylated AKT or fatty acid synthase significantly attenuates HCC in L-ALDOB-/- mice. Consistently, ALDOB down-regulation is correlated with up-regulation of IR signaling and DNL in human HCC tumor tissues. CONCLUSIONS: Our study reports a mechanism by which loss of ALDOB activates IR signaling primarily through releasing IR/ALDOB interaction to promote DNL and HCC, highlighting a potential therapeutic strategy in HCC.

Different Isocaloric Meals and Adiposity Modify Energy Expenditure and Clinical and Metabolomic Biomarkers During Resting and Exercise States in a Randomized Crossover Acute Trial of Normal-Weight and Overweight/Obese Men.

BACKGROUND: Few studies have assessed the integrative effects of diet, BMI, and exercise on postprandial changes in energy and circulating metabolic profiles. OBJECTIVES: We aimed to assess the collective effects of 3 isocaloric meals high in carbohydrate (74.2% energy), fat (64.6% energy), or protein (39.5% energy) on energy expenditure and clinical and metabolomic biomarkers under resting and exercise conditions in normal-weight and overweight/obese men. METHODS: This crossover controlled acute trial included 20 normal-weight (BMI, 18.5 to <24 kg/m2) and 20 overweight/obese (BMI ≥24 kg/m2) men aged 18-45 years. Each of 3 test meals was provided for 2 continuous days: a resting day without exercise, followed by an exercise day with a bicycling exercise of 50% maximal oxygen consumption (postprandial 90-120 minutes). Energy expenditure (exploratory outcome of primary interest) was measured using indirect calorimetry. Fasting and postprandial 2-hour serum clinical and metabolomic biomarkers (secondary interest) were measured. Mixed models were used to examine the effects of meal, time, and/or BMI category. RESULTS: On the resting day, no significant between-meal differences were detected for energy expenditure. However, high-carbohydrate and high-fat meals induced the highest postprandial 2-hour increase in glucose (0.34 ± 0.15 mmol/L) and triglyceride (0.95 ± 0.09 mmol/L), respectively, while the high-protein meal reduced glucose (-0.48 ± 0.08 mmol/L) and total cholesterol (-0.01 ± 0.03 mmol/L; all Pmeal values < 0.001). On the exercise day, a high-carbohydrate meal significantly promoted the carbohydrate oxidation rate but suppressed the fat oxidation rate (Pmeal < 0.05), while its postprandial glucose response was attenuated by bicycling (-0.31 ± 0.03 mmol/L; Pexercise < 0.001). We identified 69 metabolites as key features in discriminating between the 3 meals, and overweight/obese men had more varieties of metabolites than normal-weight men. CONCLUSIONS: Three isocaloric meals induced unique postprandial changes in clinical and metabolomic biomarkers, while exercise prevented the hyperglycemia induced by a high-carbohydrate meal. Overweight/obese men were more responsive to the meal challenges than normal-weight men. This trial was registered at clinicaltrials.gov as NCT03231618.

Different Isocaloric Meals and Adiposity Modify Energy Expenditure and Clinical and Metabolomic Biomarkers During Resting and Exercise States in a Randomized Crossover Acute Trial of Normal-Weight and Overweight/Obese Men.

BACKGROUND: Few studies have assessed the integrative effects of diet, BMI, and exercise on postprandial changes in energy and circulating metabolic profiles. OBJECTIVES: We aimed to assess the collective effects of 3 isocaloric meals high in carbohydrate (74.2% energy), fat (64.6% energy), or protein (39.5% energy) on energy expenditure and clinical and metabolomic biomarkers under resting and exercise conditions in normal-weight and overweight/obese men. METHODS: This crossover controlled acute trial included 20 normal-weight (BMI, 18.5 to <24 kg/m2) and 20 overweight/obese (BMI ≥24 kg/m2) men aged 18-45 years. Each of 3 test meals was provided for 2 continuous days: a resting day without exercise, followed by an exercise day with a bicycling exercise of 50% maximal oxygen consumption (postprandial 90-120 minutes). Energy expenditure (exploratory outcome of primary interest) was measured using indirect calorimetry. Fasting and postprandial 2-hour serum clinical and metabolomic biomarkers (secondary interest) were measured. Mixed models were used to examine the effects of meal, time, and/or BMI category. RESULTS: On the resting day, no significant between-meal differences were detected for energy expenditure. However, high-carbohydrate and high-fat meals induced the highest postprandial 2-hour increase in glucose (0.34 ± 0.15 mmol/L) and triglyceride (0.95 ± 0.09 mmol/L), respectively, while the high-protein meal reduced glucose (-0.48 ± 0.08 mmol/L) and total cholesterol (-0.01 ± 0.03 mmol/L; all Pmeal values < 0.001). On the exercise day, a high-carbohydrate meal significantly promoted the carbohydrate oxidation rate but suppressed the fat oxidation rate (Pmeal < 0.05), while its postprandial glucose response was attenuated by bicycling (-0.31 ± 0.03 mmol/L; Pexercise < 0.001). We identified 69 metabolites as key features in discriminating between the 3 meals, and overweight/obese men had more varieties of metabolites than normal-weight men. CONCLUSIONS: Three isocaloric meals induced unique postprandial changes in clinical and metabolomic biomarkers, while exercise prevented the hyperglycemia induced by a high-carbohydrate meal. Overweight/obese men were more responsive to the meal challenges than normal-weight men. This trial was registered at clinicaltrials.gov as NCT03231618.