An AI-powered patient triage platform for future viral outbreaks using COVID-19 as a disease model.

Over the last century, outbreaks and pandemics have occurred with disturbing regularity, necessitating advance preparation and large-scale, coordinated response. Here, we developed a machine learning predictive model of disease severity and length of hospitalization for COVID-19, which can be utilized as a platform for future unknown viral outbreaks. We combined untargeted metabolomics on plasma data obtained from COVID-19 patients (n = 111) during hospitalization and healthy controls (n = 342), clinical and comorbidity data (n = 508) to build this patient triage platform, which consists of three parts: (i) the clinical decision tree, which amongst other biomarkers showed that patients with increased eosinophils have worse disease prognosis and can serve as a new potential biomarker with high accuracy (AUC = 0.974), (ii) the estimation of patient hospitalization length with ± 5 days error (R2 = 0.9765) and (iii) the prediction of the disease severity and the need of patient transfer to the intensive care unit. We report a significant decrease in serotonin levels in patients who needed positive airway pressure oxygen and/or were intubated. Furthermore, 5-hydroxy tryptophan, allantoin, and glucuronic acid metabolites were increased in COVID-19 patients and collectively they can serve as biomarkers to predict disease progression. The ability to quickly identify which patients will develop life-threatening illness would allow the efficient allocation of medical resources and implementation of the most effective medical interventions. We would advocate that the same approach could be utilized in future viral outbreaks to help hospitals triage patients more effectively and improve patient outcomes while optimizing healthcare resources.

MEKK3-TGFß crosstalk regulates inward arterial remodeling.

Arterial remodeling is an important adaptive mechanism that maintains normal fluid shear stress in a variety of physiologic and pathologic conditions. Inward remodeling, a process that leads to reduction in arterial diameter, plays a critical role in progression of such common diseases as hypertension and atherosclerosis. Yet, despite its pathogenic importance, molecular mechanisms controlling inward remodeling remain undefined. Mitogen-activated protein kinases (MAPKs) perform a number of functions ranging from control of proliferation to migration and cell-fate transitions. While the MAPK ERK1/2 signaling pathway has been extensively examined in the endothelium, less is known about the role of the MEKK3/ERK5 pathway in vascular remodeling. To better define the role played by this signaling cascade, we studied the effect of endothelial-specific deletion of its key upstream MAP3K, MEKK3, in adult mice. The gene's deletion resulted in a gradual inward remodeling of both pulmonary and systematic arteries, leading to spontaneous hypertension in both vascular circuits and accelerated progression of atherosclerosis in hyperlipidemic mice. Molecular analysis revealed activation of TGFß-signaling both in vitro and in vivo. Endothelial-specific TGFßR1 knockout prevented inward arterial remodeling in MEKK3 endothelial knockout mice. These data point to the unexpected participation of endothelial MEKK3 in regulation of TGFßR1-Smad2/3 signaling and inward arterial remodeling in artery diseases.

Rumination mediates the relationship between childhood trauma and depressive symptoms in schizophrenia patients.

Rumination and childhood trauma are related to depressive symptoms in clinical and non-clinical individuals. This is the first study aimed to test the mediating effect of rumination on the relationship between childhood trauma and depressive symptoms in schizophrenia patients. A total of 313 schizophrenia patients were recruited in the present study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was adopted to evaluate depressive symptoms, the short-form Childhood Trauma Questionnaire (CTQ-SF) and the 10-item Ruminative response scale (RRS-10) were utilized to assess the childhood trauma and rumination in patients, respectively. Our results showed that 168 schizophrenia patients (53.67%) had comorbid depressive symptoms. These patients with depressive symptoms had higher levels of childhood trauma [both CTQ-SF total scores and emotional abuse (EA), emotional neglect (EN), physical neglect (PN) subscale scores] and rumination (both RRS-10 total scores and brooding, reflection subscale scores) compared to patients without depressive symptoms. The stepwise logistic regression analysis identified that EN (OR 1.196, P = 0.003), PN (OR 1.1294, P < 0.001), brooding (OR 1.291, P < 0.001) and reflection (OR 1.481, P < 0.001) could independently predict the depressive symptoms in schizophrenia patients. Moreover, RRS-10 and its subscale scores could mediate the relationship between depressive symptoms and childhood trauma, especially EA, EN and PN in schizophrenia. Our preliminary findings suggest that the rigorous assessment and psychosocial interventions of rumination are important to alleviate the influence of childhood trauma on depressive symptoms in schizophrenia patients.

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism.

IκB kinase ε (IKKε) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NFκB and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKKε remodels cellular metabolism is currently unknown. Here, we used metabolic tracer analysis to show that IKKε orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKKε upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose-derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces activating transcription factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKKε-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKKε and PSAT1 are both overexpressed, corroborating the link between IKKε and the SBP in the clinical context.

A high environmental composite quality factor score was associated with the risk of sick building syndrome among adults in northeast China.

OBJECTIVES: Epidemiological evidence regarding the association between the combination of indoor and outdoor neighborhood pollution and sick building syndrome (SBS) among adults is limited and inconsistent. A cross-sectional study was conducted to investigate the association between the environmental composite quality factor score and SBS among adults. METHODS: This study included 2594 females and 666 males aged 18-77 years enrolled from the Northeast China. The environmental composite quality factor score was computed based on factors potentially associated with SBS risk, including the outdoor neighborhood pollution sources (the housing on the street, the presence of pollutants within 100 m of the house (gutters, garbage stations, noise, chemical pollution, and dust pollution), and the presence of arterial roads, factories, and chimneys) and indoor pollution sources (redecoration, clean fuel used for heating/cooking, cooking oil fume (COF) outside kitchen, using of mosquito coil or repellent, and using of incense). We performed multivariate logistic regression analysis to calculate the odds ratios (ORs) and 95% confidence intervals (95%CIs) between environmental composite quality factor score, indoor pollution composite factor score, outdoor neighborhood pollution composite factor score, and SBS adjustment for covariates. Further, we also did the stratified analysis and constructed a weighted score to verify the results. RESULTS: Compared with the lowest environmental composite quality factor score, the ORs of the highest scores were: 1.58 (95% CI, 1.20-2.27, Ptrend = 0.001) for general symptoms; 1.73 (95% CI, 1.35-2.23, Ptrend < 0.001) for mucosal symptoms and 1.75 (95% CI, 1.34-2.29, Ptrend < 0.001) for dermal symptoms and 1.81 (95% CI, 1.36-2.42, Ptrend < 0.001) for all of the three symptoms. We also observed similar patterns with the using of weighted scores and stratified analysis. CONCLUSION: Higher exposure to indoor pollution sources and outdoor pollution sources near the residence may be associated with a higher risk of SBS in adults in northeast China.

A Novel Synthetic Interfering Peptide Tat-3L4F Attenuates Olanzapine-Induced Weight Gain Through Disrupting Crosstalk Between Serotonin Receptor 2C and Protein Phosphatase and Tensin Homolog in Rats.

BACKGROUND: Accompanied with profound efficacy, atypical antipsychotics (AAPs) contribute to metabolic adverse effects with few effective strategies to attenuate. Serotonin 5-HT2C receptor (HTR2C) plays a critical role in hyperphagia and weight gain induced by AAPs, and expression of phosphatase tensin homolog (PTEN) in the hypothalamus also affects feeding behavior and weight change. Moreover, PTEN has a physical crosstalk between PTEN and a region in the third intracellular loop (3L4F) of the HTR2C. Tat-3L4F has the property to disrupt crosstalk between PTEN and HTR2C. This is the first study to our knowledge to investigate the effect of Tat-3L4F on olanzapine-induced metabolic abnormalities and PTEN/ phosphatidylinositol 3-kinase/protein kinase B expression in the hypothalamus in rats. METHODS: The effects of Tat-3L4F were investigated through measuring body weight, food intake, and blood glucose. In addition, PTEN/phosphatidylinositol 3-kinase/protein kinase B level in the hypothalamus was detected by immunofluorescence assay and western blot. Metabolites in the liver tissue were detected by liquid chromatography-mass spectrometry and analyzed by multivariate analyses and pairwise comparison. RESULTS: Our results showed that hyperphagia and weight gain were evident in the olanzapine alone-fed rats but was attenuated after Tat-3L4F treatment. In addition, oral glucose tolerance test indicated blood glucose at 120 minutes was higher in the olanzapine alone-treated group than in groups treated with vehicle and olanzapine + Tat-3L4F (10 µmol kg-1 per day). Furthermore, compared with olanzapine alone treatment, treatment with Tat-3L4F (10 µmol kg-1 per day) significantly inhibited PTEN expression in the hypothalamus. The olanzapine alone-treated group had the highest bile acid level, followed by the olanzapine with Tat-3L4F (1 µmol kg-1) group, olanzapine with Tat-3L4F (10 µmol kg-1) group, and vehicle group. CONCLUSIONS: Our present results reveal that Tat-3L4F is a potential pharmacological strategy for suppressing hyperphagia and weight gain induced by olanzapine, which acts through disrupting crosstalk between HTR2C and PTEN as a result of PTEN downregulation in the hypothalamus.

Update on the human and mouse lipocalin (LCN) gene family, including evidence the mouse Mup cluster is result of an "evolutionary bloom".

Lipocalins (LCNs) are members of a family of evolutionarily conserved genes present in all kingdoms of life. There are 19 LCN-like genes in the human genome, and 45 Lcn-like genes in the mouse genome, which include 22 major urinary protein (Mup) genes. The Mup genes, plus 29 of 30 Mup-ps pseudogenes, are all located together on chromosome (Chr) 4; evidence points to an "evolutionary bloom" that resulted in this Mup cluster in mouse, syntenic to the human Chr 9q32 locus at which a single MUPP pseudogene is located. LCNs play important roles in physiological processes by binding and transporting small hydrophobic molecules -such as steroid hormones, odorants, retinoids, and lipids-in plasma and other body fluids. LCNs are extensively used in clinical practice as biochemical markers. LCN-like proteins (18-40 kDa) have the characteristic eight ß-strands creating a barrel structure that houses the binding-site; LCNs are synthesized in the liver as well as various secretory tissues. In rodents, MUPs are involved in communication of information in urine-derived scent marks, serving as signatures of individual identity, or as kairomones (to elicit fear behavior). MUPs also participate in regulation of glucose and lipid metabolism via a mechanism not well understood. Although much has been learned about LCNs and MUPs in recent years, more research is necessary to allow better understanding of their physiological functions, as well as their involvement in clinical disorders.

Omega-3 fatty acids ameliorate cognitive dysfunction in schizophrenia patients with metabolic syndrome.

Our previous study showed that metabolic abnormalities reduced the levels of brain-derived neurotrophic factor (BDNF) and deteriorated cognitive performance in patients with schizophrenia. Inflammation may play a key role in this process. Omega-3 fatty acids have been documented to ameliorate inflammation. Therefore, we hypothesized that omega-3 fatty acids may be of value in enhancing BDNF levels and improving cognitive function in patients with schizophrenia with metabolic syndrome (MetS). We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The enzyme-linked immunosorbent assay was used to measure the plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). Of the 80 patients who consented to the study, 72 completed this 12-week RCT. The primary outcome was the changes from baseline to 12 weeks in clinical characteristics and the levels of BDNF, CRP, IL-6 and TNF-α. There was a significant correlation between omega-3 fatty acid treatment and enhanced delayed memory factor in the RBANS assessment (Fgroup×time = 6.82; df = 1, 66; P = 0.01) when the patients completed this study. Along with cognitive improvement, omega-3 fatty acids enhanced BDNF (Fgroup×time = 4.93; df = 1, 66; P = 0.03) and reduced CRP (Fgroup×time = 17.11; df = 1, 66; P < 0.01), IL-6 (Fgroup×time = 9.71; df = 1, 66; P < 0.004) and TNF-α (Fgroup×time = 6.71; df = 1, 66; P = 0.012) levels after 12 weeks of treatment. The changes in BDNF levels are negatively correlated with the changes in TNF-α levels (r = -0.37, P = 0.03) but not with the changes in CRP and IL-6 levels. Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on cognitive function in patients with MetS, which is paralleled by enhanced BDNF levels.

A novel NAP1L4/NUTM1 fusion arising from translocation t(11;15)(p15;q12) in a myeloid neoplasm with eosinophilia and rearrangement of PDGFRA highlights an unusual clinical feature and therapeutic reaction.

NUT midline carcinoma (NMC) is an aggressive neoplasm and mainly involved in the head and neck area. The defining genetic hallmark on these tumors is that testis-specific nuclear gene (NUTM1) fuses to bromodomain protein family member 4 gene (BRD4), resulting in the formation of BRD4-NUTM1 transcript. Here, we report a case with myeloid neoplasm complicating with eosinophilia (MLN-Eo) and rearrangement of PDGFRA, which co-exists with a new nucleosome assemble protein 1-like 4 gene (NAP1L4) NAP1L4-NUTM1 fusion. The patient have unusually clinical features and therapeutic reaction to imatinib mesylate. The cloned NAP1L4-NUTM1 gene structure is also determined.

Levels of cytokines in the aqueous humor guided treatment of refractory macular edema in adult-onset coats' disease.

BACKGROUND: Two cases with refractory macular edema secondary to adult-onset Coats' disease underwent unsatisfactory treatment by intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs and retinal photocoagulation. CASE PRESENTATION: The authors highlight the guiding effect of the measurement of cytokines in the aqueous humor for the treatment of adult-onset Coats' disease with refractory macular edema. In the two cases, typical Coats' disease changes, including telangiectasis, subretinal exudation and macular edema were observed. Initial treatment consisted of intravitreal anti-VEGF drugs and retinal laser photocoagulation; however, the response was poor. Then, the aqueous humor was acquired and the cytokine concentrations were measured (Flow Cytometry Analysis, Beijing Giantmed Medical Diagnostics Lab). When the cytokine levels were tested every time there would be quality control, with a fixed concentration of cytokines samples to detect before the results reported. A low level of VEGF and a high level of inflammatory cytokines were found. Then, treatment was switched to intravitreal injection of dexamethasone implant (Ozurdex®) (Allergan, Inc., Irvine, Calif., USA), which resulted in resolution of the refractory macular edema and improvement of visual acuity in both cases. CONCLUSIONS: For refractory macular edema secondary to adult-onset Coats' disease, measurement of the levels of VEGF and inflammatory cytokines can help clinic doctors precisely investigate the molecular mechanism of macular edema and thereby find a suitable treatment.

RNF8 is responsible for ATRA resistance in variant acute promyelocytic leukemia with GTF2I/RARA fusion, and inhibition of the ubiquitin-proteasome pathway contributes to the reversion of ATRA resistance.

BACKGROUND: GTF2I-RARA is a newly identified RARA fusion gene in variant acute promyelocytic leukemia (APL) patients with t(7;17)(q11;q21). Clinical manifestation in the patient showed that it is a sort of ATRA-insensitive oncogene and is different from the classic PML-RARA in terms of therapeutic reaction. METHODS: To reveal the functional characteristics and regulating mechanism of the GTF2I-RARA fusion gene, we established a GTF2I-RARA-transfected HL60 cell model and examined its sensitivity to ATRA by western blot, MTT assay, flow cytometry, and Wright-Giemsa staining. Coimmunoprecipitation and confocal microscopy were used to examine the binding of GTF2I-RARA and transcriptional corepressors. We also performed ChIP-seq to search for potential target genes. Immunoprecipitation, ubiquitination assay, western blot, luciferase assay, and real-time PCR were used to analyze the effects of RNF8 on RARA. Flow cytometry and Wright-Giemsa staining were used to study the effect of MG132 and ATRA on the GTF2I-RARA-transfected HL60 cell model. RESULT: We confirmed resistance of GTF2I-RARA to ATRA. Compared with PML-RARA, GTF2I-RARA has a higher affinity to HDAC3 under ATRA treatment. Using the ChIP-sequencing approach, we identified 221 GTF2I-RARA binding sites in model cells and found that the RING finger protein 8 (RNF8) is a target gene of GTF2I-RARA. RNF8 participates in disease progression and therapy resistance in APL with the GTF2I-RARA transcript. Elevated RNF8 expression promotes the interaction between RARA and RNF8 and induces RARA Lys-48 linkage ubiquitylation and degradation, resulting in attenuated transcriptional activation of RARA. CONCLUSION: Our results suggest that RNF8 is a key GTF2I-RARA downstream event. Using the combination of MG132 and ATRA to treat GTF2I-RARA-HL60 cells, a synergistic effect leading to GTF2I-RARA-HL60 cell differentiation was confirmed. Taken together, the targeting of RNF8 may be an alternative choice for treatment in variant APL with GTF2I-RARA fusion.

Synthesis of 2-Amino-5-acylthiazoles by a Tertiary Amine-Promoted One-Pot Three-Component Cascade Cyclization Using Elemental Sulfur as a Sulfur Source.

A novel one-pot three-component cascade cyclization strategy for the synthesis of 2-amino-5-acylthiazoles using enaminones, cyanamide, and elemental sulfur has been developed. The reported methods have demonstrated good tolerance of various functional groups. Up to 28 2-amino-5-acylthiazole compounds bearing diverse structural differences were successfully synthesized from easily obtained starting materials with moderate to excellent yields. Our method provides an effective way for the access of valuable and potentially bioactive 2-amino-5-acylthiazole derivatives.

[General Troubleshooting and Preventive Maintenance of the Digestive Electron Microscope System].

OBJECTIVE: Improve the integrity of the digestive electron microscope equipment and reduce the cost of equipment failure maintenance. METHODS: By studying the composition and function of the digestive electron microscope system and analyzing the causes of common faults, a targeted preventive maintenance plan is developed, equipment users are graded, and a training system is established. RESULTS: The user of the device can skillfully analyze the cause of the malfunction and timely deal with the sudden failure of the diagnosis and treatment, thereby reduce the risk of diagnosis and treatment and the investment in hospital maintenance. CONCLUSIONS: Through the analysis and processing of the digestive electron microscope system, point detection leakage, grading training, preventive maintenance can significantly improve the equipment integrity rate, reduce the risk of clinical diagnosis and treatment, effectively reduce the number of equipment failures, and reduce maintenance costs.

Combination of Fluoride and SO2 Induce DNA Damage and Morphological Alterations in Male Rat Kidney.

BACKGROUND/AIMS: We investigated the combined toxic effect of sodium fluoride (NaF) and sulfur dioxide (SO2) on kidney morphological changes and DNA damage in male Wistar rats. METHODS: In this study we selected totally 96 male Wistar rats (12-week-old) then randomly group-housed them into four cages, treated with deionized water, NaF, SO2 and co-treatment of NaF and SO2 respectively. Morphological changes of kidney were detected by hematoxylin and eosin (H&E) staining at 2, 4, 6 and 8 weeks. Correspondingly, tailing ratio and comet length were measured by BAB Bs Comet Assay System, including DNA damage special unit were calculated to evaluate the grades of kidney DNA damage at the same time. RESULTS: Treated groups showed a body weight decrease when compared to control group. However, no significant difference in the relative weight of kidney was found in all four groups. It is noteworthy that at 2, 4, 6 and 8 weeks after exposure, the morphological alteration of renal tubules were observed in all treated groups, especially in group-IV. Also, at 4 and 6 weeks, notable DNA damage was found in all treated groups, as assessed by significantly increasing trend of comet length tailing ratio. CONCLUSION: The study manifests that presence of NaF and SO2 will not only induce renal tissue lesions but also impact DNA integrity. In addition, this combined exposure exhibits a synergistic effect, characterizing a dose-dependence and time correlation. These findings may provide novel insights regarding perturbations of DNA damage and its functions as a potential new mechanism, by which cautious interpretation of NaF and SO2 co-exposure evolved in both animals and human beings is necessary.

C/EBPß contributes to transcriptional activation of long non-coding RNA NEAT1 during APL cell differentiation.

Emerging evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in cancer development and cancer therapy. LncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) is indispensable during acute promyelocytic leukemia (APL) cell differentiation induced by all-trans retinoic acid (ATRA). However, the precise mechanism of NEAT1 upregulation has not been fully understood. In this study, we performed chromatin immunoprecipitation and luciferase reporter assays to demonstrate that C/EBP family transcription factor C/EBPß bind to and transactivate the promoter of lncRNA NEAT1 through the C/EBPß binding sites both around -54 bp and -1453 bp upstream of the transcription start site. Moreover, the expression of C/EBPß was increased after ATRA treatment, and the binding of C/EBPß in the NEAT1 promoter was also dramatically increased. Finally, knockdown of C/EBPß significantly reduced the ATRA-induced upregulation of NEAT1. In conclusion, C/EBPß directly activates the expression of NEAT1 through binding to the promoter of NEAT1. Knockdown of C/EBPß impairs ATRA-induced transcriptional activation of NEAT1. Our data indicate that C/EBPß contributes to ATRA-induced activation of NEAT1 during APL cell differentiation. Our results enrich our knowledge on the regulation of lncRNAs and the regulatory role of C/EBPß in APL cell differentiation.

Benefits of hyperbaric oxygen pretreatment for decompression sickness in Bama pigs.

Decompression sickness (DCS) occurs when ambient pressure is severely reduced during diving and aviation. Hyperbaric oxygen (HBO) pretreatment has been shown to exert beneficial effects on DCS in rats via heat-shock proteins (HSPs). We hypothesized that HBO pretreatment will also reduce DCS via HSPs in swine models. In the first part of our investigation, six swine were subjected to a session of HBO treatment. HSP32, 60, 70 and 90 were detected, before and at 6, 12, 18, 24 and 30 h following exposure in lymphocytes. In the second part of our investigation, another 10 swine were randomly assigned into two groups (five per group). All swine were subjected to two simulated air dives in a hyperbaric chamber with an interval of 7 days. Eighteen hours before each dive, the swine were pretreated with HBO or air: the first group received air pretreatment prior to the first dive and HBO pretreatment prior to the second; the second group were pretreated with HBO first and then air. Bubble loads, skin lesions, inflammation and endothelial markers were detected after each dive. In lymphocytes, all HSPs increased significantly (P<0.05), with the greatest expression appearing at 18 h for HSP32 and 70. HBO pretreatment significantly reduced all the determined changes compared with air pretreatment. The results demonstrate that a single exposure to HBO 18 h prior to diving effectively protects against DCS in the swine model, possibly via induction of HSPs.

Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis.

Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.

STENOFOLIA recruits TOPLESS to repress ASYMMETRIC LEAVES2 at the leaf margin and promote leaf blade outgrowth in Medicago truncatula.

The Medicago truncatula WUSCHEL-related homeobox (WOX) gene, STENOFOLIA (STF), plays a key role in leaf blade outgrowth by promoting cell proliferation at the adaxial-abaxial junction. STF functions primarily as a transcriptional repressor, but the underlying molecular mechanism is unknown. Here, we report the identification of a protein interaction partner and a direct target, shedding light on the mechanism of STF function. Two highly conserved motifs in the C-terminal domain of STF, the WUSCHEL (WUS) box and the STF box, cooperatively recruit TOPLESS (Mt-TPL) family corepressors, and this recruitment is required for STF function, as deletion of these two domains (STFdel) impaired blade outgrowth whereas fusing Mt-TPL to STFdel restored function. The homeodomain motif is required for direct repression of ASYMMETRIC LEAVES2 (Mt-AS2), silencing of which partially rescues the stf mutant phenotype. STF and LAMINALESS1 (LAM1) are functional orthologs. A single amino acid (Asn to Ile) substitution in the homeodomain abolished the repression of Mt-AS2 and STF's ability to complement the lam1 mutant of Nicotiana sylvestris. Our data together support a model in which STF recruits corepressors to transcriptionally repress its targets during leaf blade morphogenesis. We propose that recruitment of TPL/TPL-related proteins may be a common mechanism in the repressive function of modern/WUS clade WOX genes.

Placental transcriptome variation associated with season, location, and urinary prenatal pyrethroid metabolites of Thai farm-working women.

Prenatal exposure to pyrethroids is linked to adverse health effects in early life and proper placental function is critical to fetal development. This study explores the impact of prenatal pyrethroid exposure, as well as factors impacting exposure and effect, on the placental transcriptome, to understand pyrethroid exposures' relationship to placental function. The study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) recruited pregnant farm-working women from two agricultural districts in the Chiang Mai province of Thailand between 2017 and 2019. This cohort was predominantly exposed to cypermethrin (type II), alongside pyrethroids such as cyfluthrin (type II) and permethrin (type I). In 253 participants, maternal urinary pyrethroid metabolites, 3-phenoxybenzoic acid (PBA), cis-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA), and trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (TDCCA) were measured in early, middle, and late pregnancy and adjusted for urinary creatinine. The placental transcriptome was analyzed using RNA-Seq. Using generalized linear regression, we identified differentially expressed genes (DEGs) associated with the sum of each metabolite across pregnancy, as well as those associated with location of residence and season of birth. Pathway and upstream transcription factor analyses were performed to examine potential mechanisms associated with DEGs. Notably, TDCCA and CDCCA levels peaked in late pregnancy, with significant regional differences, particularly higher levels in the Fang region. Placental gene expression analysis showed no DEGs associated with individual metabolites at FDR<0.05. However, 251 DEGs by location, implicating immune response and oxidative phosphorylation pathways, were identified, while season of birth was associated with 2585 DEGs, over-represented in fibrosis signaling and metabolism pathways. Finally, transcription factor analysis identified 226 and 282 transcription factors associated with location and season, respectively, related to cell proliferation, differentiation, and the immune system. These alterations may have significant implications for fetal development and other pathologic processes, highlighting the importance of monitoring environmental exposures during pregnancy.

Aberrant patterns of spontaneous brain activity in schizophrenia: A resting-state fMRI study and classification analysis.

BACKGROUND: Schizophrenia is a prevalent mental disorder, leading to severe disability. Currently, the absence of objective biomarkers hinders effective diagnosis. This study was conducted to explore the aberrant spontaneous brain activity and investigate the potential of abnormal brain indices as diagnostic biomarkers employing machine learning methods. METHODS: A total of sixty-one schizophrenia patients and seventy demographically matched healthy controls were enrolled in this study. The static indices of resting-state functional magnetic resonance imaging (rs-fMRI) including amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated to evaluate spontaneous brain activity. Subsequently, a sliding-window method was then used to conduct temporal dynamic analysis. The comparison of static and dynamic rs-fMRI indices between the patient and control groups was conducted using a two-sample t-test. Finally, the machine learning analysis was applied to estimate the diagnostic value of abnormal indices of brain activity. RESULTS: Schizophrenia patients exhibited a significant increase ALFF value in inferior frontal gyrus, alongside significant decreases in fALFF values observed in left postcentral gyrus and right cerebellum posterior lobe. Pervasive aberrations in ReHo indices were observed among schizophrenia patients, particularly in frontal lobe and cerebellum. A noteworthy reduction in voxel-wise concordance of dynamic indices was observed across gray matter regions encompassing the bilateral frontal, parietal, occipital, temporal, and insular cortices. The classification analysis achieved the highest values for area under curve at 0.87 and accuracy at 81.28% when applying linear support vector machine and leveraging a combination of abnormal static and dynamic indices in the specified brain regions as features. CONCLUSIONS: The static and dynamic indices of brain activity exhibited as potential neuroimaging biomarkers for the diagnosis of schizophrenia.