UDP-glycosyltransferases act as key determinants of host plant range in generalist and specialist Spodoptera species.

Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these biotransformation systems differ in generalist and specialist insect species and their role in determining insect host plant range remains an open question. Here, we show that UDP-glucosyltransferases (UGTs) play a key role in determining the host range of insect species within the Spodoptera genus. Comparative genomic analyses of Spodoptera species that differ in host plant breadth identified a relatively conserved number of UGT genes in generalist species but high levels of UGT gene pseudogenization in the specialist Spodoptera picta. CRISPR-Cas9 knockouts of the three main UGT gene clusters of Spodoptera frugiperda revealed that UGT33 genes play an important role in allowing this species to utilize the poaceous plants maize, wheat, and rice, while UGT40 genes facilitate utilization of cotton. Further functional analyses in vivo and in vitro identified the UGT SfUGT33F32 as the key mechanism that allows generalist S. frugiperda to detoxify the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), a potent insecticidal phytotoxin produced by poaceous plants. However, while this detoxification capacity is conserved in several generalist Spodoptera species, Spodoptera picta, which specializes on Crinum plants, is unable to detoxify DIMBOA due to a nonfunctionalizing mutation in SpUGT33F34. Collectively, these findings provide insight into the role of insect UGTs in host plant adaptation, the mechanistic basis of evolutionary transitions between generalism and specialism and offer molecular targets for controlling a group of notorious insect pests.

Deciphering the regulatory network of the NAC transcription factor FvRIF, a key regulator of strawberry (Fragaria vesca) fruit ripening.

The NAC transcription factor ripening inducing factor (RIF) was previously reported to be necessary for the ripening of octoploid strawberry (Fragaria × ananassa) fruit, but the mechanistic basis of RIF-mediated transcriptional regulation and how RIF activity is modulated remains elusive. Here, we show that FvRIF in diploid strawberry, Fragaria vesca, is a key regulator in the control of fruit ripening and that knockout mutations of FvRIF result in a complete block of fruit ripening. DNA affinity purification sequencing coupled with transcriptome deep sequencing suggests that 2,080 genes are direct targets of FvRIF-mediated regulation, including those related to various aspects of fruit ripening. We provide evidence that FvRIF modulates anthocyanin biosynthesis and fruit softening by directly regulating the related core genes. Moreover, we demonstrate that FvRIF interacts with and serves as a substrate of MAP kinase 6 (FvMAPK6), which regulates the transcriptional activation function of FvRIF by phosphorylating FvRIF at Thr-310. Our findings uncover the FvRIF-mediated transcriptional regulatory network in controlling strawberry fruit ripening and highlight the physiological significance of phosphorylation modification on FvRIF activity in ripening.

Low temperature inhibits anthocyanin accumulation in strawberry fruit by activating FvMAPK3-induced phosphorylation of FvMYB10 and degradation of Chalcone Synthase 1.

Low temperature causes poor coloration of strawberry (Fragaria sp.) fruits, thus greatly reducing their commercial value. Strawberry fruits accumulate anthocyanins during ripening, but how low temperature modulates anthocyanin accumulation in plants remains largely unknown. We identified MITOGEN-ACTIVATED PROTEIN KINASE3 (FvMAPK3) as an important negative regulator of anthocyanin accumulation that mediates the poor coloration of strawberry fruits in response to low temperature. FvMAPK3 activity was itself induced by low temperature, leading to the repression of anthocyanin accumulation via two mechanisms. Activated FvMAPK3 acted as the downstream target of MAPK KINASE4 (FvMKK4) and SUCROSE NONFERMENTING1-RELATED KINASE2.6 (FvSnRK2.6) to phosphorylate the transcription factor FvMYB10 and reduce its transcriptional activity. In parallel, FvMAPK3 phosphorylated CHALCONE SYNTHASE1 (FvCHS1) to enhance its proteasome-mediated degradation. These results not only provide an important reference to elucidate the molecular mechanisms underlying low-temperature-mediated repression of anthocyanin accumulation in plants, but also offer valuable candidate genes for generating strawberry varieties with high tolerance to low temperature and good fruit quality.

Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

AIMS: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. METHODS: Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. RESULTS: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). CONCLUSIONS: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

White Matter Hyperintensity is Associated with Malignant Cerebral Edema in Ischemic Stroke Treated with Thrombectomy.

BACKGROUND: White matter hyperintensity (WMH) burden may lead to poor clinical outcomes after endovascular thrombectomy (EVT). But the relationship between WMH burden and cerebral edema (CED) is unclear. PURPOSE: To examine the association between WMH burden and CED and functional outcome in patients treated with EVT. STUDY TYPE: Retrospective. SUBJECT: 344 patients with acute anterior circulation large-vessel occlusion stroke who received EVT at two comprehensive stroke centers. Mean age was 62.6 ± 11.6 years and 100 patients (29.1%) were female. FIELD STRENGTH/SEQUENCE: 3T, including diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) images. ASSESSMENT: The severity of WMH was evaluated using the Fazekas scale on a FLAIR sequence before EVT. The severity of CED was assessed using CED score (three for malignant cerebral edema [MCE]) and net water uptake (NWU)/time on post-EVT cranial CT. The impact of WMH burden on MCE, NWU/time, and 3-month poor outcome (modified Rankin scale >2) after EVT were assessed. STATISTICAL TESTS: Pearson's chi-squared test, Fisher exact test, 2-tailed t test, Mann-Whitney U test, multivariable logistic regression, multivariate regression analysis, Sobel test. A P value <0.05 was considered statistically significant. RESULTS: WMH burden was not significantly associated with MCE and parenchymal hemorrhage (PH) in the whole population (P = 0.072; P = 0.714). WMH burden was significantly associated with an increased risk of MCE (OR, 1.550; 95% CI, 1.128-2.129), higher NWU/time (Coefficient, 0.132; 95% CI, 0.012-0.240), and increased risk of 3-month poor outcome (OR, 1.434; 95% CI, 1.110-1.853) in the subset of patients without PH. Moreover, the connection between WMH burden and poor outcome was partly mediated by CED in patients without PH (regression coefficient changed by 29.8%). DATA CONCLUSION: WMH burden is associated with CED, especially MCE, and poor outcome in acute ischemic stroke patients treated with EVT. The association between WMH burden and poor outcome may partly be attributed to postoperative CED. TECHNICAL EFFICACY: Stage 5.

Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway.

Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost.

Unraveling the solvent stability on the cathode surface of Li-O2 batteries by using in situ vibrational spectroscopies.

In aprotic lithium-oxygen (Li-O2) batteries, solvent properties are crucial in the charge/discharge processes. Therefore, a thorough understanding of the solvent stability at the cathode surface during the oxygen reduction/evolution reactions (ORR/OER) is essential for the rational design of high-performance electrolytes. In this study, the stability of typical solvents, a series of glyme solvents with different chain lengths, has been investigated during the ORR/OER by in situ vibrational spectroscopy measurements of sum frequency generation (SFG) spectroscopy and infrared reflection absorption spectroscopy (IRRAS). The structural evolution and decomposition mechanism of the solvents during ORR/OER have been discussed based on the observations. Our results demonstrate that superoxide (O2-) generated during the ORR plays a critical role in the stability of the solvents.

Phenethyl isothiocyanate inhibits metastasis potential of non-small cell lung cancer cells through FTO mediated TLE1 m6A modification.

N6-methyladenosine (m6A) modification is a prevalent RNA epigenetic modification, which plays a crucial role in tumor progression including metastasis. Isothiocyanates (ITCs) are natural compounds and inhibit the tumorigenesis of various cancers. Our previous studies show that ITCs inhibit the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells, and have synergistic effects with chemotherapy drugs. In this study, we investigated the molecular mechanisms underlying the inhibitory effects of ITCs on cancer cell metastasis. We showed that phenethyl isothiocyanate (PEITC) dose-dependently inhibited the cell viability of both NSCLC cell lines H1299 and H226 with IC50 values of 17.6 and 15.2 µM, respectively. Furthermore, PEITC dose-dependently inhibited the invasion and migration of H1299 and H226 cells. We demonstrated that PEITC treatment dose-dependently increased m6A methylation levels and inhibited the expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in H1299 and H226 cells. Knockdown of FTO significantly increased m6A methylation in H1299 and H226 cells, impaired their abilities of invasion and migration in vitro, and enhanced the inhibition of PEITC on tumor growth in vivo. Overexpression of FTO promoted the migration of NSCLC cells, and also mitigated the inhibitory effect of PEITC on migration of NSCLC cells. Furthermore, we found that FTO regulated the mRNA m6A modification of a transcriptional co-repressor Transducin-Like Enhancer of split-1 (TLE1) and further affected its stability and expression. TCGA database analysis revealed TLE1 was upregulated in NSCLC tissues compared to normal tissues, which might be correlated with the metastasis status. Moreover, we showed that PEITC suppressed the migration of NSCLC cells by inhibiting TLE1 expression and downstream Akt/NF-κB pathway. This study reveals a novel mechanism underlying ITC's inhibitory effect on metastasis of lung cancer cells, and provided valuable information for developing new therapeutics for lung cancer by targeting m6A methylation.

The Childbearing sense of coherence scale (CSOC-scale): development and validation.

BACKGROUND: the salutogenic theory is essential to explain an individual's ability to maintain health during the perinatal period. While previous studies mainly focused on the perspectives from a family-level orientation and a global orientation, the purpose of the present study was to develop and validate a scale, the childbearing sense of coherence scale (CSOC-scale) from the individual's perceptions of the stresses, resources, and meaningfulness of childbearing. METHODS: A total of 3 separate studies contributed to the development of the CSOC-scale between July 2022 and February 2023. In study 1, the initial item pool based on the conceptual framework of the childbearing sense of coherence and the salutogenic theory was developed. Delphi expert consultation was conducted to revise and improve items. Studies 2 and 3 were cross-sectional studies. In study 2, item analysis and explore factor analysis (EFA) (N = 351 for women, N = 256 for men) were used to screen items. In study 3, confirmatory factor analysis (CFA) and reliability analysis (N = 366 for women, N = 308 for men) were used to test the fit indices and reliability of the final scale. RESULTS: final analysis suggested the CSOC-scale includes three factors, consisting of 13 items. Confirmatory factor analysis demonstrated good model fit (χ2 = 157.448, df = 62, χ2/ df = 2.539, RMSEA = 0.065, CFI = 0.974, TLI = 0.968, SRMR = 0.029 for women; χ2 = 181.363, df = 62, χ2/ df = 2.925, RMSEA = 0.079, CFI = 0.968, TLI = 0.960, SRMR = 0.033 for men) and high factor loadings (from 0.751 to 0.929 for women; from 0.746 to 0.947 for men). Internal consistency (Cronbach's α ranging from 0.895 to 0.933 for women and 0.881 to 0.945 for men in three dimensions; Cronbach's α was 0.919 for women and 0.821 for men in the entire instrument) and split-half reliability (Spearman-Brown coefficients ranging from 0.876 to 0.921 for women and 0.841 to 0.937 for men in three dimensions; Spearman-Brown coefficient was 0.744 for women and 0.785 for men in the entire instrument) were excellent. CONCLUSIONS: the CSOC-scale has robust psychometric properties. It is reliable and valid in evaluating the childbearing sense of coherence in women and men during pregnancy. Utilisation of this scale can help healthcare professionals understand the health maintenance competencies of couples during the transition of parenthood and provide health promotion services from a salutogenic perspective.

Genome-Wide Identification of the Paulownia fortunei Aux/IAA Gene Family and Its Response to Witches' Broom Caused by Phytoplasma.

The typical symptom of Paulownia witches' broom (PaWB), caused by phytoplasma infection, is excessive branching, which is mainly triggered by auxin metabolism disorder. Aux/IAA is the early auxin-responsive gene that participates in regulating plant morphogenesis such as apical dominance, stem elongation, lateral branch development, and lateral root formation. However, no studies have investigated the response of the Aux/IAA gene family to phytoplasma infection in Paulownia fortunei. In this study, a total of 62 Aux/IAA genes were found in the genome. Phylogenetic analysis showed that PfAux/IAA genes could be divided into eight subgroups, which were formed by tandem duplication and fragment replication. Most of them had a simple gene structure, and several members lacked one or two conserved domains. By combining the expression of PfAux/IAA genes under phytoplasma stress and SA-treated phytoplasma-infected seedlings, we found that PfAux/IAA13/33/45 may play a vital role in the occurrence of PaWB. Functional analysis based on homologous relationships showed a strong correlation between PfAux/IAA45 and branching. Protein-protein interaction prediction showed that PfARF might be the binding partner of PfAux/IAA, and the yeast two-hybrid assay and bimolecular fluorescent complementary assay confirmed the interaction of PfAux/IAA45 and PfARF13. This study provides a theoretical basis for further understanding the function of the PfAux/IAA gene family and exploring the regulatory mechanism of branching symptoms caused by PaWB.

Study of Lactobacillus plantarum coated with Tremella polysaccharides to improve its intestinal adhesion.

BACKGROUND: The adhesion of probiotics to the intestine is crucial for their probiotic function. In previous studies, Tremella polysaccharides (TPS) (with sodium casein) have shown the potential to encapsulate probiotics and protect them in a simulated gastrointestinal tract. This study explored the effect of TPS (with sodium casein) on the adhesion of probiotics. RESULTS: Lactobacillus plantarum was coated with TPS and sodium casein in different proportions, and was freeze-dried. The rheological properties of the mixture of probiotics powder and mucin solution were determined by static and dynamic rheological analysis. Aqueous solutions of probiotic powder and mucin mixture exhibited pseudoplastic fluid rheological properties. The higher the proportion of TPS content, the higher the apparent viscosity and yield stress. The mixed bacterial powder and mucin fluid displayed thixotropy and was in accordance with the Herschel-Bulkley model. The TPS increased the bio-adhesive force of the probiotic powder and mucin. When using TPS as the only carbon source, the adhesion of L. plantarum to Caco-2 cells increased by 228% in comparison with glucose in vitro. Twelve adhesive proteins were also detected in the whole-cell proteome of L. plantarum. Among them, ten adhesive proteins occurred abundantly when grown with TPS as a carbon source. CONCLUSION: Tremella polysaccharides therefore possess probiotic properties and can promote the intestinal adhesion of L. plantarum. © 2024 Society of Chemical Industry.

Perceived COVID-19 Stress and Suicidal Ideation Among College Students: Meditation Roles of Family Cohesion and Unmet Interpersonal Needs.

Purpose: Few studies examined variables that might explain the link between perceived COVID-19 stress and suicidal ideation. The present study tested a multiple-sequence mediation model with family cohesion, thwarted belongingness, and perceived burdensomeness as mediators. Methods: The current study surveyed 1098 college students in China using questionnaires concerning perceived COVID-19 stress, family cohesion, unmet interpersonal needs, and suicide ideation. Results: Perceived COVID-19 stress was significantly associated with family cohesion, thwarted belongingness, perceived burdensomeness, and suicidal ideation. Family cohesion, thwarted belongingness, and perceived burdensomeness mediated the relationship between perceived COVID-19 stress and suicidal ideation separately. These factors also had multiple sequence-mediated effects between perceived COVID-19 stress and suicidal ideation. Conclusion: The study revealed pathways from perceived COVID-19 stress to suicidal ideation and suggested that interventions to increase family cohesion and reduce one's unmet interpersonal needs were beneficial in decreasing individuals' suicidal ideation.

Protein arginine methyltransferase 5 is essential for oncogene product EWSR1-ATF1-mediated gene transcription in clear cell sarcoma.

Transcription dysregulation is common in sarcomas driven by oncogenic transcription factors. Clear cell sarcoma of soft tissue (CCSST) is a rare sarcoma with poor prognosis presently with no therapy. It is characterized by a balanced t(12;22) (q13;q12) chromosomal translocation, resulting in a fusion of the Ewing's sarcoma gene EWSR1 with activating transcription factor 1 (ATF1) to give an oncogene EWSR1-ATF1. Unlike normal ATF1, whose transcription activity is dependent on phosphorylation, EWSR1-ATF1 is constitutively active to drive ATF1-dependent gene transcription to cause tumorigenesis. No EWSR1-ATF1-targeted therapies have been identified due to the challenges in targeting intracellular transcription factors. Through proteomics screening to identify potential druggable targets for CCSST, we discovered protein arginine methyltransferase 5 (PRMT5) as a novel protein to interact with EWSR1-ATF1. PRMT5 is a type II protein arginine methyltransferase to symmetrically dimethylate arginine residues in substrate proteins to regulate a diverse range of activities including gene transcription, RNA splicing, and DNA repair. We found that PRMT5 enhances EWSR1-ATF1-mediated gene transcription to sustain CCSST cell proliferation. Genetic silencing of PRMT5 in CCSST cells resulted in severely impaired cell proliferation and EWSR1-ATF1-driven transcription. Furthermore, we demonstrate that the clinical-stage PRMT5 inhibitor JNJ-64619178 potently and efficaciously inhibited CCSST cell growth in vitro and in vivo. These results provide new insights into PRMT5 as a transcription regulator and warrant JNJ-64619178 for further clinical development to treat CCSST patients.

Different Changing Patterns for Stroke Subtype Mortality Attributable to High Sodium Intake in China During 1990 to 2019.

BACKGROUND: It is unclear whether sodium intake had similar effects on mortality of stroke subtypes. The purpose of this study is to compare the long-term trends in mortality of stroke subtypes attributable to high sodium intake in China during 1990 to 2019. METHODS: Data for China in the GBD (Global Burden of Disease) 2019 study were obtained mainly from the Chinese surveillance systems and the KaiLuan Study. The trends in stroke mortality due to high sodium intake (>5 g/d) were evaluated using join-point regression and age-period-cohort methods adjusting for age, period, and cohort. RESULTS: The age-standardized mortality rates of stroke attributable to high sodium intake showed downward trends during 1990 to 2019 in China, with an average annual percentage change of -0.6 (95% CI, -0.8 to -0.4) for ischemic stroke, -2.5 (95% CI, -2.8 to -2.2) for intracerebral hemorrhage, and -6.1 (95% CI, -6.6 to -5.7) for subarachnoid hemorrhage. The curves of local drifts, which reflected the average annual percentage change of stroke mortality due to high sodium intake across age groups, showed a slow upward trend with age for ischemic stroke, a slow downward trend for intracerebral hemorrhage, and a sharp downward trend for subarachnoid hemorrhage. The high sodium-related mortality increased dramatically with age for ischemic stroke and intracerebral hemorrhage, while it reached a peak at 50 to 70 years old for subarachnoid hemorrhage. The period and cohort rate ratios of stroke mortality due to high sodium intake decreased in the past 3 decades, with the greatest decline for subarachnoid hemorrhage and the weakest decrease for ischemic stroke. Notably, men had higher high sodium-related mortality and risk but slighter declines for all stroke subtypes than women. CONCLUSIONS: Our results provided powerful evidence that high sodium-related age-standardized mortality rates and risk of stroke in China decreased in the past 3 decades, with diverse changing patterns for different stroke subtypes, highlighting that salt reduction had distinct impact on stroke subtypes.

Ofatumumab versus Teriflunomide in Multiple Sclerosis.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).

BRASSINOSTEROID-INSENSITIVE 2 regulates salt stress tolerance in Arabidopsis by promoting AGL16 activity.

Salt stress is a negative environmental factors to affecting plants. Salinity inhibits seed germination and root growth, which reduces the biomass of agricultural plants. BRASSINOSTEROID-INSENSITIVE2 (BIN2) functions as a signalling hub to integrate the perception and transduction of plant growth and stress tolerance by the phosphorylation of target proteins. However, only a small number of target molecules have been discovered thus far. In this study, we present evidence that BIN2 controls the post-transcriptional activity of AGL16. BIN2 interacts and phosphorylates AGL16, which increases AGL16 stability and transcriptional activity. Genetic testing showed that the agl16 mutant can restore the reduction in the seed germination rate and primary root growth of the bin2-1 mutant, while the overexpression of AGL16 in the bin2-3bil1bil2 mutant reduced the salt tolerance compared with bin2-3bil1bil2 in response to salt stress. Taken together, our data identify a BIN2-AGL16 core protein module that is mediates the inhibition of seed germination and primary root growth under salt stress.

Parallel selection of loss-of-function alleles of Pdh1 orthologous genes in warm-season legumes for pod indehiscence and plasticity is related to precipitation.

Pod dehiscence facilitates seed dispersal in wild legumes but results in yield loss in cultivated legumes. The evolutionary genetics of the legume pod dehiscence trait remain largely elusive. We characterized the pod dehiscence of chromosome segment substitution lines of Glycine max crossed with Glycine soja and found that the gene underlying the predominant quantitative trait locus (QTL) of soybean pod-shattering trait was Pod dehiscence 1 (Pdh1). A few rare loss-of-function (LoF) Pdh1 alleles were identified in G. soja, while only an allele featuring a premature stop codon was selected for pod indehiscence in cultivated soybean and spread to low-precipitation regions with increased frequency. Moreover, correlated interactions among Pdh1's haplotype, gene expression, and environmental changes for the developmental plasticity of the pod dehiscence trait were revealed in G. max. We found that orthologous Pdh1 genes specifically originated in warm-season legumes and their LoF alleles were then parallel-selected during the domestication of legume crops. Our results provide insights into the convergent evolution of pod dehiscence in warm-season legumes, facilitate an understanding of the intricate interactions between genetic robustness and environmental adaptation for developmental plasticity, and guide the breeding of new legume varieties with pod indehiscence.

NUAK1 promotes tumor metastasis through upregulating slug transcription in esophageal squamous cell carcinoma.

BACKGROUND: Metastasis is still a major cause of poor pathological outcome and prognosis in esophageal squamous cell carcinoma (ESCC) patients. NUAK1 has been reported highly expressed in many human cancers and is associated with the poor prognosis of cancer patients. However, the role of NUAK1 and its underlying signaling mechanism in ESCC metastasis remain unclear. METHODS: Expression of NUAK1 in ESCC was detected by real-time quantitative RT-PCR (qRT-PCR), Western blotting and immunohistochemical staining. MTT, colony formation, wound-healing and transwell assays were used to determine the role NUAK1 in vitro. Metastasis was evaluated by use of an experimental pulmonary metastasis model in BALB/c-nu/nu mice. The mechanisms were assessed by using coimmunoprecipitation, immunofluorescence and dual-luciferase reporter gene experiments. RESULTS: NUAK1 was highly expressed in ESCC tissues compared with the adjacent normal esophageal epithelial tissues. Moreover, the elevated expression of NUAK1 positively correlated with tumor invasion depth, lymph node metastasis, pathological TNM stage, and poor survival in ESCC patients. Further experiments showed that NUAK1 overexpression did not change the cell viability and colony formation of ESCC cells, while remarkably promoted the migration and invasion in vitro and experimental pulmonary metastasis in vivo. Mechanistically, NUAK1 enhanced the transcription level of Slug, which enhanced the migratory and invasive capability of ESCC cells. Consistently, silencing Slug almost completely diminished the migration and invasion of NUAK1-overexpressing ESCC cells. Further studies demonstrated that NUAK1 upregulated the transcription activity of Slug through activating the JNK/c-Jun pathway. CONCLUSION: These results demonstrated that NUAK1 promoted the metastasis of ESCC cells through activating JNK/c-Jun/Slug signaling, indicating NUAK1 is a promising therapeutic target for metastatic ESCC.

Integrative analysis of γδT cells and dietary factors reveals predictive values for autism spectrum disorder in children.

BACKGROUND: Autism spectrum disorder (ASD) includes a range of multifactorial neurodevelopmental disabilities characterized by a variable set of neuropsychiatric symptoms. Immunological abnormalities have been considered to play important roles in the pathogenesis of ASD, but it is still unknown which abnormalities are more prominent. METHODS: A total of 105 children with ASD and 105 age and gender-matched typically developing (TD) children were recruited. An eating and mealtime behavior questionnaire, dietary habits, and the Bristol Stool Scale were investigated. The immune cell profiles in peripheral blood were analyzed by flow cytometry, and cytokines (IFN-γ, IL-8, IL-10, IL-17A, and TNF-α) in plasma were examined by Luminex assay. The obtained results were further validated using an external validation cohort including 82 children with ASD and 51 TD children. RESULTS: Compared to TD children, children with ASD had significant eating and mealtime behavioral changes and gastrointestinal symptoms characterized by increased food fussiness and emotional eating, decreased fruit and vegetable consumption, and increased stool astriction. The proportion of γδT cells was significantly higher in children with ASD than TD children (ß: 0.156; 95% CI: 0.888 âˆ¼ 2.135, p < 0.001) even after adjusting for gender, eating and mealtime behaviors, and dietary habits. In addition, the increased γδT cells were evident in all age groups (age < 48 months: ß: 0.288; 95% CI: 0.420 âˆ¼ 4.899, p = 0.020; age ≥ 48 months: ß: 0.458; 95% CI: 0.694 âˆ¼ 9.352, p = 0.024), as well as in boys (ß: 0.174; 95% CI: 0.834 âˆ¼ 2.625, p < 0.001) but not in girls. These findings were also confirmed by an external validation cohort. Furthermore, IL-17, but not IFN-γ, secretion by the circulating γδT cells was increased in ASD children. Machine learning revealed that the area under the curve in nomogram plots for increased γδT cells combined with eating behavior/dietary factors was 0.905, which held true in both boys and girls and in all the age groups of ASD children. The decision curves showed that children can receive significantly higher diagnostic benefit within the threshold probability range from 0 to 1.0 in the nomogram model. CONCLUSIONS: Children with ASD present with divergent eating and mealtime behaviors and dietary habits as well as gastrointestinal symptoms. In peripheral blood, γδT cells but not αßT cells are associated with ASD. The increased γδT cells combined with eating and mealtime behavior/dietary factors have a high value for assisting in the diagnosis of ASD.

Quorum sensing unveils the sludge floccule-assisted stabilization of aerobic granules in granule-dominated sequencing batch reactors.

Floccules are another major form of microbial aggregates in aerobic granular sludge systems. Previous studies mainly attributed the persistence of floccules to their relatively faster nutrient uptake and higher growth rate over aerobic granules; however, they failed to unravel the underlying mechanism of the long-term coexistence of these two aggregates. In this work, the existence and function of the floccules in an aerobic granule-dominated sequencing batch reactor were investigated from the view of quorum sensing (QS) and quorum quenching (QQ). The results showed that though the floccules were closely associated with the granules in terms of similar community structures (including the QS- and QQ-related ones), they exhibited a relatively higher QQ-related activity but a lower QS-related activity. A compatible proportion of floccules might be helpful to maintain the QS-related activity and keep the granules stable. In addition, the structure difference was demonstrated to diversify the QS- and QQ-related activities of the floccules and the aerobic granules. These findings could broaden our understanding of the interactions between the coexistent floccules and granules in aerobic granule-dominated systems and would be instructive for the development of the aerobic granular sludge process.