Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization.

Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes.

Polygenic adaptation of a cosmopolitan pest to a novel thermal environment.

The fluctuation in temperature poses a significant challenge for poikilothermic organisms, notably insects, particularly in the context of changing climatic conditions. In insects, temperature adaptation has been driven by polygenes. In addition to genes that directly affect traits (core genes), other genes (peripheral genes) may also play a role in insect temperature adaptation. This study focuses on two peripheral genes, the GRIP and coiled-coil domain containing 2 (GCC2) and karyopherin subunit beta 1 (KPNB1). These genes are differentially expressed at different temperatures in the cosmopolitan pest, Plutella xylostella. GCC2 and KPNB1 in P. xylostella were cloned, and their relative expression patterns were identified. Reduced capacity for thermal adaptation (development, reproduction and response to temperature extremes) in the GCC2-deficient and KPNB1-deficient P. xylostella strains, which were constructed by CRISPR/Cas9 technique. Deletion of the PxGCC2 or PxKPNB1 genes in P. xylostella also had a differential effect on gene expression for many traits including stress resistance, resistance to pesticides, involved in immunity, trehalose metabolism, fatty acid metabolism and so forth. The ability of the moth to adapt to temperature via different pathways is likely to be key to its ability to remain an important pest species under predicted climate change conditions.

Pregnancy outcomes in women with severe acute respiratory syndrome coronavirus 2 reinfections compared to those with a single infection: a retrospective cohort study.

BACKGROUND: To assess pregnancy outcomes in women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection. METHODS: This was a retrospective cohort study that included pregnant women who contracted coronavirus disease 2019 (COVID-19) once or twice during pregnancy and who gave birth between 1 October 2022 and 15 August 2023 in Shanghai First Maternity and Infant Hospital (Shanghai, China). We collected their clinical data and compared the frequency of adverse pregnancy outcomes between the reinfection group and the primary infection group, such as preterm birth, fetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), common pregnancy-related conditions, birth weight, and neonatal unit admission. RESULTS: We observed a 7.7% reinfection rate among the 1,405 women who contracted COVID-19 during pregnancy. There were no significant differences in the frequency of preterm birth, FGR, HDP, other common pregnancy-related conditions, birth weight, or rate of neonatal unit admission between the reinfection and single infection groups. All our participants were unvaccinated, and all had mild symptoms. CONCLUSION: Our study showed no significant association between SARS-CoV-2 reinfection and adverse pregnancy outcomes.

Sources appointment and health risks of PM2.5-bound trace elements in a coastal city of southeastern China.

To gain a comprehensive understanding of sources and health risks of trace elements in an area of China with high population densities and low PM2.5 concentrations, 15 trace elements (Al, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Sn, Ba, Pb) in PM2.5 were monitored from December 2020 to November 2021 in a representative city, Xiamen. The concentrations of trace elements in Xiamen displayed an obvious seasonal variation and were dominated by K, Fe, Al, Ca and Zn. Based on Positive Matrix Factorization analysis, source appointment revealed that the major sources of trace elements in Xiamen were traffic, dust, biomass and firework combustion, industrial manufacture and shipping emission. According to health risk assessment combined with the source appointment results, it indicated that the average noncarcinogenic risk was below the threshold and cancer risk of four hazardous metals (Cr, Ni, As, Pb) exceeded the threshold (10-6). Traffic-related source had almost half amount of contribution to the health risk induced by PM2.5-bound trace elements. During the dust transport period or Spring Festival period, the health risks exceeded an acceptable threshold even an order of magnitude higher, suggesting that the serious health risks still existed in low PM2.5 environment at certain times. Health risk assessment reminded that the health risk reduction in PM2.5 at southeastern China should prioritize traffic-related hazardous trace elements and highlighted the importance of controlling vehicles emissions in the future.

Mutagenesis of the cleavage site of (pro)renin receptor abrogates aldosterone-salt-induced hypertension and renal injury in mice.

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.

A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury.

The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80hi and CD11bhi cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80hi macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80hi macrophages would worsen septic AKI. F4/80hi macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1dtr/wt (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1dtr/wt (F4/80 MWT) mice. F4/80 MWT and F4/80 MKO mice were subjected to sham or cecal ligation and puncture to induce sepsis. Compared to F4/80 MWT mice, F4/80 MKO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine and histologic injury scoring. Kidneys from F4/80 MKO mice elaborated higher kidney interleukin-6 levels. Mechanistically, single cell RNA sequencing identified a macrophage-endothelial cell immunoregulatory axis that underlies interleukin-6 expression. F4/80hi macrophages expressed interleukin-1 receptor antagonist and limited interleukin-6 expression in endothelial cells. In turn, anti-interleukin-6 therapy ameliorated septic AKI in F4/80 MKO mice. Thus, F4/80hi macrophages express interleukin-1 receptor antagonist and constrain interleukin-6 generation from endothelial cells to limit septic AKI, representing a targetable cellular crosstalk in septic AKI. These findings are particularly relevant owing to the efficacy of anti-interleukin-6 therapies during COVID-19 infection, a disease associated with high rates of AKI and endothelial dysfunction.

ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway.

BACKGROUND: Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. METHODS: A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. RESULTS: ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18-1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50-2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7. CONCLUSIONS: ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin-angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.

The Relationship Between Iodine Excess and Thyroid Function During Pregnancy and Infantile Neurodevelopment at 18-24 Months.

BACKGROUND: Thyroid disease is a prevalent condition during pregnancy, and excessive iodine intake can lead to changes in thyroid function. However, research on the relationship between maternal iodine excess, thyroid hormones during pregnancy, and infantile neurodevelopment is limited. OBJECTIVES: This study aimed to explore the relationship between maternal iodine excess and thyroid hormones during pregnancy and infantile neurodevelopment. The objective was to provide evidence to support and enhance the prevention of neurodevelopmental retardation in infants. METHODS: From 2016 to 2018, a prospective study was conducted from pregnancy to 18-24 mo postpartum. Maternal urinary iodine concentration (UIC), thyroid-stimulating hormone (TSH), total serum iodine (TSI), and nonprotein-bound serum iodine during pregnancy were determined. The Gesell Development Scale was used to assess neurodevelopment of infants aged 18-24 mo. The iodine status of pregnant females was divided into following 4 groups on the basis of the distribution of maternal UIC: <100 µg/L (moderate deficiency), 100-149 µg/L (mild deficiency), 150-249 µg/L (sufficiency), and >250 µg/L (above requirement). RESULTS: Our study included 469 mother-infant pairs. Compared with the maternal UIC of 150-249 µg/L during pregnancy, risk of adaptive developmental delay was increased in infants with maternal UIC ≥250 µg/L (OR: 2.38; 95% CI: 1.06, 5.35). Pregnant females with TSI >90th quantiles were more likely to have offspring with language developmental delay than those with lower TSI in 10th-90th quantiles (OR: 3.06; 95% CI: 1.09, 8.58). Risk of fine motor developmental delay was increased in infants with maternal TSH ≥2.5 mIU/L during pregnancy (OR: 4.32; 95% CI: 1.43, 13.0). CONCLUSIONS: Maternal iodine nutritional status above requirement (UIC ≥250 µg/L or TSI >90th quantiles) during pregnancy negatively affects infantile neurodevelopment. Maternal TSH ≥2.5 mIU/L during pregnancy was an independent risk factor for infantile neurodevelopment. This trial was registered at clinicaltrials.gov as NCT03710148.

Iodine Intakes of <150 µg/day or >550 µg/day are Not Recommended during Pregnancy: A Balance Study.

BACKGROUND: Adequate iodine intake during pregnancy is critical for maintaining maternal and fetal thyroid function and development. There are only limited data from iodine-balance studies to inform iodine requirements during pregnancy. OBJECTIVES: This is an iodine-balance study conducted to explore the associations among iodine intake, excretion, and retention to provide information regarding iodine requirements during pregnancy. METHODS: A 7-d iodine-balance experiment enrolled 93 healthy pregnant Chinese women from Hebei, Tanjin, and Shandong. Duplicates of all foods and beverages consumed were systematically collected and measured for iodine content. Iodine excretion was measured by collecting 24-h urine and feces samples. Simple linear regression models were used to assess relationships between total iodine intake and iodine retention, whereas mixed effect models were used to assess the relationship between daily iodine intake and iodine retention. RESULTS: The mean ± SD age of participating pregnant women was 29 ± 2 y at a median 22 (IQR: 13-30) wk of gestation. The mean 7-d iodine retention was 43.0 ± 1060 µg/7 d. A negative iodine balance was present in 56% of women whereas 44% had a positive balance. Pregnant women with iodine intakes <150 µg/d were in negative balance whereas those with intakes >550 µg/d were in positive balance. The daily iodine intake at zero balance was 343 µg/d, which was higher in women from Shandong (492 µg/d) than in those from Hebei and Tianjin (202 µg/d). CONCLUSIONS: Iodine intake at zero balance determined in pregnant women with adequate iodine nutrition is 202 µg/d, and the calculated recommended nutrient intake (RNI) is 280 µg/d. Iodine intakes of <150 µg/d and >550 µg/d are not recommended during pregnancy. This trial was registered at clinicaltrials.gov as NCT03710148.

VCAM-1+ hUC-MSCs Exert Considerable Neuroprotection Against Cerebral Infarction in Rats by Suppression of NLRP3-Induced Pyroptosis.

Mesenchymal stem/stromal cells (MSCs) are spindle-like heterogeneous cell populations with advantageous bidirectional immunomodulatory and hematopoietic support effects. Vascular cellular adhesion molecule-1 (VCAM-1)+ MSCs have been reported to exhibit immunoregulatory and proangiogenic capacities. Here, we studied the effects of VCAM-1+ human umbilical cord (hUC)-MSCs on neuroprotection against cerebral infarction. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO), and VCAM-1- and VCAM-1+ hUC-MSCs were intravenously injected into the rat 4 h post-MCAO surgery. Thereafter, modified neurological severity scores (mNSS) were determined, and the Morris water maze test, 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), Nissl, TUNEL staining, and qRT-PCR were conducted. Following induction of oxygen-glucose deprivation/reoxygenation (OGD/R), SH-SY5Y cells were co-cultured with VCAM-1- and VCAM-1+ hUC-MSCs. CCK-8, flow cytometry, ELISA, and western blot analyses were performed in vitro. Compared with VCAM-1- hUC-MSCs, administration of VCAM-1+ hUC-MSCs revealed improved therapeutic efficacy against cerebral infarction in rats, as confirmed by lower mNSS scores and infarct volumes, as well as improved learning and memory capacities. In addition, VCAM-1+ hUC-MSCs exhibited improved efficacy against neurological defects in rats with cerebral infarction, accompanied by inhibition of the NLRP3-mediated inflammatory response. VCAM-1+ hUC-MSC co-culture improved the viability and diminished NLRP3-mediated inflammatory response in OGD/R-treated SH-SY5Y cells. Moreover, NLRP3 overexpression in SH-SY5Y cells prevented the beneficial effects of VCAM-1+ hUC-MSC co-culture. Overall, our findings demonstrated the relevance of VCAM-1+ hUC-MSC-based cytotherapy for preclinical neuroprotection against cerebral infarction.

P-Selectin mediates targeting of a self-assembling phototherapeutic nanovehicle enclosing dipyridamole for managing thromboses.

Thrombotic vascular disorders, specifically thromboembolisms, have a significant detrimental effect on public health. Despite the numerous thrombolytic and antithrombotic drugs available, their efficacy in penetrating thrombus formations is limited, and they carry a high risk of promoting bleeding. Consequently, the current medication dosage protocols are inadequate for preventing thrombus formation, and higher doses are necessary to achieve sufficient prevention. By integrating phototherapy with antithrombotic therapy, this study addresses difficulties related to thrombus-targeted drug delivery. We developed self-assembling nanoparticles (NPs) through the optimization of a co-assembly engineering process. These NPs, called DIP-FU-PPy NPs, consist of polypyrrole (PPy), dipyridamole (DIP), and P-selectin-targeted fucoidan (FU) and are designed to be delivered directly to thrombi. DIP-FU-PPy NPs are proposed to offer various potentials, encompassing drug-loading capability, targeted accumulation in thrombus sites, near-infrared (NIR) photothermal-enhanced thrombus management with therapeutic efficacy, and prevention of rethrombosis. As predicted, DIP-FU-PPy NPs prevented thrombus recurrence and emitted visible fluorescence signals during thrombus clot penetration with no adverse effects. Our co-delivery nano-platform is a simple and versatile solution for NIR-phototherapeutic multimodal thrombus control.

A fiducial approach for testing the non-inferiority of proportion difference in matched-pairs design.

The non-inferiority of one treatment/drug to another is a common and important issue in medical and pharmaceutical fields. This study explored a fiducial approach for testing the non-inferiority of proportion difference in matched-pairs design. Approximate tests constructed using fiducial quantities with a combination of different parameters were proposed. Four simulation studies were employed to compare the performance of fiducial tests by comparing their type I errors and powers. The results showed that fiducial quantities with parameter 0.6 ≤ w 1 ≤ 0.8 performed satisfactorily from small to large samples. Therefore, the fiducial tests could be recommended for practical applications. The recommended fiducial tests might be a competitive alternative to other available tests. Three real data sets were analyzed to illustrate the proposed methods were competitive or even better than other tests.

Role of (pro)renin receptor in cyclosporin A-induced nephropathy.

Calcineurin inhibitors such as cyclosporin A (CsA) have been widely used to improve graft survival following solid-organ transplantation. However, the clinical use of CsA is often limited by its nephrotoxicity. The present study tested the hypothesis that activation of the (pro)renin receptor (PRR) contributes to CsA-induced nephropathy by activating the renin-angiotensin system (RAS). Renal injury in male Sprague-Dawley rats was induced by a low-salt diet combined with CsA as evidenced by elevated plasma creatinine and blood urea nitrogen levels, decreased creatinine clearance and induced renal inflammation, apoptosis and interstitial fibrosis, and elevated urinary N-acetyl-ß-d-glucosaminidase activity and urinary kidney injury molecule-1 content. Each index of renal injury was attenuated following 2 wk of treatment with the PRR decoy inhibitor PRO20. Although CsA-treated rats with kidney injury displayed increased renal soluble (s)PRR abundance, plasma sPRR, renin activity, angiotensin II, and heightened urinary total prorenin/renin content, RAS activation was attenuated by PRO20. Exposure of cultured human renal proximal tubular HK-2 cells to CsA induced expression of fibronectin and sPRR production, but the fibrotic response was attenuated by PRO20 and siRNA-mediated PRR knockdown. These findings support the hypothesis that activation of PRR contributes to CsA-induced nephropathy by activating the RAS in rats. Of importance, we provide strong proof of concept that targeting PRR offers a novel therapeutic strategy to limit nephrotoxic effects of immunosuppressant drugs.NEW & NOTEWORTHY The present study reports, for the first time, that activation of the (pro)renin receptor drives the renin-angiotensin system to induce renal injury during cyclosporin A administration. More importantly, our study has identified that antagonism with PRO20 offers a novel intervention in the management of side effects of cyclosporin A.

COVID-19 and cognitive impairment: neuroinvasive and blood‒brain barrier dysfunction.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. Although COVID-19 was initially described as a respiratory disease, there is growing evidence that SARS-CoV-2 is able to invade the brains of COVID-19 patients and cause cognitive impairment. It has been reported that SARS-CoV-2 may have invasive effects on a variety of cranial nerves, including the olfactory, trigeminal, optic, and vagus nerves, and may spread to other brain regions via infected nerve endings, retrograde transport, and transsynaptic transmission. In addition, the blood-brain barrier (BBB), composed of neurovascular units (NVUs) lining the brain microvasculature, acts as a physical barrier between nerve cells and circulating cells of the immune system and is able to regulate the transfer of substances between the blood and brain parenchyma. Therefore, the BBB may be an important structure for the direct and indirect interaction of SARS-CoV-2 with the brain via the blood circulation. In this review, we assessed the potential involvement of neuroinvasion under the SARS-CoV-2 infection, and the potential impact of BBB disorder under SARS-CoV-2 infection on cognitive impairment.

Transcriptome Analysis on Key Metabolic Pathways in Rhodotorula mucilaginosa Under Pb(II) Stress.

Rhodotorula mucilaginosa shows adaption to a broad range of Pb2+ stress. In this study, three key pathways, i.e., glycolysis (EMP), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS), were investigated under 0-2,500 mg · L-1 Pb stress, primarily based on biochemical analysis and RNA sequencing. R. mucilaginosa cells showed similar metabolic response to low/medium (500/1000 mg · L-1) Pb2+ stress. High (2,500 mg · L-1) Pb2+ stress exerted severe cytotoxicity to R. mucilaginosa. The downregulation of HK under low-medium Pb2+ suggested a correlation with the low hexokinase enzymatic activity in vivo. However, IDH3, regulating a key step of circulation in TCA, was upregulated to promote ATP feedstock for downstream OXPHOS. Then, through activation of complex I & IV in the electron transport chain (ETC) and ATP synthase, ATP production was finally enhanced. This mechanism enabled fungal cells to compensate for ATP consumption under low-medium Pb2+ toxicity. Hence, R. mucilaginosa tolerance to such a broad range of Pb2+ concentrations can be attributed to energy adaption. In contrast, high Pb2+ stress caused ATP deficiency. Then, the subsequent degradation of intracellular defense systems further intensified Pb toxicity. This study correlated responses of EMP, TCA, and OXPHOS pathways in R. mucilaginosa under Pb stress, hence providing new insights into the fungal resistance to heavy metal stress. IMPORTANCE Glycolysis (EMP), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) are critical metabolism pathways for microorganisms to obtain energy during the resistance to heavy metal (HM) stress. However, these pathways at the genetic level have not been elucidated to evaluate their cytoprotective functions for Rhodotorula mucilaginosa under Pb stress. In this study, we investigated these three pathways based on biochemical analysis and RNA sequencing. Under low-medium (500-1,000 mg · L-1) Pb2+ stress, ATP production was stimulated mainly due to the upregulation of genes associated with the TCA cycle and the electron transport chain (ETC). Such an energy compensatory mechanism could allow R. mucilaginosa acclimation to a broad range of Pb2+ concentrations (up to 1000 mg · L-1). In contrast, high (2500 mg · L-1) Pb2+ stress exerted its excessive toxicity by provoking ATP deficiency and damage to intracellular resistance systems. This study provided new insights into R. mucilaginosa resistance to HM stress from the perspective of metabolism.

Vitamin a supplementation during pregnancy in shaping child growth outcomes: A meta-analysis.

Abnormal fetal growth increases risks of childhood health complications. Vitamin A supplementation (VAS) is highly accessible, but literature inconsistency regarding effects of maternal VAS on fetal and childhood growth outcomes exists, deterring pregnant women from VAS during pregnancy. This meta-analysis aimed to analyze effects of vitamin A only or vitamin A + co-intervention during pregnancy in healthy mothers (MH) or with complications (MC, night blindness and HIV positive) on perinatal growth outcomes, also assess VAS dose impacts. The Cochrane Library, PubMed, ScienceDirect, Scopus, Embase and Web of Science databases were searched from inception to July 15, 2021. We covered subgroup analyses, including VAS in MH or MC within randomized controlled trial (RCT) or observational studies (OS). Fifty-five studies were included in this meta-analysis (426,098 pregnancies). Vitamin A decreased risk of preterm birth by 9% in MH-RCT (P < 0.001), by 62% in MH-OS (P = 0.029), by 10% in MC-RCT (P = 0.089); decreased LBW by 24% in MC-RCT (P = 0.032); increased neonatal weight in MC-RCT (SMD 0.96; P = 0.051). Besides, vitamin A + co-intervention decreased risks of preterm by 18% in MH-OS (P = 0.021); LBW by 25% in MH-OS (P < 0.001); by 32% in MC-RCT (P = 0.006); decreased neonatal defects by 33% in MH-OS (P = 0.064); decreased anemia by 25% in MH-OS (P = 0.0003); increased neonatal weight in MH-OS (SMD 0.51; P = 0.014); and increased neonatal length in MH-OS (SMD 1.83; P = 0.013). Meta-regression of VAS dose with individual outcomes was not significant, and no side effects were observed for VAS doses up to 4000 mcg (RAE/d). Regardless of maternal health conditions, VAS during pregnancy can safely and effectively improve fetal development and neonatal health even in mothers without VAD.

Exploration of the optimal range of urinary iodine concentration in Chinese pregnant women in mildly iodine-deficient and -sufficient areas.

PURPOSE: There is some uncertainty about the optimal ranges for urinary iodine concentration (UIC) during pregnancy. This study aimed to explore associations between maternal UIC and thyroid function in iodine sufficient and mildly iodine deficient areas. METHODS: It was a cross-sectional study in which 1461 healthy pregnant women were enrolled to collect their blood and urine samples during their routine antenatal care in Tianjin and Wuqiang, China. Wuqiang was a mildly iodine-deficient region, while Tianjin was iodine sufficient. UIC, free triiodothyronine (FT3), free thyroid hormone (FT4), thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), serum iodine concentration (SIC) including total serum iodine concentration (tSIC) and non-protein bound serum iodine concentration (nbSIC) were assessed during the routine antenatal care visits. RESULTS: The median UIC in pregnant women was 174 (113, 249) µg/L in Tianjin and 111 (63, 167) µg/L in Wuqiang, respectively. Compared with Tianjin, UIC, FT3 and TSH were lower, and FT4, tSIC, nbSIC, rates of TPOAb and TgAb positivity and the thyroid dysfunction rate (TDR) were higher in Wuqiang (P < 0.001). FT3, FT4, tSIC and nbSIC increased during pregnancy in Tianjin with increasing UIC, while only FT3 and nbSIC increased in Wuqiang (P < 0.05). In Tianjin, the TDR increased with UIC and peaked at UIC ≥ 500 µg/L (P = 0.002), while in Wuqiang, the TDR showed a weak "U-shaped" relationship with UIC and the rate was lowest with UIC 100-149 µg/L. CONCLUSIONS: In iodine-deficient areas, there was a lower TDR in pregnant women with UIC 100-149 µg/L. We suspected that the optimal UIC criteria recommended by WHO may be a little high for pregnant women in mild-to-moderate iodine-deficient countries.

Infection of Metarhizium anisopliae Ma6 and defense responses of host Phyllotreta striolata adults.

Entomopathogenic fungus as biological control agent plays a crucial role in the integrated management of insect pests. Metarhizium anisopliae Ma6 has been identified as a highly pathogenic strain against Phyllotreta striolata (Fabricius) (Coleoptera: Chrysomelidae), one of the most economically important and dominant insect pests damaging Brassica plants. The infection of M. anisopliae Ma6 on P. striolata was observed under stereomicroscopy and scanning electron microscopy (SEM), and biochemical defense responses of P. striolata adults after infection were investigated. The changes in total amino acids and free fatty acids, and the activities of protective enzymes, including catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD), in P. striolata adults were measured. In stereomicroscopy and SEM observations, a large number of mycelia were observed on the body surface of P. striolata on the 5th day after treatment by M. anisopliae. Many conidia were germinated and covered the body of P. striolata on the 7th day after treatment. The free fatty acid, total amino acid, CAT, POD, and SOD activities all showed an increased and then decreased trend. These results suggest that entomopathogenic fungal infection triggers the defense response of hosts, which induces changes in nutrients and antioxidant enzymes in P. striolata adults. Our findings provide useful information for understanding the potential for using M. anisopliae Ma6 as a biocontrol agent.

Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis.

Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial activation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in microglia exposed to ischemia/reperfusion both in vivo and in vitro. In addition, adenovirus-associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase 2 (MDH2) and competitively inhibited the binding of MDH2 to the CXCL2 3' untranslated region (UTR), thus protecting against MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.

Foe and friend in the COVID-19-associated acute kidney injury: an insight on intrarenal renin-angiotensin system.

Since the first reported case in December of 2019, the coronavirus disease 2019 (COVID-19) has became an international public health emergency. So far, there are more than 228,206,384 confirmed cases including 4,687,066 deaths. Kidney with high expression of angiotensin-converting enzyme 2 (ACE2) is one of the extrapulmonary target organs affected in patients with COVID-19. Acute kidney injury (AKI) is one of the independent risk factors for the death of COVID-19 patients. The imbalance between ACE2-Ang(1-7)-MasR and ACE-Ang II-AT1R axis in the kidney may contribute to COVID-19-associated AKI. Although series of research have shown the inconsistent effects of multiple common RAS inhibitors on ACE2 expression and enzyme activity, most of the retrospective cohort studies indicated the safety and protective effects of ACEI/ARB in COVID-19 patients. This review article highlights the current knowledge on the possible involvement of intrarenal RAS in COVID-19-associated AKI with a primary focus on the opposing effects of ACE2-Ang(1-7)-MasR and ACE-Ang II-AT1R signaling in the kidney. Human recombinant soluble ACE2 or ACE2 variants with preserved ACE2-enzymatic activity may be the best options to improve COVID-19-associated AKI.