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Abstract Background Preeclampsia, especially early-onset preeclampsia (EO-PE), is a pregnancy complication that has serious consequences for the health of both the mother and the fetus. Although abnormal placentation due to mitochondrial dysfunction is speculated to contribute to the development of EO-PE, the underlying mechanisms have yet to be fully elucidated. Methods The expression and localization of Siglec-6 in the placenta from normal pregnancies, preterm birth and EO-PE patients were examined by RT-qPCR, Western blot and IHC. Transwell assays were performed to evaluate the effect of Siglec-6 on trophoblast cell migration and invasion. Seahorse experiments were conducted to assess the impact of disrupting Siglec-6 expression on mitochondrial function. Co-IP assay was used to examine the interaction of Siglec-6 with SHP1/SHP2. RNA-seq was employed to investigate the mechanism by which Siglec-6 inhibits mitochondrial function in trophoblast cells. Results The expression of Siglec-6 in extravillous trophoblasts is increased in placental tissues from EO-PE patients. Siglec-6 inhibits trophoblast cell migration and invasion and impairs mitochondrial function. Mechanismly, Siglec-6 inhibits the activation of NF-κB by recruiting SHP1/SHP2, leading to increased expression of GPR20. Notably, the importance of GPR20 function downstream of Siglec-6 in trophoblasts is supported by the observation that GPR20 downregulation rescues defects caused by Siglec-6 overexpression. Finally, overexpression of Siglec-6 in the placenta induces a preeclampsia-like phenotype in a pregnant mouse model. Conclusions This study indicates that the regulatory pathway Siglec-6/GPR20 has a crucial role in regulating trophoblast mitochondrial function, and we suggest that Siglec-6 and GPR20 could serve as potential markers and targets for the clinical diagnosis and therapy of EO-PE.

BackgroundPrenatal drug use may cause toxicity to bone health in newborns. We aimed to examine whether birth outcomes mediate the association between medication use and neonatal metabolic bone disease (MBD).MethodsA prospective cohort of 10,801 pregnant women (17–49 years) and their infants followed at a single center from 1 January 2012 to 31 December 2021 were included. Based on four single drugs, comprehensive medication use was determined and categorized into three groups using latent-class analysis: group 1 included antibiotics and furosemide or less than two drugs except for MgSO4; group 2 included MgSO4 without antibiotics or furosemide; and group 3 encompassed dexamethasone and antibiotics. Mediation analysis was conducted to assess the mediating effects of prematurity, low birth weight (LBW), and small for gestational age (SGA).ResultsThere were 138 (1.3%) infants with MBD; 2,701 (25%) were born preterm, 1717 (15.9%) had LBW, and 303 (2.8%) were SGA. Pregnant women in groups 2 and 3 were 2.52 to 14.66 times more likely to deliver an infant with MBD than those in group 1. Only LBW showed a significant mediating effect on the association between comprehensive medication use and MBD, with a mediation proportion of 51.8% (45.0–64.1%, p

IntroductionFetal membrane inflammation is an integral event of parturition. However, excessive pro-inflammatory cytokines can impose threats to the fetus. Coincidentally, the fetal membranes express abundant 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which generates biologically active cortisol to promote labor through induction of prostaglandin synthesis. Given the well-recognized anti-inflammatory actions of glucocorticoids, we hypothesized that cortisol regenerated in the fetal membranes might be engaged in restraining fetus-hazardous pro-inflammatory cytokine production for the safety of the fetus, while reserving pro-labor effect on prostaglandin synthesis to ensure safe delivery of the fetus.MethodsThe hypothesis was examined in human amnion tissue and cultured primary human amnion fibroblasts as well as a mouse model.Results11β-HSD1 was significantly increased in the human amnion in infection-induced preterm birth. Studies in human amnion fibroblasts showed that lipopolysaccharide (LPS) induced 11β-HSD1 expression synergistically with cortisol. Cortisol completely blocked NF-κB-mediated pro-inflammatory cytokine expression by LPS, but STAT3-mediated cyclooxygenase 2 expression, a crucial prostaglandin synthetic enzyme, remained. Further studies in pregnant mice showed that corticosterone did not delay LPS-induced preterm birth, but alleviated LPS-induced fetal organ damages, along with increased 11β-HSD1, cyclooxygenase 2, and decreased pro-inflammatory cytokine in the fetal membranes.DiscussionThere is a feed-forward cortisol regeneration in the fetal membranes in infection, and cortisol regenerated restrains pro-inflammatory cytokine expression, while reserves pro-labor effect on prostaglandin synthesis. This dual role of cortisol regeneration can prevent excessive pro-inflammatory cytokine production, while ensure in-time delivery for the safety of the fetus.

BackgroundSpontaneous preterm birth (sPTB) is a global disease that is a leading cause of death in neonates and children younger than 5 years of age. However, the etiology of sPTB remains poorly understood. Recent evidence has shown a strong association between metabolic disorders and sPTB. To determine the metabolic alterations in sPTB patients, we used various bioinformatics methods to analyze the abnormal changes in metabolic pathways in the preterm placenta via existing datasets.MethodsIn this study, we integrated two datasets (GSE203507 and GSE174415) from the NCBI GEO database for the following analysis. We utilized the “Deseq2” R package and WGCNA for differentially expressed genes (DEGs) analysis; the identified DEGs were subsequently compared with metabolism-related genes. To identify the altered metabolism-related pathways and hub genes in sPTB patients, we performed multiple functional enrichment analysis and applied three machine learning algorithms, LASSO, SVM-RFE, and RF, with the hub genes that were verified by immunohistochemistry. Additionally, we conducted single-sample gene set enrichment analysis to assess immune infiltration in the placenta.ResultsWe identified 228 sPTB-related DEGs that were enriched in pathways such as arachidonic acid and glutathione metabolism. A total of 3 metabolism-related hub genes, namely, ANPEP, CKMT1B, and PLA2G4A, were identified and validated in external datasets and experiments. A nomogram model was developed and evaluated with 3 hub genes; the model could reliably distinguish sPTB patients and term labor patients with an area under the curve (AUC) > 0.75 for both the training and validation sets. Immune infiltration analysis revealed immune dysregulation in sPTB patients.ConclusionThree potential hub genes that influence the occurrence of sPTB through shadow participation in placental metabolism were identified; these results provide a new perspective for the development and targeting of treatments for sPTB.

IntroductionThyroid function during pregnancy fluctuates with gestational weeks, seasons and other factors. However, it is currently unknown whether there is a fetal sex-specific thyroid function in pregnant women. The purpose of this study was to investigate the fetal sex differences of maternal thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in pregnant women.MethodsThis single-center retrospective real-world study was performed by reviewing the medical records of pregnant women who received regular antenatal health care and delivered liveborn infants in Shanghai First Maternity and Infant Hospital (Pudong branch), from Aug. 18, 2013 to Jul. 18, 2020. Quantile regression was used to evaluate the relationship between various variables and TSH and FT4 concentrations. The quantile regression also evaluated the sex impact of different gestational weeks on the median of TSH and FT4.ResultsA total of 69,243 pregnant women with a mean age of 30.36 years were included. 36197 (52.28%) deliveries were boys. In the three different trimesters, the median levels (interquartile range) of TSH were 1.18 (0.66, 1.82) mIU/L and 1.39 (0.85, 2.05) mIU/L, 1.70 (1.19, 2.40) mIU/L; and the median levels (interquartile range) of FT4 were 16.63 (15.16, 18.31) pmol/L, 14.09 (12.30, 16.20) pmol/L and 13.40 (11.52, 14.71) pmol/L, respectively. The maternal TSH upper limit of reference ranges was decreased more in mothers with female fetuses during gestational weeks 7 to 12, while their FT4 upper limit of the reference ranges was increased more than those with male fetuses. After model adjustment, the median TSH level was 0.11 mIU/L lower (P

Introduction Pre-eclampsia (PE) affects about 5% of Chinese pregnant women and is a major cause of maternal and perinatal morbidity and mortality. The first trimester screening model developed by the Fetal Medicine Foundation, which uses the Bayes theorem to combine maternal characteristics and medical history together with measurements of biomarkers, has been proven to be effective and has superior screening performance to that of the traditional risk factor-based approach for the prediction of PE. Prophylactic use of low-dose aspirin in women at risk for PE has resulted in a lower incidence of preterm-PE. However, there is no consensus on the preferred aspirin dosage for the prevention of preterm-PE. Evidence has also suggested that metformin has the potential benefit in preventing PE in pregnant women who are at high risk of the disorder.Method and analysis We present a protocol (V.2.0, date 17 March 2022) for the AVERT trial, which is a multicentre, double-blinded, 3-arm randomised controlled trial (RCT) that uses an effective PE screening programme to explore the optimal dosage of aspirin and the role of metformin for the prevention of PE among high-risk pregnant women in China. We intend to recruit 66 000 singleton pregnancies without treatment of low-dose aspirin and metformin at 11–13 weeks’ gestation and all eligible women attending for their first trimester routine scan will be invited to undergo screening for preterm-PE by the combination of maternal factors, mean arterial pressure and placental growth factor. Women found to be at high risk of developing preterm-PE will be invited to take part in the RCT. This study will compare the incidence of preterm-PE with delivery at

Abstract Background The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) remains unknown. The gut microbiome and its metabolites play important roles in bile acid metabolism, and previous studies have indicated the association of the gut microbiome with ICP. Methods We recruited a cohort of 5100 participants, and 20 participants were enrolled in the severe ICP group, matched with 20 participants in the mild ICP group and 20 controls. 16S rRNA sequencing and nontargeting metabolomics were adapted to explore the gut microbiome and fecal metabolites. Results An increase in richness and a dramatic deviation in composition were found in the gut microbiome in ICP. Decreased Firmicutes and Bacteroidetes abundances and increased Proteobacteria abundances were found in women with severe but not mild ICP compared to healthy pregnant women. Escherichia-Shigella and Lachnoclostridium abundances increased, whereas Ruminococcaceae abundance decreased in ICP group, especially in severe ICP group. The fecal metabolite composition and diversity presented typical variation in severe ICP. A significant increase in bile acid, formate and succinate levels and a decrease in butyrate and hypoxanthine levels were found in women with severe ICP. The MIMOSA model indicated that genera Ruminococcus gnavus group, Lachnospiraceae FCS020 group, and Lachnospiraceae NK4A136 group contributed significantly to the metabolism of hypoxanthine, which was significantly depleted in subjects with severe ICP. Genus Acinetobacter contributed significantly to formate metabolism, which was significantly enriched in subjects with severe ICP. Conclusions Women with severe but not mild ICP harbored a unique gut microbiome and fecal metabolites compared to healthy controls. Based on these profiles, we hypothesized that the gut microbiome was involved in bile acid metabolism through metabolites, affecting ICP pathogenesis and development, especially severe ICP.

In recent years, the application of Laser powder bed fusion (LPBF) technology in the manufacturing industry has become increasingly widespread. Compared to traditional casting processes, LPBF technology allows for the production of complex-shaped and structurally unique components made of 2507 duplex stainless steel (2507DSS), thus improving production efficiency and product quality. This article focuses on determining the LPBF parameters required for printing 2507DSS, successfully fabricating samples with a density of 98.71% and subjecting them to solution treatment followed by tensile testing. The results show that the LPBF-prepared samples exhibit a strength of 1173 MPa and an elongation of 18%. The presence of island-like structures enables excellent mechanical performance in the horizontal direction. The samples subjected to solution treatment at 1100 °C exhibit a strength of 860 MPa and an elongation of 45%. It is observed that when 2507DSS undergoes solution treatment from a single-phase state, the formation of large-angle grain boundaries and residual stresses within the austenite phase occurs, and a reasonable explanation is provided. Furthermore, the article conducts electrochemical tests on the samples. The results indicate that the LPBF-prepared samples possess the same electrochemical properties as the samples treated at 1100 °C, and both outperform the cast samples. Thus, this study reveals that the proportion of phases is not the sole determining factor for the corrosion resistance of DSS, providing valuable insights for the future development of more corrosion-resistant 2507DSS materials.

Mitochondria are ubiquitous in eukaryotic cells. Normal maintenance of function is the premise and basis for various physiological activities. Mitochondrial dysfunction is commonly observed in a wide range of pathological conditions, such as neurodegenerative, metabolic, cardiovascular, and various diseases related to foetal growth and development. The placenta is a highly energy-dependent organ that acts as an intermediary between the mother and foetus and functions to maintain foetal growth and development. Recent studies have demonstrated that mitochondrial dysfunction is associated with placental disorders. Defects in mitochondrial quality control mechanisms may lead to preeclampsia and foetal growth restriction. In this review, we address the quality control mechanisms of mitochondria and the relevant pathologies of mitochondrial dysfunction in placenta-related diseases, such as preeclampsia and foetal growth restriction. This review also investigates the relation between mitochondrial dysfunction and placental disorders.

Background: Progesterone can inhibit intestinal smooth muscle contraction; however, the specific mechanism remains unclear. Besides smooth muscle cells, smooth muscle has two important mesenchymal cells, namely interstitial cells of Cajal (ICC) and PDGFRα+ cells, which induce the contraction and relaxation of smooth muscles. We aimed to explore the regulation of PDGFRα+ cells and ICC in progesterone-mediated colon slow transit in pregnant mice. Methods: Colon transit experiments were performed in vivo and in vitro to observe slow colon transit. The expression of PDGFRα and c-KIT was detected by Western blot, RT-PCR, and immunofluorescence. An isometric tension experiment was performed to investigate smooth muscle contractions. Results: The colon transit time in pregnant mice was longer than that in non-pregnant mice. Progesterone significantly blocks colonic smooth muscle contractions. However, when the relaxation and contraction of PDGFRα+ cells and ICC are blocked, progesterone cannot inhibit smooth muscle contraction. When the function of only PDGFRα+ cells are blocked, progesterone has a more obvious inhibitory effect on smooth muscle in the non-pregnant group than that in the pregnant group. However, when ICC alone was blocked, progesterone inhibited smooth muscle contractions more clearly in pregnant mice. The protein and mRNA expression of PDGFRα was higher and c-KIT was lower in pregnant mice. PDGFRα+ cells and ICC from smooth muscle all co-localize progesterone receptors. Conclusions: Under the regulation of progesterone, the relaxation function of PDGFRα+ cells is enhanced and the contraction function of ICC is weakened, leading to the slow colon transit of pregnant mice.

Abstract Objective: To investigate the association between folate levels and the risk of gestational diabetes mellitus (GDM) risk during the whole pregnancy. Design: In this retrospective cohort study of pregnant women, serum folate levels were measured before 24 gestational weeks (GW). GDM was diagnosed between 24th and 28th GW based on the criteria of the International Association of Diabetes and Pregnancy Study Groups. General linear models were performed to examine the association of serum folate with plasma glucose (i.e. linear regressions) and risk of GDM (i.e. log-binomial regressions) after controlling for confounders. Restricted cubic spline regression was conducted to test the dosage–response relationship between serum folate and the risk of GDM. Setting: A sigle, urban hospital in Shanghai, China. Participants: A total of 42 478 women who received antenatal care from April 2013 to March 2017 were included. Results: Consistent positive associations were observed between serum folate and plasma glucose levels (fasting, 1-h, 2-h). The adjusted relative risks (RR) and 95 % CI of GDM across serum folate quartiles were 1·00 (reference), 1·15 (95 % CI (1·04, 1·26)), 1·40 (95 % CI (1·27, 1·54)) and 1·54 (95 % CI (1·40, 1·69)), respectively (P-for-trend < 0·001). The positive association between serum folate and GDM remained when stratified by vitamin B12 (adequate v. deficient groups) and the GW of serum folate measurement (≤13 GW v. >13 GWs) Conclusions: The findings of this study may provide important evidence for the public health and clinical guidelines of pregnancy folate supplementation in terms of GDM prevention.

Abstract China’s rapid increase in mass excreta and its environmental discharge have attracted substantial attention. However, cropland as a main destination of excreta utilization has not been extensively evaluated. Here, a national survey was used to assess the utilization of manure in croplands across China. The data included the inputs of manure nitrogen (N), phosphorus (P), and potassium (K) for cereals, fruits, vegetables, and other crops, along with the manure proportion of total N, P, and K inputs at the county level. The results showed that the manure N, P, and K inputs were 6.85, 2.14, and 4.65 million tons (Mt), respectively, constituting 19.0%, 25.5%, and 31.1% of the total N, P, and K, respectively. The spatial distribution of the manure proportion of total inputs was lower in Eastern China and higher in Western China. The results provide a detailed description of the utilization of manure nutrients in agricultural areas throughout China, which will serve as basic support for policymakers and researchers involved in future agricultural nutrient management in China.

Early lipid accumulation is thought to contribute to liver regeneration through unclear functional mechanisms. Here the authors identify an epigenetic regulator, MIER1, that bridges the acute lipid accumulation and cell cycle gene transcription during liver regeneration after surgical resection in male mice.

Objectives: This study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines. Methods: The Cochrane Library, Embase, PubMed, Web of Science, ClinicalKey, and other COVID-19 datasets were searched from December 2019 to May 2022. Case-control studies and prospective cohort studies of COVID-19 vaccine effectiveness and safety in pregnant women were included. Results: From day 11 to day 13, after the first dose of the COVID-19 messenger RNA vaccine, the effectiveness was 54% (95% confidence interval: 0.33-0.69). On days 14 to 27, the effectiveness was 59%. There was a 14% increase in vaccine effectiveness 28 days after the first dose was given. The inactivated vaccines showed similar effectiveness. The proportions of placental abruptions, postpartum hemorrhages, miscarriages, stillbirths, premature births, and small for gestational age infants were not significantly different between vaccinated and nonvaccinated pregnant women. Fatigue and fever were also not associated with pregnancy. Conclusion: Our findings affirm that the effectiveness varies for different types of vaccines and is significantly and positively correlated with time in the pregnant population. COVID-19 vaccines have also been deemed safe for pregnant women. Thus, we developed a comprehensive understanding of the role of vaccines in pregnant women.

Background Guideline‐based hypertension management is integral to the prevention of stroke. We examine trends in antihypertensive medications prescribed after stroke and assess how well a prescriber's blood pressure (BP) medication choice adheres to clinical practice guidelines (BP‐guideline adherence). Methods and Results The FSR (Florida Stroke Registry) uses statewide data prospectively collected for all acute stroke admissions. Based on established guidelines, we defined optimal BP‐guideline adherence using the following hierarchy of rules: (1) use of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker as first‐line antihypertensive among diabetics; (2) use of thiazide‐type diuretics or calcium channel blockers among Black patients; (3) use of beta blockers among patients with compelling cardiac indication; (4) use of thiazide, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, or calcium channel blocker class as first line in all others; (5) beta blockers should be avoided as first line unless there is a compelling cardiac indication. A total of 372 254 cases from January 2010 to March 2020 are in the FSR with a diagnosis of acute ischemic stroke, hemorrhagic stroke, transient ischemic attack, or subarachnoid hemorrhage; 265 409 with complete data were included in the final analysis. Mean age was 70±14 years; 50% were women; and index stroke subtypes were 74% acute ischemic stroke, 11% intracerebral hemorrhage, 11% transient ischemic attack, and 4% subarachnoid hemorrhage. BP‐guideline adherence to each specific rule ranged from 48% to 74%, which is below quality standards of 80%, and was lower among Black patients (odds ratio, 0.7 [95% CI, 0.7–0.83]; P

Deep eutectic solvents (DESs) have gained much attention in the fabrication of advanced nanoelectrocatalysts due to their amazing template function. However, their stabilizing function for easily hydrolyzed inorganic nanomaterials is rarely studied. Here, a DES-mediated strategy was reported to synthesize octahedral Ni–Co precursor (NiCo–NH3 complex), which could be directly transformed into NiCo2O4 nanooctahedrons after thermal decomposition. The NiCo–NH3 precursor in octahedral shape was achieved with the DES-mediated crystallization in the choline chloride (ChCl)/glycerol. The ChCl/glycerol DES not only tailored the morphology of the as-prepared precursor by template effect but also inhibited its hydrolysis, ensuring the successful fabrication of octahedral NiCo–NH3 complex precursor with high yield. The NiCo–NH3 complex precursor was converted to well-defined NiCo2O4 nanooctahedrons, where the calcination temperature and time were explored in detail. It revealed that DES could participate in the conversion process to control the morphology of calcination product. The resultant NiCo2O4 nanooctahedrons demonstrated excellent electroactivity and remarkable durability for oxygen evolution reaction (OER). The present strategy not only offers an efficient OER electrocatalyst but also enriches the approaches of DESs in designing advanced nanocatalysts.

Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.

Objective To investigate the correlation between melatonin and osteoarthritis (OA) in rats. To explore the relevant mechanisms in the occurrence and development of osteoarthritis in rats, and to further understand the disease of osteoarthritis. Methods Forty healthy 6‐month‐old male SD rats were randomly divided into two groups: sham and drug intervention groups. Pre‐OA modeling, enzyme‐linked immunosorbent assay was employed to detect the levels of IL‐1β, IL‐6, COX‐2, and melatonin in the serum of the rats in each group. For OA modeling, we administered an injection of papain into the knee cavity of all rats. The levels of IL‐1β, IL‐6, and COX‐2 in the serum of rats in each group were detected 2 weeks after the modeling. Additionally, 2 weeks after the modeling, the rats in the drug intervention group were intraperitoneally injected with melatonin antagonists. The rats in the sham group were intraperitoneally injected with normal saline for 2 weeks. The levels of IL‐1β, IL‐6, and COX‐2 in the serum of each group were measured at the second, third, and fourth weeks after the drug intervention, and the levels of melatonin in the serum were measured at the second week after the drug intervention. Finally, the rats were euthanized by cervical dislocation, and pathological sections were collected from the knee joint to observe the pathological tissue changes under a microscope, and Mankin score was determined. The independent samples t‐test method was used for analysis. Results The imaging examination after the drug intervention showed that the modeling of knee osteoarthritis in rats was successful. In the pathological findings, HE staining showed a legible cartilage structure of each layer, with cartilage proliferation and partial cartilage tearing to the radial layer. The tide line was intact; toluidine blue staining revealed more obvious changes. The differences among the mean values of IL‐6, IL‐1β, and COX‐2 measured in each period were statistically significant (t = 5.50, p

The maternal-fetal interface is defined as the interface between maternal tissue and sections of the fetus in close contact. RNA methylation modifications are the most frequent kind of RNA alterations. It is effective throughout both normal and pathological implantation and placentation during pregnancy. By influencing early embryo development, embryo implantation, endometrium receptivity, immune microenvironment, as well as some implantation and placentation-related disorders like miscarriage and preeclampsia, it is essential for the establishment of the maternal-fetal interface. Our review focuses on the role of dynamic RNA methylation at the maternal-fetal interface, which has received little attention thus far. It has given the mechanistic underpinnings for both normal and abnormal implantation and placentation and could eventually provide an entirely novel approach to treating related complications.

OBJECTIVES:. Temporal trends and factors associated with the withdrawal of life-sustaining therapy (WLST) after acute stroke are not well determined. DESIGN:. Observational study (2008–2021). SETTING:. Florida Stroke Registry (152 hospitals). PATIENTS:. Acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) patients. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Importance plots were performed to generate the most predictive factors of WLST. Area under the curve (AUC) for the receiver operating curve were generated for the performance of logistic regression (LR) and random forest (RF) models. Regression analysis was applied to evaluate temporal trends. Among 309,393 AIS patients, 47,485 ICH patients, and 16,694 SAH patients; 9%, 28%, and 19% subsequently had WLST. Patients who had WLST were older (77 vs 70 yr), more women (57% vs 49%), White (76% vs 67%), with greater stroke severity on the National Institutes of Health Stroke Scale greater than or equal to 5 (29% vs 19%), more likely hospitalized in comprehensive stroke centers (52% vs 44%), had Medicare insurance (53% vs 44%), and more likely to have impaired level of consciousness (38% vs 12%). Most predictors associated with the decision to WLST in AIS were age, stroke severity, region, insurance status, center type, race, and level of consciousness (RF AUC of 0.93 and LR AUC of 0.85). Predictors in ICH included age, impaired level of consciousness, region, race, insurance status, center type, and prestroke ambulation status (RF AUC of 0.76 and LR AUC of 0.71). Factors in SAH included age, impaired level of consciousness, region, insurance status, race, and stroke center type (RF AUC of 0.82 and LR AUC of 0.72). Despite a decrease in the rates of early WLST (< 2 d) and mortality, the overall rates of WLST remained stable. CONCLUSIONS:. In acute hospitalized stroke patients in Florida, factors other than brain injury alone contribute to the decision to WLST. Potential predictors not measured in this study include education, culture, faith and beliefs, and patient/family and physician preferences. The overall rates of WLST have not changed in the last 2 decades.

Thyroid hormone (TH) action regulates brown adipose tissue thermogenic capacity through incompletely understood mechanisms. Here the authors report that T3, the active form of TH, increases thermogenic capacity via thyroid hormone receptor α-mediated hyperplasia of brown adipose tissue adipocyte progenitor cells.

Abstract Background The human amnion is an intrauterine tissue which is involved in the initiation of parturition. In-depth understanding of gene expression signatures of individual cell types in the amnion with respect to membrane rupture at parturition may help identify crucial initiators of parturition for the development of specific strategies to prevent preterm birth, a leading cause of perinatal mortality. Results Six major cell types were revealed in human amnion including epithelial cells, fibroblasts and immunocytes as well as three other cell types expressing dual cell markers including epithelial/fibroblast, immune/epithelial and immune/fibroblast markers. The existence of cell types expressing these dual cell markers indicates the presence of epithelial-mesenchymal (EMT), epithelial-immune (EIT) and mesenchymal-immune (MIT) transitions in amnion at parturition. We found that the rupture zone of amnion exhibited some specific increases in subcluster proportions of immune and EMT cells related to extracellular matrix remodeling and inflammation in labor. The non-rupture zone exhibited some common changes in subcluster compositions of epithelial and fibroblast cells with the rupture zone in labor, particularly those related to oxidative stress and apoptosis in epithelial cells and zinc ion transport in fibroblasts. Moreover, we identified that C–C motif chemokine ligand 20 (CCL20) was among the top up-regulated genes in amnion epithelial cells, fibroblasts and immunocytes in the rupture zone at parturition. Studies in pregnant mice showed that administration of CCL20 induced immunocytes infiltration to tissues at the maternal–fetal interface and led to preterm birth. Conclusions Apart from the conventional epithelial, fibroblast and immunocytes, human amnion cells may undergo EMT, EIT and FIT in preparation for parturition. Intense inflammation and ECM remodeling are present in the rupture zone, while enhanced apoptosis and oxidative stress in epithelial cells and zinc ion transport in fibroblasts are present in amnion regardless of the rupture zones at parturition. CCL20 derived from the major cell types of the amnion participates in labor onset.

Objectives: We sought to assess the incidence of hungry bone syndrome (HBS) following parathyroidectomy (PTX) for primary hyperparathyroidism (PHPT) in a cohort of multi-ethnic patients from a developed country in the Asia Pacific. Methods: One hundred and sixty-four patients who underwent PTX for PHPT between 2012 and 2019 at the 2 largest public hospitals in Singapore were identified. HBS was defined as serum albumin-adjusted calcium ≤ 2.1 mmol/L with normal or raised serum intact parathyroid hormone (iPTH) levels, manifesting on or after the 3rd day, or persisting for more than 3 days post-operatively. Results: Chinese constituted 73.8%, Malays 12.2%, Indians 9.8%, and other races 4.3%. HBS developed in 4 patients (2.4%) (95% CI, 0.8%–6.5%). HBS patients had significantly longer in-hospital stays; 20 days [IQR:15–22] vs 2 days [IQR:1–3]; P

As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. Here, the authors report a machine learning model using mass spectrometry-based liquid biopsy data for pan-cancer screening and classification.

Objective To better understand the risks of bisphosphonates in order to develop guidance for appropriate clinical usage, to compared femoral fracture healing at different time points and to explore the effects of Residronate on fracture healing. Methods Osteoporosis model was achieved by ovariectomy surgery, followed by surgical incision of left femoral shaft 4 weeks after ovariectomy surgery. Three days after fracture surgery, risedronateor saline was fed by intragastric administration. X ray examination was used to check the callus formation, Bone Mineral Density (BMD), Bone Mineral Content (BMC), biomechanical, imaging and micromorphological of bone tissue as well as the trabecular bone parameters were all examined. The femoral pathology tissue of each rat was used to analyze trabecular bone parameters, including trabecular bone volume/tissue volume (Tb. BV/TV), bone surface to tissue volume ratio (BS/TV), trabecular bone mineral density (Tb. BMD), trabecular bone number (Tb. N), trabecular bone thickness (Tb. Th) and small bone Trabecular bone space (Tb. Sp). Results Via X‐ray and pathologically, risedronate treatment promoted the callus forming at the fracture site during the following 6 weeks after osteoporotic fracture by X‐ray (P

BackgroundStudies in singletons have suggested that prenatal exposure to fine particulate matter (PM2.5) and some of its chemical components is associated with an increased risk of preterm birth (PTB). However, no study has been conducted in twins.PurposeTo examine the associations of maternal exposure to total PM2.5 mass and its carbonaceous components with PTB in twin pregnancies.MethodsA total of 1,515 pairs of twins and their mothers were enrolled from a previous twin birth cohort that had been conducted at the Shanghai First Maternity and Infant Hospital School of Medicine of Tongji University in China. Participants who had iatrogenic PTBs were excluded. Maternal exposure to total PM2.5 mass and two carbonaceous components, namely, organic carbon (OC) and black carbon (BC), was estimated by a satellite-based model. The associations between PM2.5 exposure and the risk of spontaneous PTB were evaluated by logistic regression analysis.ResultsThis study found that exposure to total PM2.5 mass and OC during the second trimester of pregnancy was significantly associated with an increased risk of spontaneous PTB. An interquartile range (IQR) increase in total PM2.5 mass and OC exposure during the second trimester was associated with 48% (OR = 1.48, 95% CI, 1.06, 2.05) and 50% (OR = 1.50, 95% CI, 1.00, 2.25) increases in the odds of PTB, respectively. However, no significant association was found between BC exposure during any exposure window and the risk of PTB.ConclusionThe findings suggest that exposure to ambient air pollution with fine particles may be a risk factor for spontaneous PTB in twin pregnancies. The middle stage of pregnancy seems to be a critical window for the impacts of PM2.5 exposure on PTB in twin pregnancies.

ZrB2-SiC-Zr2Al4C5 multi-phase ceramics with uniform structure and high density were successfully prepared through the introduction of in situ synthesized Zr2Al4C5 into ZrB2-SiC ceramic via SPS at 1800 °C. A systematic analysis and discussion of the experimental results and proposed mechanisms were carried out to demonstrate the composition-dependent sintering properties, mechanical properties and oxidation behavior. The results showed that the in situ synthesized Zr2Al4C5 could be evenly distributed in the ZrB2-SiC ceramic matrix and inhibited the growth of ZrB2 grains, which played a positive role in the sintering densification of the composite ceramics. With increasing Zr2Al4C5 content, the Vickers hardness and Young’s modulus of composite ceramics gradually decreased. The fracture toughness showed a trend that first increased and then decreased, and was increased by about 30% compared with ZrB2-SiC ceramics. The major phases resulting from the oxidation of samples were ZrO2, ZrSiO4, aluminosilicate and SiO2 glass. With increasing Zr2Al4C5 content, the oxidative weight showed a trend that first increased then decreased; the composite ceramic with 30 vol.% Zr2Al4C5 showed the smallest oxidative weight gain. We believe that the presence of Zr2Al4C5 results in the formation of Al2O3 during the oxidation process, subsequently resulting in a lowering of the viscosity of the glassy silica scale, which in turn intensifies the oxidation of the composite ceramics. This would also increase oxygen permeation through the scale, adversely affecting the oxidation resistance of the composites with high Zr2Al4C5 content.

Graphene/hexagonal boron nitride (h-BN) heterostructures have attracted a lot of research interests due to their superior electronic properties in field effect transistor devices and the novel physical properties such as fractional fractal quantum hall effect and massive Dirac fermions. Chemical vapor deposition (CVD) is the most common method to synthesize h-BN and graphene, however, the directly growth of graphene/h-BN heterostructures remains challenging. Here we report the crucial impact of hydrogen on the nucleation density, growth rate and etching rate in the h-BN CVD growth. It is found that the nucleation density increases monotonically, whereas the growth rate and etching rate first increases and then decreases with the increasing hydrogen partial pressure. Benefitting from the understanding of the crucial role of hydrogen, we successfully grow the graphene/h-BN vertical heterostructures by low pressure CVD in one-pot through the modulation of hydrogen partial pressure. The field effect transistor (FET) fabricated using graphene/h-BN heterostructure shows better performance with higher carrier mobility and lower level of doping than the one without h-BN. Our direct synthesis approach paves a new pathway for large-scale production of graphene/h-BN heterostructures and could be applied for the synthesis of other van der Waals heterostructures.

The browning of white adipose tissue has potential benefits on metabolic disorders, but the nutritional factors and neuronal signals that mediate browning remain incompletely understood. Here, the authors show that leucine deprivation can induce WAT browning via GCN2/ATF4 signaling in amygdalar PKC-δ neurons.

Iodine is an essential micronutrient for producing thyroid hormone (TH); however, iodide excess can lead to adverse thyroidal effects. Unfortunately, the lack of a proper in vitro model system hampered the studies of the effect of iodide excess on thyroid physiology and pathology. Here, we demonstrated that excessive iodide intake downregulated the genes related to TH synthesis in the thyroids of mice. Since sodium iodide has no effect on these genes in cultured cell lines, we developed a three-dimensional (3D) culture system to enable the murine thyrocytes to form organoids in vitro with thyroid follicle-like structures and function and found that the in vivo effect of iodide excess could be mimicked in these thyroid organoids. Our data indicate that iodide excess mainly activated the XBP1-mediated unfolded protein response in both murine thyroid and thyroid organoids, while activation of XBP1 was able to mimic the sodium iodide effect on genes for the synthesis of TH in murine thyroid organoids. Lastly, our results suggest that XBP1 might transcriptionally repress the genes involved in the synthesis of TH. Based on these findings, we propose that iodide excess inhibits the transcription of genes related to TH synthesis through a mechanism involving XBP1-mediated action.

Objective Preterm birth is the leading cause of child morbidity and mortality globally. We aimed to determine the impact of the COVID-19 mitigation measures implemented in China on 23 January 2020 on the incidence of preterm birth in our institution.Design Logistic regression analysis was used to investigate the association between the national COVID-19 mitigation measures implemented in China and the incidence of preterm birth.Setting Shanghai First Maternity and Infant Hospital, Shanghai China.Participants All singleton deliveries abstracted from electronic medical record between 1 January 2014 to 31 December 2020.Main outcome measures Preterm birth rate.Results Data on 164 107 singleton deliveries were available. COVID-19 mitigation measures were consistently associated with significant reductions in preterm birth in the 2-month, 3-month, 4-month, 5-month time windows after implementation (+2 months, OR 0.80, 95% CI 0.69 to 0.94; +3 months, OR 0.83, 95% CI 0.73 to 0.94; +4 months, OR 0.82, 95% CI 0.73 to 0.92; +5 months, OR 0.84, 95% CI 0.76 to 0.93). These reductions in preterm birth were obvious across various degrees of prematurity, but were statistically significant only in moderate-to-late preterm birth (32 complete weeks to 36 weeks and 6 days) subgroup. The preterm birth difference disappeared gradually after various restrictions were removed (7th–12th month of 2020, OR 1.02, 95% CI 0.94 to 1.11). There was no difference in stillbirth rate across the study time window.Conclusion Substantial decreases in preterm birth rates were observed following implementation of the national COVID-19 mitigation measures in China. Further study is warranted to explore the underlying mechanisms associated with this observation.

Abstract Amnion‐derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of a common transcription factor driving the expression of both cyclooxygenase‐2 (COX‐2) and 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1), the key enzymes in their production, may hold the key to the treatment of pre‐term labor. Here, we have found that the CCAAT enhancer binding protein δ (C/EBPδ) is such a transcription factor which underlies the feed‐forward induction of COX‐2 and 11β‐HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPδ in the amnion increases along with COX‐2 and 11β‐HSD1 at term and further increases at parturition. Knockout of C/EBPδ in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPδ pathway may be speculated to serve as a potential pharmaceutical target in the amnion for treatment of pre‐term labor.

RIPK1 integrates signals that drive both NF-κB activation and cell death pathways. Here Zhang et al. generate RIPK1 knock-in mice lacking a major ubiquitination site and demonstrate that this modification is important to suppress cell death during embryogenesis and inflammation postnatally.

Objective: Recent studies have shown that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, plays an important role in the prevention of obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD). Considering that thyroid hormone (TH) has profound effects on whole-body energy metabolism, we speculate that circulating Nrg4 levels might be altered in patients with hyperthyroidism. Design and methods: A total of 129 hyperthyroid patients and 100 healthy subjects were recruited. Of them, 39 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism. Serum Nrg4 levels were determined using the ELISA method. To further confirm the relationship between TH and Nrg4, C57BL/6 mice were treated with T3 and quantitative real-time PCR was performed to detect Nrg4 gene expression. Results: Serum Nrg4 levels were significantly elevated in hyperthyroid patients as compared with normal controls (3.84 ± 1.63 vs 2.21 ± 1.04 ng/mL, P < 0.001). After achieving euthyroidism by thionamide treatment, serum Nrg4 levels dropped markedly from 3.57 ± 1.26 to 1.94 ± 0.72 ng/ml (P < 0.001). After adjustment for potential confounders, serum Nrg4 levels were independently associated with hyperthyroidism. The upregulation of Nrg4 expression in the livers and white adipose tissues by T3 was further confirmed by animal and cell culture experiments. Conclusions: Serum Nrg4 levels were increased in patients with hyperthyroidism. The liver and white adipose tissue might be primary sources contributing to elevated serum Nrg4 concentrations.

Objective: c-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood. Methods: We generated liver-specific c-Jun knock-out (c-jun△li) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature. Primary hepatocytes were also used to explore a direct regulation of c-Jun in gluconeogenesis. Results: c-jun△li mice showed higher hepatic gluconeogenic capacity compared with control mice, and similar results were obtained in vitro. In addition, fibroblast growth factor 21 (FGF21) expression was directly inhibited by c-Jun knockdown and adenovirus-mediated hepatic FGF21 over-expression blocked the effect of c-Jun on gluconeogenesis in c-jun△li mice. Interestingly, c-jun△li mice also exhibited higher body temperature, with induced thermogenesis and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). Furthermore, the body temperature became comparable between c-jun△li and control mice at thermoneutral temperature (30 °C). Moreover, the activity of sympathetic nervous system (SNS) was increased in c-jun△li mice and the higher body temperature was inhibited by beta-adrenergic receptor blocker injection. Finally, the activated SNS and increased body temperature in c-jun△li mice was most likely caused by the signals from the brain and hepatic vagus nerve, as the expression of c-Fos (the molecular marker of neuronal activation) was changed in several brain areas controlling body temperature and body temperature was decreased by selective hepatic vagotomy. Conclusions: These data demonstrate a novel function of hepatic c-Jun in the regulation of gluconeogenesis and body temperature via FGF21 and neural signals. Our results also provide novel insights into the organ crosstalk in the regulation of the whole-body physiology. Keywords: Gluconeogenesis, Temperature, Organ crosstalk

Objective: Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders. Methods: We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice. Intracerebroventricular (ICV) cannulation of insulin was used to test the hypothalamic insulin sensitivity in the mice. Hypothalamic primary neurons were used to investigate the mechanism of Smad7 regulating hypothalamic insulin signaling. Results: We found that Smad7 expression was increased in POMC neurons in the hypothalamic ARC of HFD-fed or middle-aged mice. Furthermore, overexpression of Smad7 in POMC neurons disrupted the glucose balance, and deletion of Smad7 in POMC neurons prevented diet- or age-induced glucose disorders, which was likely to be independent of changes in body weight or food intake. Moreover, the effect of Smad7 was reversed by overexpression of AKT in the ARC. Finally, Smad7 decreased AKT phosphorylation by activating protein phosphatase 1c in hypothalamic primary neurons. Conclusions: Our results demonstrated that an excess of central Smad7 in POMC neurons disrupts glucose balance by attenuating hypothalamic insulin signaling. In addition, we found that this regulation was mediated by the activity of protein phosphatase 1c.

There is a substantial number of telerobotics and teleoperation applications ranging from space operations, ground/aerial robotics, drive-by-wire systems to medical interventions. Major obstacles for such applications include latency, channel corruptions, and bandwidth which limit teleoperation efficacy. This survey reviews the time delay problem in teleoperation systems. We briefly review different solutions from early approaches which consist of control-theory-based models and user interface designs and focus on newer approaches developed since 2014. Future solutions to the time delay problem will likely be hybrid solutions which include modeling of user intent, prediction of robot movements, and time delay prediction all potentially using time series prediction methods. Hence, we examine methods that are primarily based on time series prediction. Recent prediction approaches take advantage of advances in nonlinear statistical models as well as machine learning and neural network techniques. We review Recurrent Neural Networks, Long Short-Term Memory, Sequence to Sequence, and Generative Adversarial Network models and examine each of these approaches for addressing time delay. As time delay is still an unsolved problem, we suggest some possible future research directions from information-theory-based modeling, which may lead to promising new approaches to advancing the field.

The instability of seabed slope sediments is the main factor influencing the safety of marine resource development. Therefore, to ensure the safe operation of submarine pipelines under complex and uncertain seabed rock and soil conditions, a reliability model was developed to elucidate the trend of impact-related pipeline damage due to submarine slides. Then, a risk assessment of the damage process of submarine slides impacting pipelines was conducted, which is of great significance for the in-depth safety assessment of pipelines impacted by submarine slides. Based on the copula function, a joint probability distribution model considering the correlation among risk variables was established for rational correlation characterization. A probability analysis method of impact-related pipeline damage attributed to submarine slides based on the copula function was proposed. The Monte Carlo simulation (MCS) method was employed to simulate the random uncertainty in limited observation values and accurately determine the reliability of safe pipeline operation under the action of submarine slides. The conclusions were as follows: (1) Based on the copula function, a joint probability distribution model of risk variables with any marginal distribution function and related structure could be developed. (2) The copula function could reasonably characterize relevant nonnormal distribution characteristics of risk variables and could simulate samples conforming to the distribution pattern of the risk variables. (3) The failure probability calculated with the traditional independent normal distribution model was very low, which could result in a notable overestimation of the reliability of submarine pipelines.

Objective: Diagnosis of occult fractures by initial plain radiographs remains challenging in children in the emergency room. This study was to assess the prevalence and distribution of occult fracture in children with acute extremities injuries (AEI) and clinical suspicion of fracture.Methods: We conducted a retrospective study to review the medical records of all pediatric patients with AEI in the orthopedic emergency room from January 1, 2017, to December 31, 2019. For patients with concerning history and physical examination but negative initial radiographs, we conducted the following three diagnostic strategies according to the choic of children's parents: immediate MRI scanning, [2] immediate CT scanning, or [3] empiric cast immobilization with orthopedic follow-up radiographs at 2 weeks post-injury (late radiographs). Prevalence and distribution of occult fracture were recorded.Results: A total of 43,560 pediatric patients meet the inclusion criteria. A total of 4,916 fractures of the extremities were confirmed by initial plain radiographs, and 550 occult fractures were confirmed by immediate MRI, immediate CT, or late radiographs. The prevalence of occult fracture in the extremities was 10.1% (550/5,466). Supracondylar fractures were the most prevalent (2,325/5,466, 42.5%) but had the lowest rate of occult fractures (117/2,325, 5.0%). The highest rate of occult fracture was distal epiphyseal fracture of the tibia and fibula (49/145, 33.8%), but these had a relatively lower prevalence of fractures (145/5,466, 2.65%).Conclusions: We should be aware of the relative high prevalence of occult fractures in the extremities in children, especially when the injured site is in the high incidence area of occult fracture such as ankle.

Serum amyloid A1 (SAA1) is an acute phase protein produced mainly by the liver to participate in immunomodulation in both sterile and non-sterile inflammation. However, non-hepatic tissues can also synthesize SAA1. It remains to be determined whether SAA1 synthesized locally in the placenta participates in parturition via eliciting inflammatory reactions. In this study, we investigated this issue by using human placenta and a mouse model. We found that SAA1 mRNA and protein were present in human placental villous trophoblasts, which was increased upon syncytialization as well as treatments with lipopolysaccharides (LPS), tumor necrosis factor-α (TNF-α), and cortisol. Moreover, significant increases in SAA1 abundance were observed in the placental tissue or in the maternal blood in spontaneous deliveries without infection at term and in preterm birth with histological chorioamnionitis. Serum amyloid A1 treatment significantly increased parturition-pertinent inflammatory gene expression including interleukin-1β (IL-1β), IL-8, TNF-α, and cyclooxygenase-2 (COX-2), along with increased PGF2α production in syncytiotrophoblasts. Mouse study showed that SAA1 was present in the placental junctional zone and yolk sac membrane, which was increased following intraperitoneal administration of LPS. Intraperitoneal injection of SAA1 not only induced preterm birth but also increased the abundance of IL-1β, TNF-α, and COX-2 in the mouse placenta. Conclusively, SAA1 can be synthesized in the human placenta, which is increased upon trophoblast syncytialization. Parturition is accompanied with increased SAA1 abundance in the placenta. Serum amyloid A1 may participate in parturition in the presence and absence of infection by inducing the expression of inflammatory genes in the placenta.

Metabolic syndrome is a disorder of energy use and storage, which is characterized by central obesity, dyslipidemia, and raised blood pressure and blood sugar levels. Maternal 25-hydroxyvitamin D deficiency is known to cause metabolic changes, chronic disease, and increased adiposity in adulthood. However, the underlying mechanism of induced metabolic syndrome (MetS) in the offspring in vitamin D deficient pregnant mothers remains unclear. We identified that maternal 25-hydroxyvitamin D deficiency enhances oxidative stress, which leads to the development of MetS in the mother and her offspring. Further, immunohistochemical, Western blotting, and qRT-PCR analyses revealed that maternal 25-hydroxyvitamin D deficiency inhibited the activation of the Nrf2/carbonyl reductase 1 (CBR1) pathway in maternal placenta, liver, and pancreas, as well as the offspring's liver and pancreas. Further analyses uncovered that application of 25-hydroxyvitamin D activated the Nrf2/CBR1 pathway, relieving the oxidative stress in BRL cells, suggesting that 25-hydroxyvitamin D regulates oxidative stress in offspring and induces the activation of the Nrf2/CBR1 pathway. Taken together, our study finds that maternal 25-hydroxyvitamin D deficiency is likely to result in offspring's MetS probably via abnormal nutrition transformation across placenta. Depression of the Nrf2/CBR1 pathway in both mothers and their offspring is one of the causes of oxidative stress leading to MetS. This study suggests that 25-hydroxyvitamin D treatment may relieve the offspring's MetS.

Abstract Background Few objective tests can be performed at admission for kidney transplantation [KT] to discern risk of increased length of stay [LOS], which is important for patient counseling and is associated with increased costs and mortality. The short physical performance battery [SPPB] is an easily administered, potentially modifiable, 3-part test of lower extremity function. SPPB score is associated with longer hospital LOS in older adults, and may provide similar utility in KT recipients given that ESRD is a disease of accelerated aging. The aim of this study was to characterize the association between SPPB-derived lower extremity function and LOS. Methods The SPPB was administered at KT admission in a prospective cohort of 595 recipients (8/2009–6/2016). The independent association between SPPB impairment (score ≤ 10) and LOS was tested with an adjusted conventional generalized gamma parametric survival model. Results Impaired recipients experienced longer LOS (median: 10 vs. 8 days; P

Introduction and aim. Salidroside and curcumin (SC) formula could alleviate lipid deposition in high fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the mechanisms are still unknown, and the magnitude of potential therapeutic benefit remains understudied.Material and methods. The rats were treated with high fat diet for 14 weeks to induce NAFLD. The experiment was divided into control, model (NAFLD), SC formula and rosiglitazone groups (n = 7 in each group). Hematoxylin-eosin (H&E) staining was applied to detect liver morphological changes. Biochemical, metabolic indices and inflammation factors in liver tissue and serum were detected. Additionally, the activities of related enzymes were detected by enzyme-linked immunosorbent assay.Results. In the established rat model, typical lipid deposition and liver steatosis were observed. Liver triglyceride, free fatty acids, sera alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, fasting insulin, fasting blood glucose and homeostasis model assessment of insulin resistance were elevated in model group. Liver malondialdehyde was significantly elevated, while superoxide dismutase was significantly decreased in model group, compared with control. Moreover, tumor necrosis factor-α and Interleukin-1 were significantly prod uced in model group, compared with control. As a mechanism, high fat diet decreased tissue AMP-activated protein kinase (AMPK), phosphorylated AMPK, carnitine palmitoyltransferase 1 and increased inacetyl-CoA carboxylase (ACCase), phosphorylated ACCase. Importantly, these abnormal changes caused by high fat diet were reduced by SC formula administration.Conclusion. SC formula could ameliorate the injury caused by high fat diet. The effect was likely mediated via its influence on insulin resistance, lipid peroxidation injury and AMPK signaling pathway.

Background: Twin growth discordance is one of the leading causes of perinatal mortality in twin pregnancies. Whether prenatal exposure to fine particle (PM2.5) air pollution is associated with twin growth discordance have not been studied yet. Objective: To evaluate the associations of prenatal exposure to PM2.5 and its chemical constituents with twin growth discordance. Methods: This study included 1917 twin pairs and their mothers drawn from a previous twin birth cohort at the Shanghai First Maternity and Infant hospital in Shanghai, China. Exposure to PM2.5 total mass and 6 key chemical constituents during the whole pregnancy and each trimester of pregnancy was represented by satellite-based models. Results: Maternal exposures to PM2.5 total mass and chemical constituents of sulfate (SO42−) and ammonium (NH4+) during the third trimester were significantly associated with increased within-pair birth weight difference and intertwin birth weight discordance. The within-pair birth weight difference increased by 30.6 g (β = 30.6, 95% CI, 4.4–56.9), 19.2 g (β = 19.2, 95% CI, 0.2–38.1) and 33.2 g (β = 33.2, 95% CI, 7.9–58.6) for an IQR increase in PM2.5 total mass, SO42− and NH4+ exposure, respectively. While the intertwin birth weight discordance increased by 1.3% (β = 1.3, 95% CI, 0.3–2.2), 0.9% (β = 0.9, 95% CI, 0.2–1.6) and 1.4% (β = 1.4, 95% CI, 0.4–2.3) for the same exposure metrics. Moreover, higher SO42− and NH4+ exposure was also associated with increased risk of twin growth discordance in linear dose-response manners. Compared to the lowest quartile of SO42− (OR = 2.51, 95% CI, 1.08–5.82) and NH4+ (OR = 2.97, 95% CI, 1.16–7.58) exposure, the odds of twin growth discordance were doubled in highest quartile of exposure. Conclusion: Our results suggest that fine particle air pollution may be a risk factor for twin growth discordance. Late pregnancy seems to be a critical window for the effects of PM2.5 exposure on fetal growth in twins. Keywords: Ambient air pollution, PM2.5, Chemical constituents, Within-pair birth weight difference, Twin growth discordance

Summary: Hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) offer a promising cell resource for disease modeling and transplantation. However, differentiated HLCs exhibit an immature phenotype and comprise a heterogeneous population. Thus, a better understanding of HLC differentiation will improve the likelihood of future application. Here, by taking advantage of CRISPR-Cas9-based genome-wide screening technology and a high-throughput hPSC screening platform with a reporter readout, we identified several potential genetic regulators of HLC differentiation. By using a chemical screening approach within our platform, we also identified compounds that can further promote HLC differentiation and preserve the characteristics of in vitro cultured primary hepatocytes. Remarkably, both screenings identified histone deacetylase 3 (HDAC3) as a key regulator in hepatic differentiation. Mechanistically, HDAC3 formed a complex with liver transcriptional factors, e.g., HNF4, and co-regulated the transcriptional program during hepatic differentiation. This study highlights a broadly useful approach for studying and optimizing hPSC differentiation. : Ding and colleagues developed a broadly useful approach to study novel regulators involved in hepatic differentiation of human pluripotent stem cells, with a combination of reporter system construction, genome-wide CRISPR-Cas9-based genetic screening, and targeted chemical screening. Studies revealed HDAC3 as a key regulator in hepatic lineage determination. Keywords: human pluripotent stem cells, hepatic differentiation, genome-wide CRISPR/Cas9 screening, histone deacetylase 3, histone deacetylase inhibitor CI-994

Fibrosis is common after skeletal muscle injury, undermining tissue regeneration and function. The mechanism underlying skeletal muscle fibrosis remains unveiled. Transforming growth factor-β/Smad signaling pathway is supposed to play a pivotal role. However, how microRNAs interact with transforming growth factor-β/Smad-related muscle fibrosis remains unclear. We showed that microRNA (miR)-24-3p and miR-122-5p declined in skeletal muscle fibrosis, which was a consequence of transforming growth factor-β. Upregulating Smad4 suppressed two microRNAs, whereas inhibiting Smad4 elevated microRNAs. Luciferase reporter assay and chromatin immunoprecipitation confirmed that Smad4 directly inhibited two microRNAs. On the other hand, overexpression of these two miRs retarded fibrotic process. We further identified that Smad2 was a direct target of miR-24-3p, whereas miR-122-5p targeted transforming growth factor-β receptor-II. Both targets were important participants in transforming growth factor-β/Smad signaling. Taken together, a positive feedback loop in transforming growth factor-β/Smad4 signaling pathway in skeletal muscle fibrosis was identified. Transforming growth factor-β/Smad axis could be downregulated by microRNAs. This effect, however, was suppressed by Smad4, the downstream of transforming growth factor-β.