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Abstract Background and purpose In the context of the widespread availability of magnetic resonance imaging (MRI) and aggressive salvage irradiation techniques, there has been controversy surrounding the use of prophylactic cranial irradiation (PCI) for small-cell lung cancer (SCLC) patients. This study aimed to explore whether regular brain MRI plus salvage brain irradiation (SBI) is not inferior to PCI in patients with limited-stage SCLC (LS-SCLC). Methods This real-world multicenter study, which was conducted between January 2014 and September 2020 at three general hospitals, involved patients with LS-SCLC who had a good response to initial chemoradiotherapy and no brain metastasis confirmed by MRI. Overall survival (OS) was compared between patients who did not receive PCI for various reasons but chose regular MRI surveillance and followed salvage brain irradiation (SBI) when brain metastasis was detected and patients who received PCI. Results 120 patients met the inclusion criteria. 55 patients received regular brain MRI plus SBI (SBI group) and 65 patients received PCI (PCI group). There was no statistically significant difference in median OS between the two groups (27.14 versus 33.00 months; P = 0.18). In the SBI group, 32 patients underwent whole brain radiotherapy and 23 patients underwent whole brain radiotherapy + simultaneous integrated boost. On multivariate analysis, only extracranial metastasis was independently associated with poor OS in the SBI group. Conclusion The results of this real-world study showed that MRI surveillance plus SBI is not inferior to PCI in OS for LS-SCLC patients who had a good response to initial chemoradiotherapy.

ABSTRACT Background Feeding difficulties frequently co‐occur with multisystem disorders attributed to rare genetic diseases. In this study, we aimed to describe the genetic manifestations and phenotype spectrum in infants experiencing feeding difficulties. Methods This case series included infants under 6 months old with feeding difficulties admitted to the neonatal department of Children's Hospital, Zhejiang University School of Medicine from October 2018 to May 2022. All infants underwent whole‐exome sequencing (WES) during hospitalisation, and their clinical phenotypes and genetic results were analyzed. Results Among 28 infants studied, nine were preterm and 19 were full‐term. Median admission age was 13.5 days (IQR 6.5, 35), with a median hospital stay of 16 days (IQR 10.5, 30). Overall, 12 (42.9%) cases were complicated with multiple malformations. Abnormal muscle tone (53.6%) and neurological issues (42.9%) were notable prevalent in these infants. Cranial MR abnormalities were noted in 96.2% of cases. Based on the combined analysis of WES results and clinical phenotypes, a total of 22 (78.3%) patients displayed disease‐related genetic variation identified through WES; among them, 15 (53.6%) patients received genetic diagnoses, while 7 (25%) patients were suspected diagnoses. Positive findings were more frequent in full‐term (89.5%) than preterm infants (55.6%). Ultimately, 24 (85.7%) patients were discharged alive, with 75% requiring post‐discharge tube feeding. Following discharge, five patients developed new symptoms linked to genetic variants, and two patients died. Conclusions Feeding difficulty may constitute a facet of the phenotypic spectrum of rare genetic diseases. Whole‐exome sequencing can enhance molecular diagnosis accuracy for infants with feeding difficulties.

Abstract Background Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy with a rapid progression and high mortality rate. We aimed to explore early risk factors for mortality in patients with TTP. Methods We conducted a retrospective analysis of 42 TTP patients that were admitted to our hospital between 2000 and 2021, with a median age of 49 (29–63) years. Risk factors for mortality were evaluated using multivariate logistic regression. Receiver operating characteristic curve analysis was used to determine the cut-off value of glucose for predicting mortality in patients, which was validated by comparison to a similar cohort in the published literature. Results Elevated glucose level and reduced red blood cells (RBC) counts were risk factors for mortality in patients with TTP (glucose, odds ratio and 95% confidence interval: 2.476 [1.368–4.484]; RBC, odds ratio and 95% confidence interval: 0.095 [0.011–0.799]). The area under the curve of glucose was 0.827, and the cut-off value was 9.2 mmol/L, with a sensitivity of 75.0% and specificity of 95.8%. A total of 26 cases from the validation cohort had a sensitivity of 71.0% and a specificity of 84.0%. The change trends of the TTP-related laboratory indices differed during hospitalization. Conclusion Hyperglycemia at admission and unstable blood glucose levels during hospitalization may be potential predictors of mortality for TTP patients. The improved prognosis was associated with the recovery of platelet counts and a significant decrease in serum lactate dehydrogenase after five days of treatment.

Recycling of wasted phosphate slag (PS) into useful mineral additives shows great significance not only in carbon reduction but also contributes to the availability of green additives to cement-based materials. This work aims to explore a feasible way of disclose the mechanism of PS added cement-based materials. It was found that compressive strengths of pastes were all declined with increasing addition of PS both at early age of 2 d and long age of 28 d, increased the curing temperatures from 20 °C to 40 °C helped to improve the above situation. A remarkable increase of compressive strength in 10SF+20PS sample with the value of 55.48 MPa was obtained at 28 d. The enhanced mechanical property was related with the generation of large amount of hydration products such as C–S–H, Ca(OH)2 and AFt.

Protein engineering aimed at increasing temperature tolerance through iterative mutagenesis and high-throughput screening is often labor-intensive. Here, we developed a deep evolution (DeepEvo) strategy to engineer protein high-temperature tolerance by generating and selecting functional sequences using deep learning models. Drawing inspiration from the concept of evolution, we constructed a high-temperature tolerance selector based on a protein language model, acting as selective pressure in the high-dimensional latent spaces of protein sequences to enrich those with high-temperature tolerance. Simultaneously, we developed a variant generator using a generative adversarial network to produce protein sequence variants containing the desired function. Afterward, the iterative process involving the generator and selector was executed to accumulate high-temperature tolerance traits. We experimentally tested this approach on the model protein glyceraldehyde 3-phosphate dehydrogenase, obtaining 8 variants with high-temperature tolerance from just 30 generated sequences, achieving a success rate of over 26%, demonstrating the high efficiency of DeepEvo in engineering protein high-temperature tolerance.

Elastic materials for seat foundations come in a variety of materials, shapes, and dimensions. However, it is difficult to measure the stress-strain relationships of many elastic material combinations by conventional uniaxial compression tests. This study investigated the stress-strain relations of elastic material combinations for foam foundations using finite element analysis (FEA). First, the stress-strain relations of single-layer polymer foams and a combination of double-layer polymer foams with covering were quantified by uniaxial compression tests, and axial tensile tests quantified the properties of the covering material of the fabric. Then, based on the Ogden foam and Ogden constitutive equation of Ansys Workbench 19.2, the test data of single-layer polymer foams and covering were fitted by a non-linear least square method, and a combination of double-layer polymer foams with the covering is predicted by FEA. When the strain was 10% to 65%, the stress error between FEA and test results dropped from 95.68% to -5.08%.

Abstract Background C-reactive protein(CRP), is an inflammatory marker that weaken leptin bioavailability and insulin sensitivity to disturb energy and glucose metabolism. Polycystic ovary syndrome (PCOS) exhibit a metabolic component consisting of higher plasma CRP levels, hyperinsulinemic and hyperleptinemia. The ability of leptin to regulation of hepatic glucose production (HGP) in the absence of CRP in PCOS remain unknown. Methods Dehydroepiandrosterone (DHEA) was used to induce PCOS in rats. We assessed the effects of CRP gene knockout in PCOS model rats on body weight, energy expenditure glucose metabolism and insulin sensitivity. We conducted experiments involving the administration of leptin to both the peripheral and central systems in PCOS model rats with CRP knockout, and studied the effects on changes in glucose kinetics during hyperinsulinemic-euglycemic clamps. Results In female PCOS rats, the lack of CRP resulted in decreased leptin resistance and weight gain, increased energy expenditure, and improved insulin sensitivity. Additionally, the deletion of the CRP gene strengthened the HGP-lowering effects of leptin when administered peripherally or centrally. This effect was accompanied by a decrease in the expression of hepatic gluconeogenic enzymes and an increase in hepatic insulin signaling. Finally, inhibition of glucose production was also enhanced for central leptin administration during lipid infusion in PCOS rats. Conclusions Our findings highlight the therapeutic potential of targeting CRP to restore glucose homeostasis and insulin sensitivity for leptin in PCOS.

Abstract Background Leg weakness affects animal welfare and is one of the primary reasons for culling of boars. Low bone mineral density (BMD) is one of the primary factors contributing to leg weakness. Low BMD also appeared to be associated with severe bone pain and has the highest risk of skeletal fragility. Surprisingly, few studies have been performed on the factors influencing BMD in pigs. Therefore, the primary aim of this study was to identify the influencing factors on boar BMD. Herein, the BMD data were determined through the use of ultrasonography from 893 Duroc boars. Logistic regression model was utilized in the analysis of BMD, in which the explanatory variables in the model were lines, ages, body weights, backfat thicknesses and serum mineral element concentrations (Ca, P, Mg, Cu, Fe, Zn, Mn, Se, Pb and Cd). Results Results showed that factors significantly influencing BMD included serum Ca, P concentrations, ages and backfat thicknesses (P

Abstract Mesenchymal stem/Stromal cells (MSCs) have great therapeutic potentials, and they have been isolated from various tissues and organs including definitive endoderm (DE) organs, such as the lung, liver and intestine. MSCs have been induced from human pluripotent stem cells (hPSCs) through multiple embryonic lineages, including the mesoderm, neural crest, and extraembryonic cells. However, it remains unclear whether hPSCs could give rise to MSCs in vitro through the endodermal lineage. Here, we report that hPSC-derived, SOX17+ definitive endoderm progenitors can further differentiate to cells expressing classic MSC markers, which we name definitive endoderm-derived MSCs (DE-MSCs). Single cell RNA sequencing demonstrates the stepwise emergence of DE-MSCs, while endoderm-specific gene expression can be elevated by signaling modulation. DE-MSCs display multipotency and immunomodulatory activity in vitro and possess therapeutic effects in a mouse ulcerative colitis model. This study reveals that, in addition to the other germ layers, the definitive endoderm can also contribute to MSCs and DE-MSCs could be a cell source for regenerative medicine.

The challenge of high geo-temperature often occurred during the construction of deep buried tunnels, and to uncover the effect of varied curing temperature on hydration and microstructure evolution of cement-based composites with extremely low w/b ratio, samples were prepared with a w/b ratio of 0.18 and mixed with different fibers, silica fume and fly ash. Hydration kinetics, main hydration product phases and the evolution of C–S–H inside the samples were analyzed. It was found that the time for maximum heat release peak under 40 °C and 60 °C was earlier than that under 20 °C. The hydration heat of steel fiber composites was lower than that of PP fiber composites. 40 °C curing temperature can motivated the chemical activity of samples and promoted the hydration process, multi-stage peaks appeared at 60 °C curing condition. Q0-Q4 of C–S–H were observed in samples, and the mean silicate chain length (MCL) of C–S–H from 29Si NMR analysis was increased mostly by 15.6% with the elevated curing temperature. This study will provide much support to the safe construction of deep buried tunnels.

ABSTRACT Temperature dependency of viral diseases in ectotherms has been an important scientific issue for decades, while the molecular mechanism behind this phenomenon remains largely mysterious. In this study, deploying infection with grass carp reovirus (GCRV), a double-stranded RNA aquareovirus, as a model system, we demonstrated that the cross talk between HSP70 and outer capsid protein VP7 of GCRV determines temperature-dependent viral entry. Multitranscriptomic analysis identified HSP70 as a key player in the temperature-dependent pathogenesis of GCRV infection. Further biochemical, small interfering RNA (siRNA) knockdown, pharmacological inhibition, and microscopic approaches revealed that the primary plasma membrane-anchored HSP70 interacts with VP7 to facilitate viral entry during the early phase of GCRV infection. Moreover, VP7 functions as a key coordinator protein to interact with multiple housekeeping proteins and regulate receptor gene expression, concomitantly facilitating viral entry. This work illuminates a previously unidentified immune evasion mechanism by which an aquatic virus hijacks heat shock response-related proteins to enhance viral entry, pinpointing targeted preventives and therapeutics for aquatic viral diseases. IMPORTANCE The seasonality of viral diseases in ectotherms is a prevailing phenomenon in the aquatic environment, which causes huge economic losses every year worldwide and hinders sustainable development of the aquaculture industry. Nevertheless, our understanding of the molecular mechanism of how temperature determines the pathogenesis of aquatic viruses remains largely unexplored. In this study, by deploying grass carp reovirus (GCRV) infection as a model system, we demonstrated that temperature-dependent, primarily membrane-localized HSP70 interacts with major outer capsid protein VP7 of GCRV to bridge the virus-host interaction, reshape the host’s behaviors, and concomitantly facilitate viral entry. Our work unveils a central role of HSP70 in the temperature-dependent pathogenesis of aquatic viruses and provides a theoretical basis for the formulation of prevention and control strategies for aquatic viral diseases.

Abstract Without the dependence of depth ground truth, self‐supervised learning is a promising alternative to train monocular depth estimation. It builds its own supervision signal with the help of other tools, such as view synthesis and pose networks. However, more training parameters and time consumption may be involved. This paper proposes a monocular depth prediction framework that can jointly learn the depth value and pose transformation between images in an end‐to‐end manner. The depth network creatively employs an asymmetric convolution block instead of every square kernel layer to strengthen the learning ability of extracting image features when training. During inference time, the asymmetric kernels are fused and converted to the original network to predict more accurate image depth, thus bringing no extra computations anymore. The network is trained and tested on the KITTI monocular dataset. The evaluated results demonstrate that the depth model outperforms some State of the Arts (SOTA) approaches and can reduce the inference time of depth prediction. Additionally, the proposed model performs great adaptability on the Make3D dataset.

Suboptimal light stress in grapevines is increasing worldwide with the spread of grapevine cultivation, which can affect grapevine physiology and productivity, such as in Southern China. Abscisic acid (ABA) is an important hormone in plant adaptive responses to abiotic stress, including low light stress. However, ABA signaling pathway genes (APGs) are not well characterized in the grapevine, and little is known of their potentially mitigating role in grapevine growth under weak light stress. Our study aimed to explore the potential role of the ABA signaling pathway in the response of grapevines to suboptimal light conditions. In this study, APGs were identified in the grapevine genome, and the distribution of conserved motifs was shown to reflect their phylogenetic relationships. Gene duplication analysis indicated that segmental duplication was an important driver for gene expansion in the grapevine ABA signaling pathway. Suboptimal conditions of light were shown to seriously affect the growth of grapevine leaves and berries, with the differential regulation of APGs in the grapevine. Our study summarizes the basic characteristics of APGs in grapevine, which can now be examined further for their roles in grapevine’s response to suboptimal light conditions.

BackgroundMalignant pericardial effusion (MPE) is a serious complication in patients with advanced malignant tumors, which indicates a poor prognosis. However, its clinical manifestations lack specificity, making it challenging to distinguish MPE from benign pericardial effusion (BPE). The aim of this study was to develop and validate a scoring system based on a nomogram to discriminate MPE from BPE through easy-to-obtain clinical parameters.MethodsIn this study, the patients with pericardial effusion who underwent diagnostic pericardiocentesis in Taizhou Hospital of Zhejiang Province from February 2013 to December 2021 were retrospectively analyzed. The eligible patients were divided into a training group (n = 161) and a validation group (n = 66) according to the admission time. The nomogram model was established using the meaningful indicators screened by the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. Then, a new scoring system was constructed based on this nomogram model.ResultsThe new scoring system included loss of weight (3 points), no fever (4 points), mediastinal lymph node enlargement (2 points), pleural effusion (6 points), effusion adenosine deaminase (ADA≦18U/L) (5 points), effusion lactate dehydrogenase (LDH>1033U/L) (7 points), and effusion carcinoembryonic antigen (CEA>4.9g/mL) (10 points). With the optimal cut-off value was 16 points, the area under the curve (AUC), specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR) for identifying MPE were 0.974, 95.1%, 91.0%, 85.6%, 96.8%, 10.56 and 0.05, respectively, in the training set and 0.950, 83.3%, 95.2%, 90.9%, 90.9%, 17.50, and 0.18, respectively, in the validation set. The scoring system also showed good diagnostic accuracy in differentiating MPE caused by lung cancer from tuberculous pericardial effusion (TPE) and MPE including atypical cell from BPE.ConclusionThe new scoring system based on seven easily available variables has good diagnostic value in distinguishing MPE from BPE.

ObjectiveTo analyze the related factors of the postpartum thyroid function in women with overt hypothyroidism (OH)/subclinical hypothyroidism (SCH) and explore the effects of vitamin D categories.MethodsThyroid hormones, thyroid autoantibody, and serum 25OHD levels were continuously recorded from the first trimester of pregnancy (T1) to the 12th postpartum month. Logistic regression analysis and Cox regression analysis were used to screen the related factors of postpartum thyroid function, and the Latent Class Growth Model was performed to analyze the trajectory characteristics of serum 25OHD levels.ResultsTotally, 252 pregnant women with OH/SCH were enrolled in the study. In the 12th month postpartum, 36.5% of the patients improved thyroid function, 37.3% continued hypothyroidism, and 26.2% developed thyroid dysfunction. Vitamin D sufficiency, positive TPOAb, and positive TgAb in T1 were independent prognostic factors of postpartum thyroid function. Vitamin D sufficiency in T1 was illustrated as an independent factor of the improved postpartum thyroid function, but the protective effect for the developed postpartum thyroid dysfunction was only confirmed in TPOAb-positive patients. Cox regression analysis further confirmed the effects of vitamin D categories. Notably, the high-level 25OHD trajectory during pregnancy and postpartum could predict improved postpartum thyroid function and decrease the risk of developed postpartum thyroid dysfunction.ConclusionAppropriate vitamin D nutrition during pregnancy and postpartum may be beneficial to postpartum thyroid function.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the existing prognosis systems based on clinical variables are difficult to stratify patients accurately. Nutritional indices play a meaningful role in prognosis of solid tumors, whereas the effect on DLBCL is still equivocal. This retrospective study aimed to develop a novel model based on nutritional indices and other clinical variables to accurately differentiate the prognosis of DLBCL.MethodsA total of 129 patients pathologically diagnosed with DLBCL in Affiliated Hospital of Xuzhou Medical University from 2014 to 2018 were retrospectively recruited. The total fat area (TFA), visceral fat area (VFA) and subcutaneous fat area (SFA) at the third lumbar vertebra level spine were obtained by computed tomography (CT) to assess the effect of nutritional status on the prognosis of DLBCL. Principal component analysis was used to reduce the dimension of nutritional indices, and continuous variables were evaluated according to X-Tile and Restricted cubic spline. Univariable and multivariable Cox proportional hazard analyses were performed on potential variables. Kaplan-Meier method was utilized to evaluate survival probabilities and the differences between groups were assessed by log-rank test.ResultsX-Tile analysis divided VFA and albumin into two and three groups when applying 114.7 cm2 of VFA, 38.3 and 42.4 g/L of albumin as the optimal cut-off points, respectively. The final scoring model of nutrition-related prognostic index (NPI) comprised four independent prognostic variables. The C-index of the final model was 0.823 [95% CI (0.749~0.897)] by bootstrap resampling. Finally, a maximum score of 6 points was obtained. Compared with IPI, NCCN-IPI and GELTAMO-IPI, NPI showed better accuracy in discerning the prognostic risk of patients.ConclusionVFA and albumin were associated with the prognosis of DLBCL, and the NPI model based on nutritional indices could better stratify the prognosis of DLBCL.

Blasting demolition has been widely used in the safe and efficient demolishing of construction buildings. Blasting demolition dust is the most visible and realistic harmful material during the blasting process. The characteristics and suppression of the blasting dust are scarcely addressed in the literature. This article investigated the micromorphology characteristic of blasting demolition dust from a typical building demolition project. The dust median size value D50 was 65.890 μm, and it showed a character of smooth edge, fluffy structure, and cracks. It consists of higher content of heavy metals than conventional cement powder particles, which include Mn, Ni, Zn, and As elements. The dust cannot be wet by municipal water for its hydrophobic character. A novelty method was proposed to set a methodology to form a stable, larger volume, and surface area water droplet on a rod stand, which provided more opportunities to find out and verify the microscopic agglomeration phenomenon and effectiveness between dust and different wetting droplets. The single dust-droplet collision results can be accurately recorded by the high-speed camera with a microscope, the collision and submergence time between blasting demolition dust particle and municipal water droplet on the stand was 2 ms, while the time was 1.125 ms with surfactant solution droplet, which was much shorter than the time of municipal water. The dust-droplet microscopic collision results were shown that the blasting demolition dust can be better wet and agglomerated by a surfactant solution. In blasting demolition projects, the BDD suppression methods with surfactant solution explosion mist have the highest efficiency, which can restrict the BDD’s concentration to 10 mg/m3.

To investigate the effects of claw lesion types and bone mineral density on lameness in boars, the data of claw lesion score, gait score, and bone mineral density, measured by a Miniomin ultrasound bone densitometer, were collected from a total of 739 Duroc boars. Firstly, we discovered that the prevalence of claw lesions was as high as 95.26% in boars. The percentage of lameness of boars with SWE was higher than those with other claw lesions. Meanwhile, the results showed that the probability of lameness was higher in boars with lower bone mineral density (p < 0.05). Logistic regression models, including variables of boar age, body weight, serum mineral level, and housing type, were used to identify the influencing factors of bone mineral density in this study. The results found that bone mineral density increases with age before reaching a maximum value at 43 months of age, and begins to decrease after 43 months of age. Elevated serum Ca levels were significantly associated with an increase in bone mineral density (p < 0.05). Aside from the above findings, we also made an interesting discovery that boars in the individual pen model significantly increased bone mineral density compared to those in the individual stall model. In conclusion, claw lesions and bone mineral density were significantly associated with lameness. Age, serum Ca, and housing type are the potential influencing factors for bone mineral density in boars.

Cartilage regeneration is dependent on cellular-extracellular matrix (ECM) interactions. Natural ECM plays a role in mechanical and chemical cell signaling and promotes stem cell recruitment, differentiation and tissue regeneration in the absence of biological additives, including growth factors and peptides. To date, traditional tissue engineering methods by using natural and synthetic materials have not been able to replicate the physiological structure (biochemical composition and biomechanical properties) of natural cartilage. Techniques facilitating the repair and/or regeneration of articular cartilage pose a significant challenge for orthopedic surgeons. Whereas, little progress has been made in this field. In recent years, with advances in medicine, biochemistry and materials science, to meet the regenerative requirements of the heterogeneous and layered structure of native articular cartilage (AC) tissue, a series of tissue engineering scaffolds based on ECM materials have been developed. These scaffolds mimic the versatility of the native ECM in function, composition and dynamic properties and some of which are designed to improve cartilage regeneration. This review systematically investigates the following: the characteristics of cartilage ECM, repair mechanisms, decellularization method, source of ECM, and various ECM-based cartilage repair methods. In addition, the future development of ECM-based biomaterials is hypothesized.

Abstract Background Neonatal meningitis is a severe infectious disease of the central nervous system with high morbidity and mortality. Ureaplasma parvum is extremely rare in neonatal central nervous system infection. Case presentation We herein report a case of U. parvum meningitis in a full-term neonate who presented with fever and seizure complicated with subdural hematoma. After hematoma evacuation, the seizure disappeared, though the fever remained. Cerebrospinal fluid (CSF) analysis showed inflammation with CSF pleocytosis (1135–1319 leukocytes/μl, mainly lymphocytes), elevated CSF protein levels (1.36–2.259 g/l) and decreased CSF glucose (0.45–1.21 mmol/l). However, no bacterial or viral pathogens in either CSF or blood were detected by routine culture or serology. Additionally, PCR for enteroviruses and herpes simplex virus was negative. Furthermore, the CSF findings did not improve with empirical antibiotics, and the baby experienced repeated fever. Thus, we performed metagenomic next-generation sequencing (mNGS) to identify the etiology of the infection. U. parvum was identified by mNGS in CSF samples and confirmed by culture incubation on mycoplasma identification medium. The patient’s condition improved after treatment with erythromycin for approximately 5 weeks. Conclusions Considering the difficulty of etiological diagnosis in neonatal U. parvum meningitis, mNGS might offer a new strategy for diagnosing neurological infections.

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from the Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cutoff points of continuous variables; univariate and multivariate Cox analyses were used for variable selection, and the Kaplan–Meier curve was used to analyze the value of variables on prognosis. The C-index, Brier Score, and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio, and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in the derivation and validation cohorts by using a bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous non-Hodgkin lymphoma, and the prognosis of DLBCL patients is widely affected by multivariables. Clinical-factors-based prognostic systems stratify the prognosis of DLBCL with certain limitations, and the value of ferritin on the prognosis of DLBCL is unclear. In this study, 225 cases were retrieved from 4 centers of Huaihai Lymphoma Working Group (HHLWG) as the derivation cohort, and 66 cases were from the other 6 centers of HHLWG as external validation cohort. X-Tile program divided ferritin into three groups when applying 175.00 and 391.90 μg/L as the optimal cutoff points. Based on multivariable analysis, ferritin appeared to be a stronger predictor. A total of three variables (ferritin, age, and lactate dehydrogenase) were included for the development of the nomogram. The C-indexes were 0.73 and 0.70 in the derivation and validation cohort, and the calibration curve showed the consistency between the nomogram prediction and the actual observation. In conclusion, Ferritin-based nomogram enhanced the prognostic value of IPI in DLBCL.

Abstract There are no licensed drugs for nonalcoholic fatty liver disease (NAFLD), and there is a lack of consensus on the best outcome measures for controlled trials. This systematic review aimed to evaluate the efficacy of GLP‐1 RAs in the management of NAFLD, the degree of heterogeneity in trial design and the robustness of conclusions drawn from these clinical trials. We searched publication databases and clinical trial registries through 2 November 2019 for clinical trials with NAFLD. We evaluated improvements in histological findings, noninvasive markers of hepatic steatosis, inflammation, and fibrosis, insulin resistance and anthropometric measures. Our final analysis included 24 clinical trials, comprising 6313 participants with a mean duration of 37 weeks. Four clinical trials, including RCT (n = 1), single‐arm studies (n = 2) and case series studies (n = 1), used biopsy‐confirmed liver histological change as their end‐points. The remaining studies (n = 20) used surrogate end‐points. GLP‐1 RAs were effective for the improvement in hepatic inflammation, hepatic steatosis and fibrosis. More importantly, GLP‐1 RAs showed promise in improving the histological features of NASH. In addition, 8 ongoing trials were identified. In this systematic review of published and ongoing clinical trials of the efficacy of GLP‐1RAs for NAFLD, we found that GLP‐1 RAs are effective for hepatic steatosis and inflammation, with the potential to reverse fibrosis. Further prospective studies of sufficient duration using histological end‐points are needed to fully assess the efficacy of GLP‐1 RAs in the management of NAFLD.

Microplastic fibers (MFs) pollute aquatic habitats globally via sewage release, stormwater runoff, or atmospheric deposition. Of the synthetic MFs, polyester (PES) and polypropylene (PP) are the most common. Field studies show that fish ingest large quantities of MFs. However, few laboratory studies have addressed host responses, particularly at the organ and tissue levels. Adult Japanese medaka (Oryzias latipes), a laboratory model fish, were exposed to aqueous concentrations of PES or PP MFs (10,000 MFs/L) for 21 days. Medaka egested 1,367 ± 819 PES MFs (0.1 ± 0.04 mg) and 157 ± 105 PP MFs (1.4 ± 0.06 mg) per 24 hrs, with PP egestion increasing over time. Exposure did not result in changes in body condition, gonadosomatic- or hepatosomatic indices. PES exposure resulted in no reproductive changes, but females exposed to PP MFs produced more eggs over time. MF exposure did not affect embryonic mortality, development, or hatching. Scanning electron microscopy (SEM) of gills revealed denuding of epithelium on arches, fusion of primary lamellae, and increased mucus. Histologic sections revealed aneurysms in secondary lamellae, epithelial lifting, and swellings of inner opercular membrane that altered morphology of rostral most gill lamellae. SEM and histochemical analyses showed increased mucous cells and secretions on epithelium of foregut; however, overt abrasions with sloughing of cells were absent. For these reasons, increased focus at the tissue and cell levels proved necessary to appreciate toxicity associated with MFs.

Summary: Estrogen drives breast cancer (BCa) progression by directly activating estrogen receptor α (ERα). However, because of the stochastic nature of gene transcription, it is important to study the estrogen signaling pathway at the single-cell level to fully understand how ERα regulates transcription. Here, we performed single-cell transcriptome analysis on ERα-positive BCa cells following 17β-estradiol stimulation and reconstructed the dynamic estrogen-responsive transcriptional network from discrete time points into a pseudotemporal continuum. Notably, differentially expressed genes show an estrogen-stimulated metabolic switch that favors biosynthesis but reduces estrogen degradation. Moreover, folate-mediated one-carbon metabolism is reprogrammed through the mitochondrial folate pathway and polyamine and purine synthesis are upregulated coordinately. Finally, we show AZIN1 and PPAT are direct ERα targets that are essential for BCa cell survival and growth. In summary, our study highlights the dynamic transcriptional heterogeneity in ERα-positive BCa cells upon estrogen stimulation and uncovers a mechanism of estrogen-mediated metabolic switch. : Zhu et al. perform single-cell RNA-seq to reveal a dynamic transcriptional network in ERα+ breast cancer cells following estrogen stimulation and show that estrogen signaling promotes breast cancer cell survival and growth by mediating a metabolic switch in which folate-mediated one-carbon metabolism is reprogrammed via the mitochondrial folate pathway. Keywords: breast cancer, single-cell RNA sequencing, estrogen receptor α, metabolic switch

In an ultrasonic sensor system based on π phase-shifted fiber Bragg gratings (πFBGsÞ, a cost-effective way for sensor demodulation is to set the laser wavelength at the center of the steep spectral slope of the πFBG refection spectrum. Frequency noise of the laser source ultimately limits the signal-to-noise ratio (SNR) of the sensor system. Here, we demonstrate a noise cancelation method based on a pair of πFBGs, which is capable of improving the SNR of system beyond the limitation set by the laser frequency noise. In this method, one of the gratings is used as the sensor to detect the acoustic signal, and the other grating, isolated from the signal, is used as a reference that gives the noise information. Employing a data postprocessing method, the noise is subtracted from the original detected signal. We show that the SNR of the sensor system can be improved by up to 20 dB using this method.

Developing highly efficient catalyst systems for phenol–quinone transformation is of great significance in the chemical/biological industries. Herein, we reported a novel heterogenous catalytic system based on Co(Salphen) supramolecular polymers (CSP), which delivered an excellent catalytic performance in the oxidation of 2,3,6-trimethylphenol (TMP) under mild conditions. The CSP were constructed through a simple self-assembled process between BiCo(Salphen) complex and 4,4-dipyridine. By applying BiCo-BiPy1:1 CSP as the catalyst, 2,3,5-trimethyl-1,4-benzoquinone (TMBQ) could be obtained with an excellent conversion (>99%) and selectivity over 99% under mild reaction conditions (30 °C, 0.1 MPa). In addition, it can be recycled at least five times without substantial decline in catalytic activities (conversion and selectivity), suggesting its excellent stability and recyclability. This work may provide guidance on designing and building valuable catalysts for environmentally friendly and cost-effective oxidation reactions.

Early intervention with fecal microbiota transplantation (FMT) improves the growth performance and intestinal barrier function of piglets. Accelerating intestinal oxygen concentration is beneficial for symbiotic bacterial colonization. Saccharomyces boulardii (SB) is an aerobic fungus, which may contribute to the colonization of anaerobic symbiotic bacteria by competing for oxygen. Clostridium butyricum (CB) improves intestinal barrier function and performance, via regulating the gut microbiota composition of piglets. The objective of this study was to investigate the effect of early intervention with FMT combining CB and SB on growth performance, diarrhea, and intestinal barrier function in piglets. A total of 77 litters of neonatal piglets assigned to one of six treatments, which treated with antibiotics (AB), placebo (CON), and FMT (FMT), FMT-added CB (FMT+C), FMT-added SB (FMT+S), and FMT-added CB and SB (FMT+C+S), respectively. FMT+C+S treated piglets had higher body weight (BW) and average daily gain (ADG) both in weaning and finial period, and it significantly increased the levels of fecal mucin-2 (MUC2), fecal short-chain fatty acids (SCFAs), and relative abundance of fecal Lactobacillus spp., and Bifidobacterium genus. Moreover, early intervention with FMT+C+S reduced the diarrhea rate during the experiment. FMT+C+S also decreased the level of plasma diamine oxidase (DAO) and D-lactate (D-LA), and relative abundance of fecal E. coli during the suckling period. In summary, early intervention with FMT combining CB and SB improved the growth performance, intestinal barrier function, fecal SCFAs concentration, and fecal Lactobacillus and Bifidobacterium of piglets.

Aberrant activation of signaling pathways is frequently observed and reported to be associated with the progression and poor prognosis of prostate cancer (PCa). We aimed to identify key biological processes regulated by androgen receptor (AR) using gene co-expression network from single cell resolution. The bimodal index was used to evaluate whether two subpopulations exist among the single cells. Gene expression among single cells revealed averaging pitfalls and bimodality pattern. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of highly correlated genes. Twenty-nine gene modules were identified and AR-regulated modules were screened by significantly overlapping reported androgen induced differentially expressed genes. The biological function “generation of precursor metabolites and energy” was significantly enriched by AR-regulated modules with bimodality, presenting differential androgen response among subpopulations. Integrating with public ChIP-seq data, two genes FECH, and CROT has AR binding sites. Public in vitro studies also show that androgen regulates FECH and CROT. After receiving androgen deprivation therapy, patients lowly express FECH and CROT. Further survival analysis indicates that FECH/CROT signature can predict PCa recurrence. We reveal the heterogeneous function of “generation of precursor metabolites and energy” upon androgen stimulation from the perspective of single cells. Inhibitors targeting this biological process will facilitate to prevent prostate cancer progression.

We previously identified three glycosylphosphatidylinositol (GPI)-anchored proteins including Ecm33, as multicopy suppressors of the phenotypes of a mutant allele of cis4(+) that encodes a zinc transporter in fission yeast. Here, we further identified two multicopy suppressor genes, ubi1 (+) and ubc4 (+), encoding ubiquitin-ribosomal fusion protein and ubiquitin conjugating enzyme E2, respectively. In addition, Ubi1 or Ubc4 overexpression failed to suppress the phenotypes of the double deletion of cis4 (+) and pub1 (+) gene, which encodes a HECT-type ubiquitin ligase E3. During exponential phase GFP-Ecm33 localized at the growing cell tips of the cell surface and the medial region in wild-type cells. Notably, during the post-exponential and stationary phase, GFP-Ecm33 in wild-type cells was internalized and mostly localized to the Golgi/endosomes, but it was still stably localized at the cell surface in Δpub1 cells. The Δpub1 cells showed osomoremedial phenotypes to various drugs indicating their defects in cell wall integrity. Altogether, our findings reveal a novel role for Pub1 in endocytosis of Ecm33 and regulation of cell wall integrity in fission yeast.

A combination of hyperthermia with radiotherapy and chemotherapy for various solid tumors has been practiced clinically. However, hyperthermic therapy has side effects, such as thrombocytopenia. Up to now, the pathogenesis of hyperthermia-induced thrombocytopenia remains unclear. Previous studies have shown that hyperthermia induces platelet apoptosis. However, the signaling pathways and molecular mechanisms involved in hyperthermia-induced platelet apoptosis have not been determined. Here we show that hyperthermia induced intracellular reactive oxygen species (ROS) production and mitochondrial ROS generation in a time-dependent manner in platelets. The mitochondria-targeted ROS scavenger Mito-TEMPO blocked intracellular ROS and mitochondrial ROS generation. By contrast, inhibitors of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nitric oxide synthase, cyclooxygenase and lipoxygenase did not. Furthermore, Mito-TEMPO inhibited hyperthermia-induced malonyldialdehyde production and cardiolipin peroxidation. We also showed that hyperthermia-triggered platelet apoptosis was inhibited by Mito-TEMPO. Furthermore, Mito-TEMPO ameliorated hyperthermia-impaired platelet aggregation and adhesion function. Lastly, hyperthermia decreased platelet manganese superoxide dismutase (MnSOD) protein levels and enzyme activity. These data indicate that mitochondrial ROS play a pivotal role in hyperthermia-induced platelet apoptosis, and decreased of MnSOD activity might, at least partially account for the enhanced ROS levels in hyperthermia-treated platelets. Therefore, determining the role of mitochondrial ROS as contributory factors in platelet apoptosis, is critical in providing a rational design of novel drugs aimed at targeting mitochondrial ROS. Such therapeutic approaches would have potential clinical utility in platelet-associated disorders involving oxidative damage.