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Purpose: Osteoporosis and sarcopenia usually coexist in older population. The concept of osteosarcopenia has been proposed in recent years. However, studies on the relationship between osteosarcopenia and the risk of fracture are rare, and the association is unclear at present. This study aimed to investigate the association between osteosarcopenia evaluated based on chest computed tomography (CT) and osteoporotic vertebral fracture (OVF). Methods: This study recruited 7906 individuals aged 50 years and older who did not have OVFs and underwent chest CT for physical examination between July 2016 and September 2019. Subjects were followed up annually until June 2023. Osteosarcopenia was defined by a low muscle area of the erector spinae (< 25.4 cm2) and the bone attenuation (Hounsfield unit, HU < 135). Genant’s grades were used to define OVFs. Control subjects were selected by Propensity Score Matching at a ratio 20:1. Cox proportional hazards models were used to assess the associations between osteosarcopenia and OVFs. Results: Of the 7906 participants included, 95 had a new OVF within a median follow-up of 3 years. A total of 1900 control subjects were matched. Individuals in the osteosarcopenia group had a higher prevalence of spinal fractures than those in normal group (16.4% vs. 0.4%, P < 0.001). Osteosarcopenia was independently associated with OVF (adjusted hazard ratio (aHR): 12.67, 95% confidence interval (CI) 3.79–42.40) and severe OVF (aHR = 14.07, 95% CI 1.84–107.66). Similar trends were observed in males, females and those subjects aged older than 60 years. Osteosarcopenia had good predictive efficacy for OVF (area under the curve = 0.836). A nomogram was also developed for clinical application. Conclusion: Osteosarcopenia assessed based on chest CT was associated with OVF, and osteosarcopenia has good performance for vertebral fracture prediction.

Three EMS mutant wheat lines with varied mobility of Wx-A1 and Wx-B1 were identified. In the mutant lines M2-97-8 and M2-104-2, Wx-B1 showed slightly faster mobility compared to those of wild line, and Wx-A1 in the mutant line M2-101-1 has a greatly faster mobility, which co-migrates with Wx-D1. The results of gene sequencing indicated that SNP mutations appeared within exon of Wx-1and further resulted in the mutation of amino acid residues in the mutant lines. The prediction analysis showed that the isoelectric point of the mutants M2-97-8 and M2-104-2 was more basic than that of the wild type while the isoelectric point of M2-101-1 was not changed; and the Waxy protein of the three mutations were all around 66 kDa. The SDS-PAGE results revealed that the mobility variation of Wx-B1 of M2-97-8 and M2-104-2 is due to the change of isoelectric point, while M2-101-1 may be caused by variation or modification of protein structure but not by the change of isoelectric point. The prokaryotic expression results further indicated that these mutated Wx-A1 and Wx-B1 genes migrated faster than those of wild Wx-A1 and Wx-B1 and were consistent with the results of molecular weight prediction. Although, the increased or decreased contents of total starch and amylose were observed in Wx-A1 or Wx-B1mutant, the correlation between the contents of total starch and amylose and the mutant Wx-A1 and Wx-B1 subunits cannot be determined. These mutants can not only increase the polymorphism of Waxy gene to investigate the function of these alleles, but also be valuable for wheat quality breeding.

1.5-mm thick Al–Mg-Li alloy plates were successfully lap welded using refill friction stir spot welding (RFSSW), and the microstructure and mechanical properties of the joints were investigated. The results show that dynamic recrystallization (DRX) has occurred in the stir zone (SZ) of the joint, forming fine equiaxed grains with an average size of 10 μm. There is a strong texture in the base material, while no obvious texture in the SZ. The void defect at the horizontal surface and the lack of mixing defect at the vertical interface are the most important factor influencing the lap shear strength and the cross tension strength, respectively. The maximum lap shear strength is 6.2 kN, and the maximum cross tension strength is 2.7 kN. In addition, there are three fracture modes that can be observed after the tensile-shear tests, i.e., parent sheet fracture, plug type fracture, and interface fracture, while only plug type fracture mode presents after the cross tension tests.

Background: Roux‐en‐Y gastric bypass (RYGB) has been widely reported to be safe and feasible, and has a powerful effect on improving metabolism and weight loss in patients with a high body mass index (BMI). A few studies have focused on the comparison of RYGB with medical treatment in type 2 diabetes (T2D) patients with a lower BMI. Objectives: To compare the metabolic effects and safety of RYGB versus medical treatment during a 2 years follow-up in T2D patients with a BMI of 25 to 32.5 kg/m2. Methods: This retrospective and multicenter cohort study participants were extracted from the T2D patients with a lower BMI (25–32.5 kg/m2) from three bariatric centers between 2009 and 2018. Propensity score matching (PSM) was used to minimize bias, and each patient in the surgical group was matched 1:2 to the patients in the medical group with the closest propensity score. Finally, 71 patients who received RYGB and 142 patients who underwent medical treatment with a 2 years follow-up were enrolled to compare the effects of RYGB and medical treatment. The primary endpoint was achievement of the triple endpoint (the simultaneous achievement of hemoglobin A1c (HbA1c) < 7.0%, fasting low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL (2.6 mmol/L), and systolic blood pressure (SBP) < 130 mmHg at the year-1 visit). Changes in weight, BMI, medication usage, complications, and adverse events were assessed. Results: In total, 213 patients (mean age of 47.4 ± 9.5 years, 70.4% male, mean BMI of 28.6 ± 2.2 kg/m2) were included in this study. At the end of the first year, 17 patients (23.9%) in the surgical group and 10 (7.0%) in the medical group had achieved the composite triple endpoint (OR 4.64; 95% CI 1.82–11.81; p= 0.001). Additionally, 43 patients (60.6%) in the surgical group and 11 patients (19.7%) in the medical group experienced remission of T2D. However, more complications were observed in the surgical group (36 vs. 22, p< 0.01). Conclusions: Among T2D patients with a BMI between 25.0 and 32.5 kg/m2, RYGB was more effective than medical treatment in resolving metabolic disorders and also resulted in more complications. The risk for complications should be considered in the clinical decision-making process for T2D patients with a low BMI.

Purpose: Plenty of studies have examined the long term effect of weight loss on bone mineral density. This study aimed to explore the effects of 10% weight loss on early changes in bone metabolism as well as the possible influencing factors. Methods: Overweight and obese outpatients (BMI > 24.0 kg/m2) were recruited from the nutrition clinic and followed a calorie-restricted, high-protein, low-carbohydrate diet program. Dietary intake, body composition, serum procollagen type I N-propeptide (PINP), β-Crosslaps, PTH, 25(OH) VitD, a series of inflammatory cytokines and adipokines were measured for the participants before starting to lose weight and after 10% weight loss (NCT 04207879). Results: A total of 75 participants were enrolled and 37 participants achieved a weight loss of at least 10%. It was found that PINP decreased (p= 0.000) and the β-Crosslaps increased (p= 0.035) in female participants. Decreases in PTH (p= 0.001), serum IL-2 (p= 0.013), leptin (p= 0.001) and increases in 25(OH) VitD (p= 0.001), serum ghrelin (p= 0.033) were found in 37 participants after 10% of their weight had been lost. Change in PINP was detected to be significantly associated with change in lean body mass (r= 0.418, p= 0.012) and change in serum ghrelin(r= − 0.374, p= 0.023). Conclusions: Bone formation was suppressed and bone absorption was increased in female subjects after a 10% weight loss. Bone turnover was found to be associated with lean body mass and affected by the circulating ghrelin level.

NIVO en adjuvant a significativement prolongé la survie sans récidive (SSR) versus PBO dans le mélanome de stade IIB/C dans l’essai randomisé de phase III Checkmate 76K (HR : 0,42 ; IC95 % [0,30–0,59]). Pour la première fois, une sélection de BMs et leur association avec la SSR ont été analysées dans le mélanome de stade précoce traité avec un agent anti-PD-1.

Abstract: This study presents the reliability of diamond-like carbon (DLC) ultrathin films fabricated by DC magnetron sputtering as the gate dielectric layer in metal–insulator–semiconductor (MIS) devices. Stress-induced leakage current (SILC) and time-dependent dielectric breakdown (TDDB) measurements were performed to determine the reliability of the devices. The MIS device with DLC film deposited at 1100-V bias exhibited little variation of SILC under different constant voltage stress times and had a long TDDB lifetime. The results indicate excellent reliability of DLC films used as gate dielectrics. Moreover, several soft breakdown events occurred during TDDB measuring. An extended percolation model was adopted for explanation of the current versus time characteristics.

Mesenchymal stem cells (MSCs) constitute an important repair system, but may be impaired by exposure to cardiovascular risk factors. Consequently, adipose tissue-derived MSCs from pigs with the metabolic syndrome (MetS) show decreased vitality. A growing number of microRNAs (miRNAs) are recognized as key modulators of senescence, but their role in regulating senescence in MSC in MetS is unclear. We tested the hypothesis that MetS upregulates in MSC expression of miRNAs that can serve as post-transcriptional regulators of senescence-associated (SA) genes. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet (n= 6 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs up-or down-regulated in MetS-MSCs compared with Lean-MSCs. Functional pathways of SA genes targeted by miRNAs were analyzed using gene ontology. MSC senescence was evaluated by p16 and p21 immunoreactivity, H2AX protein expression, and SA-β-Galactosidase activity. In addition, gene expression of p16, p21, MAPK3 (ERK1) and MAPK14, and MSC migration were studied after inhibition of SA-miR-27b. Senescence biomarkers were significantly elevated in MetS-MSCs. We found seven upregulated miRNAs, including miR-27b, and three downregulated miRNAs in MetS-MSCs, which regulate 35 SA genes, particularly MAPK signaling. Inhibition of miR-27b in cultured MSCs downregulated p16 and MARP3 genes, and increased MSC migration. MetS modulates MSC expression of SA-miRNAs that may regulate their senescence, and the p16 pathway seems to play an important role in MetS-induced MSC senescence.

The alterations induced in gut microbiota by tacrolimus may affect immune function and organ transplantation. Mice were treated with high-dose tacrolimus for 14 days. The fecal microbiota were analyzed by pyrosequencing the 16S rRNA genes, and the effect on metabolism was predicted using the sequence data. The subgroups of T cells in the serum, gut-associated lymphoid tissue, and draining lymph nodes were determined by flow cytometry. Tacrolimus treatment significantly altered the relative abundance of Allobaculum, Bacteroides,and Lactobacillusand CD4+CD25hiFoxP3+regulatory T cells in the colonic mucosa and the circulation. These were significantly increased after either tacrolimus treatment or treatment by fecal microbiota transfer from tacrolimus-treated donors. Further, treatment with low-dose tacrolimus plus fecal microbiota transfer from high-dose tacrolimus–altered mice increased skin allograft survival rate in a skin transplantation model. Thus, high-dose tacrolimus alters the compositions and taxa of the gut microbiota. Administration of these conditioned gut microbiota plus low-dose tacrolimus resulted in regulation of colonic and systemic immune responses and an increased allograft survival rate. This study demonstrated a new strategy for controlling allograft rejection by combining an immunosuppressive agent with gut microbiome transplantation.

The alterations induced in gut microbiota by tacrolimus may affect immune function and organ transplantation. Mice were treated with high‐dose tacrolimus for 14 days. The fecal microbiota were analyzed by pyrosequencing the 16S rRNAgenes, and the effect on metabolism was predicted using the sequence data. The subgroups of T cells in the serum, gut‐associated lymphoid tissue, and draining lymph nodes were determined by flow cytometry. Tacrolimus treatment significantly altered the relative abundance of Allobaculum,Bacteroides,and Lactobacillusand CD4+CD25hiFoxP3+regulatory T cells in the colonic mucosa and the circulation. These were significantly increased after either tacrolimus treatment or treatment by fecal microbiota transfer from tacrolimus‐treated donors. Further, treatment with low‐dose tacrolimus plus fecal microbiota transfer from high‐dose tacrolimus–altered mice increased skin allograft survival rate in a skin transplantation model. Thus, high‐dose tacrolimus alters the compositions and taxa of the gut microbiota. Administration of these conditioned gut microbiota plus low‐dose tacrolimus resulted in regulation of colonic and systemic immune responses and an increased allograft survival rate. This study demonstrated a new strategy for controlling allograft rejection by combining an immunosuppressive agent with gut microbiome transplantation. In a mouse model, gut microbiome transplantation plus low‐dose tacrolimus results in the suppression of colonic and systemic immune responses and an increased allograft survival rate.

ABSTRACTNovel high-entropy and medium-entropy stainless steels (MESS), containing a high amount of alloying elements, were designed and prepared by arc melting. These high-entropy and MESS possess a simple phase constitution, mainly solid solution phases, and noticeably exhibit excellent anti-corrosion properties in sulphuric acid. In particular, an austenitic Fe65Cr13Co4.75Mn4.75Mo4.75Ni4.75Cu3(at.-%) alloy has a higher hardness of 182 HV and better corrosion resistance than those of the 00Cr19Ni14Mn2 austenitic stainless steel prepared under the same condition; a ferritic precipitation hardening Fe65Cr13Al3.167Co3.167Mn3.167Mo3.167Ni3.167Ti3.167Cu3(at.-%) alloy was also developed, with a higher hardness of 584 HV and even better corrosion resistance.

Novel high-entropy and medium-entropy stainless steels (MESS), containing a high amount of alloying elements, were designed and prepared by arc melting. These high-entropy and MESS possess a simple phase constitution, mainly solid solution phases, and noticeably exhibit excellent anti-corrosion properties in sulphuric acid. In particular, an austenitic Fe65Cr13Co4.75Mn4.75Mo4.75Ni4.75Cu3(at.-%) alloy has a higher hardness of 182 HV and better corrosion resistance than those of the 00Cr19Ni14Mn2 austenitic stainless steel prepared under the same condition; a ferritic precipitation hardening Fe65Cr13Al3.167Co3.167Mn3.167Mo3.167Ni3.167Ti3.167Cu3(at.-%) alloy was also developed, with a higher hardness of 584 HV and even better corrosion resistance.

Implant surfaces play important roles in regulating protein adsorption and determining subsequent cell responses, including cell attachment, proliferation, migration and differentiation. With rapid developments in micro- and nano-fabrication methods and additive manufacturing (3D printing) technologies, precisely controlled patterns such as partially ordered or ordered patterns can now be generated on bone implant surfaces, rather than restricted to randomly roughened surfaces. Over the last two decades, much effort has been dedicated to manipulating cell responses through surface topographical modifications. This review discusses the recent developments and understanding of surface topography in prompting or enhancing desired cell responses, particularly the roles of ordered and partially ordered surface topography under in vitroconditions. In addition, the challenges to translate research findings into implant applications are addressed.

The joining of the North and South China blocks marks the formation of the united East Asian continent, which is an integral part of Pangea. The amalgamation of these two continental blocks also resulted in the formation of the world‐class ultrahigh pressure orogenic belt, namely the Dabie–Sulu orogenic belt. Figuring out the time of the initial collision between the two continents is critical for resolving questions such as the duration and the geodynamic processes of the orogeny. A Triassic joining time has been suggested by the geochronology of the eclogite facies rocks in this orogenic belt. However, paleomagnetic and paleontological studies suggested a Permian docking time for these continental blocks. In this paper, we present new metamorphic ages of rocks from northern Dabie and the Permo–Triassic intracontinental orogen of South China, which are all closely associated with this continental collisional event. New age dating results, as well as a synthesis of recent studies on metamorphic rocks occurring in southeastern North China and the Cathaysia Block of South China, show that the onset of the collisional orogenesis along the eastern part of the orogenic belt dates back to the Middle Permian (270–252 Ma). Considering these data and other geological records, we provide a new tectonic model for the major continents of East Asia, in which we show that the initial collision between North and South China occurred in the east during the Middle Permian, and then propagated westward. Continental collisions forming mountains and closing seaways in East Asia thus apparently occurred before the end‐Permian mass extinction, suggesting these paleogeographic changes might have also preconditioned and facilitated the end‐Permian biospheric crisis in the region. Orogenic belts are the loci of convergent plate interactions and they provide a window for observing Earth's deep crustal geodynamic processes. Metamorphic rocks in orogenic belts occur with varying metamorphic grades, whose temperatures, pressures, and ages are critical factors for understanding the history of plate interactions. Previous geochronological studies on eclogite facies rocks in the Dabie–Sulu orogenic belt, which is the result of the continental collision between North and South China blocks, have yielded mainly Triassic metamorphic ages. On the other hand, the paleomagnetic and paleontological data support an earlier collisional age during the Permian. This study targeted metamorphic rocks from the southern margin of North China, the northern Dabie orogen, and South China, all of which escaped deep subduction. They all show Permian metamorphic ages (270–252 Ma), which collectively indicate the Permian continental collision between North and South China. This new constraint on the initial continental collision between the two continental blocks is consistent not only with the paleomagnetic and paleontological data but also with the proposal of a diachronous collisional model for the Central China Orogenic belt with a westward younging trend. The continental collision between North and South China resulted in the formation of the East Asian continent within PangeaNew geochronological results constraining the orogenesis reveal the onset of collision during the PermianThe Permian collision might have also preconditioned and facilitated the end‐Permian biospheric crisis in the region The continental collision between North and South China resulted in the formation of the East Asian continent within Pangea New geochronological results constraining the orogenesis reveal the onset of collision during the Permian The Permian collision might have also preconditioned and facilitated the end‐Permian biospheric crisis in the region

In order to minimise transverse wall thickness variation of seamless steel tube produced by stretch reduction, an explicit coupled thermomechanical FE model was established to simulate the stretch reduction process and corresponding experiments were carried out to validate the accuracy of the model. In addition, the plastic flow behaviour of metal in both radial and circumferential directions during forming process was analysed, and the influence of temperature on plastic flow behavior is investigated. Analysis results show that: first, the circumferential flow direction of metal is from roll groove root to roll gap in single pass rolling. Circumferential flowability of metal near the ±30° position of the roll groove shape angle is the most active, and the circumferential flowability of metal near groove root and gap is much weaker. Second, in the entire stretch reduction process, metal flows from positions of roll groove root and gap to the ±30° position of roll groove angle along the circumference. Third, temperature has huge influence on transverse flow behaviour. Metal temperature near the ±30° position of roll groove shape is higher than the temperature of roll groove root and gap. This lowers the deformation resistance of the material so the flowability from roll groove root and gap positions towards the±30° position is strengthened, leading to the transverse wall thickness variation.

Background: This review looks into the herbs Gingko biloba, Polygala tenuifolia, and Lycii fructus for their widely studied neuroprotective properties. In particular, we investigated memory enhancing effect of these herbs, and their potential synergetic effect on memory with new data. Sixmonth treated mice demonstrated shorter escape latency in water maze and shorter arrival time in a consolidated memory task. Immunochemistry showed evident increase in superoxide dismutase activities in the prefrontal cortex, implying protection against free radicals during aging. Discrete increase of catecholaminergic neurons was found in the prefrontal cortex, hippocampus, corpus striatum, and midbrain, suggesting better memory and better control on mood and behavior. Necrotic cells in the brain decreased as indicated by immunocytochemistry of lactic dehydrogenase. Terminal deoxynucleotidyl transferase dUTP nick end labeling showed no apoptotic cells in most brain areas in high dose group. Biochemistry revealed increase of dopaminergic cells in treatment groups at prefrontal cortex, and in the hippocampus and cerebellum of the high dose group. Most 6-month groups showed increase of serotonin in all three areas. For the high dose group, GABA increased in the hippocampus but not prefrontal cortex, which would help induce sleep at night. Protein kinase C increased in most groups at prefrontal cortex, hippocampus and cerebellum, signifying increase of possible signal transduction pathways for memory or other nervous activations. Conclusion: Our results intimate that the interaction of the three herbs exerts beneficial effects on memory, associated cognitive function, and necrosis. Future investigations based on the present data shall aid development of clinically relevant medication.

GATA3, a critical transcription factor involved in the development of the mammary gland, also plays important roles in mammary tumorigenesis by regulating transcription in coordination with two essential DNA repair factors, PARP1 and BRCA1. However, whether and how GATA3 participates in the process of DNA repair, which is often associated with tumorigenesis, has not been investigated. Here we demonstrate that GATA3 is required for the repair of DNA double-strand breaks (DSBs) by homologous recominbation (HR). Mechanistic studies indicate that at both the protein and the mRNA level, depleting GATA3 leads to reduced expression of CtIP, an essential HR factor involved in end resection, thereby suppressing the repair of DSBs by HR and sensitizing cells to etoposide induced DNA DSBs. Further studies indicate that upon the occurrence of DNA DSBs GATA3 directly binds to the CtIP promoter at the region of −2119 to −2130 and −2274 to −2285, and promotes the transcription of CtIP. Overexpression of CtIP in GATA3 depleted cells rescues the decline of HR, and cell survival in the presence of etoposide. In addition, through data mining analysis, we observed an extremely strong correlation between the expression levels of GATA3 and CtIP in paratumors, but the correlation turned insignificant in mammary tumors. Using vectors encoding GATA3 with mutations frequently occurring in mammary tumors, we found that several mutations on GATA3 led to a dysregulation of CtIP, and therefore HR repair. In summary, our data delineates the regulatory mechanisms of GATA3 in DNA DSB repair and strongly suggests that it might act as a tumor suppressor by promoting CtIP expression and HR to stabilize genomes.

Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A+TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1+) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10highmacrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10highM2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1+myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1+myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1+myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.

Background: Primary erythromelalgia (PE) is a dominant inherited disorder characterized by recurrent pain, redness, and warmth of the extremities that is caused by gain-of-function mutations in Nav1.7 encoding gene SCN9A. Most of the PE-causing mutations of Nav1.7 have been shown to be able to render Nav1.7-expressing cells hyperexcitable, however in most PE cases the symptoms are refractory to treatment with sodium channel blockers and the mechanism underlying the intractability has not been clearly clarified. Objective: To identify the mutation of SCN9A in a Chinese Han family with typical symptoms of PE and study the electrophysiological effect of the identified mutation. Methods: A Chinese Han family with typical symptoms of PE was collected and the proband's response to treatment was recorded. All the exons and flanking intronic sequences of SCN9A were amplified with PCR and sequenced. Several online programs were used to predict the damaging effect of variants. The functional effect of variants was studied by voltage-clamp analysis in CHO-K1 cells. Results: The PE symptoms of the proband are refractory to all kinds of reported medications. Sequence analysis of SCN9A showed that a novel c.2477T>A (p. F826Y) mutation co-segregated with the disease phenotype. Several online programs predicted that the F826Y mutation has a deleterious effect on the gene product. Voltage-clamp analysis showed that while compared with the wild-type channel, activation of the F826Y mutant channel was shifted by 7.7 mV in a hyperpolarizing direction, whereas steadystate inactivation was shifted by 4.3 mV in a depolarizing direction. Conclusion: A novel disease-causing SCN9A Mutation (F826Y) was identified in a Chinese family with typical PE symptoms refractory to treatment. F826Y of Nav1.7 could render DRG neurons hyperexcitable, contributing to the pathogenesis of PE.

A plant trial of the production of 60Si2Mn–Cr spring steel using silicon–manganese combined with aluminium to deoxidise was performed, and the characteristics of inclusions during ladle furnace refining, calcium treatment and in billets were investigated by scanning electron microscope–energy dispersive spectroscopy and thermodynamic calculations. The formation mechanisms of oxide and CaS inclusions are discussed. The experimental observation and thermodynamic analysis showed that calcium treatment cannot entirely modify large-size MgO·Al2O3spinel inclusions into homogeneous CaO–MgO–Al2O3inclusions, but formed a liquid xCaO·yAl2O3layer on its surface. When the Al content was 0.05 mass%, [Mg], [Ca] and [O] in molten steel could be controlled at 2.7∼5 ppm, 2.5∼8 ppm and 4.1∼5.2 ppm, respectively, to achieve inclusions in the low melting point region. A large amount of CaS was generated in the present process due to a higher sulphur concentration in the molten steel and an excessive amount of Ca–Si wire. To avoid/reduce its formation, the sulphur concentration should be controlled to below 70 ppm.

Hyperactivation of transforming growth factor-β (TGF-β) signaling pathway is a common feature of hepatocellular carcinoma (HCC) progression. However, the driver factors leading to enhanced TGF-β activity are not well characterized. Here, we explore the mechanisms that loss of Krüppel-like factor 4 (KLF4) exacerbates oncogenic TGF-β signaling in human HCC. The expression of KLF4 and TGF-β signaling components in primary HCC and their clinicopathologic relevance and significance was evaluated by using tissue microarray and immunohistochemistry. Cellular and molecular impacts of altered KLF4 expression and TGF-β signaling were determined using immunofluorescence, western blot, reverse-transcriptase PCR, chromatin immunoprecipitation and promoter reporter assays. Loss of KLF4 expression in primary HCC closely correlated with decreased Smad7 expression, increased p-Smad2/3 expression and independently predicts reduced overall and relapse-free survival after surgery. TGF-β signaling components were expressed in most HCC cells, and activation of TGF-β signaling promoted cell migration and invasion. Enforced KLF4 expression blocked TGF-β signal transduction and inhibited cell migration and invasion via activation of Smad7 transcription, whereas deletion of its C-terminal zinc-finger domain diminished this effect. KLF4 protein physically interacts with the Smad7 promoter. Promoter deletion and point mutation analyses revealed that a region between nucleotides –15 bp and –9 bp of the Smad7 promoter was required for the induction of Smad7 promoter activity by KLF4. Our data indicate that KLF4 suppresses oncogenic TGF-β signaling by activation of Smad7 transcription, and that loss of KLF4 expression in primary HCC may contribute to activation of oncogenic TGF-β signaling and subsequent tumor progression.

A plant trial of the production of 60Si2Mn–Cr spring steel using silicon–manganese combined with aluminium to deoxidise was performed, and the characteristics of inclusions during ladle furnace refining, calcium treatment and in billets were investigated by scanning electron microscope–energy dispersive spectroscopy and thermodynamic calculations. The formation mechanisms of oxide and CaS inclusions are discussed. The experimental observation and thermodynamic analysis showed that calcium treatment cannot entirely modify large-size MgO·Al2O3spinel inclusions into homogeneous CaO–MgO–Al2O3inclusions, but formed a liquid xCaO·yAl2O3layer on its surface. When the Al content was 0.05 mass%, [Mg], [Ca] and [O] in molten steel could be controlled at 2.7~5 ppm, 2.5~8 ppm and 4.1~5.2 ppm, respectively, to achieve inclusions in the low melting point region. A large amount of CaS was generated in the present process due to a higher sulphur concentration in the molten steel and an excessive amount of Ca–Si wire. To avoid/reduce its formation, the sulphur concentration should be controlled to below 70 ppm.

PurposeTo quantitatively determine the size and contractility of the superior oblique (SO) muscle in primary SO overaction (PSOOA).Patients and methodsA prospective, observational study was conducted on 12 patients with PSOOA, and 10 healthy, orthotropic subjects. Sets of contiguous, 2 mm slice thickness, quasi-coronal magnetic resonance imaging were obtained during different gazes, giving pixel resolution of 0.391 mm. Cross-sectional areas of the SO muscles were determined in primary position, supraduction, and infraduction to evaluate size and contractility. The cross-sectional areas of SO muscle were compared with those of controls in the primary position to detect hypertrophy or atrophy and changes in contractility could be detected during the vertical gaze. All statistical calculations were performed using PROC MIXED (SAS 9.4).ResultsThere was no difference between the ipsilesional (affected eye), contralesional (unaffected eye), and normal SO muscle cross-sections: 0.176±0.018 cm2, 0.175±0.005 cm2, and 0.173±0.015 cm2, respectively (P=0.82). The maximum contractility of SO muscle on the ipsilesional (affected) side was 0.097±0.024 cm2, and was different than on the contralesional (unaffected) side: 0.067±0.015 cm2and in control subjects: 0.063±0.018 cm2(P=0.0002).ConclusionsIn PSOOA, the ipsilesional SO is more contractile than the contralesional SO muscle and different than in controls, with no difference in SO muscle size in primary position, which suggests that excessive innervation rather than muscle hypertrophy underlies PSOOA.

The biological function of MAGEC2, a cancer/testis antigen highly expressed in various cancers, remains largely unknown. Here we demonstrate that expression of MAGEC2 induces rounded morphology and amoeboid-like movement of tumor cells in vitroand promotes tumor metastasis in vivo. The pro-metastasis effect of MAGEC2 was mediated by signal transducer and activator of transcription 3 (STAT3) activation. Mechanistically, MAGEC2 interacts with STAT3 and inhibits the polyubiquitination and proteasomal degradation of STAT3 in the nucleus of tumor cells, resulting in accumulation of phosphorylated STAT3 and enhanced transcriptional activity. Notably, expression levels of MAGEC2 and phosphorylated STAT3 are positively correlated and both are associated with incidence of metastasis in human hepatocellular carcinoma. This study not only reveals a previously unappreciated role of MAGEC2 in promoting tumor metastasis, but also identifies a new molecular mechanism by which MAGEC2 sustains hyperactivation of STAT3 in the nucleus of tumor cells. Thus, MAGEC2 may represent a new antitumor metastasis target for treatment of cancer.

Blindness afflicts ~39 million people worldwide. Retinal ganglion cells are unable to regenerate, making this condition irreversible in many cases. Whole-eye transplantation (WET) provides the opportunity to replace diseased retinal ganglion cells, as well as the entire optical system and surrounding facial tissue, if necessary. Recent success in face transplantation demonstrates that this may be a promising treatment for what has been to this time an incurable condition. An animal model for WET must be established to further enhance our knowledge of nerve regeneration, immunosuppression, and technical aspects of surgery. A systematic review of the literature was performed to evaluate studies describing animal models for WET. Only articles in which the eye was completely enucleated and reimplanted were included. Study methods and results were compared. In the majority of published literature, WET can result in recovery of vision in cold-blooded vertebrates. There are a few instances in which mammalian WET models demonstrate survival of the transplanted tissue following neurovascular anastomosis and the ability to maintain brief electroretinogram activity in the new host. In this study we review in cold-blooded vertebrates and mammalian animal models for WET and discuss prospects for future research for translation to human eye transplantation.