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Diamond Si is a semiconductor with an indirect band gap that is the basis of modern semiconductor technology. Although many metastable forms of Si were observed using diamond anvil cells for compression and chemical precursors for synthesis, no metallic phase at ambient conditions has been reported thus far. Here we report the prediction of pure metallic Si allotropes with open channels at ambient pressure, unlike a cubic diamond structure in covalent bonding networks. The metallic phase termed P6/m-Si6 can be obtained by removing Na after pressure release from a novel Na-Si clathrate called P6/m-NaSi6, which is predicted through first-principles study at high pressure. We identify that both P6/m-NaSi6 and P6/m-Si6 are stable and superconducting with the critical temperatures of about 13 and 12 K at ambient pressure, respectively. The prediction of new Na-Si and Si clathrate structures presents the possibility of exploring new exotic allotropes useful for Si-based devices. [ABSTRACT FROM AUTHOR]

The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors ( Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori -positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula , Streptococcus oralis , and Prevotella intermedia , was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori -negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori -positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori -negative GCs., Importance: Our study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori -negative GCs., Competing Interests: The authors declare no conflict of interest.

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4 + T helper type 1 and effector CD8 + T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV.IMPORTANCECytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT03382405)., Competing Interests: All authors are employees of Moderna, Inc., and may hold stock/stock options in the company.

After Epstein-Barr virus (EBV) genome replication and encapsidation in the nucleus, nucleocapsids are translocated into the cytoplasm for subsequent tegumentation and maturation. The EBV BGLF4 kinase, which induces partial disassembly of the nuclear lamina, and the nuclear egress complex BFRF1/BFLF2 coordinately facilitate the nuclear egress of nucleocapsids. Here, we demonstrate that within EBV reactivated epithelial cells, viral capsids, tegument proteins, and glycoproteins are clustered in the juxtanuclear concave region, accompanied by redistributed cytoplasmic organelles and the cytoskeleton regulator IQ-domain GTPase-activation protein 1 (IQGAP1), close to the microtubule-organizing center (MTOC). The assembly compartment (AC) structure was diminished in BGLF4-knockdown TW01-EBV cells and BGLF4-knockout bacmid-carrying TW01 cells, suggesting that the formation of AC structure is BGLF4-dependent. Notably, glycoprotein gp350/220 was observed by confocal imaging to be distributed in the perinuclear concave region and surrounded by the endoplasmic reticulum (ER) membrane marker calnexin, indicating that the AC may be located within a globular structure derived from ER membranes, adjacent to the outer nuclear membrane. Moreover, the viral capsid protein BcLF1 and tegument protein BBLF1 were co-localized with IQGAP1 near the cytoplasmic membrane in the late stage of replication. Knockdown of IQGAP1 did not affect the AC formation but decreased virion release from both TW01-EBV and Akata + cells, suggesting IQGAP1-mediated trafficking regulates EBV virion release. The data presented here show that BGLF4 is required for cytoskeletal rearrangement, coordination with the redistribution of cytoplasmic organelles and IQGAP1 for virus maturation, and subsequent IQGAP1-dependent virion release.IMPORTANCEEBV genome is replicated and encapsidated in the nucleus, and the resultant nucleocapsids are translocated to the cytoplasm for subsequent virion maturation. We show that a cytoplasmic AC, containing viral proteins, markers of the endoplasmic reticulum, Golgi, and endosomes, is formed in the juxtanuclear region of epithelial and B cells during EBV reactivation. The viral BGLF4 kinase contributes to the formation of the AC. The cellular protein IQGAP1 is also recruited to the AC and partially co-localizes with the virus capsid protein BcLF1 and tegument protein BBLF1 in EBV-reactivated cells, dependent on the BGLF4-induced cytoskeletal rearrangement. In addition, virion release was attenuated in IQGAP1-knockdown epithelial and B cells after reactivation, suggesting that IQGAP1-mediated trafficking may regulate the efficiency of virus maturation and release., Competing Interests: The authors declare no conflict of interest.

Objective: To explore the relationship between expression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and improvement of macular structure in patients with wet age-related macular degeneration (wAMD) after anti-vascular endothelial growth factor (VEGF) therapy. Methods: A before-after study was carried out. A total of 110 patients (110 eyes) with wAMD who were admitted to Department of Ophthalmology, People's Hospital Affiliated to Shandong First Medical University between August 2019 and December 2021 were enrolled, and all patients were given vitreous injection of anti-VEGF drug (ranibizumab or bevacizumab). The aqueous humor was collected to detect mRNA levels of NLRP3, cysteinyl aspartate specific protease-1 (Caspase-1), apoptosis-associated speck-like protein (ASC) and interleukin (IL) 1β by fluorescence quantitative PCR. The levels of IL-1β, IL-18, tumor necrosis factor α (TNF-α) and VEGF in aqueous humor were detected by enzyme-linked immunosorbent assay (ELISA). The correlation between the above indexes and central macular thickness (CMT) in wAMD patients was analyzed by multivariate linear regression analysis. Results: In the 110 wAMD patients, there were 68 males and 42 females, with a mean age of (68.7±7.6) years. Compared with those before treatment, mRNA levels of NLRP3 (1.65±0.27, 1.34±0.19 vs 1.97±0.23, both P <0.017), Caspase-1 (1.47±0.15, 1.29±0.17 vs 1.53±0.18, both P <0.017), ASC (1.33±0.14, 1.21±0.18 vs 1.47±0.12, both P <0.017) and IL-1β (1.78±0.21, 1.46±0.17 vs 2.21±0.24, both P <0.017), and levels of IL-1β [(26.9±5.7), (20.3±4.6) vs (33.6±8.3) ng/L, both P <0.017], IL-18 [(32.7±7.6), (23.3±6.9) vs (46.4±9.4) ng/L, both P <0.017], TNF-α [(39.4±6.6), (21.7±6.3) vs (52.9±9.1) ng/L, both P <0.017] and VEGF [(35.7±10.2), (23.4±6.7) vs (65.4±19.3) ng/L, both P <0.017] were decreased after the first and second injection. Moreover, the above-mentioned indexes after second injection were lower than those after the first injection (all P <0.017). The results of multivariate linear regression analysis showed that NLRP3 mRNA (the first injection: β=53.750, P <0.001; the second injection: β=94.648, P <0.001), IL-1β (the first injection: β=1.356, P =0.021; the second injection: β=2.008, P =0.003), IL-18 (the first injection: β=1.984, P <0.001; the second injection: β=1.251, P =0.003) and VEGF (the first injection: β=1.875, P <0.001; the second injection: β=2.119, P <0.001) had linear relationships with CMT. Conclusion: The decrease of NLRP3 inflammasome and its products in aqueous humor may be related to the improvement of macular structure in wAMD patients after anti-VEGF therapy.

Objective: To detect the expression of cartilage oligomeric matrix protein (COMP) in the synovial chondromatosis of the temporomandibular joint (TMJSC), and to discuss the possible interactions between COMP, transforming growth factor (TGF)-β3, TGF-β1 and bone morphogenetic protein-2 (BMP-2) in the development of this neoplastic disease., Methods: Patients in Peking University School and Hospital of Stomatology from January 2011 to February 2020 were selected, who had complete medical records, TMJSC was verified histologically after operation. The expressions of COMP, TGF-β3, TGF-β1 and BMP-2 in the TMJSC of the temporomandibular joint were detected by immunohistochemistry and quantitative real-time PCR (RT-PCR) at the protein level and mRNA level respectively, compared with the normal synovial tissue of temporomandibular joint. The histological morphology, protein expression and distribution of TMJSC tissues were observed microscopically, and the positive staining proteins were counted and scored. SPSS 22.0 statistical software was used to analyze the expression differences between the related proteins in TMJSC tissue and the normal synovial tissue of temporomandibular joint and to compare their differences. P < 0.05 indicated that the difference was statistically significant., Results: Immunohistochemical results showed that the positive expression of COMP in TMJSC tissues was mostly found in synovial tissues and chondrocytes adjacent to synovial tissues, and the difference was statistically significant, compared with the normal temporomandibular joint synovial tissues. The positive expression of COMP was significantly different between recurrent TMJSC and non-recurrent ones. The positive expressions of TGF-β3, TGF-β1 and BMP-2 were higher than the normal synovial tissue, and were also mostly found in the synovial cells and adjacent chondrocytes, which was further confirmed by Western blot. According to the RT-PCR results, the expressions of COMP , TGF-β3 , TGF-β1 and BMP-2 in TMJSC were higher than those in the normal synovial tissue., Conclusion: The expression of COMP in TMJSC of temporomandibular joint increased significantly, compared with the normal synovial tissue. There may be interactions between COMP and cytokines related to the proliferation and differentiation, like TGF-β3, TGF-β1 and BMP-2, which may play a potential role in the pathogenesis of TMJSC.

Objective: To investigate the association between maternal pre-pregnant body mass index and gestational weight gain, as well as their interaction on neonatal birthweight. Methods: We built a cohort in Anqing Municipal Hospital from January 2014 to March 2015, enrolling pregnant women who decided to give birth in this hospital. All women were asked to fill a questionnaire for basic information collection. Medical information of both pregnant women and their newborns were obtained through electronic medical record. Chi-square analysis, multinomial logistic regression, multiplicative and additive interaction methods were used to analyze the association between pre-pregnant body mass index and gestational weight gain as well as their interactions on birth weight of the neonates. Results: A total of 2 881 pregnant women were included in this study. Of the 2 881 newborns, 359 (12.46 % ) were small for gestational age (SGA) and 273 (9.48 % ) were large for gestational age (LGA). After adjusting the possible confounding factors, results from the multinomial logistic regression showed that pre-pregnancy underweight women were more possible to deliver SGA (a RR =1.33, 95 %CI : 1.02-1.73). If the gestational weight gain was below the recommended criteria, the risk of SGA (a RR =1.64, 95 %CI : 1.23-2.19) might increase. Pre-pregnancy overweight/obese could increase the risk of being LGA (a RR =1.86, 95 %CI : 1.33-2.60). Maternal gestational weight gain above the recommendation level was associated with higher rates of LGA (a RR =2.03, 95 %CI : 1.49-2.78). Results from the interaction analysis showed that there appeared no significant interaction between pre-pregnancy BMI and gestational weight on birthweight. Conclusion: Pre-pregnancy body mass index and gestational weight gain were independently associated with neonatal birthweight while pre-pregnancy BMI and gestational weight gain did not present interaction on birthweight.

Objective: To evaluate and compare the detection consistency of hepatitis B surface antigen (HBsAg) by two immunoassays: enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescent immunoassay (ECLIA). Methods: A prospective study was conducted among 2 296 pregnant women recruited consecutively from January 1, 2014 to January 31, 2015 in a hospital. Blood samples were collected from them for the detection of HBsAg by using ELISA and ECLIA, Kappa test was performed on the results. Nested polymerase chain reaction and sequencing of HBV S gene were also performed in all samples. Phylogenetic analysis was performed using Mega 6.0 software. Results: The two methods had high detection consistence of HBsAg ( Kappa =0.71). There were significant differences in detection result of B genotype and adw2 serotype HBV strains between two methods. Among 123 identified HBV strains, 113 belonged to genotype B and available for further analysis. The difference in detection of substitution rates between two methods or different positive groups were not significant. Compared with ELISA single positive group, the ECLIA single positive group had completely different substitution sites. Conclusion: The two methods had high detection consistence of HBsAg, but there were still 32.4% HBV DNA positive cases in ELISA/ECLIA single positive group, and complete complementary substitution sites between ELISA single positive group and ECLIA single positive group. Our results suggested that more effective detection procedure should be considered for the possible impact of the HBV silent transmission and infection.

Objective: Intrahepatic cholestasis during pregnancy (ICP) and its relation to incidence of preterm birth (PTB) were under study. Methods: A prospective cohort study was carried out that including all the hospitalized pregnant women with live singleton births, from January 2014 to March 2015 in Anqing Municipal Hospitals. Informed consent was followed in every pregnant woman with related demographic information collected through questionnaire and hospital electronic medical record system. Both univariate and multi-variate statistical methods were used to analyze the relations between ICP and incidence of PTB. Results: A total of 2 758 pregnant women were included in this study. The incidence proportions of ICP and PTB appeared as 7.25 % and 16.28 % respectively. Results from the logistic regression analysis showed that ICP increased the risk of both overall PTB ( RR =2.33, 95 %CI : 1.67-3.25) and medically indicated PTB ( RR =8.46, 95 %CI : 5.45-13.12), but not the spontaneous PTB ( RR =0.94, 95 %CI : 0.57-1.54). Conclusion: ICP seemed to have increased the risk on medically indicated PTB but not the spontaneous PTB.

Talipes equinovarus is a common congenital deformity. COL9A1 polymorphisms are associated with the development of articular cartilage-related diseases. In the current study, we evaluated the relationship between COL9A1 rs1135056, rs35470562, and rs592121 genetic polymorphisms and risk of congenital talipes equinovarus. Between January 2013 and July 2015, 87 children with congenital talipes equinovarus and 174 control subjects were recruited from the Fourth People's Hospital of Shaanxi and the First Hospital of Yulin. Genotyping of COL9A1 rs1135056, rs35470562, and rs592121 was performed using polymerase chain reaction-restriction fragment length polymorphism. Using conditional regression analysis, the AA genotype of COL9A1 rs35470562 was found to be significantly associated with increased risk of congenital talipes equinovarus compared to the GG genotype [odds ratio (OR) = 2.60, 95% confidence interval (CI) = 1.06-6.32]. In addition, under a recessive model, rs35470562 AA carriers were observed to be at higher risk for this condition in comparison to individuals with GG or GA genotypes (OR = 2.23, 95%CI = 1.03-5.04). However, no significant relationship was established between the COL9A1 rs1135056 and rs592121 polymorphisms and congenital talipes equinovarus in any of the genetic models tested. In conclusion, our results indicate that the COL9A1 rs35470562 variant may contribute to congenital talipes equinovarus susceptibility in the Chinese population examined.

Background: Drugs are the major therapeutic intervention provided by most doctors throughout their careers. The General Medical Council expects all medical students to be competent to prescribe at the point of graduation., Aims: The aim of this study was to assess the views of Foundation Year 1 (FY1) doctors who had recently graduated from the University of Edinburgh about their training and competence in relation to the use of drugs based on their early clinical experience., Method: A questionnaire was constructed based on Tomorrow's Doctors 2002 and distributed to FY1 doctors who graduated in August 2005., Results: Responses were received from 100 (39.8%) of the doctors who graduated in 2005. Only 32% respondents considered themselves 'competent to prescribe' at the point of graduation. Less than 50% of respondents felt comfortable in providing information about possible treatments to allow patients to make informed decisions about their care. The majority of respondents complained about a lack of formal teaching and practice at basic clinical skills relating to drug therapy., Conclusion: Many graduates feel under-prepared to take on prescribing responsibilities after graduation. These findings emphasise the need to ensure that all medical curricula are able to provide sufficient learning opportunities and robust assessment in this important area of clinical practice.

Introduction: This study compares the efficacy of abdominal and vaginal routes in correcting severe uterovaginal or vault prolapses by examining their primary surgical outcomes., Methods: A retrospective study was conducted on operations performed from March 1998 to December 2001. The classifications of uterovaginal prolapse and vault prolapse were based on the Halfway system. It involved 177 women with at least grade 4 uterovaginal prolapse or grade 3 vault prolapse, and had undergone vaginal sacrospinous ligament fixation or abdominal sacrocolpopexy. The subjects were divided into two groups: 113 women who had an abdominal sacrocolpopexy and 64 women who had a vaginal sacrospinous ligament fixation. The primary surgical outcome measures was classified as cured, improved or failure according to our definition at their last follow-up., Results: The abdominal sacrocolpopexy group had significantly greater intra-operative blood loss, operating time, haematuria, longer postoperative catheterisation and hospitalisation. Vaginal sacrospinous ligament fixation had more suture erosion. 95.6 percent of women with abdominal sacrocolpopexy were cured compared to 79.7 percent with vaginal sacrospinous ligament fixation. Five (4.4 percent) patients in the abdominal sacrocolpopexy group and six (9.4 percent) in the vaginal sacrospinous ligament fixation group defaulted their six-month follow-up with a mean follow-up of 18.1 months (range 0.9-48.1 months) and 13.2 months (range 1.1-29.1 months), respectively., Conclusion: Abdominal sacrocolpopexy is more effective in correcting severe uterovaginal or vault prolapses but it is associated with higher intra- and post-operative morbidity compared to vaginal sacrospinous ligament fixation. Vaginal sacrospinous ligament fixation is preferred in patients with medical disorders.

1. To obtain some insight into the renoprotective mechanism of the new calcium antagonist efonidipine hydrochloride, we evaluated the acute effects of efonidipine on proteinuria, glomerular haemodynamics and the tubuloglomerular feedback (TGF) mechanism in anaesthetized 24-25-week-old spontaneously hypertensive rats (SHR) with glomerular injury. 2. Efonidipine infusion at 10 micrograms/kg per h following a bolus dose of 10 micrograms/kg, i.v., reduced systemic blood pressure (BP) and renal vascular resistance, whereas renal plasma flow (RPF), glomerular filtration rate (GFR), filtration fraction, urine volume and urinary sodium excretion were unaltered. Urinary protein excretion was clearly diminished from 163 +/- 25 to 105 +/- 24 ng/min per g kidney weight. 3. Micropuncture experiments revealed that the maximal reduction of proximal stop-flow pressure (SFP), an index of glomerular capillary pressure (Pgc), induced by loop of Henle perfusion was significantly less with efonidipine treatment (6.7 +/- 1.0% of SFP with no loop flow) than in control (23.8 +/- 3.1%). In the presence of efonidipine, SFP at half-maximal reduction (SFP1/2max), which approximates Pgc at the in vivo steady state tubular flow rate, remained unchanged compared with control (36.9 +/- 0.8 vs 35.3 +/- 0.7 mmHg, respectively) and the slope of dependency on mean BP was not different between control and efonidipine. 4. These results indicate that efonidipine attenuates the TGF response in SHR by dilating the afferent arteriole, thus maintaining the level of RPF and GFR despite reduced renal perfusion pressure. Constant GFR and SFP1/2max under efonidipine suggest that single nephron GFR and Pgc remain unaltered and that a marked reduction in proteinuria is achieved without changes in single nephron GFR or Pgc of superficial nephrons.

To elucidate the roles of endogenous endothelin (ET) and nitric oxide (NO) in tubuloglomerular feedback (TGF), the effects of FR139317, a specific ET-A receptor antagonist, and NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor on TGF were studied in Sprague-Dawley rats. FR139317 (1.5 mg/kg/hr i.v.) reversed the systemic pressor and renal vasoconstrictor responses induced by ET-1 (2 nmol/kg/hr i.v.), but did not alter the early proximal flow rate (EPFR) reduction in response to a loop perfusion with an artificial tubular fluid at 40 nl/min (47 +/- 3 vs. 47 +/- 3% in controls). L-NNA (0.2 mg/kg + 2 micrograms/kg/min i.v.) had no effect on systemic blood pressure (BP), renal hemodynamics or EPFR measured at zero perfusion (31 +/- 2 vs. 31 +/- 2 nl/min in controls), but enhanced the EPFR reduction during loop perfusion to 77 +/- 3%. Loop perfusion with 10(-3) M L-NNA in perfusate also increased the EPFR reduction to 70 +/- 7%. In conclusion, inhibition of NO synthesis enhances the TGF-mediated reduction of nephron GFR. This indicates an active participation of endogenous NO in the control of afferent arteriolar tone. endogenous ET does not influence TGF via the ET-A receptor.