A rare germline BMP15 missense mutation causes hereditary ovarian immature teratoma in human.

Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte-specific RNA sequencing revealed that abnormal activation of the H-Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.

Field-free switching of perpendicular magnetization by two-dimensional PtTe2/WTe2 van der Waals heterostructures with high spin Hall conductivity.

The key challenge of spin-orbit torque applications lies in exploring an excellent spin source capable of generating out-of-plane spins while exhibiting high spin Hall conductivity. Here we combine PtTe2 for high spin conductivity and WTe2 for low crystal symmetry to satisfy the above requirements. The PtTe2/WTe2 bilayers exhibit a high in-plane spin Hall conductivity σs,y ≈ 2.32 × 105 × h/2e Ω-1 m-1 and out-of-plane spin Hall conductivity σs,z ≈ 0.25 × 105 × h/2e Ω-1 m-1, where h is the reduced Planck's constant and e is the value of the elementary charge. The out-of-plane spins in PtTe2/WTe2 bilayers enable the deterministic switching of perpendicular magnetization at room temperature without magnetic fields, and the power consumption is 67 times smaller than that of the Pt control case. The high out-of-plane spin Hall conductivity is attributed to the conversion from in-plane spin to out-of-plane spin, induced by the crystal asymmetry of WTe2. Our work establishes a low-power perpendicular magnetization manipulation based on wafer-scale two-dimensional van der Waals heterostructures.

Balancing the Ion/Electron Transport of Graphite Anodes by a La-Doped TiNb2O7 Functional Coating for Fast-Charging Li-Ion Batteries.

A functional coating layer (FCL) is widely applied in fast-charging lithium-ion batteries to improve the sluggish Li+ transport kinetics of traditional graphite anodes. However, blindly increasing the Li+ conductivity for FCL reduces the overall electron conductivity of the anodes. Herein, we decoupled the effect of La-doping on TiNb2O7 (TNO) in terms of the phase evolution, Li+/electron transport, and lithiation behavior, and then proposed a promising La0.1TNO FCL with balanced Li+/electron transport for a fast-charging graphite anode. By optimizing the doping concentration of La, more holes are introduced into the TNO as electron carriers without causing lattice distortion, thus maintaining the fast Li+ diffusion channel in TNO. As a result, the graphite with La0.1TNO FCL delivers an excellent capacity of 220.2 mAh g-1 (96.3% retention) after 450 cycles at 3 C, nearly twice that of the unmodified one.

Field-Free Manipulation of Two-Dimensional Ferromagnet CrTe2 by Spin-Orbit Torques.

Electrical manipulation of magnetic states in two-dimensional ferromagnetic systems is crucial in information storage and low-dimensional spintronics. Spin-orbit torque presents a rapid and energy-efficient method for electrical control of the magnetization. In this letter, we demonstrate a wafer-scale spin-orbit torque switching of two-dimensional ferromagnetic states. Using molecular beam epitaxy, we fabricate two-dimensional heterostructures composed of low crystal-symmetry WTe2 and ferromagnet CrTe2 with perpendicular anisotropy. By utilizing out-of-plane spins generated from WTe2, we achieve field-free switching of the CrTe2 perpendicular magnetization. The threshold switching current density in CrTe2/WTe2 is 1.2 × 106 A/cm2, 20 times smaller than that of the CrTe2/Pt control sample even with an external magnetic field. In addition, the switching behavior can be modulated by external magnetic fields and crystal symmetry. Our findings demonstrate a controllable and all-electric manipulation of perpendicular magnetization in a two-dimensional ferromagnet, representing a significant advancement toward the practical implementation of low-dimensional spintronic devices.

Study on Gamma sensory flicker for Insomnia.

OBJECTIVES: Insomnia has been the subject of much systematic research because it is a risk factor for a variety of diseases. There is some evidence that gamma sensory stimulation therapy has also been demonstrated to improve sleep quality for people with Alzheimer's disease. However, it is unclear whether this method is effective for treating insomnia. The principal objective of this project was to investigate the efficacy and safety of gamma sensory flicker in improving the sleep quality of insomnia patients. METHODS: Thirty-seven participants with insomnia were recruited for this prospective observational study. For a duration of 8 weeks, participants were exposed to flicker stimulation through a light and sound device. RESULTS: During the main phase of the study, adherence rates averaged 92.21%. Additionally, no severe adverse events were reported for flicker treatment. Analysis of sleep diaries indicated that 40 Hz flickers can enhance sleep quality by reducing sleep onset latencies, and arousals, and increasing total sleep duration. CONCLUSIONS: Gamma sensory flicker improves sleep quality in people suffering from insomnia.

Hereditary spherocytosis before and after splenectomy and risk of hospitalization for infection.

BACKGROUND: The infectious burden in hereditary spherocytosis (HS) children before splenectomy has rarely been reported and the risk of severe postsplenectomy infection is controversial. METHODS: We conducted a retrospective study of pediatric patients with HS to evaluate the risk of infection presplenectomy and postsplenectomy. The primary outcome was any bacterial, Mycoplasma, or fungal infection that required hospitalization. The secondary outcomes were sepsis and septic shock. Appendectomized children were matched on age at surgery and enrolled as controls. RESULTS: In all, 232 patients were included. Before splenectomy, the primary outcome was identified in 51 (22.0%) patients, and the secondary outcome was identified in 1 (0.4%) patient. After splenectomy, the primary and secondary outcomes were detected in 8 (4.1%) and 1 (0.5%) patients, respectively. The risk of infection was higher presplenectomy than postsplenectomy (OR, 6.6; 95% CI, 3.0-14.2). HS patients had a higher risk of infection than the controls before surgery (OR, 3.7; 95% CI, 2.3-5.9) but not after surgery (OR, 1.4; 95% CI, 0.6-3.6). CONCLUSIONS: HS patients who require splenectomy later in life had a high incidence of hospitalization for infections. In contrast, postsplenectomy risk of hospitalization involving infection or severe infection was low. IMPACT: Patients with hereditary spherocytosis who require splenectomy later in life have a high risk of hospital admission for infections, especially those with severe hereditary spherocytosis. With vaccines or postoperative antibiotics, splenectomy does not increase the risk of infection or severe infections. Splenectomy may reduce the risk of hospitalization for infections by alleviating the complications of hereditary spherocytosis. With vaccines, prophylaxis, or advanced antibiotics, the benefits of splenectomy in children with hereditary spherocytosis and a heavy disease burden may outweigh the risks.

Clinical features and treatment outcomes of infantile appendicitis: a multicentre study.

Appendicitis in infants is a life-threatening condition that is seldom studied. Our purpose was to conduct a comprehensive evaluation of appendicitis in this age group. This was a multicenter retrospective study. Patients aged under one year with surgically confirmed appendicitis during January, 2010 to May, 2022 were identified from four institutional databases. The patients were grouped as neonates or older infants based on their age at the onset of symptoms associated with acute appendicitis. The study encompassed 98 infants, with median age of 66.5 (IQR, 13.8-176.0) days. Neonates were more likely to exhibit abdominal distension (64.9%) and fever (56.8%), while older infants more frequently presented with fever (88.5%) and vomiting (49.2%). Most patients (76.5%) were misdiagnosed during their initial clinical encounter, with a -rate was 3.1% (3 deaths), with neonates exhibiting a rate of 5.4%, and older infants 1.6%. Compared to older infants, neonates showed a higher incidence of appendiceal perforation (OR, 2.9; 95%CI, 1.1-8.1), mechanical ventilation (OR, 9.5; 95%CI, 3.1-29.2), and ICU admission (OR, 16.1; 95%CI, 5.6-45.7). However, there were no significant differences in mortality rates, 30-day readmission rates, and surgical complications between the two groups. CONCLUSION: Although most infants with appendicitis were misdiagnosed during the first clinical encounter, the observed mortality rates were considerably lower than previously reported. While neonates and infants over 28 days displayed differing clinical presentations and disease severity, their outcomes were similar. WHAT IS KNOWN: • Appendicitis in infants is a critical yet underemphasized health concern, often misdiagnosed at initial clinical encounters due to its atypical presentation and non-specific symptoms. • The mortality rates in the neonates with appendicitis was 23% during the past decades. WHAT IS NEW: • The neonates and older infants displayed differing clinical presentations and disease severity. The treatment outcomes were similar. • The mortality rate for infantile appendicitis (3.1%) was significantly lower than historically reported.

A case report of laparoscopic surgery for Mayer-Rokitansky-Küster-Hauser syndrome with preservation of functional primordial uterus.

BACKGROUND: In the past, the primary treatment for MRKH syndrome (Mayer-Rokitansky-Küster-Hauser syndrome) with a functional primordial uterus was surgical removal of the functional primordial uterus. In rare instances, the endometrium of the functional primordial uterus is well developed, and surgical preservation of the functional primordial uterus provides the possibility of preserving reproductive function for these patients. CASE PRESENTATION: A 14-year-old female was diagnosed with type I MRKH syndrome with a functional primordial uterus through physical examination and imaging investigations. We freed the functional primordial uterus through laparoscopic surgery and excised a portion of the lower myometrium to create an outlet at a lower uterine segment, which we then intermittently anastomosed to the tip of the artificial vagina. The patient recovered well after the surgery, and a re-examination showed no significant abnormalities. CONCLUSION: We were successful in preserving the functional primordial uterus using laparoscopic surgery in a patient with MRKH syndrome and connecting it to an artificial vagina through reconstructive surgery to ensure unobstructed menstrual drainage and preserve the reproductive potential of the patient.

Relationship between IgE-mediated allergy and complicated appendicitis in children.

PURPOSE: To investigate the relationship of IgE-mediated allergy and complicated appendicitis (CA) and overall prognosis. METHODS: We retrospectively analyzed a consecutive series of patients with acute appendicitis (AA) who received appendectomy at Beijing Children's Hospital between July 1, 2018 and June 30, 2020. Patients were classified into two groups, with or without IgE-mediated allergies. Logistic regression adjusting for age, duration of symptoms, WBC count, neutrophil count, C-reactive protein (CRP), Appendicolith and presence of allergy was used to evaluate the association between CA and IgE-mediated allergy. RESULTS: In total, 1156 patients were included. 162 (14.0%) of the patients had IgE-mediated allergy while 994 (86.0%) did not. Children with allergies had a decreased chance of developing CA after adjustment for age, duration of symptoms, WBC count, Neutrophil count, CRP, and appendicolith present rate (adjusted OR = 0.582, 0.364-0.929, P = 0.023). There were no significant differences in operative time, length of hospital stay (LOS), readmission, or adhesive intestinal obstruction rate between allergy and non-allergy patients. CONCLUSIONS: IgE-mediated allergy is related to a reduction risk of CA in the pediatric population and may not affect the prognosis of patients received appendectomy.

Intracellular receptor EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K-/eNOS-dependent manner during inflammation.

Coagulopathy is associated with both inflammation and infection, including infections with novel severe acute respiratory syndrome coronavirus-2, the causative agent Coagulopathy is associated with both inflammation and infection, including infection with novel severe acute respiratory syndrome coronavirus-2, the causative agent of COVID-19. Clot formation is promoted via cAMP-mediated secretion of von Willebrand factor (vWF), which fine-tunes the process of hemostasis. The exchange protein directly activated by cAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a regulatory role in suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized our EPAC1-null mouse model and revealed increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1 in vitro mimicked the EPAC1-/- phenotype. In addition, EPAC1 regulated tumor necrosis factor-α-triggered vWF secretion from human umbilical vein endothelial cells in a manner dependent upon inflammatory effector molecules PI3K and endothelial nitric oxide synthase. Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, both in vivo and in vitro. Our data delineate a novel regulatory role for EPAC1 in vWF secretion and shed light on the potential development of new strategies to control thrombosis during inflammation.

The utility of shear wave elastography and serum biomarkers for diagnosing biliary atresia and predicting clinical outcomes.

To investigate the utility of liver stiffness measurement by shear wave elastography (SWE) and several commonly used biomarkers in differentiating biliary atresia (BA) from other causes of cholestasis (non-BA) patients within 45 days and in predicting the postoperative prognosis. A consecutive series of medical records of patients presenting with cholestasis within 45 days in our institution between February 2016 and December 2020 was collected. The BA diagnosis was confirmed by intraoperative cholangiography (IOC). Other causes of cholestasis were confirmed by IOC, liver biopsy, genetic analysis, or recovery after conservative treatment. Preoperative and postoperative data were analyzed. A total of 156 patients were included, consisting of BA (n = 83) and non-BA (n = 73) cases. SWE and serum gamma-glutamyl transferase (GGT) showed better discriminative utility. The optimal cutoff values for SWE and GGT were > 7.10 kPa and > 195.4 U/L, with AUC of 0.82 (95% CI, 0.76-0.89; p < 0.0001) and 0.87 (95% CI, 0.82-0.93; p < 0.0001), respectively. Subgroup analysis showed the increased discriminative performance of SWE with age. Multivariable logistic regression analysis showed better diagnostic performance for SWE (adjusted OR, 35.03; 95% CI, 7.12-172.50) and GGT (adjusted OR, 24.70; 95% CI, 6.55-93.18) after adjusting for other confounders. The 30-day postoperative to preoperative serum direct bilirubin (DB) level, DB (post-30:pre), of > 0.3 showed the best predictive value for the need of liver transplantation, with HR of 6.15 (95% CI 1.95-19.38, P = 0.042).Conclusion: Serum GGT level and liver stiffness measurement by SWE showed the best discriminative utility. The diagnostic performance of SWE increased with age. A DB (post-30:pre) value > 0.3 was associated with the need for liver transplantation in later life. What is Known: • Liver stiffness measurement by shear wave elastography (SWE) could help discriminate biliary atresia (BA) from other causes of cholestasis, with sensitivity of 70-90%. • The postoperative total bilirubin less than 2 mg/dL within the first 3 months was a predictor of transplant-free survival. What is New: • The diagnostic performance of liver stiffness measurement by SWE increased with age. • The 30-day postoperative direct bilirubin (DB) level to preoperative DB level, DB (post-30:pre), is a predictor for short-term clinical outcomes.

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors†.

Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes with copy number alterations (deletion and duplication region), functional annotation was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region and duplication region. In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YSTs). Moreover, POU5F1 was the most significant mutated gene with mutation frequency >10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region and duplication region) was found in two YST and nuclear staining in two dysgerminomas tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I (DExD/H-box helicase 58)-like receptor, Toll-like receptor and nuclear factor (NF)-kappa. Keratin 4 (KRT4), ribosomal protein L14 (RPL14), proprotein convertase subtilisin/kexin type 6 (PCSK6), poly(A)-binding protein cytoplasmic 3 (PABPC3), and sterile alpha and TIR motif containing 1 (SARM1) mutations were detected in both peripheral blood and tumor samples. Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

H. pylori infection induces CXCL8 expression and promotes gastric cancer progress through downregulating KLF4.

Tumour-derived CXCL8 facilitates the movement of myeloid-derived suppressor cells, which are able to restrain antitumour immune responses to the tumour microenvironment. Kruppel-like factor 4 (KLF4) is a potential tumour suppressor in gastric cancer (GC). However, knowledge regarding correlations between KLF4 and CXCL8 in GC is limited. We use cellular and molecular biological methods to assess whether these two factors interact in GC. Expression CXCL8 and KLF4 was altered in human GC tissues compared to normal gastric tissues in opposite ways. Additionally, cytotoxin-associated gene A protein (CagA) gene transduction or Helicobacter pylori (H. pylori) infection upregulated CXCL8 expression. Knockdown of KLF4 expression increased CXCL8 protein and RNA expression, whereas its overexpression had the opposite effect. CXCL8-mediated enhancement of GC cell migration and proliferation was reversed by upregulation of KLF4 expression. Further mechanistic research revealed that KLF4 binds the CXCL8 promoter, suppressing CXCL8 transcription. Moreover, CXCL8 stimulation reduced KLF4 protein expression and promoted GC cell proliferation and migration, eventually promoting neoplasm growth in vivo. Together, our findings demonstrate that CagA promotes CXCL8 and inhibits KLF4. CXCL8 is a decisive downstream target gene of KLF4, and KLF4 negatively regulates CXCL8 in GC. Furthermore, CXCL8's negative regulation of KLF4 in vivo and in vitro, indicates that CagA may downregulate KLF4 by inducing CXCL8 expression, low expression of KLF4 further promotes that of CXCL8, forming a vicious circle in GC. Targeted KLF4 activation might improve the immunosuppressive microenvironment through direct negative regulation of CXCL8, providing a new potential target to strengthen the efficacy of immunotherapy in GC patients.

The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model.

The superoxide dismutase 1 (SOD1) mutation is one of the most notable causes of amyotrophic lateral sclerosis (ALS), and modifying the mutant SOD1 gene is the best approach for the treatment of patients with ALS linked to the mutations in this gene. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas9)/sgRNA delivered by the adeno-associated virus (AAV) system is a powerful tool for genome editing in the central nervous system (CNS). Here, we tested the capacity of the AAV-SaCas9-sgRNA system to modify mutant SOD1 in SOD1G93A transgenic mice and found that AAV9-SaCas9-sgRNA5 deleted the SOD1 gene, improved the lifespan of SOD1G93A mice by 54.6%, and notably ameliorated the performance of ALS transgenic mice. An immunochemical analysis showed that the expression of mutant SOD1 was very weak in motor neurons expressing SaCas9-sgRNA5. Consequently, the area showing muscle atrophy was more notably restored in the group treated with SaCas9-sgRNA5 compared with the group treated with SaCas9-sgLacZ. In addition, deep sequencing did not show the indel mutation in the gene highly matched to sgRNA5. Hence, AAV9-SaCas9-sgRNA-based gene editing is a feasible potential treatment for patients with ALS linked to SOD1 mutations.

Clinical Features and Short-term Outcomes of 102 Patients with Coronavirus Disease 2019 in Wuhan, China.

BACKGROUND: In December 2019, a series of pneumonia cases of unknown cause emerged in Wuhan, Hubei, China. In this study, we investigate the clinical and laboratory features and short-term outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS: All patients with COVID-19 admitted to Wuhan University Zhongnan Hospital in Wuhan, China, between 3 January and 1 February 2020 were included. All those patients were with laboratory-confirmed infections. Epidemiological, clinical, and radiological characteristics; underlying diseases; laboratory tests; treatments; complications; and outcomes data were collected. Outcomes were followed up at discharge until 15 February 2020. RESULTS: The study cohort included 102 adult patients. The median age was 54 years (interquartile ranger, 37-67 years), and 48.0% were female. A total of 34 patients (33.3%) were exposed to a source of transmission in the hospital setting (as health-care workers, patients, or visitors) and 10 patients (9.8%) had a familial cluster. There were 18 patients (17.6%) who were admitted to the intensive care unit (ICU), and 17 patients died (mortality, 16.7%; 95% confidence interval, 9.4-23.9%). Those patients who survived were younger, were more likely to be health-care workers, and were less likely to suffer from comorbidities. They were also less likely to suffer from complications. There was no difference in drug treatment rates between the survival and nonsurvival groups. Those patients who survived were less likely to require admission to the ICU (14.1% vs 35.3% of those admitted). Chest imaging examinations showed that patients who died were more likely to have ground-glass opacity (41.2% vs 12.9% in survivors). CONCLUSIONS: The mortality rate was high among the COVID-19 patients described in our cohort who met our criteria for inclusion in this analysis. The patient characteristics seen more frequently in those who died were the development of systemic complications following onset of the illness and a severity of disease requiring admission to the ICU. Our data support those described by others indicating that COVID-19 infection results from human-to-human transmission, including familial clustering of cases, and from nosocomial transmission. There were no differences in mortality among those who did or did not receive antimicrobial or glucocorticoid drug treatments.

Increased talin-vinculin spatial proximities in livers in response to spotted fever group rickettsial and Ebola virus infections.

Talin and vinculin, both actin-cytoskeleton-related proteins, have been documented to participate in establishing bacterial infections, respectively, as the adapter protein to mediate cytoskeleton-driven dynamics of the plasma membrane. However, little is known regarding the potential role of the talin-vinculin complex during spotted fever group rickettsial and Ebola virus infections, two dreadful infectious diseases in humans. Many functional properties of proteins are determined by their participation in protein-protein complexes, in a temporal and/or spatial manner. To resolve the limitation of application in using mouse primary antibodies on archival, multiple formalin-fixed mouse tissue samples, which were collected from experiments requiring high biocontainment, we developed a practical strategic proximity ligation assay (PLA) capable of employing one primary antibody raised in mouse to probe talin-vinculin spatial proximal complex in mouse tissue. We observed an increase of talin-vinculin spatial proximities in the livers of spotted fever Rickettsia australis or Ebola virus-infected mice when compared with mock mice. Furthermore, using EPAC1-knockout mice, we found that deletion of EPAC1 could suppress the formation of spatial proximal complex of talin-vinculin in rickettsial infections. In addition, we observed increased colocalization between spatial proximity of talin-vinculin and filamentous actin-specific phalloidin staining in single survival mouse from an ordinarily lethal dose of rickettsial or Ebola virus infection. These findings may help to delineate a fresh insight into the mechanisms underlying liver specific pathogenesis during infection with spotted fever rickettsia or Ebola virus in the mouse model.

Elevated levels of adiponectin associated with major adverse cardiovascular and cerebrovascular events and mortality risk in ischemic stroke.

BACKGROUND: Adiponectin plays role in multiple metabolic pathways. Previous studies in cardiovascular disease evaluated the association between adiponectin and clinical outcomes, yielding conflicting results. The aim of this study was to investigate the association of adiponectin with major adverse cardiovascular and cerebrovascular events (MACCE) and mortality in Chinese patients with first-ever acute ischemic stroke (AIS). METHODS: This was a prospective, multicenter cohort study. From September 2009 through October 2015, all patients with AIS from 3 stroke centers in Shandong were included. Serum levels of adiponectin at admission were tested. The prognostic role of adiponectin to predict the MACCE and mortality within 3 years was evaluated by multivariable-adjusted Cox proportional hazards models. RESULTS: This study included 4274 patients (median age 68 years [interquartile ranges {IQR}: 61-76]; 53.2% men). There were 794 deaths and 899 MACCE events. Higher serum levels of adiponectin on admission were found in patients with MACCE events and nonsurvivors (P < 0.001 and P < 0.001). In multivariable models adjusted for factors that confirmed in the univariate model, elevated serum levels of adiponectin were associated with a higher risk of MACCE (Quartile[Q]4 vs. Q1, Hazard ratio[HR] = 4.95 [95% confidence interval {CI}: 3.03-7.06]) and mortality (Q4 vs. Q1, HR = 5.63 [95% CI 3.15-7.99]). Adiponectin improved the prognostic value of the National Institutes of Health Stroke Scale (NIHSS) to predict MACCE (combined areas under the curve [AUC], 0.76; 95% CI 0.68-0.88; P = 0.001) and mortality (0.78[0.69-0.91]; P < 0.01). Subgroups analysis indicated that the prognostic role of adiponectin was more pronounced in women and patients with high levels of N-terminal-pro B-type natriuretic peptide(NT-pro BNP) (P < 0.001 and P < 0.001). CONCLUSIONS: Elevated serum levels of adiponectin were associated with a higher risk of MACCE and mortality independent of traditional risk factors in ischemic stroke patients.

MicroRNA-185 reduces the expression of hepatitis B virus surface antigen by targeting PRKCH in HepG2 2.2.15 cells.

MicroRNAs (miRNAs) are single-stranded noncoding RNAs with 18 to 25 nucleotides and play critical roles in a wide spectrum of biological processes. We repored that miR-185 inhibited hepatitis B surface antigen (HBsAg) expression and hepatitis B virus (HBV) replication without affecting the proliferation of HepG2 2.2.15 cells, compared with the controls. We identified that protein kinase C eta (PRKCH) is a direct target gene of miR-185 that affects HBV replication and protein expression and that the miR-185 may suppress HBV replication. Our results provide more information for gene therapy in HBV infection. Keywords: miR-185; HBV; HBV surface antigen; viral replication; PRKCH.

A new role for host annexin A2 in establishing bacterial adhesion to vascular endothelial cells: lines of evidence from atomic force microscopy and an in vivo study.

Understanding bacterial adhesion is challenging and critical to our understanding of the initial stages of the pathogenesis of endovascular bacterial infections. The vascular endothelial cell (EC) is the main target of Rickettsia, an obligately intracellular bacterium that causes serious systemic disease in humans and animals. But the mechanism(s) underlying bacterial adherence to ECs under shear stress from flowing blood prior to activation are unknown for any bacteria. Although host surface annexin a2 (ANXA2) has been identified to participate in efficient bacterial invasion of epithelial cells, direct evidence is lacking in the field of bacterial infections of ECs. In the present study, we employ a novel, anatomically based, in vivo quantitative bacterial-adhesion-to-vascular-EC system, combined with atomic force microscopy (AFM), to examine the role of endothelial luminal surface ANXA2 during rickettsial adherence to ECs. We also examined whether ANXA2 antibody affected binding of Staphylococcus aureus to ECs. We found that deletion of ANXA2 impeded rickettsial attachment to the ECs in vitro and blocked rickettsial adherence to the blood vessel luminal surface in vivo. The AFM studies established that EC surface ANXA2 acts as an adherence receptor for rickettsiae, and that rickettsial adhesin OmpB is the associated bacterial ligand. Furthermore, pretreatment of ECs with anti-ANXA2 antibody reduced EC surface-associated S. aureus. We conclude that the endothelial surface ANXA2 plays an important role in initiating pathogen-host interactions, ultimately leading to bacterial anchoring on the vascular luminal surface.

Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis.

Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia. Many progressive neuroinflammatory disorders show disruption of the CX3CL1/CX3CR1 communication system. But the exact role of the CX3CL1/CX3CR1 in ALS pathology remains unknown. F1 nontransgenic/CX3CR1+/- females were bred with SOD1G93A/CX3CR1+/- males to produce F2 SOD1G93A/CX3CR1-/-, SOD1G93A/CX3CR1+/+. We analyzed end-stage (ES) SOD1G93A/CX3CR1-/- mice and progression-matched SOD1G93A/CX3CR1+/+ mice. Our study showed that the male SOD1G93A/CX3CR1-/- mice died sooner than male SOD1G93A/CX3CR1+/+ mice. In SOD1G93A/CX3CR1-/- mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-κB pathway was activated; the autophagy-lysosome degradation pathway and the autophagosome maturation were impaired. Our results indicated that the absence of CX3CR1/CX3CL1 signaling in the central nervous system (CNS) may worsen neurodegeneration. The CX3CL1/CX3CR1 communication system has anti-inflammatory and neuroprotective effects and plays an important role in maintaining autophagy activity. This effort may lead to new therapeutic strategies for neuroprotection and provide a therapeutic target for ALS patients.