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Subcutaneous insulin resistance syndrome caused by obesity, induration at the injection site, skin temperature and other factors is common clinically, whereas resistance events caused by edema are relatively rare. This article introduced a case of a woman with type 2 diabetes mellitus with heart failure edema. Her blood glucose control was significantly associated with the level of edema. Excluding other factors, it can be concluded that edema might lead to subcutaneous insulin resistance syndrome, even if the edema at the injection site is not obvious., This article introduced a case of a woman with type 2 diabetes mellitus with heart failure edema. Her blood glucose control was significantly associated with the level of edema. Excluding other factors, it can be concluded that edema might lead to insulin subcutaneous malabsorption, even if the edema at the injection site is not obvious.

Patients with COVID‐19 may be recurrence positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RNA after being cured and discharged from the hospital. The aim of this study was to explore independent influencing factors as markers for predicting positive SARS‐CoV‐2 RNA recurrence. The study included 601 COVID‐19 patients who were cured and discharged from the Public and Health Clinic Centre of Chengdu from January 2020 to March 2021, and the recurrence positive of patients within 6 weeks after SARS‐CoV‐2 RNA turned negative was followed up. We used propensity score matching to eliminate the influence of confounding factors, and multivariate Logistic regression analysis was used to determine the independent influencing factors for positive SARS‐CoV‐2 RNA recurrence. Multivariate Logistic regression showed that the elevated serum potassium (odds ratio [OR] = 6.537, 95% confidence interval [CI]: 1.864–22.931, p = 0.003), elevated blood chlorine (OR = 1.169, 95% CI: 1.032–1.324, p = 0.014) and elevated CD3+CD4+ count (OR = 1.003, 95% CI: 1.001–1.004, p

Background Postoperative moderate and severe anemia (PMSA) has been a serious perioperative complication in primary total knee arthroplasty (TKA). However, the ideal cutoff values to predict PMSA is still undetermined. The aim of this study was (1) to identify the risk factors associated with PMSA and (2) to establish the cutoff values of preoperative hemoglobin (HB) associated with increased PMSA in primary TKA. Methods We identified 474 patients undergoing primary TKA and separated those in which PMSA (HB was less than 110 g/L on postoperative day 1 and 3) was developed from those without PMSA. Multivariate logistic regression model was used to identify independent risk factors for PMSA. Area under the receiver-operator curve (AUC) was used to determine the best-supported preoperative HB cutoff across all the patients. Results The PMSA rate in primary TKA was 53.2%. Significant risk factors were lower preoperative HB (OR [odds ratio] = 1.138, 95% CI [confidence interval] = 1.107–1.170, p p A preoperative HB cutoff value that maximized the AUC was 138.5 g/L for men (sensitivity: 79.4%, specificity: 75.0%) and 131.5 g/L for women (sensitivity: 74.7%, specificity: 80.5%), respectively. Conclusion We should recognize and consider the related risk factors to establish specific, personalized risk assessment for PMSA, including preoperative HB and intraoperative blood loss. Of these, preoperative HB was a referable tool to predict PMSA in primary TKA.

Due to the important role of N6-methyladenosine (m6A) in breast cancer, single nucleotide polymorphisms (SNPs) in genes with m6A modification may also be involved in breast cancer pathogenesis. In this study, we used a public genome-wide association study dataset to identify m6A-SNPs associated with breast cancer and to further explore their potential functions. We found 113 m6A-SNPs associated with breast cancer that reached the genome-wide suggestive threshold (5.0E-05), and 86 m6A-SNPs had eQTL signals. Only six genes were differentially expressed between controls and breast cancer cases in GEO datasets (GSE15852, GSE115144, and GSE109169), and the SNPs rs4829 and rs9610915 were located next to the m6A modification sites in the 3ʹUTRs of TOM1L1 and MAFF, respectively. In addition, we found that polyadenylate-binding protein cytoplasmic 1 might have a potential interaction with rs4829 (TOM1L1) and rs9610915 (MAFF). In summary, these findings indicated that the SNPs rs4829 and rs9610915 are potentially associated with breast cancer because they had eQTL signals, altered gene expression, and were located next to the m6A modification sites in the 3ʹUTRs of their coding genes. However, further studies are still needed to clarify how genetic variation affects the epigenetic modification, m6A, and its subsequent functions in the pathogenesis of breast cancer.

The current study was designed to explore the role and underlying mechanism of lncRNA taurine up‐regulated gene 1 (TUG1) in cardiac hypertrophy. Mice were treated by transverse aortic constriction (TAC) surgery to induce cardiac hypertrophy, and cardiomyocytes were treated by phenylephrine (PE) to induce hypertrophic phenotype. Haematoxylin‐eosin (HE), wheat germ agglutinin (WGA) and immunofluorescence (IF) were used to examine morphological alterations. Real‐time PCR, Western blots and IF staining were used to detect the expression of RNAs and proteins. Luciferase assay and RNA pull‐down assay were used to verify the interaction. It is revealed that TUG1 was up‐regulated in the hearts of mice treated by TAC surgery and in PE‐induced cardiomyocytes. Functionally, overexpression of TUG1 alleviated cardiac hypertrophy both in vivo and in vitro. Mechanically, TUG1 sponged and sequestered miR‐34a to increase the Dickkopf 1 (DKK1) level, which eventually inhibited the activation of Wnt/β‐catenin signalling. In conclusion, the current study reported the protective role and regulatory mechanism of TUG1 in cardiac hypertrophy and suggested that TUG1 may serve as a novel molecular target for treating cardiac hypertrophy.

Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

Background The prevalence of CGG repeat expansion mutation in FMR1 gene varies among different populations. In this study, we investigated the prevalence of this mutation in women of reproductive age from northern China. Methods A total of 11,891 pre-conceptional or pregnant women, including 5037 pregnant women and 7357 women with the history of spontaneous abortion or induced abortion due to delayed growth of the embryos, were recruited. The number of CGG repeats in FMR1 was measured by the TRP-PCR method. We also offered genetic counseling and prenatal diagnosis to the women carrying pre-mutation or full mutation alleles. Results The prevalence of pre-mutation in reproductive women in northern China was 1/410, higher than that in southern China and Korea but lower than that in western countries. We also found that the prevalence of pre-mutation was relatively high (1/320) in women with abortion history. Conclusion Screening for CGG repeat expansion mutation in FMR1 should be recommended to the women with the history of spontaneous abortion or induced abortion due to delayed growth of the embryos.

Aiming at breaking down the bottleneck problems of different scale of poultry farms, the low profitability of poultry farming, and backward information management in China, a safe and efficient information management system for poultry farming was designed. This system consists of (1) a management system application layer, (2) a data service layer, and (3) an information sensing layer. The information sensing layer obtains and uploads production and farming information through the wireless sensor network built in the poultry house. The use of a cloud database as an information storage carrier in the data service layer eliminates the complex status of deploying local server clusters, and it improves the flexibility and scalability of the system. The management system application layer contains many sub-function modules including poultry disease detection functions to realize the visual management of farming information and health farming, each module operates independently and cooperates with each other to form a set of information management system for poultry farming with wide functional coverage, high service efficiency, safety, and convenience. The system prototype has been tested for the performance of wireless sensor network and cloud database, and the results show that the prototype is capable of acquiring and managing poultry farming information.

Ixodes scapularis ticks transmit multiple pathogens, including Borrelia burgdorferi sensu stricto, and encode many proteins harboring epidermal growth factor (EGF)-like domains. We show that I. scapularis produces multiple orthologs for Bm86, a widely studied tick gut protein considered as a target of an anti-tick vaccine, herein termed as Is86. We show that Is86 antigens feature at least three identifiable regions harboring EGF-like domains (termed as EGF-1, EGF-2, and EGF-3) and are differentially upregulated during B. burgdorferi infection. Although the RNA interference-mediated knockdown of Is86 genes did not show any influences on tick engorgement or B. burgdorferi sensu stricto persistence, the immunization of murine hosts with specific recombinant EGF antigens marginally reduced spirochete loads in the skin, in addition to affecting tick blood meal engorgement and molting. However, given the borderline impact of EGF immunization on tick engorgement and pathogen survival in the vector, it is unlikely that these antigens, at least in their current forms, could be developed as potential vaccines. Further investigations of the biological significance of Is86 (and other tick antigens) would enrich our knowledge of the intricate biology of ticks, including their interactions with resident pathogens, and contribute to the development of anti-tick measures to combat tick-borne illnesses.

Aggregation of misfolded α-synuclein (α-syn) is the major component of Lewy bodies and neurites in Parkinson’s disease (PD) and related α-synucleinopathies. Some α-syn mutations (e.g., A53T) in familial PD recapitulate the α-syn pathology in transgenic mice, which supports the importance of pathologic α-syn in driving the pathogenesis of α-synucleinopathies. Lymphocyte activation gene 3 (Lag3) is a receptor of α-syn fibrils facilitating pathologic α-syn spread; however, the role of Lag3 in mediating the pathogenesis in α-syn transgenic mice is not clear. Here, we report that depletion of Lag3 in human α-syn A53T transgenic (hA53T) mice significantly reduces the level of detergent-insoluble α-syn aggregates and phosphorylated ser129 α-syn, and inhibits activation of microglia and astrocytes. The absence of Lag3 significantly delays disease progression and reduces the behavioral deficits in hA53T transgenic mice leading to prolonged survival. Taken together, these results show that Lag3 contributes to the pathogenesis in the α-syn A53T transgenic mouse model.

Colon cancer treatments include surgery, radiotherapy, and chemotherapy. Chemotherapy using 5-fluorouracil (5-FU) has been widely applied to treat colorectal cancer (CRC). However, it is important to explore the use of chemotherapy drugs in combination with other agents to decrease severe adverse effects.This study aimed to investigate the effects of curcumin in combination with 5-FU on the proliferation, migration, and apoptosis of CRC SW620 cell line both in vitro and in vivo.Flow cytometry was used to study the effect of curcumin on chemotherapy-induced apoptosis in CRC cells. The mechanism of curcumin's enhanced antitumor effect in vivo was investigated using gene knockdown, TUNEL, western blot, qRT-PCR and immunohistochemistry.The results showed a synergistic effect of the two compounds on CRC cells. Considerable reduction in the proliferation and migration of SW620 cells was observed in the combination treatment group. Significantly increased apoptosis rate extended the survival of immunodeficient mice in the combination group as compared to that of the 5-FU group (p0.05). The results showed that curcumin significantly inhibited pERK signaling and downregulated L1 expression in SW620 cells.We conclude that curcumin promotes chemosensitivity of CRC cells to 5-FU by downregulating L1 expression. Our findings provide experimental evidence for the synergism between curcumin and 5-FU, which can be utilized in clinical applications for reducing the toxicity and adverse effects of 5-FU.

Background There are many progesterone (P) elevation-related indicators for predicting pregnancy outcomes, including the serum P, P-to-oestradiol ratio (P/E2), P-to-follicle index (PFI), and P-to-mature oocyte index (PMOI); however, due to inconsistencies in study populations and controlled ovarian hyperstimulation (COH) protocols among studies, these indicators are controversial. Moreover, no researchers have included these four commonly used indicators in one study to compare their predictive efficacies. The objective of this study was to compare the predictive value of P-related indicators for pregnancy outcomes of women undergoing the short-acting GnRH agonist long protocol. Methods A total of 612 infertile women undergoing IVF/ICSI were recruited for this study. Serum samples were obtained on the morning of HCG injection for serum P and E2 measurements. Transvaginal ultrasound was performed to determine the follicle count (≥ 14 mm in diameter). The number of mature oocytes was observed in the embryo laboratory after oocyte retrieval. Results In cases of P 2 between the pregnant group and the non-pregnant group. The PFI and PMOI of the pregnant group were significantly lower than those of the non-pregnant group. According to the stratified analysis of the ovarian response, only the PMI and PMOI of the pregnant women in the normal ovarian response group were lower than those of the non-pregnant women. To compare the predictive value of the PFI and PMOI in IVF/ICSI outcomes, the patients were divided into four groups. The good-quality embryo rate and clinical pregnancy rate were highest in Group A (low PFI and low PMOI) and lowest in Group D (high PFI and high PMOI). In the two groups with discordant PFI and PMOI, namely Group B (low PFI and high PMOI) and Group C (high PFI and low PMOI), the good-quality embryo rate and clinical pregnancy rate were not significantly different. Conclusions The PFI and PMOI had equal value in predicting clinical pregnancy outcomes in the normal ovarian response group undergoing the short-acting GnRH agonist long protocol. Each clinical centre can choose one of the indicators according to their actual situation in clinical practice and establish individual cut-off values for PFI and PMOI based on their own hormonal measurements.

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and disability but no specific or effective treatment. In the last two decades, much has been learned about the pathologic mechanisms of ICH. It is now known that after ICH onset, immune and inflammatory responses contribute to blood–brain barrier disruption, edema development, and cell death processes, jointly resulting in secondary brain injury. However, the translation of potential therapies from preclinical to clinical success has been disappointing. With the development of new laboratory technology, recent progress has been made in the understanding of ICH pathomechanisms, and promising therapeutic targets have been identified. This review provides an update of recent progress on ICH and describes the prospects for further preclinical studies in this field. Our goal is to discuss new therapeutic targets and directions for the treatment of ICH and promote the effective transformation from preclinical to clinical trials.

The spirochete Borrelia burgdorferisensu lato is the causative agent of Lyme disease (LD). The spirochetes produce the CspZ protein that binds to a complement regulator, factor H (FH). Such binding downregulates activation of host complement to facilitate spirochete evasion of complement killing. However, vaccination with CspZ does not protect against LD infection. In this study, we demonstrated that immunization with CspZ-YA, a CspZ mutant protein with no FH-binding activity, protected mice from infection by several spirochete genotypes introduced via tick feeding. We found that the sera from CspZ-YA-vaccinated mice more efficiently eliminated spirochetes and blocked CspZ FH-binding activity than sera from CspZ-immunized mice. We also found that vaccination with CspZ, but not CspZ-YA, triggered the production of anti-FH antibodies, justifying CspZ-YA as an LD vaccine candidate. The mechanistic and efficacy information derived from this study provides insights into the development of a CspZ-based LD vaccine.

Borrelia burgdorferi conserved gene products BB0406 and BB0405, members of a common B. burgdorferi paralogous gene family, share 59% similarity. Although both gene products can function as potential porins, only BB0405 is essential for infection. Here we show that, despite sequence homology and coexpression from the same operon, both proteins differ in their membrane localization attributes, antibody accessibility, and immunogenicity in mice. BB0406 is required for spirochete survival in mammalian hosts, particularly for the disseminated infection in distant organs. We identified that BB0406 interacts with laminin, one of the major constituents of the vascular basement membrane, and facilitates spirochete transmigration across host endothelial cell barriers. A better understanding of how B. burgdorferi transmigrates through dermal and tissue vascular barriers and establishes disseminated infections will contribute to the development of novel therapeutics to combat early infection.

Pyrochlore leaching using hydrofluoric, sulfuric, and hydrochloric acids has been studied via experimental methods for years, but the interactions between niobium atoms on the pyrochlore surface and different acids have not been investigated. In this work, first-principles calculations based on density functional theory were used to elucidate the leaching performance of these three acids from the viewpoint of geometrical and electronic structures. The calculation results indicate that sulfate, chloride, and fluoride anions influence the geometric structure of pyrochlore (100) to different extents, decreasing in the order: sulfate, fluoride, chloride. Orbitals of O1 and O2 atoms of sulfate hybridized with those of surface niobium atom. Fluorine orbitals hybridized with those of surface niobium atoms. However, no obvious overlap exists between any orbitals of chlorine and surface niobium, revealing that chlorine does not interact chemically with surface niobium atoms.

Sulforaphane (SFN), one of the isothiocyanates, abundantly existed in quite a few of cruciferous vegetables and exhibits effective anticancer activities in our previous experiments. However, its effects on bladder cancer cell invasion and metastasis have only begun to be explored. Here, we investigated the effect of microRNA on bladder cancer cell invasion and the underlying molecular mechanism. According to the gene chip results, SFN obviously increased microRNA-200c (miR-200c) expression, one of the short noncoding RNAs that acts as considerable modulator in epithelial mesenchymal transition (EMT). Moreover, SFN dose-dependently induced EMT hallmark E-cadherin and down-regulated vimentin and transcriptional repressor ZEB1 at the level of transcription and translation, and these effects can be reversed by miR-200c inhibitor transfection. Remarkably, Transwell assay showed that cell invasiveness ability can be eradicated by silencing of ZEB1. Therefore, these findings firmly suggest that SFN inhibited bladder cancer cell invasion through reversing EMT via targeting miR-200c/ZEB1 axis.

Peripheral nerve injury is a common disease that affects more than 20 million people in the United States alone and remains a major burden to society. The current gold standard treatment for critical-sized nerve defects is autologous nerve graft transplantation; however, this method is limited in many ways and does not always lead to satisfactory outcomes. The limitations of autografts have prompted investigations into artificial neural scaffolds as replacements, and some neural scaffold devices have progressed to widespread clinical use; scaffold technology overall has yet to be shown to be consistently on a par with or superior to autografts. Recent advances in biomimetic scaffold technologies have opened up many new and exciting opportunities, and novel improvements in material, fabrication technique, scaffold architecture, and lumen surface modifications that better reflect biological anatomy and physiology have independently been shown to benefit overall nerve regeneration. Furthermore, biomimetic features of neural scaffolds have also been shown to work synergistically with other nerve regeneration therapy strategies such as growth factor supplementation, stem cell transplantation, and cell surface glycoengineering. This review summarizes the current state of neural scaffolds, highlights major advances in biomimetic technologies, and discusses future opportunities in the field of peripheral nerve regeneration.

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m2, iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.

Although high uric acid levels have been reported to be a risk factor for cardiovascular disease and stroke, the relationship between serum uric acid (SUA) levels and cardioembolic stroke (CES) has not been fully elucidated. In this study, we sought to investigate the relationship between the risk of CES and SUA levels. We hypothesized that SUA concentrations are associated with CES.We retrospectively analyzed 2350 patients with acute ischemic stroke who were admitted to the Seoul National University Hospital between 2002 and 2010. The participants were stratified into five groups according to SUA levels obtained within 24h after stroke onset. The association between SUA levels and CES was evaluated using multivariable logistic regression models.Of the 2350 patients, 412 (27.7%) were classified with CES, and 1077 (72.3%) were classified with non-CES, including LAA (large artery atherosclerosis) and SVO (small vessel occlusion). Among the acute stroke patients, SUA levels were higher in those with atrial fibrillation and other cardiovascular risk factors. Compared with the non-CES patients, the CES patients were more likely to fall in the highest quintile of SUA level. Multivariate analysis revealed that the patients with SUA concentrations in the highest quintile were associated with CES (OR=2.59, 95% CI: 1.35-4.97), test for trend P0.001. Similar results were obtained for gender-based subgroups by (in men, OR=2.34, 95% CI: 1.06-5.15 and in women OR=3.41, 95% CI: 1.15-10.07), test for trend P0.01 and P0.001, respectively.SUA level is associated with the risk of CES in acute ischemic stroke patients of both sexes. Further prospective clinical trials of lowering SUA to prevent CES may be worth considering.

Glibenclamide (GBC) improves cerebral outcome after cardiac arrest (CA) in rats. We aim to investigate the effect of GBC on electrophysiological recovery and to explore the mechanism of neuroprotective effect of GBC in the acute stage of brain injury after the return of spontaneous circulation (ROSC) in a rodent model of CA. 16 anesthetized male Wistar rats subjected to 8-min asphyxia-CA were randomly assigned to the GBC or control group (N=8 each group). GBC was administered with a loading dose of 10ug/kg via i. p. injection 10 min after ROSC and was followed by a maintenance dose of 1.6ug/kg per 8 hours throughout the first 24 hours. Quantitative measures of EEG-information quantity (qEEG-IQ) and neurological deficit score (NDS) were used to predict and evaluate the functional outcome. There was a significant improvement of NDS in rats treated with GBC compared with the control group (p < 0.01). Compared to the control group, the rats treated with GBC showed qEEG-IQ scores that indicated better recovery (p < 0.001). Meanwhile, early qEEG-IQ was significantly correlated with 72-hr NDS as early as 45min after ROSC. Furthermore, on the molecular basis, the NLRP3 inflammasome was strongly activated in the hippocampal CA1 area 3 days after CA in control rats, but was suppressed with GBC treatment. Taken together, GBC treatment markedly improved electrophysiological and neurologic outcomes of the acute brain injury after CA. These neuroprotective effects may be associated with the attenuation of inflammatory response via down-regulation of NLRP3 inflammasome signal.

Cardiac arrest (CA) is a serious disease with high rates of mortality and disability worldwide. Currently, neither pharmacological intervention nor therapeutic hypothermia can reverse the neural injury caused by CA. Neural stem cell therapy is a promising treatment for brain injury. We investigated the effects of the intracerebroventricular (ICV) administration of human neural stem cells (hNSCs) on global brain ischemia injury after CA. Twelve Long–Evans rats (4 Male and 8 female) subjected to 8-min asphyxia-CA were randomly assigned to hNSC treatment (n=7) or control group (n=5). The hNSCs were slowly infused into the left lateral ventricule 3 hours after resuscitation. An additional two rats subjected to 8-min asphyxia-CA were euthanized at 4 weeks after resuscitation to confirm the survival and function of transplanted PKH26 pre-labeled hNSCs using brain slides and whole cell patch clamp. Electrophysiological monitoring, quantitative EEG value (qEEG-IQ) and neurological deficit score (NDS) were used to evaluate the functional outcome. Immunofluorescence staining was used to investigate the survival of neurons and to track the migration of hNSCs. There was a significant improvement on the behavior tests evaluated as a subgroup of NDS (p < 0.05) in the NSCs group compared to the control group. Immunofluorescence co-staining of PKH26 and NeuN verified the neuronal differentiation from transplanted PKH26+ hNSCs in the hippocampus CA1 and cortex 4 weeks after CA. The whole-cell patch clamp technique confirmed the spontaneous firing activity that was recorded in cell-attached mode from the functionally mature neurons derived from transplanted cells. Transplanted hNSCs via ICV administration markedly improved neurologic outcomes after CA. Further studies are needed to elucidate the neuroprotective mechanism.

Background In general, anti-Müllerian hormone (AMH) is positively associated with antral follicle count (AFC). However, there is often discordance between the AMH level and AFC in clinical practice. In cases of discordance, which indicator should be chosen to predict ovarian response and subsequently develop an ovulation induction protocol? The objective of this study was to investigate which indicator was more accurate in predicting ovarian response and pregnancy outcomes when the AMH level and AFC were discordant. Methods A total of 1121 infertile women undergoing IVF/ICSI were recruited in this study. During the study period, patients were subjected to individualized controlled ovarian hyperstimulation (COH) protocols according to specific characteristics. The AMH levels and AFCs were measured on days 2–3 of the menstrual cycle. Serum samples were obtained to determine AMH levels. Transvaginal ultrasound was performed to determine the AFC. All patients were divided into four groups: Group A had AFCs and AMH levels in the normal range; Group B had normal AFCs and low AMH levels; Group C had low AFCs and normal AMH levels; and Group D had low AFCs and AMH levels. Results Two hundred three women (18.11%) showed discordant AFCs and AMH levels. In the two groups with discordant AFCs and AMH levels, namely, Group B and Group C, the oocyte yield, good-quality embryo rate and clinical pregnancy rate were significantly higher in Group B than in Group C. The incidence of poor ovarian response (POR) was significantly lower in Group B than in Group C. According to the stratified analysis of age, for the three categories above the age of 30, oocyte yield was higher in Group B than in Group C. In all age categories, the clinical pregnancy rate was higher in Group B than in Group C. Conclusions Our study demonstrated that approximately one in five patients in clinical practice showed discordance between AFCs and AMH levels. In view of the AFC being better than AMH for predicting POR, the AFC should be the preferred indicator for predicting ovarian response to subsequently develop an optimal individualized COH protocol.

In this review, we summarize recent research related to intracerebral hemorrhage (ICH) and offer new insight into its pathomechanisms. These underlying pathomechanisms of ICH provide clues for development of novel drugs or drug target screening. Specifically, recent research has provided evidence that iron chelators, lipid peroxidation/ferroptosis inhibitors, antagonists or agonists of prostaglandin E2 receptors (EP1/3 or EP2), and nonsteroidal anti-inflammatory drugs protect against ICH-induced brain edema and secondary brain tissue damage, and inhibit the toxicity of related tissue damage products. This review will provide a theoretical basis for testing new compounds that may have potential for future clinical trials.

Background The purpose of the study was to determine blood loss, transfusion risk, and incidence of immediate postoperative complications in normal, overweight, and I–II obese patients undergoing simultaneous bilateral total knee arthroplasty (SBTKA). Method We identified 1070 SBTKA procedures, and separated the patients into three groups on the basis of body mass index (BMI), including normal (BMI: 18.0–24.9 kg/m2), overweight (BMI: 25.0–29.9 kg/m2), and obese groups (BMI: ≥ 30.0 kg/m2). The primary outcome was total blood loss and secondary outcomes were dominant and hidden blood loss, transfusion rate and volume, hemoglobin (Hb) and hematocrit drop and other complications. Results Patient's blood volume increased gradually among normal, overweight, and obese groups. There was no significant difference in blood loss or incidence of complications among the three groups, while the transfusion rate in the normal group was higher than that in overweight (36.0% vs 27.6%, p = 0.007) and obese groups (36.0% vs 24.6%, p = 0.006). In addition, the independent risk factors for complications among all groups following SBTKA included lower level of preoperative Hb (p = 0.040), general anesthesia (p = 0.002), drain use (p = 0.005), and transfusion (p Conclusions I–II obesity does not increase patient's blood loss, transfusion risk, or immediate postoperative complications following SBTKA. Obese and overweight patients may have lower transfusion needs compared with normal patients because of their higher basal blood volume. The risk factors for complications after SBTKA are lower level of preoperative Hb, general anesthesia, drain use and transfusion.

Non-small-cell lung cancer (NSCLC) is an extremely debilitating respiratory malignancy. However, the pathogenesis of NSCLC has not been fully clarified. The main objective of our study was to identify potential microRNAs (miRNAs) and their regulatory mechanism in NSCLC. Using a systematic review, two NSCLC-associated miRNA data sets (GSE102286 and GSE56036) were obtained from Gene Expression Omnibus, and the differentially expressed miRNAs (DE-miRNAs) were accessed by GEO2R. Survival analysis of candidate DE-miRNAs was conducted using the Kaplan-Meier plotter database. To further illustrate the roles of DE-miRNAs in NSCLC, their potential target genes were predicted by miRNet and were annotated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) program. Moreover, the protein-protein interaction (PPI) and miRNA-hub gene regulatory network were established using the STRING database and Cytoscape software. The function of DE-miRNAs in NSCLC cells was evaluated by transwell assay. Compared with normal tissues, a total of eight DE-miRNAs was commonly changed in two data sets. The survival analysis showed that six miRNAs (miR-21-5p, miR-31-5p, miR-708-5p, miR-30a-5p, miR-451a, and miR-126-3p) were significantly correlated with overall survival. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that target genes of upregulated miRNAs were enriched in pathways in cancer, microRNAs in cancer and proteoglycans in cancer, while the target genes of downregulated miRNAs were mainly associated with pathways in cancer, the PI3K-Akt signaling pathway and HTLV-I infection. Based on the miRNA-hub gene network and expression analysis, PTEN, EGFR, STAT3, RHOA, VEGFA, TP53, CTNNB1, and KRAS were identified as potential target genes. Furthermore, all six miRNAs exhibited significant effects on NSCLC cell invasion. These findings indicate that six DE-miRNAs and their target genes may play important roles in the pathogenesis of NSCLC, which will provide novel information for NSCLC treatments.

Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron-dependent accumulation of lethal lipid peroxidation. First identified in cancer cells in 2012, ferroptosis has significant implications in several nervous system disorders. Studies have revealed the presence of iron accumulation, lipid peroxidation, glutathione reduction, and glutathione peroxidase 4 inhibition in various brain diseases, and ferroptotic inhibitors have been shown to protect neurons and improve cognitive function in experimental cellular and/or animal models. In this chapter, we describe the role that ferroptotic mechanisms play in different brain diseases and discuss how this knowledge can be harnessed to prevent and treat nervous system diseases.

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10 mg/kg) daily at 10:00 a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1β, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.

215 Background: Esophageal squamous cell carcinoma (ESCC) is a lethal cancer with a high unmet medical need. Camrelizumab, an anti-PD-1 monoclonal antibody, significantly improved overall survival (OS) and objective response rate (ORR) in Chinese patients (pts) with advanced ESCC compared with chemotherapy, with a manageable safety profile in phase III randomized trial (ESCORT). However, the absolute long-term survival benefiting from PD-1 inhibitors is limited, and new effective treatments are needed. Here, our study aimed to assess the efficacy and safety of combination with camrelizumab and apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC. Methods: This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg intravenous camrelizumab every two weeks plus 250 mg oral apatinib daily in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results: At data cutoff (Sept 11, 2020), 36 pts were enrolled, 7 females and 29 males, and 25 pts had lymph node metastases. Twelve pts received radiotherapy and 25 underwent surgery. Twenty-five pts were included in the efficacy analysis with median follow-up time of 5.0 months and 36 pts in the safety analysis with median follow-up time of 4.6 months. The primary endpoint ORR without confirmation was 40 % with complete response in two pts (8%) and partial response in eight pts (32%). Thirteen pts (52%) had stable disease, and the DCR was 92%. The median PFS and OS were not reached. A total of 72.2% of pts had AEs, and 30.6% of pts experienced grade 3 AEs. The most common AEs (all grade, grade≥3) were elevated aspartate aminotransferase (30.6%, 19.4%), elevated alanine aminotransferase (30.6%, 13.9%), hypertension (25%, 2.8%),neutrophil (25%, 5.6%), thrombocytopenia (25%, 0%), leukopenia (22.2%, 2.8%), anemia (11.1%, 0%), proteinuria (11.1%, 0%), hematochezia (8.3%, 0%), reactive cutaneous capillary endothelial proliferation (5.6%, 2.8%), pruritus (5.6%, 0%), esophageal fistula (5.6%, 0%), fatigue (2.8%, 0%) and hypothyroidism (2.8%, 0%). Conclusions: This is the first study to explore the combination of PD-1 inhibitor and anti-angiogenesis inhibitor as a second-line treatment for advanced ESCC. Camrelizumab plus apatinib demonstrated encouraging clinical efficacy and acceptable safety as second-line treatment, and might be a favorable option for pts with advanced ESCC. Further phase III randomized trials are warranted. Clinical trial information: NCT03736863.

The present research investigates sodium hypochlorite, hydrogen peroxide, sodium metabisulfite and copper sulfate as activators to lessen the depressant effect of cyanide. The results indicate that the zinc recovery exceeded 93%, 90%, 85% and 95% at the dosages: sodium hypochlorite 1.5 ml/L, hydrogen peroxide 2 ml/L, sodium metabisulfite 1.67 × 10−3 mol/L and copper sulfate 2 × 10−3 mol/L, respectively. According to the results of FTIR spectrum and zeta potential, it is suggested that the studied marmatite was depressed due to the adsorption of CN− on the surfaces of marmatite by chemical bonds, and moreover the afore enhanced activators can present Zn C N bonds on the surfaces of depressed marmatite by oxidation or ionic adsorption, respectively, and hence activate the depressed marmatite for flotation.

Peripheral nerve injuries often lead to incomplete recovery and contribute to significant disability to approximately 360,000 people in the USA each year. Stem cell therapy holds significant promise for peripheral nerve regeneration, but maintenance of stem cell viability and differentiation potential in vivo are still major obstacles for translation. Using a made-in-house 96-well vertical electrical stimulation (ES) platform, we investigated the effects of different stimulating pulse frequency, duration and field direction on human neural crest stem cell (NCSC) differentiation. We observed dendritic morphology with enhanced neuronal differentiation for NCSCs cultured on cathodes subject to 20 Hz, 100μs pulse at a potential gradient of 200 mV/mm. We further evaluated the effect of a novel cell-based therapy featuring optimized pulsatile ES of NCSCs for in vivo transplantation following peripheral nerve regeneration. 15 mm critical-sized sciatic nerve injuries were generated with subsequent surgical repair in sixty athymic nude rats. Injured animals were randomly assigned into five groups (N = 12 per group): blank control, ES, NCSC, NCSC + ES, and autologous nerve graft. The optimized ES was applied immediately after surgical repair for 1 h in ES and NCSC + ES groups. Recovery was assessed by behavioral (CatWalk gait analysis), wet muscle-mass, histomorphometric, and immunohistochemical analyses at either 6 or 12 weeks after surgery (N = 6 per group). Gastrocnemius muscle wet mass measurements in ES + NCSC group were comparable to autologous nerve transplantation and significantly higher than other groups (p 0.05). Quantitative histomorphometric analysis and catwalk gait analysis showed similar improvements by ES on NCSCs (p 0.05). A higher number of viable NCSCs was shown via immunochemical analysis, with higher Schwann cell (SC) differentiation in the NCSC + ES group compared to the NCSC group (p 0.05). Overall, ES on NCSC transplantation significantly enhanced nerve regeneration after injury and repair, and was comparable to autograft treatment. Thus, ES can be a potent alternative to biochemical and physical cues for modulating stem cell survival and differentiation. This novel cell-based intervention presents an effective and safe approach for improved outcomes after peripheral nerve repair.

Borrelia burgdorferi is the causative agent of Lyme disease that persists in a complex enzootic life cycle, involving Ixodes ticks and vertebrate hosts. The microbe invades ticks and vertebrate hosts in spite of active immune surveillance and potent microbicidal responses, and establishes long-term infection utilising mechanisms that are yet to be unravelled. The pathogen can cause multi-system disorders when transmitted to susceptible mammalian hosts, including in humans. In the past decades, several studies identified a limited number of B. burgdorferi gene-products critical for pathogen persistence, transmission between the vectors and the host, and host-pathogen interactions. This review will focus on the interactions between B. burgdorferi proteins, as well as between microbial proteins and host components, protein and non-protein components, highlighting their roles in pathogen persistence in the mammalian host. A better understanding of the contributions of protein interactions in the microbial virulence and persistence of B. burgdorferi would support development of novel therapeutics against the infection.

Nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which is composed of an NLRP3 domain, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) domain, and procaspase-1, plays an important role in the immune pathophysiology of the secondary damage induced by intracerebral hemorrhage (ICH). This study aims to investigate whether pre-stroke treatment with fimasartan, an angiotensin II receptor blocker, has anti-inflammatory effects on ICH by inhibiting the activation of the NLRP3 inflammasome. Sprague-Dawley rats were divided into five groups: sham, vehicle, low-dose (0.5 mg/kg) and regular-doses (1.0 and 3.0 mg/kg) fimasartan. These rats were treated for 30 days before the induction of collagenase-induced ICH and continuously 3 days after surgery. The mean blood pressure (BP) in the low-dose fimasartan group was not significantly different from that of control, and BP in the regular-dose groups was decreased in a dose-dependent manner. Pretreatment with low-dose fimasartan attenuated ICH-induced edema and improved neurological functions. Activation of the NLRP3/ASC/caspase-1 and the NF-κB pathways after ICH was markedly reduced by low-dose fimasartan. The double immunofluorescence staining of brain cells showed a significant decrease in the co-localization of NLRP3 with Iba1 (microglia marker) positive cells by fimasartan treatment. Cultured microglia cells stimulated by hemolysate demonstrated significant activation of the inflammasome, which was reduced by fimasartan. Pretreatment with a low-dose fimasartan alleviated brain damage after acute ICH by inhibiting the NLRP3 inflammasome without lowering MBP. Our study suggests pre-stroke administration of fimasartan could potentially attenuate ICH-induced secondary brain injury by targeting the inflammasome.

The potential efficacy of sulforaphane in protecting alcohol-induced hepatic injury in vivo and its underlying mechanism were investigated. Male C57BL/6 mice were orally administrated with broccoli sprout extract (BSE) containing sulforaphane [7.6, 25.2, and 50.4 mg/kg of body weight (bw)] once a day for 14 days. At the 13th day, mice were challenged with alcohol (5 g/kg of bw) every 12 h for 3 times, which increased malondialdehyde (MDA) levels (4.44 ± 1.24 nmol/mg of protein, p0.01) in the liver. Our results showed that low-, medium-, and high-dose BSE markedly reversed the decrease of antioxidant capacity through enhancing glutathione (GSH) (2.07 ± 0.31 mg/g of protein, p0.05; 2.31 ± 0.32 mg/g of protein, p0.01; and 2.46 ± 0.21 mg/g of protein, p0.01), superoxide dismutase (SOD) (483.20 ± 62.76 units/mg of protein; 500.81 ± 49.82 units/mg of protein, p0.05; and 605.00 ±64.32 units/mg of protein, p0.01), glutathione peroxidase (GSH-Px) (318 ± 60.74 units/mg of protein; 400.67 ± 72.47 units/mg of protein, p0.01; and 394.72 ± 62.97 units/mg of protein, p0.01), and glutathione S-transferase (GST) (31.84 ± 6.34 units/mg of protein, p0.05; 30.34 ± 6.40 units/mg of protein, p0.05; and 38.08 ± 7.05 units/mg of protein, p0.01) in the liver. The protective actions are also associated activation of phase 2 enzymes via nuclear erythoriod-2-related factor 2 (Nrf2). The endoplasmic reticulum (ER)-stress-specific proteins, such as glucose-regulated protein 78 (GRP78), activating transcription factor 6, and protein kinase RNA (PKR)-like ER kinase (PERK), were also significantly attenuated by BSE. These results indicate that BSE protects the liver against alcohol challenge via upregulating antioxidant capacity and downregulating ER stress.

Borrelia burgdorferi is one of the few extracellular pathogens capable of establishing persistent infection in mammals. The mechanisms that sustain long-term survival of this bacterium are largely unknown. Here we report a unique innate immune evasion strategy of B. burgdorferi, orchestrated by a surface protein annotated as BBA57, through its modulation of multiple spirochete virulent determinants. BBA57 function is critical for early infection but largely redundant for later stages of spirochetal persistence, either in mammals or in ticks. The protein influences host IFN responses as well as suppresses multiple host microbicidal activities involving serum complement, neutrophils, and antimicrobial peptides. We also discovered a remarkable plasticity in BBA57-mediated spirochete immune evasion strategy because its loss, although resulting in near clearance of pathogens at the inoculum site, triggers nonheritable adaptive changes that exclude detectable nucleotide alterations in the genome but incorporate transcriptional reprograming events. Understanding the malleability in spirochetal immune evasion mechanisms that ensures their host persistence is critical for the development of novel therapeutic and preventive approaches to combat long-term infections like Lyme borreliosis.

The ability to cultivate Borreliella (Borrelia) burgdorferi is a cornerstone of Lyme disease research. For blood, plasma is the preferred source of culture material ([1][1][–][2][3][3]). Studies in the United States have used EDTA as the anticoagulant ([1][1], [2][2], [4][4][–][5][6][6]). Our

Borrelia burgdorferi is maintained in nature by a tick-rodent infection cycle where it traverses and colonizes a variety of host and vector tissues. A tick-borne murine model has been developed to study Lyme disease in the laboratory, which has a substantial impact in advancing our knowledge of spirochete infectivity and pathogenesis. Here, we detail a microinjection-based method for rapid and efficient infection of ticks with B. burgdorferi. While laboratory generation of B. burgdorferi-infected nymphs via natural larval engorgement on infected hosts and subsequent molting could take several weeks to months, the microinjection-based infection procedure requires only a few hours to generate infected ticks and allows introduction of defined quantities of spirochetes, including mutant isolates that are attenuated for infection in mice and thus cannot be naturally acquired by ticks. We also describe a quantitative PCR-based protocol for the measurement of B. burgdorferi in tick and murine hosts targeting spirochete RNA that is highly efficient, reproducible, and a better surrogate of active infection.

Spleen tyrosine kinase (SYK), a non-receptor protein tyrosine kinase, is reported to be related to cell survival after A/H (anoxia/hypoglycemia) insult. However, the role of SYK in cardiocyte survival under A/H injury remains unclear. In this study, we aimed to gain insight into the role and molecular mechanism of SYK in cardiocytes exposed to A/H stress. The mRNA and protein expressions of SYK in H9c2 cardiocytes exposed to A/H injury, separately detected by real-time quantitative PCR and Western blot, were both robustly up-regulated. Then we overexpressed SYK in H9c2 with A/H injury, and found that cell viability was significantly increased and LDH leakage was decreased. Moreover, apoptosis measured by annexin V-fluorescein isothiocyanate/propidium iodide and reactive oxygen species (ROS) identified by 2', 7'-dichlorofluorescin diacetate were markedly inhibited in H9c2 with A/H injury following SYK overexpression. Furthermore, we observed that SYK could induce HO-1 expression by regulating the Akt phosphorylation level in H9c2 with A/H injury, protecting H9c2 from the injury induced by A/H treatment.

YAS, Ozlem BUYUKTANIR/0000-0002-7641-7350; KUMAR, MANISH/0000-0001-7997-5676 WOS: 000401986300023 PubMed: 28453837 Borrelia burgdorferi genome harbors several paralogous gene families (pgf) that can encode immunogenic proteins of unknown function. Protein-protein interaction assays using a transmission-blocking vaccine candidate, BBA52, as bait identified an interacting partner in spirochetes-a member of pgf 54, annotated as BBI39. We show that BBI39 is a surface-exposed membrane antigen that is immunogenic during spirochete infection, despite the gene being primarily transcribed in the vector with a transient expression in the host only at tick-bite sites. Immunization of rodents with BBI39, or a diverse paralog, BBI36, or their combination impaired pathogen acquisition by the vector, transmission from ticks to hosts, or induction of disease. High-titer BBI39 immunoglobulin G antibodies, which have borreliacidal properties, could be generated through routine subcutaneous or oral immunization, further highlighting use of BBI39 proteins as novel Lyme disease vaccines that can target pathogens in the host or in ticks. National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01AI080615] This work was supported by funding from the National Institute of Allergy and Infectious Diseases (R01AI080615 to U.P.).

Intracerebral hemorrhage (ICH) is a common and severe cerebrovascular disease that has high mortality. Few survivors achieve self-care. Currently, patients receive only symptomatic treatment for ICH and benefit poorly from this regimen. Inflammatory cytokines are important participants in secondary injury after ICH. Increases in proinflammatory cytokines may aggravate the tissue injury, whereas increases in anti-inflammatory cytokines might be protective in the ICH brain. Inflammatory cytokines have been studied as therapeutic targets in a variety of acute and chronic brain diseases; however, studies on ICH are limited. This review summarizes the roles and functions of various pro- and anti-inflammatory cytokines in secondary brain injury after ICH and discusses pathogenic mechanisms and emerging therapeutic strategies and directions for treatment of ICH.

Borrelia burgdorferi gene product BB0323 is required for cell fission and pathogen persistence in vivo. Here, we show that BB0323, which is conserved among globally prevalent infectious strains, supports normal spirochaete growth and morphology even at early phases of cell division. We demonstrate that native BB0323 undergoes proteolytic processing at the C-terminus, at a site after the first 202 N-terminal amino acids. We further identified a periplasmic BB0323 binding protein in B. burgdorferi, annotated as BB0104, having serine protease activity responsible for the primary cleavage of BB0323 to produce discrete N- and C-terminal polypeptides. These two BB0323 polypeptides interact with each other, and either individually or as a complex, are associated with multiple functions in spirochaete biology and infectivity. While N-terminal BB0323 is adequate to support cell fission, the C-terminal LysM domain is dispensable for this process, despite its ability to bind B. burgdorferi peptidoglycan. However, the LysM domain or the precisely processed BB0323 product is essential for mammalian infection. As BB0323 is a membrane protein crucial for B. burgdorferi survival in vivo, exploring its function may suggest novel ways to interrupt infection while enhancing our understanding of the intricate spirochaete fission process.

Borrelia burgdorferi bba57 is a conserved gene encoding a potential lipoprotein of unknown function. Here we show that bba57 is up-regulated in vivo and is required for early murine infection and potential spirochete transmission process. Although BBA57 is dispensable for late murine infection, the mutants were unable to induce disease. We show that BBA57, an outer membrane and surface-exposed antigen, is a major trigger of murine Lyme arthritis; even in cases of larger challenge inocula, which allow their persistence in joints at a level similar to wild-type spirochetes, bba57 mutants are unable to induce joint inflammation. We further showed that BBA57 deficiency reduces the expression of selected “neutrophil-recruiting” chemokines and associated receptors, causing significant impairment of neutrophil chemotaxis. New approaches to combat Lyme disease may include strategies to interfere with BBA57, a novel virulence factor and a trigger of murine Lyme arthritis.

YAS, Ozlem BUYUKTANIR/0000-0002-7641-7350 WOS: 000380746400021 PubMed: 27271745 High-temperature requirement protease A (HtrA) represents a family of serine proteases that play important roles in microbial biology. Unlike the genomes of most organisms, that of Borrelia burgdorferi notably encodes a single HtrA gene product, termed BbHtrA. Previous studies identified a few substrates of BbHtrA; however, their physiological relevance could not be ascertained, as targeted deletion of the gene has not been successful. Here we show that BbhtrA transcripts are induced during spirochete growth either in the stationary phase or at elevated temperature. Successful generation of a BbhtrA deletion mutant and restoration by genetic complementation suggest a nonessential role for this protease in microbial viability; however, its remarkable growth, morphological, and structural defects during cultivation at 37 degrees C confirm a high-temperature requirement for protease activation and function. The BbhtrA-deficient spirochetes were unable to establish infection of mice, as evidenced by assessment of culture, PCR, and serology. We show that transcript abundance as well as proteolytic processing of a borrelial protein required for cell fission and infectivity, BB0323, is impaired in BbhtrA mutants grown at 37 degrees C, which likely contributed to their inability to survive in a mammalian host. Together, these results demonstrate the physiological relevance of a unique temperature-regulated borrelial protease, BbHtrA, which further enlightens our knowledge of intriguing aspects of spirochete biology and infectivity. National Science Foundation ChinaNational Natural Science Foundation of China [81501772, 81171611]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI080615, AI116620, AI083640] This work, including the efforts of Meiping Ye, was funded by National Science Foundation China (81501772 and 81171611). This work, including the efforts of Utpal Pal, was funded by NIH (AI080615 and AI116620). This work, including the efforts of X. Frank Yang, was funded by NIH (AI083640).