•HIR induced hippocampal neurons apoptosis and brain injury in young mice.•HIR affected mitochondrial dynamics in a fission-dominant manner in hippocampus.•HIR led to hippocampus injury by inducing ...Drp1 translocation to mitochondria.•Calcineurin induced Drp1 translocation by mediating Drp1 Ser637 dephosphorylation.
Hepatic ischemia reperfusion (HIR) has been found to induce brain injury and cognitive dysfunction. Dynamin-related protein 1 (Drp1) mediated mitochondrial fission involves oxidative stress, apoptosis and several neurological diseases. In this study, we investigated whether Drp1 translocation to mitochondria was implicated in HIR induced hippocampus injury in young mice, and further detected the role of calcineurin in the regulation of mitochondrial dynamics. 2-week C57BL/6 mice were chosen to make HIR model. Western blot was used to detect mitochondrial dynamics regulating proteins in whole hippocampal tissues and extracted mitochondria. Transmission electron microscopy was used to observe mitochondrial morphology. TUNEL staining and ELISA (serum S100β/NSE concentrations) were used to evaluate neurons apoptosis and brain injury respectively. Drp1 inhibitor Mdivi-1 and calcineurin inhibitor FK506 were utilized to further confirm the role of Drp1 and calcineurin. Results showed that HIR affected mitochondrial dynamics in a fission-dominant manner with translocation of Drp1 to mitochondria in hippocampus of young mice. HIR induced increased expression of calcineurin and dephosphorylation of Drp1 at Ser637 in hippocampus. Treatment with Mdivi-1 and FK506 upregulated the phosphorylation of Drp1, inhibited Drp1 translocation to mitochondria, and alleviated mitochondrial fragmentation after HIR. What’s more, Mdivi-1 and FK506 restrained cytochrome c release and cleaved caspase-3 expression, ameliorated hippocampal neurons apoptosis, and decreased serum S100β/NSE concentrations as well. These data suggest that calcineurin mediated Drp1 dephosphorylation and translocation to mitochondria play a crucial role in HIR induced mitochondrial fragmentation and neurons apoptosis in hippocampus.
Molecular understanding of neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could accelerate vaccine design and drug discovery. We analyzed 294 ...anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53-neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme 2 (ACE2)-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate the design of antigens that elicit this type of neutralizing response.
The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and ...library approach, we engineered stable HA stem antigens ("mini-HAs") based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.
Highlights • The specific mechanisms of brain injury associated with liver transplantation are not yet elucidated. • Autogenous orthotropic liver autotransplantation causes hippocampus damage as a ...remote organ. • Propofol attenuates hippocampal ischemia-reperfusion injury via modulating JAK2/STAT3 pathway.
Aquatic birds harbor diverse influenza A viruses and are a major viral reservoir in nature. The recent discovery of influenza viruses of a new H17N10 subtype in Central American fruit bats suggests ...that other New World species may similarly carry divergent influenza viruses. Using consensus degenerate RT-PCR, we identified a novel influenza A virus, designated as H18N11, in a flat-faced fruit bat (Artibeus planirostris) from Peru. Serologic studies with the recombinant H18 protein indicated that several Peruvian bat species were infected by this virus. Phylogenetic analyses demonstrate that, in some gene segments, New World bats harbor more influenza virus genetic diversity than all other mammalian and avian species combined, indicative of a long-standing host-virus association. Structural and functional analyses of the hemagglutinin and neuraminidase indicate that sialic acid is not a ligand for virus attachment nor a substrate for release, suggesting a unique mode of influenza A virus attachment and activation of membrane fusion for entry into host cells. Taken together, these findings indicate that bats constitute a potentially important and likely ancient reservoir for a diverse pool of influenza viruses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012-2013. Here we describe an antibody, F045-092, that possesses broadly neutralizing activity against ...the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045-092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045-092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics.
Inadvertent intraoperative hypothermia (core temperature <36°C) is a frequently preventable complication with several adverse consequences. Our study aimed to determine the overall incidence of ...inadvertent intraoperative hypothermia and its risk factors associated with clinical outcomes in this national survey in China.
We conducted a national cross-sectional study with 30 days postoperative follow-up from November 2014 through August 2015. A total of 3132 eligible patients underwent general anesthesia were randomly selected from 28 hospitals in the nationwide of China.
The overall incidence of intraoperative hypothermia was as high as 44.3%, in which cumulative incidence rates of hypothermia being 17.8%, 36.2%, 42.5% and 44.1% within 1 h, 2 h, 3 h and 4 h respectively following induction of anesthesia. All patients were warmed passively by covering of surgical draping, sheets or cotton blankets, whereas only 14.2% of patients received active warming with space heaters or electric heater or electronic blankets. Compared to normothermic patients, patients with hypothermia is associated with more postoperative ICU admit, longer PACU and more postoperative hospital days, but no difference in surgical site infection (SSI) rates or 30-day mortality. Several factors were shown to be associated with decreased risk of hypothermia. They are active warming (OR = 0.46, 95% CI 0.26-0.81), BMI ≥ 25 (OR = 0.54, 95% CI 0.45-0.65), higher baseline core temperature (OR = 0.04, 95% CI 0.03-0.06), and higher ambient temperature (OR = 0.83, 95% CI 0.78-0.88). Risk factors associated with an increased risk of hypothermia included major-plus surgery (OR = 1.49, 95% CI 1.23-1.79), and long anesthesia (>2 h) (OR = 2.60, 95% CI 2.09-3.24).
The incidence of intraoperative hypothermia in China is high, and the rate of active warming of patients during operation is low. Hypothermia is associated with more postoperative shivering, increased ICU admissions, and longer postoperative hospital days.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oxidative stress and excessive nitric oxide (NO) production play considerable roles in infarction-induced injury impairing cardiac functions. Crocin is the active constituent of Crocus sativus ...(saffron) with antioxidant properties and has protective effects against disturbances induced by ischemia in many organs. The present study aimed to investigate the protective effects and the underlying mechanisms of crocin on myocardial infarction (MI)-induced injury in rats in vivo. MI rats were intraperitoneally injected with crocin at different doses for seven successive days after coronary ligation. Infarct size, hemodynamic studies, and capillary density were evaluated. Levels of oxidative stress, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and their corresponding phosphorylation expressions were then measured. Crocin decreased infarct size, left ventricular (LV) end-diastolic pressure, and LV minimum dP/dt while increased LV maximum dP/dt and percentage of LV fractional shortening dose dependently. Capillary density was markedly increased after crocin treatment. Crocin enhanced superoxide dismutase activity and reduced malondialdehyde levels as well as inhibited excessive production of NO through downregulating iNOS as well as upregulating eNOS during MI-induced injury. This study reveals that crocin improves MI-induced impairments in cardiac function, which is associated with its antioxidant properties.
Current flu vaccines provide only limited coverage against seasonal strains of influenza viruses. The identification of V H 1-69 antibodies that broadly neutralize almost all influenza A group 1 ...viruses constituted a breakthrough in the influenza field. Here, we report the isolation and characterization of a human monoclonal antibody CR8020 with broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7, which cause severe human infection. The crystal structure of Fab CR8020 with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V H 1-69 group 1 antibodies. Thus, a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes and, hence, enable development of a universal flu vaccine and broad-spectrum antibody therapies.
Acute kidney injury (AKI) poses a significant concern in elderly patients undergoing laparoscopic abdominal surgery due to increased vulnerability arising from aging, comorbidities, and ...surgery-related factors. Early detection and intervention are crucial for mitigating short- and long-term consequences. This study aims to investigate the correlation between preoperative Geriatric Nutritional Risk Index (GNRI), neutrophil-to-lymphocyte ratio (NLR), and the occurrence of postoperative AKI in elderly patients undergoing laparoscopic abdominal surgery, as well as to assess the predictive value of their combined detection for postoperative AKI.BackgroundAcute kidney injury (AKI) poses a significant concern in elderly patients undergoing laparoscopic abdominal surgery due to increased vulnerability arising from aging, comorbidities, and surgery-related factors. Early detection and intervention are crucial for mitigating short- and long-term consequences. This study aims to investigate the correlation between preoperative Geriatric Nutritional Risk Index (GNRI), neutrophil-to-lymphocyte ratio (NLR), and the occurrence of postoperative AKI in elderly patients undergoing laparoscopic abdominal surgery, as well as to assess the predictive value of their combined detection for postoperative AKI.A retrospective study involving 347 elderly patients (aged 60 years or older) undergoing laparoscopic abdominal surgery explored the relationship between preoperative GNRI, NLR, and postoperative AKI. GNRI was calculated based on serum albumin and body weight ratios, while NLR was derived from preoperative blood tests.MethodsA retrospective study involving 347 elderly patients (aged 60 years or older) undergoing laparoscopic abdominal surgery explored the relationship between preoperative GNRI, NLR, and postoperative AKI. GNRI was calculated based on serum albumin and body weight ratios, while NLR was derived from preoperative blood tests.The combined GNRI and NLR test demonstrated superior predictive value (area under the curve AUC = 0.87) compared to individual markers. Multivariate logistic analysis identified age, American Society of Anesthesiologists (ASA) grade, comorbidities, preoperative GNRI, and NLR as independent risk factors for AKI. Correlation analysis affirmed a negative correlation between preoperative GNRI and AKI severity, and a positive correlation between preoperative NLR and AKI severity.ResultsThe combined GNRI and NLR test demonstrated superior predictive value (area under the curve AUC = 0.87) compared to individual markers. Multivariate logistic analysis identified age, American Society of Anesthesiologists (ASA) grade, comorbidities, preoperative GNRI, and NLR as independent risk factors for AKI. Correlation analysis affirmed a negative correlation between preoperative GNRI and AKI severity, and a positive correlation between preoperative NLR and AKI severity.The preoperative GNRI and NLR have clinical values in predicting postoperative AKI in elderly patients undergoing laparoscopic abdominal surgery.ConclusionThe preoperative GNRI and NLR have clinical values in predicting postoperative AKI in elderly patients undergoing laparoscopic abdominal surgery.
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