DNA-Packing Portal and Capsid-Associated Tegument Complexes in the Tumor Herpesvirus KSHV.

Assembly of Kaposi's sarcoma-associated herpesvirus (KSHV) begins at a bacteriophage-like portal complex that nucleates formation of an icosahedral capsid with capsid-associated tegument complexes (CATCs) and facilitates translocation of an ∼150-kb dsDNA genome, followed by acquisition of a pleomorphic tegument and envelope. Because of deviation from icosahedral symmetry, KSHV portal and tegument structures have largely been obscured in previous studies. Using symmetry-relaxed cryo-EM, we determined the in situ structure of the KSHV portal and its interactions with surrounding capsid proteins, CATCs, and the terminal end of KSHV's dsDNA genome. Our atomic models of the portal and capsid/CATC, together with visualization of CATCs' variable occupancy and alternate orientation of CATC-interacting vertex triplexes, suggest a mechanism whereby the portal orchestrates procapsid formation and asymmetric long-range determination of CATC attachment during DNA packaging prior to pleomorphic tegumentation/envelopment. Structure-based mutageneses confirm that a triplex deep binding groove for CATCs is a hotspot that holds promise for antiviral development.

Cryo-EM structures of herpes simplex virus type 1 portal vertex and packaged genome.

Herpesviruses are enveloped viruses that are prevalent in the human population and are responsible for diverse pathologies, including cold sores, birth defects and cancers. They are characterized by a highly pressurized pseudo-icosahedral capsid-with triangulation number (T) equal to 16-encapsidating a tightly packed double-stranded DNA (dsDNA) genome1-3. A key process in the herpesvirus life cycle involves the recruitment of an ATP-driven terminase to a unique portal vertex to recognize, package and cleave concatemeric dsDNA, ultimately giving rise to a pressurized, genome-containing virion4,5. Although this process has been studied in dsDNA phages6-9-with which herpesviruses bear some similarities-a lack of high-resolution in situ structures of genome-packaging machinery has prevented the elucidation of how these multi-step reactions, which require close coordination among multiple actors, occur in an integrated environment. To better define the structural basis of genome packaging and organization in herpes simplex virus type 1 (HSV-1), we developed sequential localized classification and symmetry relaxation methods to process cryo-electron microscopy (cryo-EM) images of HSV-1 virions, which enabled us to decouple and reconstruct hetero-symmetric and asymmetric elements within the pseudo-icosahedral capsid. Here we present in situ structures of the unique portal vertex, genomic termini and ordered dsDNA coils in the capsid spooled around a disordered dsDNA core. We identify tentacle-like helices and a globular complex capping the portal vertex that is not observed in phages, indicative of herpesvirus-specific adaptations in the DNA-packaging process. Finally, our atomic models of portal vertex elements reveal how the fivefold-related capsid accommodates symmetry mismatch imparted by the dodecameric portal-a longstanding mystery in icosahedral viruses-and inform possible DNA-sequence recognition and headful-sensing pathways involved in genome packaging. This work showcases how to resolve symmetry-mismatched elements in a large eukaryotic virus and provides insights into the mechanisms of herpesvirus genome packaging.

Pediatric-inspired regimen for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: a prospective study from China.

Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

Application of sourdough in gluten-free bakery products.

ABSTRACTSIn recent years, the demand for gluten-free (GF) bakery products has grown rapidly due to the remarkable rising number of celiac patients and the increasing health awareness of GF products. However, GF products generally suffer from defects such as poor sensorial level, low nutritional value, high prices and short shelf life. Sourdough is the important starter culture applied in bakery field, and it has been proven to be ideal for enhancing the overall quality of bakery products. This review aims to systematically reviewed the application of sourdough in GF bakery products and its improvement to GF bakery products in terms of texture, shelf life, nutrition and flavor. Its positive effects derive from the complex metabolic activities of sourdough microorganisms, such as acidification, proteolysis, production of exopolysaccharides (EPS), activation of endogenous enzymes, and production of antibacterial substances. Finally, researchers are encouraged to expand the use of sourdough in GF bakery products to increase the variety of GF products. And the technical and nutritional potential of sourdough should be developed more widely.

Tangeretin attenuates acute lung injury in septic mice by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis.

OBJECTIVE: NLRP3 inflammasome-mediated pyroptosis of macrophage acts essential roles in the progression of sepsis-induced acute lung injury (ALI). Tangeretin (TAN), enriched in citrus fruit peel, presents anti-oxidative and anti-inflammatory effects. Here, we aimed to explore the potentially protective effect of TAN on sepsis-induced ALI, and the underlying mechanism of TAN in regulating NLRP3 inflammasome. MATERIAL AND METHODS: The effect of TAN on sepsis-induced ALI and NLRP3 inflammasome-mediated pyroptosis of macrophage were examined in vivo and in vitro using a LPS-treated mice model and LPS-induced murine macrophages, respectively. The mechanism of TAN regulating the activation of NLRP3 inflammasome in sepsis-induced ALI was investigated with HE staining, Masson staining, immunofluorescent staining, ELISA, molecular docking, transmission electron microscope detection, qRT-PCR, and western blot. RESULTS: TAN could evidently attenuate sepsis-induced ALI in mice, evidenced by reducing pulmonary edema, pulmonary congestion and lung interstitial fibrosis, and inhibiting macrophage infiltration in the lung tissue. Besides, TAN significantly suppressed inflammatory cytokine IL-1ß and IL-18 expression in the serum or bronchoalveolar lavage fluid (BALF) samples of mice with LPS-induced ALI, and inhibited NLRP3 inflammasome-mediated pyroptosis of macrophages. Furthermore, we found TAN inhibited ROS production, preserved mitochondrial morphology, and alleviated excessive mitochondrial fission in LPS-induced ALI in mice. Through bioinformatic analysis and molecular docking, Polo-like kinase 1 (PLK1) was identified as a potential target of TAN for treating sepsis-induced ALI. Moreover, TAN significantly inhibited the reduction of PLK1 expression, AMP-activated protein kinase (AMPK) phosphorylation, and Dynamin related protein 1 (Drp1) phosphorylation (S637) in LPS-induced ALI in mice. In addition, Volasertib, a specific inhibitor of PLK1, abolished the protective effects of TAN against NLRP3 inflammasome-mediated pyroptosis of macrophage and lung injury in the cell and mice septic models. CONCLUSION: TAN attenuates sepsis-induced ALI by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis, and TAN is a potentially therapeutic candidate against ALI through inhibiting pyroptosis.

Development of a time-resolved immunochromatographic test strip for rapid and quantitative determination of retinol-binding protein 4 in urine.

Urine retinol-binding protein 4 (RBP4) has recently been reported as a novel earlier biomarker of chronic kidney disease (CKD) which is a global public health problem with high morbidity and mortality. Accurate and rapid detection of urine RBP4 is essential for early monitor of impaired kidney function and prevention of CKD progression. In the present study, we developed a time-resolved fluorescence immunochromatographic test strip (TRFIS) for the quantitative and rapid detection of urine RBP4. This TRFIS possessed excellent linearity ranging from 0.024 to 12.50 ng/mL for the detection of urine RBP4, and displayed a good linearity (Y = 239,581 × X + 617,238, R2 = 0.9902), with the lowest visual detection limit of 0.049 ng/mL. This TRFIS allows for quantitative detection of urine RBP4 within 15 min and shows high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 8%, respectively. Additionally, this TRFIS was applied to detect RBP4 in the urine samples from healthy donors and patients with CKD, and the results of TRFIS could efficiently discern the patients with CKD from the healthy donors. The developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range, and is suitable for rapid and quantitative determination of urine RBP4.

Molecular epidemiology and characteristics of respiratory syncytial virus among hospitalized children in Guangzhou, China.

BACKGROUND: Human respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection and hospitalization, especially in children. Highly mutagenic nature and antigenic diversity enable the RSV to successfully survive in human population. We conducted a molecular epidemiological study during 2017-2021 to investigate the prevalence and genetic characteristics of RSV. METHODS: A total of 6499 nasopharyngeal (NP) swabs were collected from hospitalized children at Department of Pediatrics, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, China. All NP swab specimens were preliminary screened for common respiratory viruses and then tested for RSV using specific PCR assays. Partial G genes of RSV were amplified for phylogenetic analysis and genetic characterization. RESULTS: The overall detection rate for common respiratory viruses was 16.12% (1048/6499). Among those, 405 specimens (6.20%, 405/6499) were found positive for RSV. The monthly distribution of RSV and other respiratory viruses was variable, and the highest incidence was recorded in Autumn and Winter. Based on the sequencing of hypervariable region of G gene, 93 RSV sequences were sub-grouped into RSV-A (56, 60.2%) and RSV-B (37, 39.8%). There was no coinfection of RSV-A and RSV-B in the tested samples. Phylogenetic analysis revealed that RSV-A and RSV-B strains belonged to ON1 and BA9 genotypes respectively, indicating predominance of these genotypes in Guangzhou. Several substitutions were observed which may likely change the antigenicity and pathogenicity of RSV. Multiple glycosylation sites were noticed, demonstrating high selection pressure on these genotypes. CONCLUSION: This study illustrated useful information about epidemiology, genetic characteristics, and circulating genotypes of RSV in Guangzhou China. Regular monitoring of the circulating strains of RSV in different parts of China could assist in the development of more effective vaccines and preventive measures.

Pectin mediates the mechanism of host blood glucose regulation through intestinal flora.

Pectin is a complex polysaccharide found in plant cell walls and interlayers. As a food component, pectin is benefit for regulating intestinal flora. Metabolites of intestinal flora, including short-chain fatty acids (SCFAs), bile acids (BAs) and lipopolysaccharides (LPS), are involved in blood glucose regulation. SCFAs promote insulin synthesis through the intestine-GPCRs-derived pathway and hepatic adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway to promote hepatic glycogen synthesis. On the one hand, BAs stimulate intestinal L cells and pancreatic α cells to secrete Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) through receptors G protein-coupled receptor (TGR5) and farnesoid X receptor (FXR). On the other hand, BAs promote hepatic glycogen synthesis through AMPK pathway. LPS inhibits the release of inflammatory cytokines through Toll-like receptors (TLRs)-myeloid differentiation factor 88 (MYD88) pathway and mitogen-activated protein kinase (MAPK) pathway, thereby alleviating insulin resistance (IR). In brief, both SCFAs and BAs promote GLP-1 secretion through different pathways, employing strategies of increasing glucose consumption and decreasing glucose production to maintain normal glucose levels. Notably, pectin can also directly inhibit the release of inflammatory cytokines through the -TLRs-MYD88 pathway. These data provide valuable information for further elucidating the relationship between pectin-intestinal flora-glucose metabolism.

Ultrasound-assisted extraction of tamarind xyloglucan: an effective approach to reduce the viscosity and improve the α-amylase inhibition of xyloglucan.

BACKGROUND: Water extraction (WE) is the classical extraction method for tamarind xyloglucan (XyG), but its low yield, high viscosity and poor dispersion in aqueous solution are not conducive to the industrial applications. To promote the industrial application of tamarind XyG, an ultrasonic-assisted extraction (UAE) method for extracting low-viscosity XyG from tamarind kernel powder was proposed. RESULTS: The yield of UAE-XyG was higher (502.33 ± 0.036 g kg-1 ) than that of WE-XyG (163.43 ± 0.085 g kg-1 ). UAE reduced the molecular weight, monosaccharide content and apparent viscosity of XyG. The hypoglycemic experiment in vitro showed that UAE-XyG had a stronger inhibitory effect on α-amylase activity than WE-XyG, but its glucose dialysis retardation index was lower. CONCLUSION: In sum, UAE is a type of extraction method that could effectively improve the yield of XyG and reduce its viscosity to expand its application without reducing its physiological activity. UAE exhibits an excellent potential in the extraction of XyG. © 2022 Society of Chemical Industry.

High total bilirubin-to-uric acid ratio predicts poor sleep quality after acute ischemic stroke: a prospective nested case-control study.

BACKGROUND: Sleep disorders are prevalent after stroke, resulting in high recurrence rates and mortality. But the biomarkers of sleep disorders in stroke patients remain to be elucidated. This study aimed to explore the relationship between total bilirubin-to-uric acid ratio (TUR) and sleep quality after acute ischemic stroke (AIS). METHODS: Three hundred twenty-six AIS patients were recruited and followed up 1 month after stroke in our study. Serum total bilirubin and uric acid levels were obtained within 24 h after admission. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality 1 month after stroke. We conducted receiver operating characteristic (ROC) curve analysis and screened the optimal biomarker to differentiate sleep disorders after stroke. Then the TUR was stratified according to the best cut-off value (0.036) of the ROC and further analysed by binary logistic regression analysis. Additionally, the interaction was used to explore the difference in its effect on post-stroke sleep quality in different subgroups. RESULTS: Three hundred thirty-one patients (40.2%) were considered as having poor sleep quality during the one-month follow-up. Compared to patients with good sleep, patients with poor sleep were more likely to have higher TUR (IQR), 0.05 (0.03-0.06) versus 0.03 (0.02-0.04), P < 0.001. After adjusting for confounding factors, binary regression analysis demonstrated that a high TUR (≥0.036) was independently related to post-stroke poor sleep quality (OR = 3.75, 95% CI = 2.02-6.96, P < 0.001). CONCLUSIONS: High TUR is associated with an increased risk of poor sleep quality in AIS patients, especially in females, diabetics, and patients with hyperlipidaemia.

The prognostic factors in acute myeloid leukaemia with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm).

The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p < 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p < 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.

Puerarin Alleviates LPS-Induced H9C2 Cell Injury by Inducing Mitochondrial Autophagy.

ABSTRACT: Sepsis leads to the damage of multiple organs, and thereby adversely affects the cardiovascular system. At present, no effective method has been found to treat myocardial injury caused by sepsis. Although Puerarin was reported to attenuate lipopolysaccharide (LPS)-induced mitochondrial injury in H9C2 cells, the effects of Puerarin in sepsis-induced myocardial injury remain unclear. In this study, H9C2 cells were stimulated with LPS, CCK-8 assays were performed to assess cell viability, and flow cytometry and TUNEL staining were used to assess cell apoptosis. Levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and enzyme activity were investigated using commercial kits. Reactive oxygen species (ROS) levels in H9C2 cells were detected by flow cytometry. Autophagosomes in the mitochondria of H9C2 cells were observed by transmission electron microscope, and protein expression was assessed by western blotting. Furthermore, in vivo experiments were applied to test the function of Puerarin in sepsis. We found that Puerarin significantly reversed LPS-induced decreases in H9C2 cell viability by inhibiting apoptosis. The ROS levels in H9C2 cells were significantly upregulated by LPS, but that effect was markedly reduced by Puerarin. In addition, Puerarin attenuated LPS-induced mitochondrial injury in H9C2 cells by regulating dynamin-related protein 1 (Drp1) and mitofusin 1 (MFN1). LPS decreased enzyme activity and reduced the levels of ADP, ALP, and AMP in mitochondria; however, those effects were reversed by Puerarin. Puerarin and Torin1 reversed LPS-induced inhibition of autophagy in the mitochondria of H9C2 cells via mediation of p62, LC3B, Pink1, and Parkin. Puerarin notably inhibited the progression of sepsis in vivo . Puerarin inhibited LPS-induced H9C2 cell injury by inducing mitochondrial autophagy, which acts as a mechanism for preventing myocardial injury caused by sepsis.

Low serum transthyretin levels predict stroke-associated pneumonia.

BACKGROUND AND AIMS: Stroke-associated pneumonia (SAP) is commonly seen in ischemic stroke patients. Low transthyretin levels are found to be correlated with stroke. This study aims to investigate the potential relationship between transthyretin levels and SAP. METHODS AND RESULTS: In total, 920 patients were involved in our study. Serum transthyretin levels were measured within 24 h at admission. We defined SAP according to the modified Centers for Disease Control criteria. In the study population, 123 (13.4%, 77 men, 46 women) were diagnosed with SAP. In the multivariable analysis, we found that serum transthyretin levels were significantly lower in SAP compared with non-SAP patients (231 ± 80 vs. 279 ± 75; P < 0.001) after adjusting for confounders. Meanwhile, we discovered that low transthyretin levels (≤252 mg/L) were independently associated with the development of SAP (OR 3.370; 95% CI: 1.763-6.441; P < 0.001). Moreover, patients with SAP had a worse clinical outcome than those without SAP at discharge. In addition, dysphagia, leukocyte count and NLR (neutrophil-to-lymphocyte ratio) were also found to be associated with SAP. CONCLUSION: We found that low transthyretin levels significantly increased the risk of SAP. Patients with high risk of developing SAP could be early identified and prevented timely.

Hypertension as an independent risk factor for severity and mortality in patients with COVID-19: a retrospective study.

PURPOSE OF THE STUDY: Hypertension is one of the most common comorbidities in COVID-19 pneumonia. However, whether it is an independent factor on the severity and mortality of COVID-19 has not been studied. STUDY DESIGN: In this study, 736 patients with a PCR-confirmed diagnosis of COVID-19 were included from 12 January 2020 to 25 March 2020. All patients were divided into two groups according to whether or not they were hypertensive. After propensity score matching (PSM) to remove the interference of mismatches in the baseline data, the clinical characteristics and outcomes of angiotensin II receptor blocker (ARB)/ACE inhibitors application were analysed. RESULTS: A total of 220 (29.9%) patients were hypertensive, and 516 (70.1%) patients were not hypertensive. PSM eliminated demographic and comorbidity differences between the two groups. Of all participants, 32 patients died (4.3% mortality), including 17 out of 220 in the hypertension group (7.7%) and 15 out of 516 in the non-hypertension group (2.9%). The incidence of intensive care unit (ICU) stay in the hypertension group (12.8%) was higher than in the non-hypertension group (5.3%) (p<0.05). Logistic regression analysis showed that hypertension was an independent risk factor for death, not other comorbidities. Kaplan-Meier analysis showed that mortality was higher in the hypertension group than in the non-hypertension group before and after PSM (p<0.05). There was no statistically significant difference in ICU therapy, mortality and hospitalisation time between hypertensive patients with or without ARBs/ACE inhibitors (p>0.05). CONCLUSION: Hypertension was an independent risk factor for the severity and mortality of patients with COVID-19. ARBs/ACE inhibitors should not be discontinued in hypertensive patients with COVID-19.

Molecular typing of human adenoviruses among hospitalized patients with respiratory tract infections in a tertiary Hospital in Guangzhou, China between 2017 and 2019.

BACKGROUND: Human Adenoviruses (HAdVs) cause a wide array of illnesses in all age groups. They particularly cause frequent morbidity among children. In China, human adenovirus types 3, 4, 7, 11, 14, 21, and 55 have caused at least seven outbreaks since 2000. However, limited studies are available regarding the epidemiological patterns and diversity of HAdVs types among hospitalized patients with respiratory tract infections (RTIs). METHODS: To understand the epidemiology and subtype distribution of HAdV infections associated with RTIs in China, nasal swab (NS) clinical samples were collected from 4129 patients in a Guangzhou hospital between August 2017 and October 2019. PCR, sequencing, and phylogenetic analysis were performed on these specimens to identify HAdV subtypes. RESULTS: HAdV was successfully sequenced in 99 (2.4%) of the 4129 NS specimens, with the highest HAdV prevalence (6.3%) found in children between the ages of 5 and 10 years. Among HAdV-positive specimens, the most prevalent genotypes identified were HAdV-B3 (55.6%) and HAdV-B7 (25.3%). The most common symptoms in the HAdV-infected patients were fever (100%), cough (80.8%), and rhinorrhea (71.8%). HAdV infections were detected throughout the year with a relatively higher prevalence in summer. CONCLUSION: All ages suffer adenovirus infections, but young children are at the greatest risk. This study data demonstrates that at least three species of HAdVs (species B, C, and E) are circulating in Guangzhou City, China. As antiviral therapies and type-specific vaccines become available, such epidemiological data will be useful in guiding therapy and public health interventions.

Uric acid played a role in the association between gender and deep vein thrombosis in patients with stroke.

BACKGROUND AND AIMS: Gender-specific differences were found in serum uric acid (SUA) levels and the risk of isolated distal deep vein thrombosis (IDDVT). This study aimed to explore the association among gender, SUA, and IDDVT in stroke patients. METHODS AND RESULTS: Finally, 3404 patients were recruited and divided into two groups: IDDVT (n = 1233) and Non-IDDVT (n = 2171) groups. Propensity score matching (PSM) was conducted to match the patients. Binary logistic regression was adopted to explore the association between SUA and IDDVT, with the SUA divided into quartiles. After PSM, 975 patients were included in each group. Non-IDDVT group had a larger proportion of male than IDDVT group (64.9% vs. 52.7%, p < 0.001). Moreover, males showed higher SUA levels than females (316.7 ± 102.1 vs. 261.8 ± 94.0 µmol/L, t = 12.1, p < 0.001). The highest quartile of SUA (≥346 µmol/L) showed a lower risk of IDDVT (OR = 0.629, p = 0.001), while the lowest quartile (≤225 µmol/L) showed a higher risk of IDDVT (OR = 1.361, p = 0.022). CONCLUSION: In patients with stroke, SUA played a protective role in IDDVT. Females had a higher risk of IDDVT, which may be owing to the lower SUA levels than males. In clinical practice, more attention should be paid to the risk of IDDVT in females, especially those with lower SUA levels.

Individualized predictions of early isolated distal deep vein thrombosis in patients with acute ischemic stroke: a retrospective study.

BACKGROUND: Although isolated distal deep vein thrombosis (IDDVT) is a clinical complication for acute ischemic stroke (AIS) patients, very few clinicians value it and few methods can predict early IDDVT. This study aimed to establish and validate an individualized predictive nomogram for the risk of early IDDVT in AIS patients. METHODS: This study enrolled 647 consecutive AIS patients who were randomly divided into a training cohort (n = 431) and a validation cohort (n = 216). Based on logistic analyses in training cohort, a nomogram was constructed to predict early IDDVT. The nomogram was then validated using area under the receiver operating characteristic curve (AUROC) and calibration plots. RESULTS: The multivariate logistic regression analysis revealed that age, gender, lower limb paralysis, current pneumonia, atrial fibrillation and malignant tumor were independent risk factors of early IDDVT; these variables were integrated to construct the nomogram. Calibration plots revealed acceptable agreement between the predicted and actual IDDVT probabilities in both the training and validation cohorts. The nomogram had AUROC values of 0.767 (95% CI: 0.742-0.806) and 0.820 (95% CI: 0.762-0.869) in the training and validation cohorts, respectively. Additionally, in the validation cohort, the AUROC of the nomogram was higher than those of the other scores for predicting IDDVT. CONCLUSIONS: The present nomogram provides clinicians with a novel and easy-to-use tool for the prediction of the individualized risk of IDDVT in the early stages of AIS, which would be helpful to initiate imaging examination and interventions timely.

Therapeutic perspectives of heat shock proteins and their protein-protein interactions in myocardial infarction.

Myocardial infarction (MI) is one of major causes of human death around the world. Heat shock proteins (HSPs) are a large family of conserved proteins, which can promote correct protein folding, maintain protein stability, and regulate cell metabolism, cellular homeostasis and other biological processes as molecular chaperones. Notable, HSPs are involved in MI-related pathophysiology, such as apoptosis, inflammatory response and oxidative stress. Here, we review recent studies and systematically summarize the role of HSPs in MI and myocardial ischemia/reperfusion injury (MIRI) and discuss the role of direct and indirect protein-protein interactions (PPI) of HSP complexes in the pathophysiology and therapeutic strategies of myocardial infarction. A comprehensive understanding of the cardioprotective role of PPIs of HSP complexes in myocardial infarction can provide new insights for MI or MIRI therapy.

Differentiation and Characterization of Excitatory and Inhibitory Synapses by Cryo-electron Tomography and Correlative Microscopy.

As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure ∼12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25-60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABAA receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions.SIGNIFICANCE STATEMENT To understand functional properties of neuronal synapses, it is desirable to analyze their structure at molecular resolution. We have developed an integrative approach combining cryo-electron tomography and correlative fluorescence microscopy to visualize 3D ultrastructural features of intact excitatory and inhibitory synapses in their native state. Our approach shows that inhibitory synapses contain uniform thin sheet-like postsynaptic densities (PSDs), while excitatory synapses contain previously known mesh-like PSDs. We discovered "discus-shaped" ellipsoidal synaptic vesicles, and their distributions along with regular spherical vesicles in synaptic types are characterized. High-resolution tomograms further allowed identification of putative neurotransmitter receptors and their heterogeneous interaction with synaptic scaffolding proteins. The specificity and resolution of our approach enables precise in situ analysis of ultrastructural organization underlying distinct synaptic functions.