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Abstract Peripheral nerve injury (PNI) occurs due to damage of peripheral nerves, with healthcare professionals playing significant roles in PNI rehabilitation. This study aimed to explore the knowledge, attitudes, and practices (KAP) towards PNI rehabilitation among healthcare professionals. This cross-sectional study was conducted on June 2023 in China and healthcare professionals were enrolled. A total of 611 valid questionnaires were collected, with 62.52% female respondents. Mean scores for KAP were 14.26 ± 2.044 (possible range: 0–19), 29.77 ± 3.622 (possible range: 7–35), and 41.55 ± 9.523 (possible range: 11–55), respectively. Multivariate logistic regression revealed positive associations of professional titles (OR = 1.743, 95% CI: 1.083–2.804), occupation (OR = 1.833, 95% CI: 1.151–2.919), and involvement in treatment or care of PNI patients (OR = 1.462, 95% CI: 1.024–2.088) with knowledge. Knowledge (OR = 1.155, 95% CI: 1.042–1.280), gender (OR = 2.140, 95% CI: 1.255–3.646), education (OR = 2.258, 95% CI: 1.131–4.507), and involvement in treatment or care of PNI patients (OR = 2.463, 95% CI: 1.460–4.155) were positively associated with attitude. Attitude (OR = 1.214, 95% CI: 1.148–1.283), bachelor's degree education (OR = 0.548, 95% CI: 0.326–0.919), master's degree or higher (OR = 0.545, 95% CI: 0.308–0.964), having rehabilitation training for PNI (OR = 2.485, 95% CI: 1.633–3.781), and involvement in treatment or care of PNI patients (OR = 2.093, 95% CI: 1.395–3.138) were independently associated with practice. Healthcare professionals exhibited moderate knowledge, positive attitudes, and moderate practices towards the PNI rehabilitation. Those involved in the treatment or care of PNI have significantly higher KAP. Targeted interventions were needed to enhance understanding and promote proactive engagement in clinical practice.

Abstract Background The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application. Results The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest. Conclusions The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization. Graphical Abstract

Abstract The triglyceride glucose-body mass index (TyG-BMI) is a convenient and clinically significant indicator of insulin resistance. This study aims to investigate the correlation between TyG-BMI and the onset of new-onset diabetes and determine an optimal reflection point for TyG-BMI. An analysis was conducted on 1917 participants from the risk evaluation of cancers in Chinese diabetic individuals: a lONgitudinal (REACTION) study. Participants were categorized based on their TyG-BMI, and the relationship between TyG-BMI and the incidence of new-onset diabetes was explored through logistic regression models, smoothed curve fitting with restricted cubic spline, and a two-piecewise logistic regression model. The mean age of the participants was 57.60 ± 8.89 years, with 66.5% being females. The mean TyG-BMI was 223.3 ± 32.8. Ultimately, 137 individuals (7.1%) progressed to diabetes after three years. After adjusting for covariates, TyG-BMI exhibited a positive correlation with new-onset diabetes (odd ratios (OR) for each standard deviation increase = 1.330, 95% CI 1.110–1.595). The relationship between TyG-BMI and new-onset diabetes was non-linear, with a inflcetion point at 202.9. This study reveals a positive non-linear relationship between TyG-BMI and the risk of new-onset diabetes in Chinese middle-aged and elderly individuals. When TyG-BMI exceeds 202.9, there is a significantly heightened risk of new-onset diabetes. These findings offer valuable insights for preventing new-onset diabetes.

Abstract While several COVID-19 vaccines have been in use, more effective and durable vaccines are needed to combat the ongoing COVID-19 pandemic. Here, we report highly immunogenic self-assembling SARS-CoV-2 spike-HBsAg nanoparticles displaying a six-proline-stabilized WA1 (wild type, WT) spike S6P on a HBsAg core. These S6P-HBsAgs bound diverse domain-specific SARS-CoV-2 monoclonal antibodies. In mice with and without a HBV pre-vaccination, DNA immunization with S6P-HBsAgs elicited significantly more potent and durable neutralizing antibody (nAb) responses against diverse SARS-CoV-2 strains than that of soluble S2P or S6P, or full-length S2P with its coding sequence matching mRNA-1273. The nAb responses elicited by S6P-HBsAgs persisted substantially longer than by soluble S2P or S6P and appeared to be enhanced by HBsAg pre-exposure. These data show that genetic delivery of SARS-CoV-2 S6P-HBsAg nanoparticles can elicit greater and more durable nAb responses than non-nanoparticle forms of stabilized spike. Our findings highlight the potential of S6P-HBsAgs as next generation genetic vaccine candidates against SARS-CoV-2.

Abstract Background Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)‐based therapy can ameliorate high fat‐diet (HFD) and immobilization (IM)‐induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC‐derived exosomes (MSC‐EXO) on diabetes‐ and obesity‐induced muscle atrophy. Methods Diabetic db/db mice, mice fed with high‐fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC‐EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross‐sectional area (CSA) was used to evaluate muscle mass. RNA‐seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. Results hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P

Vaccines against the WA1 SARS-CoV2 strain confer protection against other variants. However, the mechanisms underlying cross-protection are not fully understood. Here, the authors develop a method for rapid analysis of single B cells from patient samples and show that infection with a variant elicits convergent, public B cell responses to other variants.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a primary target of neutralizing antibodies and a key component of licensed vaccines. Substantial mutations in RBD, however, enable current variants to escape immunogenicity generated by vaccination with the ancestral (WA1) strain. Here, we produce and assess self-assembling nanoparticles displaying RBDs from WA1 and BA.5 strains by using the SpyTag:SpyCatcher system for coupling. We observed both WA1- and BA.5-RBD nanoparticles to degrade substantially after a few days at 37 °C. Incorporation of nine RBD-stabilizing mutations, however, increased yield ~five-fold and stability such that more than 50% of either the WA1- or BA.5-RBD nanoparticle was retained after one week at 37 °C. Murine immunizations revealed that the stabilized RBD-nanoparticles induced ~100-fold higher autologous neutralization titers than the prefusion-stabilized (S2P) spike at a 2 μg dose. Even at a 25-fold lower dose where S2P-induced neutralization titers were below the detection limit, the stabilized BA.5-RBD nanoparticle induced homologous titers of 12,795 ID50 and heterologous titers against WA1 of 1767 ID50. Assessment against a panel of β-coronavirus variants revealed both the stabilized BA.5-RBD nanoparticle and the stabilized WA1-BA.5-(mosaic)-RBD nanoparticle to elicit much higher neutralization breadth than the stabilized WA1-RBD nanoparticle. The extraordinary titer and high neutralization breadth elicited by stabilized RBD nanoparticles from strain BA.5 make them strong candidates for next-generation COVID-19 vaccines.

Summary: Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or TBK1 alleviates podocyte injury and improves renal functions in cultured podocytes or mouse models of diabetes and obesity. These results suggest that the mtDNA-cGAS-STING pathway promotes podocyte injury and is a potential therapeutic target for DKD or other obesity-related kidney diseases.

New vaccine delivery technologies, such as mRNA, have played a critical role in the rapid and efficient control of SARS-CoV-2, helping to end the COVID-19 pandemic. Enveloped virus-like particles (eVLPs) are often more immunogenic than protein subunit immunogens and could be an effective vaccine platform. Here, we investigated whether the genetic delivery of eVLPs could achieve strong immune responses in mice as previously reported with the immunization of in vitro purified eVLPs. We utilized Newcastle disease virus-like particles (NDVLPs) to display SARS-CoV-2 prefusion-stabilized spikes from the WA-1 or Beta variant (S-2P or S-2Pᵦ, respectively) and evaluated neutralizing murine immune responses achieved by a single-gene-transcript DNA construct for the WA-1 or Beta variant (which we named S-2P-NDVLP-1T and S-2Pᵦ-NDVLP-1T, respectively), by multiple-gene-transcript DNA constructs for the Beta variant (S-2Pᵦ-NDVLP-3T), and by a protein subunit–DNA construct for the WA-1 or Beta variant (S-2P-TM or S-2Pᵦ-TM, respectively). The genetic delivery of S-2P-NDVLP-1T or S-2Pᵦ-NDVLP-1T yielded modest neutralizing responses after a single immunization and high neutralizing responses after a second immunization, comparable to previously reported results in mice immunized with in vitro purified S-2P-NDVLPs. Notably, genetic delivery of S-2Pᵦ-NDVLP-3T yielded significantly higher neutralizing responses in mice after a second immunization than S-2Pᵦ-NDVLP-1T or S-2Pᵦ-TM. Genetic delivery also elicited high spike-specific T-cell responses. Collectively, these results indicate that genetic delivery can provide an effective means to immunize eVLPs and that a multiple-gene transcript eVLP platform may be especially efficacious and inform the design of improved vaccines.

Abstract Background Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on β-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results Our results showed that bmMDEs reversed diabetic β-cell dedifferentiation and improved β-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function. Conclusions These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM.

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants.

Abstract Background Mesenchymal stem cell (MSC)-based therapy is currently considered to be an effective treatment strategy for diabetes and hepatic disorders, such as liver cirrhosis and non-alcoholic fatty liver disease. Exosomes are important mediators of cellular connections, and increasing evidence has suggested that exosomes derived from MSCs may be used as direct therapeutic agents; their mechanisms of action, however, remain largely unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSC-derived exosomes (HucMDEs) on hepatic glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). Methods HucMDEs were used to treat T2DM rats, as well as palmitic acid (PA)-treated L-O2 cells, in order to determine the effects of HucMDEs on hepatic glucose and lipid metabolism. To evaluate the changes in autophagy and potential signaling pathways, autophagy-related proteins (BECN1, microtubule-associated protein 1 light chain 3 beta [MAP 1LC3B]), autophagy-related genes (ATGs, ATG5, and ATG7), AMP-activated protein kinase (AMPK), and phosphorylated AMPK (p-AMPK) were assessed by Western blotting. Results HucMDEs promoted hepatic glycolysis, glycogen storage, and lipolysis, and reduced gluconeogenesis. Additionally, autophagy potentially contributed to the effects of HucMDE treatment. Transmission electron microscopy revealed an increased formation of autophagosomes in HucMDE-treated groups, and the autophagy marker proteins, BECN1 and MAP 1LC3B, were also increased. Moreover, autophagy inhibitor 3-methyladenine significantly reduced the effects of HucMDEs on glucose and lipid metabolism in T2DM rats. Based on its phosphorylation status, we found that the AMPK signaling pathway was activated and induced autophagy in T2DM rats and PA-treated L-O2 cells. Meanwhile, the transfection of AMPK siRNA or application of the AMPK inhibitor, Comp C, weakened the therapeutic effects of HucMDEs on glucose and lipid metabolism. Conclusions These findings demonstrate that HucMDEs improved hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway, which provides novel evidence suggesting the potential for HucMDEs in clinically treating T2DM patients.

In this study, a ratio-dependent predator-prey model is investigated. The local stability and global stability of the nonnegative boundary equilibrium and positive equilibrium of the model are discussed, respectively. Sufficient condition is obtained for the existence of Hopf bifurcation at the positive equilibrium.

Background. This research evaluated the link between normal thyroid hormone levels and sarcopenia in patients with type 2 diabetes mellitus (T2DM). Methods. This cross-sectional study enrolled 312 euthyroid patients with T2DM from Qilu Hospital of the Shandong University, China. Body composition, grip strength, and physical performance were assessed as per the 2019 consensus guidelines of the Asian Working Group for Sarcopenia. Binary logistic regression was used to examine the correlation between thyroid hormone levels and sarcopenia and its components. Results. The prevalence of sarcopenia was 26.9%. Following adjustments for potential confounders, a high-normal serum free triiodothyronine (FT3) level (odds ratio OR=0.522, 95% confidence interval (CI): 0.304–0.895, P=0.018), a low-normal serum free thyroxine (FT4) level (OR=1.126, 95% CI: 1.009–1.258, P=0.034), and a heightened FT3/FT4 ratio (OR=0.923, 95% CI: 0.879–0.969, P=0.001) were linked to a low prevalence of sarcopenia. Considering the components of sarcopenia, FT3 concentration was positively associated with muscle strength (OR=0.525, 95% CI: 0.305–0.902, P=0.020) and physical performance (OR=0.443, 95% CI: 0.259–0.758, P=0.003), while FT4 concentration was negatively linked to muscle mass (OR=1.114, 95% CI: 1.009–1.232, P=0.036). The FT3/FT4 ratio was positively linked to muscle mass (OR=0.943, 95% CI: 0.905–0.981, P=0.006), muscle strength (OR=0.945, 95% CI: 0.901–0.992, P=0.021), and physical performance (OR=0.934, 95% CI: 0.894–0.975, P=0.002). Nevertheless, thyroid-stimulating hormone concentration was not associated with sarcopenia. Conclusion. A high FT3/FT4 ratio was significantly linked to a lowered risk of sarcopenia in euthyroid patients with T2DM.

Summary: SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier and caused widespread disease in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterize 198 antibodies isolated from four COVID-19+ subjects and identify 14 SARS-CoV-2 neutralizing antibodies. One targets the N-terminal domain (NTD), one recognizes an epitope in S2, and 11 bind the receptor-binding domain (RBD). Three anti-RBD neutralizing antibodies cross-neutralize SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs to the ACE2 receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency and antibody epitope specificity regulates the in vivo protective potential of anti-SARS-CoV-2 antibodies. All four cross-neutralizing antibodies neutralize the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.

Objective The objective of this study was to evaluate the influence of secondhand smoke (SHS) exposure during childhood on type 2 diabetes mellitus, hypertension, hyperlipidaemia and coronary heart disease among Chinese non-smoking women.Methods In this cross-sectional study, the SHS exposure data in childhood were obtained using a questionnaire survey. Self-reported childhood SHS exposure was defined as the presence of at least one parent who smoked during childhood.Results Of the 6522 eligible participants, 2120 Chinese women who had never smoked were assessed. The prevalence of SHS exposure in the entire population was 28.1% (596). SHS exposure during childhood was not significant for the standard risk factors of type 2 diabetes mellitus (p=0.628) and hypertension (p=0.691). However, SHS was positively associated with hyperlipidaemia (p=0.037) after adjusting for age, obesity, education status, physical activity, alcohol consumption, current SHS exposure status, diabetes mellitus and hypertension. In addition, childhood SHS increased the occurrence of coronary heart disease (p=0.045) among non-smokers after further adjusting for hyperlipidaemia.Conclusion SHS exposure during childhood is associated with prevalent hyperlipidaemia and coronary heart disease in adulthood among non-smoking Chinese women.

Sequence signatures of multidonor broadly neutralizing influenza antibodies can be used to quantify the prevalence of B cells with virus-neutralizing potential to accelerate development of broadly protective vaccine strategies. Antibodies of the same class share similar recognition modes and developmental pathways, and several antibody classes have been identified that neutralize diverse group 1- and group 2-influenza A viruses and have been observed in multiple human donors. One such multidonor antibody class, the HV6-1-derived class, targets the stem region of hemagglutinin with extraordinary neutralization breadth. Here, we use an iterative process to combine informatics, biochemical, and structural analyses to delineate an improved sequence signature for HV6-1-class antibodies. Based on sequence and structure analyses of known HV6-1 class antibodies, we derived a more inclusive signature (version 1), which we used to search for matching B-cell transcripts from published next-generation sequencing datasets of influenza vaccination studies. We expressed selected antibodies, evaluated their function, and identified amino acid-level requirements from which to refine the sequence signature (version 2). The cryo-electron microscopy structure for one of the signature-identified antibodies in complex with hemagglutinin confirmed motif recognition to be similar to known HV6-1-class members, MEDI8852 and 56.a.09, despite differences in recognition-loop length. Threading indicated the refined signature to have increased accuracy, and signature-identified heavy chains, when paired with the light chain of MEDI8852, showed neutralization comparable to the most potent members of the class. Incorporating sequences of additional class members thus enables an improved sequence signature for HV6-1-class antibodies, which can identify class members with increased accuracy.

The re-emergence of Zika virus (ZIKV) caused widespread infections that were linked to Guillain-Barré syndrome in adults and congenital malformation in fetuses, and epidemiological data suggest that ZIKV infection can induce protective antibody responses. A more detailed understanding of anti-ZIKV antibody responses may lead to enhanced antibody discovery and improved vaccine designs against ZIKV and related flaviviruses. Here, we applied recently-invented library-scale antibody screening technologies to determine comprehensive functional molecular and genetic profiles of naturally elicited human anti-ZIKV antibodies in three convalescent individuals. We leveraged natively paired antibody yeast display and NGS to predict antibody cross-reactivities and coarse-grain antibody affinities, to perform in-depth immune profiling of IgM, IgG, and IgA antibody repertoires in peripheral blood, and to reveal virus maturation state-dependent antibody interactions. Repertoire-scale comparison of ZIKV VLP-specific and non-specific antibodies in the same individuals also showed that mean antibody somatic hypermutation levels were substantially influenced by donor-intrinsic characteristics. These data provide insights into antiviral antibody responses to ZIKV disease and outline systems-level strategies to track human antibody immune responses to emergent viral infections.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infection and continues to infect humans, thereby contributing to a high mortality rate (34.3% in 2019). In the absence of an available licensed vaccine and antiviral agent, therapeutic human antibodies have been suggested as candidates for treatment. In this study, human monoclonal antibodies were isolated by sorting B cells from patient's PBMC cells with prefusion stabilized spike (S) probes and a direct immunoglobulin cloning strategy. We identified six receptor-binding domain (RBD)-specific and five S1 (non-RBD)-specific antibodies, among which, only the RBD-specific antibodies showed high neutralizing potency (IC50 0.006-1.787 μg/ml) as well as high affinity to RBD. Notably, passive immunization using a highly potent antibody (KNIH90-F1) at a relatively low dose (2 mg/kg) completely protected transgenic mice expressing human DPP4 against MERS-CoV lethal challenge. These results suggested that human monoclonal antibodies isolated by using the rationally designed prefusion MERS-CoV S probe could be considered potential candidates for the development of therapeutic and/or prophylactic antiviral agents for MERS-CoV human infection.

Background. More and more studies focus on the relationship between the gastrointestinal microbiome and type 2 diabetes, but few of them have actually explored the relationship between enterotypes and type 2 diabetes. Materials and Methods. We enrolled 134 patients with type 2 diabetes and 37 nondiabetic controls. The anthropometric and clinical indices of each subject were measured. Fecal samples of each subject were also collected and were processed for 16S rDNA sequencing. Multiple logistic regression analysis was used to determine the associations of enterotypes with type 2 diabetes. Multiple linear regression analysis was used to explore the relationship between lipopolysaccharide levels and insulin sensitivity after adjusting for age, BMI, TG, HDL-C, DAO, and TNF-α. The correlation analysis between factors and microbiota was identified using Spearman correlation analysis. The correlation analysis between factors was identified using partial correlation analysis. Results. Gut microbiota in type 2 diabetes group exhibited lower bacterial diversity compared with nondiabetic controls. The fecal communities from all subjects clustered into two enterotypes distinguished by the levels of Bacteroides and Prevotella. Logistic regression analysis showed that the Bacteroides enterotype was an independent risk factor for type 2 diabetes by decreasing insulin sensitivity. The levels of lipopolysaccharide and tumor necrosis factor-alpha were higher in the Bacteroides enterotype compared to the Prevotella enterotype. Partial correlation analysis showed that lipopolysaccharide was closely associated with diamine oxidase, tumor necrosis factor-alpha, and Gutt insulin sensitivity index after adjusting for multiple covariates. Furthermore, the level of lipopolysaccharide was found to be an independent risk factor for insulin sensitivity. Conclusions. We identified two enterotypes, Bacteroides and Prevotella, among all subjects. Our results showed that the Bacteroides enterotype was an independent risk factor for type 2 diabetes, which was due to increased levels of lipopolysaccharide causing decreased insulin sensitivity.

Objective. Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD). Even after strict control of obesity, hyperglycemia, and hypertension, some patients still progress rapidly. Previous studies suggested diabetic dyslipidemia might be one of the factors responsible for this high residual risk. This study aims to explore the impact of long-term lipid control on renal outcome in new-onset type 2 diabetes mellitus (T2DM). Methods. We conducted a 3-year follow-up study, involving 283 subjects with new-onset T2DM, and observed the effect of baseline and follow-up metabolic abnormalities, especially dyslipidemia, on the early damage of kidney function using multiple logistic regression analysis. Results. After 3 years follow-up, patients achieved a better control of body weight, hypertension, and blood glucose. The most reduced eGFR group shared the least reduced BMI and LDL-C, as well as the greatest increase in TG levels. Only TG in the follow-up, not any of the baseline data, nor obesity, blood glucose, BP, or LDL-C in the follow-up, was found to be significantly correlated with the most reduced eGFR. Compared with patients with constantly abnormal TG levels, the risks were even higher in the subjects who experienced a transition from normal TG to hypertriglyceridemia (OR=2.576 versus OR=2.184, after multiple adjustment), and by tight controlling of TG, patients started with abnormal baseline TG levels could reduce the risk of DKD progression to the same low levels as the TG-constantly-normal group. Conclusion. This study emphasized the importance of long-term TG control in East Asian patients with new-onset T2DM: TG control can delay the decline of kidney function in the early stage of DKD, and reversal of hypertriglyceridemia may undo the risks of the past. It is time to pay more attention to the control of TG in new-onset T2DM.

The Fokas–Lenells equation and its multi-component coupled forms have attracted the attention of many mathematical physicists. The Fokas–Lenells equation and two coupled Fokas–Lenells equations are investigated from the perspective of Lie symmetries and conservation laws. The three systems have been turned into real multi-component coupled systems by appropriate transformations. By procedures of symmetry analysis, Lie symmetries of the three real systems are obtained. Explicit conservation laws are constructed using the symmetry/adjoint symmetry pair method, which depends on Lie symmetries and adjoint symmetries. The relationships between the multiplier and the adjoint symmetry are investigated.

Abstract Background Islet dysfunction and destruction are the common cause for both type 1 and type 2 diabetes mellitus (T2DM). The islets of Langerhans are highly vascularized miniorgans, and preserving the structural integrity and full function of the microvascular endothelium is vital for protecting the islets from the infiltration of immune cells and secondary inflammatory attack. Mesenchymal stromal cell (MSC)-based therapies have been proven to promote angiogenesis of the islets; however, the underlying mechanism for the protective role of MSCs in the islet endothelium is still vague. Methods In this study, we used MS-1, a murine islet microvascular endothelium cell line, and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow-derived MSCs under oxidative stress in vitro. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase 3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as well as eNOS phosphorylation/activation. The changes of VCAM-1, eNOS, and the β-catenin expression were also tested in the isolated islets of T2DM rats infused with MSCs. Results We observed that treating MS-1 cells with H2O2 triggered significant apoptosis, induction of VCAM expression, and reduction of eNOS phosphorylation. Importantly, coculturing MS-1 cells with MSCs prevented oxidative stress-induced apoptosis, eNOS inhibition, and VCAM elevation in MS-1 cells. Similar changes in VCAM-1 and eNOS phosphorylation could also be observed in the islets isolated from T2DM rats infused with MSCs. Moreover, MSCs cocultured with MS-1 in vitro or their administration in vivo could both result in an increase of β-catenin, which suggested activation of the β-catenin-dependent Wnt signaling pathway. In MS-1 cells, activation of the β-catenin-dependent Wnt signaling pathway partially mediated the protective effects of MSCs against H2O2-induced apoptosis and eNOS inhibition. Furthermore, MSCs produced a significant amount of Wnt4 and Wnt5a. Although both Wnt4 and Wnt5a participated in the interaction between MSCs and MS-1 cells, Wnt4 exhibited a protective role while Wnt5a seemed to show a destructive role in MS-1 cells. Conclusions Our observations provide evidence that the orchestration of the MSC-secreted Wnts could promote the survival and improve the endothelial function of the injured islet endothelium via activating the β-catenin-dependent Wnt signaling in target endothelial cells. This finding might inspire further in-vivo studies.

Summary: Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV. : Wang et al. report the structural and functional characterization of the Middle East respiratory syndrome coronavirus (MERS-CoV)-neutralizing antibody G2. G2 recognizes a conserved epitope on the MERS-CoV S1 N-terminal domain (S1-NTD) and neutralizes MERS-CoV by interfering with binding to host receptor dipeptidyl peptidase-4 (DPP4). The findings are relevant for understanding the viral attachment mechanism and for the development of S1-NTD-based vaccines. Keywords: MERS-CoV, coronavirus, crystal structure, electron microscopy, DPP4, receptor-binding, membrane fusion

ABSTRACT Influenza vaccines targeting the highly conserved stem of the hemagglutinin (HA) surface glycoprotein have the potential to protect against pandemic and drifted seasonal influenza viruses not covered by current vaccines. While HA stem-based immunogens derived from group 1 influenza A viruses have been shown to induce intragroup heterosubtypic protection, HA stem-specific antibody lineages originating from group 2 may be more likely to possess broad cross-group reactivity. We report the structure-guided development of mammalian-cell-expressed candidate vaccine immunogens based on influenza A virus group 2 H3 and H7 HA stem trimers displayed on self-assembling ferritin nanoparticles using an iterative, multipronged approach involving helix stabilization, loop optimization, disulfide bond addition, and side-chain repacking. These immunogens were thermostable, formed uniform and symmetric nanoparticles, were recognized by cross-group-reactive broadly neutralizing antibodies (bNAbs) with nanomolar affinity, and elicited protective, homosubtypic antibodies in mice. Importantly, several immunogens were able to activate B cells expressing inferred unmutated common ancestor (UCA) versions of cross-group-reactive human bNAbs from two multidonor classes, suggesting they could initiate elicitation of these bNAbs in humans. IMPORTANCE Current influenza vaccines are primarily strain specific, requiring annual updates, and offer minimal protection against drifted seasonal or pandemic strains. The highly conserved stem region of hemagglutinin (HA) of group 2 influenza A virus subtypes is a promising target for vaccine elicitation of broad cross-group protection against divergent strains. We used structure-guided protein engineering employing multiple protein stabilization methods simultaneously to develop group 2 HA stem-based candidate influenza A virus immunogens displayed as trimers on self-assembling nanoparticles. Characterization of antigenicity, thermostability, and particle formation confirmed structural integrity. Group 2 HA stem antigen designs were identified that, when displayed on ferritin nanoparticles, activated B cells expressing inferred unmutated common ancestor (UCA) versions of human antibody lineages associated with cross-group-reactive, broadly neutralizing antibodies (bNAbs). Immunization of mice led to protection against a lethal homosubtypic influenza virus challenge. These candidate vaccines are now being manufactured for clinical evaluation.

Infection with Middle East respiratory syndrome coronavirus (MERS-CoV) could be asymptomatic or cause mild influenza-like illness. Therefore, the prevalence of MERS-CoV infections in the general population could be underestimated, which necessitates active surveillance to determine the epidemiological importance of asymptomatic cases. The aim of this study is to evaluate the performance of various serological assays and to estimate the seroprevalence of anti-MERS-CoV antibodies in high- and low-risk groups in Qatar. A total of 4858 samples were screened, including 4719 samples collected from healthy blood donors (BD) over a period of five years (2012-2016), 135 samples from baseline case contacts (CC) collected from individuals in close contact with three positive PCR-confirmed patients (CP), and four samples from MERS-CoV CP. Initial screening using anti-MERS-CoV IgG (IgG rS1-ELISA kit) revealed ten reactive samples from BD (10/4719, 0.21%), one from CC (1/135, 0.74%), and three from CP (3/4, 75%). Samples from CP but not from BD were also reactive by whole-virus anti-MERS-CoV IgG (n=3/4) and IgM (n=1/4) indirect immunefluorescent tests (IIFT) and pseudoparticle neutralization test (ppNT). The reactive sample from CC was also confirmed by ppNT. Surprisingly, one out of thirteen (7.7%) randomly selected IgG rS1-ELISA-negative BD samples from the initial screening was reactive by the IgM-IIFT (but not by the IgG-IIFT) and was subsequently confirmed by ppNT. All IgG rS1-ELISA-reactive samples from BD exhibited considerable reactivity to the four circulating human coronaviruses (HKU1, OC43, 229E, and NL63). Cross-reactivity with SARS was only reported for samples from CP using IgG and IgM-IIFT. In conclusion, we report a low prevalence of anti-MERS antibodies in the general population, which coincides with the low number of all reported cases by the time of our study (2017) in Qatar (n=21). The false-positive results and the observed cross-reactivity between MERS-CoV and other circulating human coronavirus necessitate more detailed evaluation of available serological assays.

Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 10(12) AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization.

The COVID-19 pandemic highlights an urgent need for vaccines that confer protection from SARS-CoV-2 infection. One approach to an effective COVID-19 vaccine may be through the display of SARS-CoV-2 spikes on the surface of virus-like particles, in a manner structurally mimicking spikes on a native virus. Here we report the development of Newcastle disease virus-like particles (NDVLPs) displaying the prefusion-stabilized SARS-CoV-2 spike ectodomain (S2P). Immunoassays with SARS-CoV-2-neutralizing antibodies revealed the antigenicity of S2P-NDVLP to be generally similar to that of soluble S2P, and negative-stain electron microscopy showed S2P on the NDVLP surface to be displayed with a morphology corresponding to its prefusion conformation. Mice immunized with S2P-NDVLP showed substantial neutralization titers (geometric mean ID50 = 386) two weeks after prime immunization, significantly higher than those elicited by a molar equivalent amount of soluble S2P (geometric mean ID50 = 17). Neutralizing titers at Week 5, two weeks after a boost immunization with S2P-NDVLP doses ranging from 2.0 to 250 μg, extended from 2125 to 4552, and these generally showed a higher ratio of neutralization versus ELISA than observed with soluble S2P. Overall, S2P-NDVLP appears to be a promising COVID-19 vaccine candidate capable of eliciting substantial neutralizing activity.

Aims. This article performed a retrospective cohort study to estimate the annual incidence rates of diabetes and to assess the utility of HbA1c as a predictor for progression to diabetes in Chinese community adults aged 40 years or older. Methods. In all, 2778 nondiabetic subjects (including 1901 women) underwent HbA1c testing and oral glucose tolerance test (OGTT) measurements at baseline and after 3 years. Diabetes and prediabetes were defined using the WHO criteria. The HbA1c cutoff points were evaluated to predict the future risks of diabetes. Relative risk (RR) was calculated using the chi-square test. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive efficiency of fasting plasma glucose (FPG), 2 hr postprandial plasma glucose (2hPG), and HbA1c for progression to diabetes. A superior cutoff point was defined as the point on the ROC curve with a larger Youden index. Results. Overall, 7.5% (210/2778) of the subjects progressed to diabetes, yielding an annual 2.5% diabetes incidence rate. Additionally, 4.5% (100/2227) of the subjects with normal glucose tolerance (NGT) and 19.6% (110/561) of the subjects with prediabetes progressed to diabetes, and the relative risk of progression to diabetes was 5.188 times higher in subjects with prediabetes than in subjects with NGT (p

MERS-CoV is present in dromedary camels throughout the Middle East and Africa. Dromedary camels are the primary zoonotic reservoir for human infections. Interruption of the zoonotic transmission chain from camels to humans, therefore, may be an effective strategy to control the ongoing MERS-CoV outbreak. Here we show that vaccination with an adjuvanted MERS-CoV Spike protein subunit vaccine confers complete protection from MERS-CoV disease in alpaca and results in reduced and delayed viral shedding in the upper airways of dromedary camels. Protection in alpaca correlates with high serum neutralizing antibody titers. Lower titers of serum neutralizing antibodies correlate with delayed and significantly reduced shedding in the nasal turbinates of dromedary camels. Together, these data indicate that induction of robust neutralizing humoral immune responses by vaccination of naïve animals reduces shedding that potentially could diminish the risk of zoonotic transmission.

In sickle cell disease (SCD), the inflammatory properties of high-density lipoprotein (HDL) can be changed by cell-free hemoglobin (Hb), which is released into the blood during hemolysis. Hb in the plasma of SCD patients or mice can bind with HDL specifically inducing an inflammatory reaction. In our study, we found increased amounts of inflammatory factor proteins in the chronic oxidative state of SCD with higher levels of Hb, haptoglobin (Hp) and hemopexin (Hx) in the apolipoprotein A-I (ApoA-1) particles of HDL and the role of HDL is changed from being anti-inflammatory to proinflammatory. Our results also suggest Hp and Hx, the scavengers of Hb in HDL, are positively associated with inflammatory levels in SCD patients. HDL retained its inflammatory inhibition role in Hp-/- mice, with less Hb accumulation. Hx may further prevent inflammatory reaction because its level will be even higher when lack of Hx. We therefore demonstrated that Hp is indispensable during the process whereby Hb associates with HDL and plays a clear proinflammatory role. Therefore, it is essential to break the binding between Hb and Hp for treatment. The dissociation of Hb/Hp/Hx complexes may also play an important role in the study of other inflammatory angiogenesis-related diseases.

Objective. To investigate changes in the glycated hemoglobin A1c (A1c) level and those in β cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. Design and Methods. A total of 818 newly diagnosed diabetic individuals who were ≥40 years of age were recruited. The subjects were grouped by A1c values (

Betatrophin and irisin are two recently identified hormones which may participate in regulating pancreatic β-cell function. However, the associations of these two hormones with β-cell function remain unclear. The present study aims to demonstrate the associations of circulating betatrophin and irisin levels with β-cell function, assessed by the area under the curve (AUC) of C-peptide, and the possible correlation between these two hormones in previously diagnosed type 2 diabetes mellitus (T2DM) patients. In total, 20 age-, sex-, and body mass index- (BMI-) matched normal glucose tolerance (NGT) subjects and 120 previously diagnosed T2DM patients were included in this study. Partial correlation analysis was used to evaluate the relationships between these two hormones and indexes of β-cell function and insulin resistance. Our results showed that betatrophin levels were significantly elevated, while irisin levels were significantly decreased, in patients with T2DM compared with NGT subjects. However, partial correlation analysis showed that betatrophin levels did not correlate with β-cell function-related variables or insulin resistance-related variables before or after controlling multiple covariates, while irisin correlated positively with insulin sensitivity but is not associated with β-cell function-related variables. Besides, no correlation was observed between betatrophin and irisin levels. Hence we concluded that betatrophin and irisin were not associated with β-cell function in previously diagnosed T2DM patients.

C-peptide has been reported to be a marker of subclinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients, whereas its role in coronary artery disease (CAD) has not been clarified, especially in diabetics with differing body mass indices (BMIs).This cross-sectional study included 501 patients with T2DM. First, all subjects were divided into the following two groups: CAD and non-CAD. Then, binary logistic regression was used to determine the risk factors for CAD for all patients. To clarify the role of obesity, we re-divided all subjects into two additional groups (obese and non-obese) based on BMI. Finally, binary logistic regression was used to determine the risk factors for CAD for each weight group.The patients with CAD showed a higher BMI and fasting C-peptide level in addition to an increased prevalence of traditional risk factors for CAD, such as hypertension, insulin resistance, higher cholesterol, cysteine-C (Cys-C) and lower estimated glomerular filtration rate (eGFR). Logistic regression analysis showed that fasting C-peptide (OR=1.513, p=0.005), insulin treatment (OR=1.832, p=0.027) hypertension (OR=1.987, p=0.016) and hyperlipidemia (OR=4.159, p

ObjectiveTo investigate how the glucose variability between fasting and a 2-h postload glucose state (2-h postload plasma glucose [2hPG]-fasting plasma glucose [FPG]) is associated with chronic kidney disease (CKD) in middle-aged and elderly Chinese patients previously diagnosed with type 2 diabetes.Design and methodsThis cross-sectional study included 1054 previously diagnosed type 2 diabetes patients who were 40 years of age and older. First, the subjects were divided into two groups based on a glycated hemoglobin (HbA1c) value of 7%. Each group was divided into two subgroups, with or without CKD. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the glomerular filtration rate (GFR). CKD was defined as eGFRResultsIn the patients with HbA1c levels ≥7%, the 2hPG-FPG was significantly associated with decreased eGFR and an increased risk of CKD independent of age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, smoking, and drinking, as well as fasting insulin, cholesterol, triglyceride, and HbA1c levels. The patients with 2hPG-FPG values ≥144 mg/dl showed an increased odds ratio (OR) of 2.640 (P = 0.033). Additionally, HbA1c was associated with an increased risk of CKD in patients with HbA1c values ≥7%.ConclusionsThe short-term glucose variability expressed by 2hPG-FPG is closely associated with decreased eGFR and an increased risk of CKD in patients with poor glycemic control (HbA1c≥7%).

A delayed predator-prey system with Holling type II functional response and stage structure for both the predator and the prey is investigated. By analyzing the corresponding characteristic equations, the local stability of each of the feasible equilibria of the system is addressed and the existence of a Hopf bifurcation at the coexistence equilibrium is established. By means of persistence theory on infinite dimensional systems, it is proved that the system is permanent. By using Lyapunov functions and the LaSalle invariant principle, the global stability of each of the feasible equilibria of the model is discussed. Numerical simulations are carried out to illustrate the main theoretical results.

An ecoepidemiological predator-prey model with stage structure for the predator and time delay due to the gestation of the predator is investigated. The effects of a prey refuge with disease in the prey population are concerned. By analyzing the corresponding characteristic equations, the local stability of each of the feasible equilibria of the model is discussed. Further, it is proved that the model undergoes a Hopf bifurcation at the positive equilibrium. By means of appropriate Lyapunov functions and LaSalle’s invariance principle, sufficient conditions are obtained for the global stability of the semitrivial boundary equilibria. By using an iteration technique, sufficient conditions are derived for the global attractiveness of the positive equilibrium.

A ratio-dependent predator-prey model incorporating a prey refuge with disease in the prey population is formulated and analyzed. The effects of time delay due to the gestation of the predator and stage structure for the predator on the dynamics of the system are concerned. By analyzing the corresponding characteristic equations, the local stability of a predator-extinction equilibrium and a coexistence equilibrium of the system is discussed, respectively. Further, it is proved that the system undergoes a Hopf bifurcation at the coexistence equilibrium, when τ=τ0. By comparison arguments, sufficient conditions are obtained for the global stability of the predator-extinction equilibrium. By using an iteration technique, sufficient conditions are derived for the global attractivity of the coexistence equilibrium of the proposed system.

OBJECTIVE: To investigate the relationship between lipid profiles [including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] and a mild decline in the estimated glomerular filtration rate (eGFR) in subjects with normal serum lipid levels. DESIGN AND METHODS: In this study, we included 2647 participants who were ≥ 40 years old and had normal serum lipid levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the GFR. A mildly reduced eGFR was defined as 60-90 mL/min/1.73 m(2). First, multiple linear regression analysis was used to estimate the association of lipid profiles with the eGFR. Then, the levels of each lipid component were divided into four groups, using the 25th, 50th and 75th percentiles as cut-off points. Finally, multiple logistic regression analysis was used to investigate the association of different lipid components with the risk of mildly reduced eGFR. RESULTS: In the group with a mildly reduced eGFR, TG and LDL-C levels were significantly increased, but HDL-C levels were significantly decreased. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), smoking and drinking, only TC and TG were independently related to the eGFR. Additionally, only TG showed a linear relationship with an increased risk of a mildly reduced eGFR, with the highest quartile group (TG: 108-150 mg/dl [1.22-1.70 mmol/L]) having a significantly increased risk after adjusting for the above factors. CONCLUSIONS: Triglyceride levels are closely associated with a mildly reduced eGFR in subjects with normal serum lipid levels. Dyslipidemia with lower TG levels could be used as new diagnostic criteria for subjects with mildly reduced renal function.

OBJECTIVE: To investigate whether fluctuations between the fasting and 2-h postload glucose ([2-hPBG]-fasting blood glucose [FBG]) states are associated with glomerular hyperfiltration (GHF) in middle-aged and elderly Chinese patients with newly diagnosed diabetes. DESIGN AND METHODS: In this study, we included 679 newly diagnosed diabetes patients who were ≥ 40 years old. All the subjects were divided into two groups; those with HbA1c

The Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome.Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination.