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The durability and protective effect of naturally acquired antibodies against hepatitis E virus (HEV) reinfection and clinical progression remain unclear in humans. In a 103-month longitudinal analysis of 7032 adult placebo recipients (aged 16 to 65 years) from a phase 3 HEV vaccine trial in China, we demonstrated that baseline anti-HEV IgG seropositivity (n = 3194) conferred over 50% higher protection against reinfection compared with seronegative individuals (n = 3838), with this protective effect remaining consistent over 8.5 years. A non-linear dose-response relationship was observed, whereby baseline anti-HEV IgG concentrations ≥0.25 WHO units/mL were associated with at least a 50% reduction in infection risk, with higher baseline antibody levels correlated with a lower risk of infection. Natural immunity provided approximately 70% protection against clinically apparent hepatitis E in the cohort, with 10 symptomatic cases identified over a decade of active surveillance. Six were hospitalized, all of whom were baseline seronegative. These findings establish that natural HEV immunity provides durable, though incomplete, protection. Hepatitis E virus is a leading cause of acute viral hepatitis and antibodies can persist for years post-infection. Here, the authors quantify the protective effects of naturally acquired immunity against subclinical and clinical hepatitis E infection using data from a placebo arm of a vaccine trial in China.

The effectiveness of the hepatitis E vaccine in high-risk groups, such as chronic hepatitis B (CHB) patients, remains understudied. A key clinical manifestation of CHB is the persistent positivity of hepatitis B surface antigen (HBsAg). We conducted a test-negative design study involving 2,926 HBsAg-positive individuals (born 1941–1991; median age 49.0; male-to-female ratio of 1.4), identified through a hepatitis surveillance system, as part of the phase 3 trial (NCT01014845) of the recombinant hepatitis E vaccine HEV 239 (Hecolin). This system monitored suspected hepatitis cases and performed diagnoses across 11 townships in Dongtai, Jiangsu, China, from 2007 to 2017. Vaccine effectiveness of HEV 239 was assessed by comparing vaccination status between confirmed 96 hepatitis E cases and 2830 test-negative controls, using logistic regression adjusted for sex and age. We found that HEV 239 vaccination was associated with a reduced risk of hepatitis E among HBsAg-positive individuals, with an estimated effectiveness of 72.1% [95% confidence interval (CI) 11.2–91.2], and 81.5% (95% CI 35.9–94.6) among phase 3 trial participants. Our findings show that HEV 239 is highly effective in HBsAg-positive adults, supporting its future recommended use in this population. Effectiveness of the hepatitis E vaccine HEV 239 amongst high-risk groups isn’t well studied. Here, Zhuang et al. analyse a decade of surveillance data (2007–2017) from Dongtai, China, and estimate HEV 239 effectiveness of 72% amongst hepatitis B virus infected people.

The emergence of Rocahepevirus ratti genotype 1 (rat hepatitis E virus; rat HEV) in humans presents an unprecedented threat; however, the risk of rat HEV transmission to humans is not well understood. Here, we report the “Distinguishing Antibody Response Elicitation (DARE)” method, which distinguishes exposure to rat HEV. We use four study sets from China for large-scale population analysis: set 1 (hospital visit) and set 3 (ALT abnormality) from Yunnan province, a biodiversity hotspot, and set 2 (received physical examination) and set 4 (ALT abnormality) from Jiangsu province, a non-hotspot control region. rat HEV exposure risk is significantly higher in Yunnan, with 21.97% (190 of 865) in set 1 and 13.97% (70 of 501) in set 3, compared to 0.75% (9 of 1196) in Jiangsu’s set 2. Six spillover infections for rat HEV are identified in set 1, with one case of abnormal ALT. The rat-1d strains carried by rats are closely related to those human infections. Our study reveals the substantial spillover burden posed by rat HEV in biodiversity hotspots and highlights the utility of DARE method for proactive surveillance of public health emergencies. Rat hepatitis E virus (HEV) can infect humans, but the extent of spillover isn’t well studied. Here the authors develop a serological test that distinguishes exposure to rat HEV from other HEV infection and show substantial spillover in a biodiversity hotspot in China. The method can support surveillance of rat HEV.

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.

Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes. However, research on the role of Marco in regulating neuroinflammation has reported conflicting results. In the present study, we examined the role Marco played in triggering neuroinflammation and its underlying mechanisms. The results demonstrated that silencing the Marco gene resulted in a significantly reduced neuroinflammatory response and vice versa. α-Syn stimulation in Marco overexpressing cells induced a pronounced inflammatory response, suggesting that Marco alone could trigger an inflammatory response. We also found that TLR2 significantly promoted Marco-mediated neuroinflammation, indicating TLR2 was an important co-receptor of Marco. Knocking down the TLR2 gene in microglia and mouse substantia nigra resulted in decreased expression of Marco. Subsequent mechanistic studies showed that deleting the SRCR domain of Marco resulted in disruption of the inflammatory response and the interaction between TLR2 and Marco. This suggested that TLR2 binds directly to the SRCR domain of Marco and regulates Marco-mediated neuroinflammation. In summary, this investigation revealed that TLR2 could potentiate Marco-mediated neuroinflammation by interacting with the SRCR domain of Marco, providing a new target for inhibiting neuroinflammation in neurodegenerative diseases. Graphical Abstract

Hepatitis E virus (HEV) is an important cause of acute hepatitis, however, is highly neglected and largely underreported. This study aimed to describe the detailed epidemiology of hepatitis E (HE) through a 10-year surveillance. A community-based active hepatitis surveillance was conducted between November 2007 and October 2017 in 11 townships of Dongtai City in China, involving 355,673 residents. Serum samples were obtained from patients presenting with hepatitis symptoms for more than 3 days. Serum alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (ULN) were considered acute hepatitis. Samples were subsequently tested for IgG and IgM anti-HEV antibodies, HEV RNA, and hepatitis B surface antigen (HBsAg). The data indicated the incidence of HE fluctuated downward from 2007 to 2017, with an average annual age-standardized incidence of 17.50 per 100,000, exceeding the 10.26 per 100,000 in the National Notifiable Disease Report System (NNDRS). The incidence was notably higher among males (20.95 per 100,000) and individuals aged 50-69 years (37.47 per 100,000). Genotype 4 (HEV-4) was the predominantly circulating genotype during the study period. Furthermore, the study revealed the incidence of hepatitis with HEV and hepatitis B virus (HBV) co-infection was 4.99 per 100,000. The active surveillance system identified a higher incidence of HE compared to NNDRS, with a decreased prevalence over a 10-year period. While efforts are still needed to prevent HE in high-risk populations, including individuals with hepatitis B and the elderly.

The intranasal SARS-CoV-2 vaccine dNS1-RBD (Pneucolin®), based on a live-attenuated influenza virus vector, has obtained Emergency Use Authorization in China for individuals aged 18 years and older. Here, we conducted a single-center, double-blind, placebo-controlled, age de-escalation phase 1 clinical trial to evaluate the safety of the dNS1-RBD in children aged 3–17 years (ChiCTR2300068044). Sixty-three participants received 2 intranasal doses of the vaccine or placebo at days 0 and 14. Safety assessments included adverse events/reactions within 30 days and serious adverse events (SAEs) over 12 months. Blood and nasal secretion samples were collected to further monitor blood indices and viral shedding. The vaccine group showed similar adverse reaction rates to the placebo group (39.0% vs 36.4%), with no SAEs related to vaccination. Data suggested that the dNS1-RBD vaccine is well-tolerated in children aged 3–17 years, and warrants further studies on its safety, immunogenicity and efficacy in this population.

Telomere biology plays a critical and complex role in the initiation and progression of cancer. Several recent studies have provided evidence that rs401681 polymorphisms in intronic region of cleft lip and palate trans-membrane 1-like (CLPTM1L) gene sequence are associated with pancreatic cancer (PC) development, but a comprehensive synopsis is not available. We performed a meta-analysis of 6 case–control studies that included 8,253 pancreatic cancer cases and 37,646 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95 % confidence intervals (CIs). Overall, this meta-analysis showed that rs401681 allele T was associated with a significantly increased PC risk (OR = 1.17, 95 % CI = 1.12–1.22, P heterpgeneity  = 0.596 and I 2  = 0). Similarly, in the subgroup analysis by ethnicity, a significantly increased risk was found among Asians (OR = 1.15, 95 % CI = 1.07–1.24, P heterpgeneity  = 0.297 and I 2  = 8.0 %) and among Caucasian (OR = 1.13, 95 % CI = 1.02–1.26, P heterpgeneity  = 0.385 and I 2  = 0). No publication bias was found in the present study. This meta-analysis suggests that T allele of CLPTM1L–telomerase reverse transcriptase rs401681 polymorphism is associated with an increased PC risk, especially among Chinese. Further large and well-designed studies are needed to confirm this association.

Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16–65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4–91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.

Parkinson’s disease (PD) is a prevalent neurodegenerative disease, characterized by movement disorders and non-motor symptoms like cognitive impairment and depression. Degeneration of dopaminergic neurons in the substantia nigra and Lewy bodies have long been considered as main neuropathological changes. However, recent magnetic resonance imaging (MRI) studies have shown that white matter lesions (WMLs) were present in PD patients. WMLs are characterized by loss or impairment of myelin sheath in central nerve fibers, which are closely correlated with motor and cognitive dysfunction in PD. WMLs alterations precede nigrostriatal neuronal losses and can independently affect the clinical severity or characteristics of motor coordination in PD patients. Currently, the exact mechanism of WMLs involvement in the occurrence and development of PD remains unclear. It is speculated that WMLs may participate in the pathogenesis of PD by disrupting important connections in brain or promoting axonal degeneration. In this review, we will discuss the pathological changes and mechanisms of WMLs, elaborate the impact of WMLs on the progression of PD, clarify the importance of WMLs in PD pathogenesis, and thus provide novel targets for PD treatments.