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Abstract Background Aging is a prominent risk factor for diverse diseases; therefore, an in-depth understanding of its physiological mechanisms is required. Nonhuman primates, which share the closest genetic relationship with humans, serve as an ideal model for exploring the complex aging process. However, the potential of the nonhuman primate animal model in the screening of human aging markers is still not fully exploited. Multiomics analysis of nonhuman primate peripheral blood offers a promising approach to evaluate new therapies and biomarkers. This study explores aging-related biomarker through multilayer omics, including transcriptomics (mRNA, lncRNA, and circRNA) and proteomics (serum and serum-derived exosomes) in rhesus monkeys (Macaca mulatta). Results Our findings reveal that, unlike mRNAs and circRNAs, highly expressed lncRNAs are abundant during the key aging period and are associated with cancer pathways. Comparative analysis highlighted exosomal proteins contain more types of proteins than serum proteins, indicating that serum-derived exosomes primarily regulate aging through metabolic pathways. Finally, eight candidate aging biomarkers were identified, which may serve as blood-based indicators for detecting age-related brain changes. Conclusions Our results provide a comprehensive understanding of nonhuman primate blood transcriptomes and proteomes, offering novel insights into the aging mechanisms for preventing or treating age-related diseases.

Fluorosis due to high fluoride levels in drinking water profoundly affects the development of human skeletal and dental structures. Sodium butyrate (NaB) has been found to regulate overall bone mass and prevent pathological bone loss. However, the mechanism of NaB action on fluorosis remains unclear. In this study, a rat model of fluorosis induced by 100 mg/L sodium fluoride was used to investigate the impact of NaB on bone homeostasis and serum metabolomics. It was found that NaB significantly reduced the levels of bone resorption markers CTX-Ⅰ and TRACP-5B in fluorosis rats. Moreover, NaB increased calcium and magnesium levels in bone, while decreasing phosphorus levels. In addition, NaB improved various bone microstructure parameters, including bone mineral density (BMD), trabecular thickness (Tb. Th), trabecular bone separation (Tb. SP), and structural model index (SMI) in the femur. Notably, NaB intervention also enhanced the antioxidant capacity of plasma in fluorosis rats. Furthermore, a comprehensive analysis of serum metabolomics by LC-MS revealed a significant reversal trend of seven biomarkers after the intervention of NaB. Finally, pathway enrichment analysis based on differential metabolites indicated that NaB exerted protective effects on fluorosis by modulating arginine and proline metabolic pathways. These findings suggest that NaB has a beneficial effect on fluorosis and can regulate bone homeostasis by ameliorating metabolic disorders.

Spatially, ecological infrastructure (EI) is a multi-scale and cross-level ecological network promoting sustainable urban development. Due to the distinct features of different scales, researchers have emphasized the importance of the multi-scale EI construction, which calls for support from a framework for scientific evaluation. Thus, based on the nature-based solutions (NbS) criteria, this study proposes a multi-scale EI construction benefits (MECBs-NbS) evaluation framework with scale differences and chooses the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) as a case study. The results show that: (1) the MECBs-NbS evaluation framework is fairly applicable; (2) in 2020, the ecological benefits of EI construction for building ecological security patterns at the macro-scale (GBA urban agglomeration) by around 203.63 billion RMB; for improving human-nature harmony, the ecological, physical, and social benefits of EI construction at the meso-scale (Huizhou city) were about 358.50 billion RMB; while the EI construction benefit of completing engineering tasks at micro-scale (site) was about 34.85 million RMB; (3) overall, with the built-up area as the center, as scale decreased, the EI construction benefits gradually changed from being dominated by ecological benefits to being dominated by social benefits; (4) by supporting the status quo analysis before construction and the benefit assessment following construction, this evaluation framework may not only support the planning, design and management of EI, but also serve as a crucial tool to encourage public participation and evaluate the performance of government work. This study aims to provide a new perspective on the multi-scale evaluation of EI construction that will support and improve urban resilience.

Abstract In recent years, the prevalence of allergic diseases has increased significantly, causing great concern, and wheat, as one of the top 8 food allergens, is a common allergy trigger. Nevertheless, reliable estimates of the positivity rate of wheat allergens in the allergic population in China are still lacking. The systematic review and meta-analysis aims to evaluate the positive detection rate of wheat allergens in the Chinese allergic population and further provide a reference for the prevention of allergy. CNKI, CQVIP, WAN-FANG DATA, Sino Med, PubMed, Web of Science, Cochrane Library, and Embase databases were retrieved. Related research and case reports about the positive rate of wheat allergen in the Chinese allergic population published from inception to June 30, 2022, were searched, and meta-analysis was performed using Stata software. The pooled positive rate of wheat allergens and 95% confidence interval were calculated by random effect models, and the publication bias was evaluated using Egger’s test. A total of 13 articles were included for the final meta-analysis, in which wheat allergen detection methods involved only serum sIgE testing and SPT assessment. The results showed that the wheat allergen positivity detection rate in Chinese allergic patients was 7.30% (95% CI 5.68–8.92%). Subgroup analysis showed that the positivity rate of wheat allergens was influenced by region, but hardly by age and assessment method. The positive rates of wheat allergy in the population with allergic diseases were 2.74% (95% CI 0.90–4.58%) and 11.47% (95% CI 7.08–15.87%) in southern and northern China, respectively. In particular, the positive rates of wheat allergens were greater than 10% in Shaanxi, Henan and Nei Mongol, all of which belong to the northern region. These results suggest that wheat allergens are an important cause of sensitization in allergic populations from northern China, and therefore attention should be paid to early prevention in high-risk populations.

The recent emergence of COVID-19 variants has necessitated the development of new vaccines that stimulate the formation of high levels of neutralizing antibodies against S antigen variants. A new strategy involves the intradermal administration of heterologous vaccines composed of one or two doses of inactivated vaccine and a booster dose with the mutated S1 protein (K-S). Such vaccines improve the immune efficacy by increasing the neutralizing antibody titers and promoting specific T cell responses against five variants of the RBD protein. A viral challenge test with the B.1.617.2 (Delta) variant confirmed that both administration schedules (i.e. “1 + 1” and “2 + 1”) ensured protection against this strain. These results suggest that the aforementioned strategy is effective for protecting against new variants and enhances the anamnestic immune response in the immunized population.

Abstract Objectives This study aimed to examine the associations between body composition and vital capacity index (VCI) among medical students of Shenyang, China. Study design The design of this study is a cross-sectional study. Methods Participants were 2063 individuals (17–25 years) from a medical college in Shenyang, who participated in this survey from April to May 2017. Height, weight, fat mass (FM), fat free mass (FFM), protein mass (PM), total body water (TBW), mineral mass (MM), vital capacity were measured, then BMI and VCI were calculated. Stepwise multiple linear regression analysis was used to evaluate the effect of body composition on VCI of participants in different genders. In addition, subgroup analysis was carried out according to BMI levels. Results Male students showed significantly higher height, weight, BMI, FFM, PM, TBW, MM, VC, and VCI, but lower FM in comparison with female students. Stepwise multiple linear regression analysis showed that in both sexes FM was negatively correlated with VCI which represents pulmonary function (r 0; P = 0.050). Conclusion Overall, FM is highly negatively correlated with the VCI of Chinese medical students of both genders. However, there was a positive correlation between FM and VCI among low-weight male students.

Background: Rhesus macaques and humans are closely related genetically and share similar physiological and pathological characteristics. Exploring the impact of diet on the early establishment of gut microbiota in non-human primates can provide relevant clinical models for healthy infant growth and development. At present, few writers have focused on the composition and changes of the intestinal microbes of infant rhesus macaques throughout their progression from birth to formula feeding after weaning. In this study, we used 16S rRNA sequencing technology to explore the composition of the intestinal flora of rhesus macaques at different ages and analyzed the trends in the microbial changes. Results: The results showed that the relative abundance of Bifidobacterium and Lactobacillus in the intestinal flora of infant rhesus macaques significantly decreased, and Prevotella increased with age. Bifidobacterium longum and Bifidobacterium breve are effective biomarkers to predict grouping. The metabolic pathways enriched in early life mainly concentrated in glycosphingolipid biosynthesis (lacto and neolacto series) and the degradation and metabolism of alcohols and esters. Conclusions: We found that age was an important factor that affected the changes in the intestinal flora. This study revealed the change trend of flora in breastfed and formula-fed infant rhesus monkeys in different growth months, and found that the dominant flora changed greatly. This research provides a medically relevant theoretical basis for understanding the healthy development of infants.

Abstract Emerging SARS-CoV-2 variants and the gradually decreasing neutralizing antibodies over time post vaccination have led to an increase in incidents of breakthrough infection across the world. To investigate the potential protective effect of the recombinant protein subunit COVID-19 vaccine targeting receptor-binding domain (RBD) (PS-RBD) and whole inactivated virus particle vaccine (IV) against the variant strains, in this study, rhesus macaques were immunized with PS-RBD or IV vaccine, followed by a Beta variant (B.1.351) challenge. Although neutralizing activity against the Beta variant was reduced compared with that against the prototype, the decreased viral load in both upper and lower respiratory tracts, milder pathological changes, and downregulated inflammatory cytokine levels in lung tissues after challenge demonstrated that PS-RBD and IV still provided effective protection against the Beta variant in the macaque model. Furthermore, PS-RBD-induced macaque sera possessed general binding and neutralizing activity to Alpha, Beta, Delta, and Omicron variants in our study, though the neutralizing antibody (NAb) titers declined by varying degrees, demonstrating potential protection of PS-RBD against current circulating variants of concern (VOCs). Interestingly, although the IV vaccine-induced extremely low neutralizing antibody titers against the Beta variant, it still showed reduction for viral load and significantly alleviated pathological change. Other correlates of vaccine-induced protection (CoP) like antibody-dependent cellular cytotoxicity (ADCC) and immune memory were both confirmed to be existing in IV vaccinated group and possibly be involved in the protective mechanism.

Abstract Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2. To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants, we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine, followed by challenging with emerging SARS-CoV-2 variants of concern (VOCs). These vaccinated animals produced neutralizing antibodies against Alpha, Beta, Delta, and Omicron variants, although there were certain declinations of geometric mean titer (GMT) as compared with prototypic SARS-CoV-2. Of note, in vivo this prototypic vaccine not only reduced the viral loads in nasal, throat and anal swabs, pulmonary tissues, but also improved the pathological changes in the lung infected by variants of Alpha, Beta, and Delta. In summary, the prototypic SARS-CoV-2 inactivated vaccine in this study protected against VOCs to certain extension, which is of great significance for prevention and control of COVID-19.

Current COVID-19 vaccines are effective countermeasures to control the SARS-CoV-2 virus pandemic by inducing systemic immune responses through intramuscular injection. However, respiratory mucosal immunization will be needed to elicit local sterilizing immunity to prevent virus replication in the nasopharynx, shedding, and transmission. In this study, we first compared the immunoprotective ability of a chimpanzee replication–deficient adenovirus–vectored COVID-19 vaccine expressing a stabilized pre–fusion spike glycoprotein from the ancestral SARS-CoV-2 strain Wuhan–Hu–1 (BV-AdCoV-1) administered through either aerosol inhalation, intranasal spray, or intramuscular injection in cynomolgus monkeys and rhesus macaques. Compared with intranasal administration, aerosol inhalation of BV-AdCoV-1 elicited stronger humoral and mucosal immunity that conferred excellent protection against SARS-CoV-2 infection in rhesus macaques. Importantly, aerosol inhalation induced immunity comparable to that obtained by intramuscular injection, although at a significantly lower dose. Furthermore, to address the problem of immune escape variants, we evaluated the merits of heterologous boosting with an adenovirus–based Omicron BA.1 vaccine (C68–COA04). Boosting rhesus macaques vaccinated with two doses of BV-AdCoV-1 with either the homologous or the heterologous C68–COA04 vector resulted in cross–neutralizing immunity against WT, Delta, and Omicron subvariants, including BA.4/5 stronger than that obtained by administering a bivalent BV-AdCoV-1/C68–COA04 vaccine. These results demonstrate that the administration of BV-AdCoV-1 or C68–COA04 via aerosol inhalation is a promising approach to prevent SARS-CoV-2 infection and transmission and curtail the pandemic spread.

Because of the relatively limited understanding of coronavirus disease 2019 (COVID-19) pathogenesis, immunological analysis for vaccine development is needed. Mice and macaques were immunized with an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine prepared by two inactivators. Various immunological indexes were tested, and viral challenges were performed on day 7 or 150 after booster immunization in monkeys. This inactivated SARS-CoV-2 vaccine was produced by sequential inactivation with formaldehyde followed by propiolactone. The various antibody responses and specific T cell responses to different viral antigens elicited in immunized animals were maintained for longer than 150 days. This comprehensive immune response could effectively protect vaccinated macaques by inhibiting viral replication in macaques and substantially alleviating immunopathological damage, and no clinical manifestation of immunopathogenicity was observed in immunized individuals during viral challenge. This candidate inactivated vaccine was identified as being effective against SARS-CoV-2 challenge in rhesus macaques.

To explore the relationship between the changes in the physiological period and the fecal microbial population of female rhesus monkeys by measuring microbial composition of fecal samples and the serum hormones. Blood and fecal samples were collected from six female adult rhesus monkeys during the menstrual period (MP), ovulation period (OP), and Luteal period (LP). Serum estradiol (E2) and progesterone (P) levels were determined by the chemiluminescence method and the stool samples were subjected to high-throughput 16S rRNA sequencing. The highest level of E2 and P secretions were during the MP, and LP, respectively. Stool samples produced valid sequences and the number of operational taxonomic unit/OTU was: 810056/3756 (MP), 845242/4159 (OP), 881560/3970 (LP). At the phylum level, the three groups of Firmicutes and Bacteroides accounted for > 95%. The dominant flora at the LP was Bacteroides (53.85%), the dominant flora at the MP and OP was Firmicutes, 64.08 and 56.53%, respectively. At the genus level, the dominant genus at the LP was Prevotella, the dominant genera at the MP were Prevotella, Oncococcus, Streptococcus, and Kurtella. The dominant genera at OP were Prevotella and Nocococcus. At the phylum level, P levels were negatively correlated to Firmicutes, Actinomycetes Actinobacteria, and Fibrobacteres, but positively correlated to Bacteroidetes. Likewise, E2 was positively correlated to Proteobacteria but negatively correlated to Euryarchaeota. At the genus level, P hormone showed a significant correlation with 16 bacterial species, and E2 was significantly correlated to seven bacterial species. Function prediction analysis revealed a high similarity between the MP and OP with six differentially functional genes (DFGs) between them and 11 DFGs between OP and LP (P < 0.05). Fecal microbiota types of female rhesus monkeys varied with different stages of the menstrual cycle, possibly related to changes in hormone levels.

In most cases, recurrent chronic colitis is caused by the recurrence of acute colitis after incomplete recovery and re-exposure to irritating factors, and the gut microbiome, which is the largest micro-ecosystem in the human body, plays a crucial role in the development of colitis. Plant polysaccharides have always been reported to have the ability for anti-inflammation, and they are closely related to the gut microbiome. Lycium barbarum Glycopeptide (LbGP), the most potent component obtained by further isolation and purification from Lycium barbarum fruit, has been shown to inhibit inflammation in animal models. However, its therapeutic efficacy in colitis and its mechanism in gut microbiota regulation have not been fully studied. In our study, the dextran sulfate sodium (DSS)-induced mouse model was used to dynamically evaluate the effect of LbGP in the treatment of acute colitis and the mechanism from the perspective of the gut microbiome through the 16S rDNA sequence. The results showed that LbGP treatment significantly alleviated acute colitis and improved the gut microbiome compared with that in the model group. Harmful bacteria, such as Lachnoclostridium spp. and Parabacteroides_distasonis, were inhibited and probiotics, such as Bacteroides_acidifaciens, Lactobacillus spp., Turicibacter spp., and Alistipes spp., were increased by LbGP treatment. Further, a Random Forest analysis with 10-fold cross-validation identified a family named Muribaculaceae representing colitis development and recovery upon LbGP treatment. In conclusion, our study demonstrated the capability of LbGP to prevent the development of acute colitis by regulating the composition and diversity of the gut microbiota and highlighted the dynamic process of gut microbiota with the colitis progression. Further, it provides evidence to develop LbGP as a functional food supplement and future drug acting on intestinal disease.

Bacterial pneumonia is one of the leading causes of death worldwide and exerts a significant burden on health-care resources. Antibiotics have long been used as first-line drugs for the treatment of bacterial pneumonia. However, antibiotic therapy and traditional antibiotic delivery are associated with important challenges, including drug resistance, low bioavailability, and adverse side effects; the existence of physiological barriers further hampers treatment. Fortunately, these limitations may be overcome by the application of nanotechnology, which can facilitate drug delivery while improving drug stability and bioavailability. This review summarizes the challenges facing the treatment of bacterial pneumonia and also highlights the types of nanoparticles that can be used for antibiotic delivery. This review places a special focus on the state-of-the-art in nanomaterial-based approaches to the delivery of antibiotics for the treatment of pneumonia.

Reinfection risk is a great concern with regard to the COVID-19 pandemic because a large proportion of the population has recovered from an initial infection, and previous reports found that primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques without viral presence and pathological injury; however, a high possibility for reinfection at the current stage of the pandemic has been proven. We found the reinfection of SARS-CoV-2 in Syrian hamsters with continuous viral shedding in the upper respiratory tracts and few injuries in the lung, and nasal mucosa was exploited by SARS-CoV-2 for replication and shedding during reinfection; meanwhile, no viral replication or enhanced damage was observed in the lower respiratory tracts. Consistent with the mild phenotype in the reinfection, increases in mRNA levels in cytokines and chemokines in the nasal mucosa but only slight increases in the lung were found. Notably, the high levels of neutralizing antibodies in serum could not prevent reinfection in hamsters but may play roles in benefitting the lung recovery and symptom relief of COVID-19. In summary, Syrian hamsters could be reinfected by SARS-CoV-2 with mild symptoms but with obvious viral shedding and replication, and both convalescent and vaccinated patients should be wary of the transmission and reinfection of SARS-CoV-2.

Abstract Background The gut microbiome is closely associated with the health of the host; although the interaction between the bacterial microbiome and the whole virome has rarely been studied, it is likely of medical importance. Examination of the interactions between the gut bacterial microbiome and virome of rhesus monkey would significantly contribute to revealing the gut microbiome composition. Methods Here, we conducted a metagenomic analysis of the gut microbiome of rhesus monkeys in a longitudinal cohort treated with an antibiotic cocktail, and we documented the interactions between the bacterial microbiome and virome. The depletion of viral populations was confirmed at the species level by real-time PCR. We also detected changes in the gut metabolome by GC-MS and LC-MS. Results A majority of bacteria were depleted after treatment with antibiotics, and the Shannon diversity index decreased from 2.95 to 0.22. Furthermore, the abundance-based coverage estimator (ACE) decreased from 104.47 to 33.84, and the abundance of eukaryotic viruses also changed substantially. In the annotation, 6 families of DNA viruses and 1 bacteriophage family were present in the normal monkeys but absent after gut bacterial microbiome depletion. Intriguingly, we discovered that changes in the gut bacterial microbiome composition may promote changes in the gut virome composition, and tryptophan, arginine, and quinone may play roles in the interaction between the bacterial microbiome and virome. Conclusion Our results indicated that the clearly altered composition of the virome was correlated with depletion in the bacterial community and that metabolites produced by bacteria possibly play important roles in the interaction.

The COVID-19 has emerged as an epidemic, causing severe pneumonia with a high infection rate globally. To better understand the pathogenesis caused by SARS-CoV-2, we developed a rhesus macaque model to mimic natural infection via the nasal route, resulting in the SARS-CoV-2 virus shedding in the nose and stool up to 27 days. Importantly, we observed the pathological progression of marked interstitial pneumonia in the infected animals on 5-7 dpi, with virus dissemination widely occurring in the lower respiratory tract and lymph nodes, and viral RNA was consistently detected from 5 to 21 dpi. During the infection period, the kinetics response of T cells was revealed to contribute to COVID-19 progression. Our findings implied that the antiviral response of T cells was suppressed after 3 days post infection, which might be related to increases in the Treg cell population in PBMCs. Moreover, two waves of the enhanced production of cytokines (TGF-α, IL-4, IL-6, GM-CSF, IL-10, IL-15, IL-1β), chemokines (MCP-1/CCL2, IL-8/CXCL8, and MIP-1β/CCL4) were detected in lung tissue. Our data collected from this model suggested that T cell response and cytokine/chemokine changes in lung should be considered as evaluation parameters for COVID-19 treatment and vaccine development, besides of observation of virus shedding and pathological analysis.

Rat hepatitis E virus (rat HEV) was first identified in wild rats and was classified as the species Orthohepevirus C in the genera Orthohepevirus, which is genetically different from the genotypes HEV-1 to HEV-8, which are classified as the species Orthohepevirus A. Although recent reports suggest that rat HEV transmits to humans and causes hepatitis, the infectivity of rat HEV to non-human primates such as cynomolgus and rhesus monkeys remains controversial. To investigate whether rat HEV infects non-human primates, we inoculated one cynomolgus monkey and five rhesus monkeys with a V-105 strain of rat HEV via an intravenous injection. Although no significant elevation of alanine aminotransferase (ALT) was observed, rat HEV RNA was detected in fecal specimens, and seroconversion was observed in all six monkeys. The partial nucleotide sequences of the rat HEV recovered from the rat HEV-infected monkeys were identical to those of the V-105 strain, indicating that the infection was caused by the rat HEV. The rat HEV recovered from the cynomolgus and rhesus monkeys successfully infected both nude and Sprague-Dawley rats. The entire rat HEV genome recovered from nude rats was identical to that of the V-105 strain, suggesting that the rat HEV replicates in monkeys and infectious viruses were released into the fecal specimens. These results demonstrated that cynomolgus and rhesus monkeys are susceptible to rat HEV, and they indicate the possibility of a zoonotic infection of rat HEV. Cynomolgus and rhesus monkeys might be useful as animal models for vaccine development.

Urban parks play a distinctive and important role in satisfying residents’ demands on leisure and recreation, and thus have become the focus of research in the field of urban planning and sustainable development. This paper used equity as indicator to combine both the supply and demand sides of urban park service. Taking Xiamen as the study case, the relationship between spatial distribution of population and park services was analyzed. The results show that while population density has a significant spatial relationship with urban park service level at the city scale, Xiamen has the problem of neglecting the equity of urban park service between people and regions within the city. The proposed approach builds up the linkage between urban park service and urban population in order to evaluate the performance of urban park. Although the mechanism remains to be discussed, this study provides a useful auxiliary tool for constructing a guideline for urban green space planning, since urban park is increasingly seen as a kind of restricted public resource and ensuring its equity should be an important task for city mangers.

Abstract Coxsackievirus A16 (CA16) is a member of the Picornaviridae family and causes mild and self-limiting hand, foot, and mouth disease (HFMD) in infants and young children. CA16 infection can also progress to central nervous system (CNS) complications; however, the underlying mechanism by which CA16 penetrates the blood-brain barrier (BBB) and then causes CNS damage remains unclear. This study aimed to explore the mechanism of CA16 neurotropic tropism by establishing an in vitro BBB model with CA16 infection and an in vivo CA16 rhesus monkey infant infection model. The results showed that CA16 infection induced increased permeability of the BBB accompanied by upregulation of matrix metalloproteinase 9 (MMP9) expression. Subsequently, high-throughput miRNA sequencing technology and bioinformatics analysis revealed that miR-1303 may regulate BBB permeability by targeting MMP9. Next, we used dual-luciferase, qRT-PCR, and western blot assays to provide evidence of MMP9 targeting by miR-1303. Further experiments revealed that CA16 infection promoted the degradation of junctional complexes (Claudin4, Claudin5, VE-Cadherin, and ZO-1), likely by downregulating miR-1303 and upregulating MMP9. Finally, EGFP-CA16 infection could enter the CNS by facilitating the degradation of junctional complexes, eventually causing neuroinflammation and injury to the CNS, which was confirmed using the in vivo rhesus monkey model. Our results indicate that CA16 might penetrate the BBB and then enter the CNS by downregulating miR-1303, which disrupts junctional complexes by directly regulating MMP9 and ultimately causing pathological CNS changes. These results provide new therapeutic targets in HFMD patients following CA16 infection.

Ventilator-associated pneumonia (VAP) infection caused by carbapenem-resistant Enterobacteriaceae (CRE) is becoming more prevalent, thus seriously affecting patient outcomes. In this paper, we studied the drug resistance mechanism and epidemiological characteristics of CRE, and analyzed the infection and prognosis factors of VAP caused by CRE, to provide evidence for effective control of nosocomial infection in patients with VAP. A total of 58 non-repetitive CRE strains of VAP were collected from January 2016 to June 2018. To explore the risk factors of CRE infection, 1:2 group case control method was used to select non CRE infection patients at the same period as the control group. Among the 58 CRE strains, the most common isolates included Klebsiella pneumoniae and Escherichia coli. All strains were sensitive to polymyxin B, which features better sensitivity to other antibiotics such as minocycline, trimethoprim/sulfamethoxazole, and amikacin. Multiple drug resistance genes were detected at the same time in most strains. KPC-2 was the most common carbapenemase-resistant gene in Klebsiella pneumoniae, whereas NDM-1 was more common in Escherichia coli. The risk factors correlated with CRE infection included intensive care unit (ICU) occupancy time >7 days (OR = 2.793; 95% CI 1.439~5.421), antibiotic exposure during hospital stay including those to enzyme inhibitors (OR = 1.977; 95% CI 1.025~3.812), carbapenems (OR = 3.268; 95% CI 1.671~6.392), antibiotic combination therapy(OR = 1.951; 95% CI 1.020~3.732), and nerve damage (OR = 3.013; 95% CI 1.278~7.101). Multivariable analysis showed that ICU stay >7 days (OR = 1.867; 95% CI 1.609~20.026), beta-lactamase inhibitor antibiotics (OR = 7.750; 95% CI 2.219~27.071), and carbapenem (OR = 9.143; 95% CI 2.259~37.01) are independent risk factors for VAP carbapenem caused by Carbapenem-resistant Enterobacteriaceae. A high resistance rate of CRE isolated from VAP indicated that the infected patients featured higher mortality and longer hospital stay time than the control group. Multiple risk factors for CRE infection and their control can effectively prevent the spread of VAP.

Rhesus macaque is an important animal model in biomedical research, especially human disease, developmental, translational, and pre-clinical research. Blood physiological and biochemical parameters are important markers for physiology, pathology, and toxicology research. However, these parameters have not been systematically reported for Chinese rhesus macaques. To characterize the reference for these parameters, this study collected 1805 Chinese rhesus macaques living in Southwestern China. A total of 24 blood physiological indexes and 27 biochemical parameters were determined. Sex and age were found to affect these parameters. In conclusion, a comprehensive and systematic reference of hematological and biochemical parameters for Chinese rhesus macaque was established in this work on the basis of a large cohort. Such reference will benefit biomedical research employing rhesus macaques as animal models.

As the most basic unit of the national economy and administrative management, the low-carbon transformation of the vast counties is of great significance to China’s overall greenhouse gas emission reduction. Although the low-carbon evaluation (LCE) indicator system and benchmarks have been extensively studied, most benchmarks ignore the needs of the evaluated object at the development stage. When the local economy develops to a certain level, it may be restricted by static low-carbon target constraints. This study reviews the relevant research on LCE indicator system and benchmarks based on convergence. The Environmental Kuznets Curve (EKC), a dynamic benchmark system for per capita carbon emissions (PCCEs), is proposed for low-carbon counties. Taking Changxing County, Zhejiang Province, China as an example, a dynamic benchmark for PCCEs was established by benchmarking the Carbon Kuznets Curve (CKC) of best practices. Based on the principles of best practice, comparability, data completeness, and the CKC hypothesis acceptance, the best practice database is screened, and Singapore is selected as a potential benchmark. By constructing an econometric model to conduct an empirical study on Singapore’s CKC hypothesis, the regression results of the least squares method support the CKC hypothesis and its rationality as a benchmark. The result of the PCCE benchmarks of Changxing County show that when the per capita income of Changxing County in 2025, 2030, and 2035 reaches USD 19,172.92, USD 24,483.01, and USD 29,366.11, respectively, the corresponding benchmarks should be 14.95 tons CO2/person, 14.70 tons CO2/person, and 13.55 tons CO2/person. For every 1% increase in the county’s per capita income, the PCCE allowable room for growth is 17.6453%. The turning point is when the per capita gross domestic product (PCGDP) is USD 20,843.23 and the PCCE is 15.03 tons of CO2/person, which will occur between 2025 and 2030. Prior to this, the PCCE benchmark increases with the increase of PCGDP. After that, the PCCE benchmark decreases with the increase of PCGDP. The system is economically sensitive, adaptable to different development stages, and enriches the methodology of low-carbon indicator evaluation and benchmark setting at the county scale. It can provide scientific basis for Chinese county decision makers to formulate reasonable targets under the management idea driven by evaluation indicators and emission reduction targets and help counties explore the coordinated paths of economic development and emission reduction in different development stages. It has certain reference significance for other developing regions facing similar challenges of economic development and low-carbon transformation to Changxing County to formulate scientific and reasonable low-carbon emission reduction targets.

The regional allocation of carbon emission quotas is of great significance to realize the carbon emission target. Basing on the combination of the multi-index method and the improved equal-proportion distribution method, and fully considering the differences in economic factors, population factors, energy factors, technological factors among cities, China’s 2030 carbon intensity reduction target was allocated. The results indicate that: (1) Under the target constraint of 60% reduction in CO2 emissions per unit of Gross Domestic Product (GDP) (carbon intensity) in 2030 compared to 2005, the carbon intensity target reduction rate (CITRR) of 285 Chinese cities is between 17.65% and 141.14%, with an average reduction rate of 51.52%; (2) the CITRR of cities presents significant spatial positive correlation, and the Global Moran I correlation index is 0.38; and (3) the distribution trend of CITRR is the same as the general trend of economic development of China, showing a basic trend of gradual decline from south to north and from coastal to inland. The allocation method takes into account fairness and efficiency, and reflects the differences between cities, so that the allocation results are likely to be accepted by all parties. Meanwhile, this method breaks the limitation of the lack of city’s data and is likely to implement in actual operation. Cities should choose distinguished low-carbon economic development paths, in combination with their characteristics of economic and social development, and carry out inter-city cooperation to promote carbon emission reduction steadily.

Herpes simplex virus type 1(HSV-1) presents a conundrum to public health worldwide because of its specific pathogenicity and clinical features. Some experimental vaccines, such as the recombinant viral glycoproteins, exhibit the viral immunogenicity of a host-specific immune response, but none of these has achieved a valid epidemiological protective efficacy in the human population. In the present study, we constructed an attenuated HSV-1 strain M3 through the partial deletion of UL7, UL41, and the latency-associated transcript (LAT) using the CRISPR/Cas9 system. The mutant strain exhibited lowered infectivity and virulence in macaques. Neutralization testing and ELISpot detection of the specific T-cell responses confirmed the specific immunity induced by M3 immunization and this immunity defended against the challenges of the wild-type strain and restricted the entry of the wild-type strain into the trigeminal ganglion. These results in rhesus macaques demonstrated the potential of the attenuated vaccine for the prevention of HSV-1 in humans.

As one of the major pathogens for human herpetic diseases, herpes simplex virus type 1 (HSV1) causes herpes labialis, genital herpes and herpetic encephalitis. Our aim here was to investigate the infectious process of HSV1 in rhesus macaques and the pathological features induced during this infection. Clinical symptoms that manifested in the rhesus macaque during HSV1 infection included vesicular lesions and their pathological features. Viral distribution in the nervous tissues and associated pathologic changes indicated the typical systematic pathological processes associated with viral distribution of HSV1.Interestingly, vesicular lesions recurred in oral skin or in mucosa associated with virus shedding in macaques within four to five months post‐infection,and viral latency‐associated transcript (LAT) mRNA was found in the trigeminal ganglia (TG)on day 365 post‐infection. Neutralization testing and enzyme‐linked immunospot (ELISpot) detection of specific T cell responses confirmed the specific immunity induced by HSV1 infection. Thus, rhesus macaques could serve as an infectious model for HSV1 due to their typical clinical symptoms and the pathological recurrence associated with viral latency in nervous tissues.

A total of 290 tree-ring samples, collected from six sites in the West Qinling Mountains of China, were used to develop six new standard tree-ring chronologies. In addition, 73 proxy records were assembled in collaboration with Chinese and international scholars, from 27 publically available proxy records and 40 tree-ring chronologies that are not available in public datasets. These records were used to reconstruct annual mean temperature variability in the West Qinling Mountains over the past 500 years (AD 1500-1995), using a modified point-by-point regression (hybrid PPR) method. The results demonstrate that the hybrid PPR method successfully integrates the temperature signals from different types of proxies, and that the method preserves a high degree of low-frequency variability. The reconstruction shows greater temperature variability in the West Qinling Mountains than has been found in previous studies. Our temperature reconstruction for this region shows: 1) five distinct cold periods, at approximately AD 1520-1535, AD 1560-1575, AD 1610-1620, AD 1850-1875 and AD 1965-1985, and four warm periods, at approximately AD 1645-1660, AD 1705-1725, AD 1785-1795 and AD 1920-1945; 2) that in this region, the 20(th) century was not the warmest period of the past 500 years; and 3) that a dominant and persistent oscillation of ca. 64 years is significantly identified in the 1640-1790 period.

Coxsackievirus B1 (CVB1), an enterovirus with multiple clinical presentations, has been associated with potential long‐term consequences, including hand, foot, and mouth disease (HFMD), in some patients. However, the related animal models, transmission dynamics, and long‐term tissue tropism of CVB1 have not been systematically characterized. In this study, we established a model of CVB1 respiratory infection in rhesus macaques and evaluated the clinical symptoms, viral load, and immune levels during the acute phase (0–14 days) and long‐term recovery phase (15–30 days). We also investigated the distribution, viral clearance, and pathology during the long‐term recovery period using 35 postmortem rhesus macaque tissue samples collected at 30 days postinfection (d.p.i.). The results showed that the infected rhesus macaques were susceptible to CVB1 and exhibited HFMD symptoms, viral clearance, altered cytokine levels, and the presence of neutralizing antibodies. Autopsy revealed positive viral loads in the heart, spleen, pancreas, soft palate, and olfactory bulb tissues. HE staining demonstrated pathological damage to the liver, spleen, lung, soft palate, and tracheal epithelium. At 30 d.p.i., viral antigens were detected in visceral, immune, respiratory, and muscle tissues but not in intestinal or neural tissues. Brain tissue examination revealed viral meningitis‐like changes, and CVB1 antigen expression was detected in occipital, pontine, cerebellar, and spinal cord tissues at 30 d.p.i. This study provides the first insights into CVB1 pathogenesis in a nonhuman primate model of HFMD and confirms that CVB1 exhibits tissue tropism following long‐term infection. [ABSTRACT FROM AUTHOR]

Coxsackievirus B3 (CVB3) is the pathogen causing hand, foot and mouth disease (HFMD), which manifests across a spectrum of clinical severity from mild to severe. However, CVB3-infected mouse models mainly demonstrate viral myocarditis and pancreatitis, failing to replicate human HFMD symptoms. Although several enteroviruses have been evaluated in Syrian hamsters and rhesus monkeys, there is no comprehensive data on CVB3. In this study, we have first tested the susceptibility of Syrian hamsters to CVB3 infection via different routes. The results showed that Syrian hamsters were successfully infected with CVB3 by intraperitoneal injection or nasal drip, leading to nasopharyngeal colonization, acute severe pathological injury, and typical HFMD symptoms. Notably, the nasal drip group exhibited a longer viral excretion cycle and more severe pathological damage. In the subsequent study, rhesus monkeys infected with CVB3 through nasal drips also presented signs of HFMD symptoms, viral excretion, serum antibody conversion, viral nucleic acids and antigens, and the specific organ damages, particularly in the heart. Surprisingly, there were no significant differences in myocardial enzyme levels, and the clinical symptoms resembled those often associated with common, mild infections. In summary, the study successfully developed severe Syrian hamsters and mild rhesus monkey models for CVB3-induced HFMD. These models could serve as a basis for understanding the disease pathogenesis, conducting pre-trial prevention and evaluation, and implementing post-exposure intervention. [ABSTRACT FROM AUTHOR]