The function of brown adipose tissue at different sites of the body in Brandt's voles during cold acclimation.

Ambient temperatures have great impacts on thermoregulation of small mammals. Brown adipose tissue (BAT), an obligative thermogenic tissue for small mammals, is localized not only in the interscapular depot (iBAT), but also in supraclavicular, infra/subscapular, cervical, paravertebral, and periaortic depots. The iBAT is known for its cold-induced thermogenesis, however, less has been paid attention to the function of BAT at other sites. Here, we investigated the function of BAT at different sites of the body during cold acclimation in a small rodent species. As expected, Brandt's voles (Lasiopodomys brandtii) consumed more food and reduced the body mass gain when they were exposed to cold. The voles increased resting metabolic rate and maintained a relatively lower body temperature in the cold (36.5 ± 0.27 °C) compared to those in the warm condition (37.1 ± 0.36 °C). During cold acclimation, the uncoupling protein 1 (UCP1) increased in aBAT (axillary), cBAT (anterior cervical), iBAT (interscapular), nBAT (supraclavicular), and sBAT (suprascapular). The levels of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, were higher in cBAT and iBAT in the cold than in the warm group. The pAMPK/AMPK and pCREB/CREB were increased in cBAT and iBAT during cold acclimation, respectively. These data indicate that these different sites of BAT play the cold-induced thermogenic function for small mammals.

Coordination cages integrated into swelling poly(ionic liquid)s for guest encapsulation and separation.

Coordination cages have been widely reported to bind a variety of guests, which are useful for chemical separation. Although the use of cages in the solid state benefits the recycling, the flexibility, dynamicity, and metal-ligand bond reversibility of solid-state cages are poor, preventing efficient guest encapsulation. Here we report a type of coordination cage-integrated solid materials that can be swelled into gel in water. The material is prepared through incorporation of an anionic FeII4L6 cage as the counterion of a cationic poly(ionic liquid) (MOC@PIL). The immobilized cages within MOC@PILs have been found to greatly affect the swelling ability of MOC@PILs and thus the mechanical properties. Importantly, upon swelling, the uptake of water provides an ideal microenvironment within the gels for the immobilized cages to dynamically move and flex that leads to excellent solution-level guest binding performances. This concept has enabled the use of MOC@PILs as efficient adsorbents for the removal of pollutants from water and for the purification of toluene and cyclohexane. Importantly, MOC@PILs can be regenerated through a deswelling strategy along with the recycling of the extracted guests.

A comprehensive meta-analysis on the association of SGLT2is and GLP-1RAs with vascular diseases, digestive diseases and fractures.

AIM: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are two new classes of antidiabetic agents. We aimed to evaluate the association between these two drug classes and risk of various vascular diseases, digestive diseases and fractures. METHODS: Large randomized trials of SGLT2is and GLP-1RAs were included. Outcomes of interest were the various serious adverse events related to vascular diseases, digestive diseases and fractures. We performed meta-analyses using synthesize risk ratio (RR) and 95% confidence interval (CI) as effect size. RESULTS: We included 27 large trials. SGLT2is had significant association with less hypertension (RR 0.70, 95% CI 0.54-0.91), hypertensive crisis (RR 0.63, 95% CI 0.47-0.84), varicose vein (RR 0.34, 95% CI 0.13-0.92), and vomiting (RR 0.55, 95% CI 0.31-0.97); but more spinal compression fracture (RR 1.73, 95% CI 1.02-2.92) and tibia fracture. GLP-1RAs had significant association with more deep vein thrombosis (RR 1.92, 95% CI 1.23-3.00), pancreatitis (RR 1.54, 95% CI 1.07-2.22), and cholecystitis acute (RR 1.51, 95% CI 1.08-2.09); but less rib fracture (RR 0.59, 95% CI 0.35-0.97). Sensitivity analyses suggested that our findings were robust. CONCLUSIONS: SGLT2is may have protective effects against specific vascular and digestive diseases, whereas they may increase the incidence of site-specific fractures (e.g., spinal compression fracture). GLP-1RAs may have protective effects against site-specific fractures (i.e., rib fracture), whereas they may increase the incidence of specific vascular and digestive diseases. These findings may help to make a choice between SGLT2is and GLP-1RAs in clinical practice.

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML.

Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO hematopoietic stem and/or progenitor cells (HSPCs) expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.

Boldness suppresses hoarding behavior in food hoarding season and reduces over-wintering survival in a social rodent.

The "pace-of-life" syndrome (POLS) framework can encompass multiple personality axes that drive important functional behaviors (e.g., foraging behavior) and that co-vary with multiple life history traits. Food hoarding is an adaptive behavior important for an animal's ability to adapt to seasonal fluctuations in food availability. However, the empirical evidence for the relationships between animal personality and hoarding behavior remains unclear, including its fitness consequences in the POLS framework. In this study, the Mongolian gerbil (Meriones unguiculatus), a social rodent, was used as a model system to investigate how boldness or shyness is associated with food hoarding strategies during the food hoarding season and their impact on over-winter survival and reproduction at both individual and group levels. The results of this study showed that, compared with shy gerbils, bold gerbils had a lower effort foraging strategy during the food hoarding season and exhibited lower over-winter survival rates. However, bold-shy personality differences had no effect on over-winter reproduction. These findings suggest that the personality is a crucial factor influencing the foraging strategy during the food hoarding season in Mongolian gerbils. Personality may be related to energy states or the reaction to environmental changes (e.g., predation risk and food availability) in bold or shy social animals. These results reflect animal life history trade-offs between current versus future reproduction and reproduction versus self-maintenance, thereby helping Mongolian gerbils in adapting to seasonal fluctuations in their habitat.

Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis.

BACKGROUND & AIMS: Unrestricted endoplasmic reticulum (ER) stress and the continuous activation of ER associated protein degradation (ERAD) pathway might lead to the aggravation of non-alcoholic steatohepatitis (NASH). Derlin-1 has been considered to be an integral part of the ERAD pathway, which is involved in the regulation of the transport and excretion of protein degradation products within ER. However, the regulatory role and mechanism of Derlin-1 in NASH remains unclear. METHODS: The expression of Derlin-1 was firstly detected in the liver of normal and NASH animal model and patient. Then, western diet (WD)-induced NASH mice were administrated with the lentivirus-mediated Derlin-1 knockdown or overexpression. Finally, RIPK3 knockout mice were used to explore the mechanism. The liver injury, hepatic steatosis, inflammation, and fibrosis as well as ER stress signal pathway were evaluated. RESULTS: The levels of Derlin-1 were significantly elevated in the liver of WD-fed mice and NASH patients when compared to the control group. Furthermore, Derlin-1 knockdown attenuated WD-induced liver injury, lipid accumulation, inflammatory response, and fibrosis. Conversely, overexpression of Derlin-1 presented the completely opposite results. Mechanistically, Derlin-1 enhanced ER stress pathways and led to necroptosis, and RIPK3 knockout dramatically reduced Derlin-1 expression and reversed the progression of NASH aggravated by Derlin-1. CONCLUSIONS: Notably, Derlin-1 is a critical modulator in NASH. It may accelerate the progression of NASH by regulating the activation of the ERAD pathway and further aggravating the ER stress, which might be involved in RIPK3-mediated necroptosis. Therefore, targeting Derlin-1 as a novel intervention point holds the potential to delay or even reverse NASH.

Metal-organic cages for gas adsorption and separation.

The unique high surface area and tunable cavity size endow metal-organic cages (MOCs) with superior performance and broad application in gas adsorption and separation. Over the past three decades, for instance, numerous MOCs have been widely explored in adsorbing diverse types of gas including energy gases, greenhouse gases, toxic gases, noble gases, etc. To gain a better understanding of the structure-performance relationships, great endeavors have been devoted to ligand design, metal node regulation, active metal site construction, cavity size adjustment, and function-oriented ligand modification, thus opening up routes toward rationally designed MOCs with enhanced capabilities. Focusing on the unveiled structure-performance relationships of MOCs towards target gas molecules, this review consists of two parts, gas adsorption and gas separation, which are discussed separately. Each part discusses the cage assembly process, gas adsorption strategies, host-guest chemistry, and adsorption properties. Finally, we briefly overviewed the challenges and future directions in the rational development of MOC-based sorbents for application in challenging gas adsorption and separation, including the development of high adsorption capacity MOCs oriented by adsorbability and the development of highly selective adsorption MOCs oriented by separation performance.

Hypothalamic Neuromodulation of Hypothermia in Domestic Animals.

When an organism detects decreases in their core body temperature, the hypothalamus, the main thermoregulatory center, triggers compensatory responses. These responses include vasomotor changes to prevent heat loss and physiological mechanisms (e.g., shivering and non-shivering thermogenesis) for heat production. Both types of changes require the participation of peripheral thermoreceptors, afferent signaling to the spinal cord and hypothalamus, and efferent pathways to motor and/or sympathetic neurons. The present review aims to analyze the scientific evidence of the hypothalamic control of hypothermia and the central and peripheral changes that are triggered in domestic animals.

Increased knee torsional misalignment associated with femoral torsion is related to non-contact anterior cruciate ligament injury: a case-control study.

BACKGROUND: Altered axial biomechanics of the knee are recognized as a risk factor for non-contact anterior cruciate ligament (ACL) injury. However, the relationship of knee and segmental torsion to non-contact ACL and combined anterolateral ligament (ALL) injury is unclear. This study aims to determine the relationship of knee and segmental torsion to non-contact ACL injury and to explore their relationship with ALL injuries. METHODS: We divided 122 patients with arthroscopically confirmed non-contact ACL injuries into an ACL injury group (isolated ACL injury, 63 patients) and an ACL + ALL injury group (ACL combined with ALL injury,59 patients). Additionally, 90 normal patients with similar age, gender and body mass index (BMI) were matched as a control group. The tibial tubercle-trochlear groove (TT-TG) distance, distal femoral torsion (DFT), posterior femoral condylar torsion (PFCT) and proximal tibial torsion (PTT) were measured using magnetic resonance imaging (MRI). We assessed the differences between the groups using an independent samples t test and utilized receiver operating characteristic (ROC) curves to determine the cut-off value for the increased risk of ACL injury. RESULTS: In patients with ACL injury, the measurements of the TT-TG (11.8 ± 3.1 mm), DFT (7.7° ± 3.5°) and PFCT (3.6° ± 1.3°) were significantly higher compared to the control group (9.1 ± 2.4 mm, 6.3° ± 2.7° and 2.8° ± 1.3°, respectively; P < 0.05), but the PTT did not differ between the two groups. The TT-TG, DFT and PFCT were not significantly larger in patients combined with ALL injury. ROC curve analysis revealed ACL injury is associated with TT-TG, DFT and PFCT. CONCLUSIONS: Knee torsional alignment is associated with ACL injury, predominantly in the distal femur rather than the proximal tibia. However, its correlation with ALL injury remains unclear. These findings may help identify patients at high risk for non-contact ACL injury and inform the development of targeted prevention and treatment strategies.

Multi-parametric assessment of cardiac magnetic resonance images to distinguish myocardial infarctions: A tensor-based radiomics feature.

AIM: This study assessed the myocardial infarction (MI) using a novel fusion approach (multi-flavored or tensor-based) of multi-parametric cardiac magnetic resonance imaging (CMRI) at four sequences; T1-weighted (T1W) in the axial plane, sense-balanced turbo field echo (sBTFE) in the axial plane, late gadolinium enhancement of heart short axis (LGE-SA) in the sagittal plane, and four-chamber views of LGE (LGE-4CH) in the axial plane. METHODS: After considering the inclusion and exclusion criteria, 115 patients (83 with MI diagnosis and 32 as healthy control patients), were included in the present study. Radiomic features were extracted from the whole left ventricular myocardium (LVM). Feature selection methods were Least Absolute Shrinkage and Selection Operator (Lasso), Minimum Redundancy Maximum Relevance (MRMR), Chi-Square (Chi2), Analysis of Variance (Anova), Recursive Feature Elimination (RFE), and SelectPersentile. The classification methods were Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF). Different metrics, including receiver operating characteristic curve (AUC), accuracy, F1- score, precision, sensitivity, and specificity were calculated for radiomic features extracted from CMR images using stratified five-fold cross-validation. RESULTS: For the MI detection, Lasso (as the feature selection) and RF/LR (as the classifiers) in sBTFE sequences had the best performance (AUC: 0.97). All features and classifiers of T1 + sBTFE sequences with the weighted method (as the fused image), had a good performance (AUC: 0.97). In addition, the results of the evaluated metrics, especially mean AUC and accuracy for all models, determined that the T1 + sBTFE-weighted fused method had strong predictive performance (AUC: 0.93±0.05; accuracy: 0.93±0.04), followed by T1 + sBTFE-PCA fused method (AUC: 0.85±0.06; accuracy: 0.84±0.06). CONCLUSION: Our selected CMRI sequences demonstrated that radiomics analysis enables to detection of MI accurately. Among the investigated sequences, the T1 + sBTFE-weighted fused method with the highest AUC and accuracy values was chosen as the best technique for MI detection.

The function role of HIGD1A in nonalcoholic steatohepatitis from chronic hepatitis B.

BACKGROUND: Accompanied by the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the coexistence of chronic hepatitis B (CHB) and NAFLD has increased. In the context of CHB, there is limited understanding of the factors that influence the development of NASH. METHODS: We enrolled CHB combined NAFLD patients who had liver biopsy and divided them to NASH vs. non-NASH groups. A whole transcriptome chip was used to examine the expression profiles of long noncoding RNAs (lncRNAs) and mRNA in biopsied liver tissues. The function analysis of HIGD1A were performed. We knocked down or overexpressed HIGD1A in HepG2.2.15 cells by transient transfection of siRNA-HIGD1A or pcDNA-HIGD1A. In vivo investigations were conducted using hepatitis B virus (HBV) transgenic mice. RESULTS: In 65 patients with CHB and NAFLD, 28 were patients with NASH, and 37 were those without NASH. After screening 582 differentially expressed mRNAs, GO analysis revealed differentially expressed mRNAs acting on nicotinamide adenine dinucleotide phosphate (NADPH), which influenced redox enzyme activity. KEGG analysis also shown that they were involved in the NAFLD signaling pathway. The function analysis revealed that HIGD1A was associated with the mitochondrion. Then, both in vivo and in vitro CHB model, HIGD1A was significantly higher in the NASH group than in the non-NASH group. HIGD1A knockdown impaired mitochondrial transmembrane potential and induced cell apoptosis in HepG2.2.15 cells added oleic acid and palmitate. On the contrary, hepatic HIGD1A overexpression ameliorated free fatty acids-induced apoptosis and oxidative stress. Furthermore, HIGD1A reduced reactive oxygen species (ROS) level by increasing glutathione (GSH) expression, but Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/Acetyl-CoA carboxylase (ACC) pathway was not involved. CONCLUSION: Both in vivo and in vitro CHB model, an upward trend of HIGD1A was observed in the NASH-related inflammatory response. HIGDIA played a protective role in cells against oxidative stress. Our data suggested that HIGD1A may be a positive regulator of NASH within the CHB context.

Phylogenetic signal in gut microbial community rather than in rodent metabolic traits.

Host phylogeny and environment have all been implicated in shaping the gut microbiota and host metabolic traits of mammals. However, few studies have evaluated phylogeny-associated microbial assembly and host metabolic plasticity concurrently, and their relationships on both short-term and evolutionary timescales. We report that the branching order of a gut microbial dendrogram was nearly congruent with phylogenetic relationships of seven rodent species, and this pattern of phylosymbiosis was intact after diverse laboratory manipulations. Laboratory rearing, diet or air temperature (Ta) acclimation induced alterations in gut microbial communities, but could not override host phylogeny in shaping microbial community assembly. A simulative heatwave reduced core microbiota diversity by 26% in these species, and led to an unmatched relationship between the microbiota and host metabolic phenotypes in desert species. Moreover, the similarity of metabolic traits across species at different Tas was not correlated with phylogenetic distance. These data demonstrated that the gut microbial assembly showed strong concordance with host phylogeny and may be shaped by environmental variables, whereas host metabolic traits did not seem to be linked with phylogeny.

Role of exosomes in prostate cancer bone metastasis.

Bone is a preferred metastatic site of prostate cancer (PCa), and most patients with PCa metastases develop osteogenic bone metastasis, which manifests as disturbed bone structure and poor bone quality. However, the underlying mechanisms of PCa bone metastasis remain unclear. In recent years, increasing evidence has implicated extracellular vesicles, especially exosomes, in PCa bone metastasis. Exosomes are 30-150 nm in diameter, enclosing a cargo of biomolecules, such as DNA, RNA, and proteins. Exosomes play a functional role in intercellular communication, modulate the functions of recipient cells, and potentially modulate bone microenvironment changes, thereby influencing the development of PCa bone metastasis. This review summarizes the involvement of exosomes in the imbalance between bone resorption and formation, and establishing a pre-metastatic niche in bone marrow, as well as potential clinical applications of exosomes in therapeutic strategies for treating patients with advanced PCa with bone metastasis.

Genome-wide association analysis of type II resistance to Fusarium head blight in common wheat.

Background: Fusarium head blight (FHB) is a disease affecting wheat spikes caused by some Fusarium species and leads to cases of severe yield reduction and seed contamination. Identifying resistance genes/QTLs from wheat germplasm may help to improve FHB resistance in wheat production. Methods: Our study evaluated 205 elite winter wheat cultivars for FHB resistance. A high-density 90K SNP array was used for genotyping the panel. A genome-wide association study (GWAS) from cultivars from three different environments was performed using a mixed linear model (MLM). Results: Sixty-six significant marker-trait associations (MTAs) were identified (P < 0.001) on fifteen chromosomes that explained the phenotypic variation ranging from 5.4 to 11.2%. Some important new MTAs in genomic regions involving FHB resistance were found on chromosomes 2A, 3B, 5B, 6A, and 7B. Six MTAs at 92 cM on chromosome 7B were found in cultivars from two different environments. Moreover, there were 11 MTAs consistently associated with diseased spikelet rate and diseased rachis rate as pleiotropic effect loci and D_contig74317_533 on chromosome 5D was novel for FHB resistance. Eight new candidate genes of FHB resistance were predicated in wheat in this study. Three candidate genes, TraesCS5D02G006700, TraesCS6A02G013600, and TraesCS7B02G370700 on chromosome 5DS, 6AS, and 7BL, respectively, were perhaps important in defending against FHB by regulating intramolecular transferase activity, GTP binding, or chitinase activity in wheat, but further validation in needed. In addition, a total of five favorable alleles associated with wheat FHB resistance were discovered. These results provide important genes/loci for enhancing FHB resistance in wheat breeding by marker-assisted selection.

Role of gut microbiota in the postnatal thermoregulation of Brandt's voles.

Homeothermy is crucial for mammals. Postnatal growth is the key period for young offspring to acquire gut microbiota. Although gut microbiota may affect mammal thermogenesis, the impact of developmental regulation of gut microbiota on the ability of young pups to produce heat remains unclear. Antibiotics were used to interfere with the establishment of gut microbiota during the development of Brandt's voles, and their thermogenic development and regulatory pathways were determined. Deprivation of microbiota by antibiotics inhibits the development of thermogenesis in pups. Butyric acid and bile acid, as metabolites of gut microbiota, participated in the thermoregulation of pups. We propose that gut microbiota promote the development of thermoregulation through the butyric acid-free fatty acid receptor-2-uncoupling protein-1 or the deoxycholic acid-Takeda-G-protein-receptor-5-uncoupling protein-1 pathway in pups. These results show a relationship between gut microbiota and thermogenesis and expand the mechanism of postnatal development of thermogenesis in small mammals.

Melatonin reduced colon inflammation but had no effect on energy metabolism in ageing Mongolian gerbils (Meriones unguiculatus).

In photoperiod-sensitive wild animals, the secretion of melatonin (MT) is modulated by external photoperiod, and MT affects inflammation and the ageing process. The beneficial effects of MT in delaying the progress of ageing have been reported in laboratory mice and rats. However, little is known about MT in wild mammals. In the current study, we investigated energy metabolism, microbial community structure and colon homeostasis in ageing Mongolian gerbils (Meriones unguiculatus) through exogenous supplementation of MT to test the hypothesis that MT has beneficial effects on gut homeostasis in ageing gerbils. Exogenous MT supplementation had no effect on energy metabolism in Mongolian gerbils but reduced the levels of circulating tumor necrosis factor-α (TNF-α), immune globulin G (IgG) and corticosterone (CORT). The increase in the level of inflammation in ageing animals was related to changes in the structure and diversity of the gut microbiota. At the genus level, the relative abundance of Prevotella, Treponema, Corynebacterium, and Sphingomonas was increased in ageing animals and decreased significantly by the treatment of MT. Christensenella and Lactobacillus were attenuated in ageing animals, and tended to be enhanced by MT treatment. Functions related to glycosphingolipid biosynthesis-ganglio series and lipopolysaccharide biosynthesis (metabolisms of cofactors, vitamins and glycan) were increased in ageing animals and decreased significantly by the treatment of MT. Our data suggest that a supplement of MT could improve colon homeostasis through changing the composition of gut microbiota and reducing inflammation in ageing gerbils.

Continuous venovenous hemodiafiltration versus standard medical therapy for the prevention of rhabdomyolysis-induced acute kidney injury: a retrospective cohort study.

AIM: To determine whether continuous venovenous hemodiafiltration (CVVHDF) plus standard medical therapy (SMT) vs. SMT alone prevents rhabdomyolysis (RM)-induced acute kidney injury (AKI) and analyze the related health economics. METHODS: This retrospective cohort study involved 9 RM patients without AKI, coronary heart disease, or chronic kidney disease treated with CVVHDF plus SMT (CVVHDF + SMT group). Nine matched RM patients without AKI treated with SMT only served as controls (SMT group). Baseline characteristics, biochemical indexes, renal survival data, and health economic data were compared between groups. In the CVVHDF + SMT group, biochemical data were compared at different time points. RESULTS: At 2 and 7 days after admission, serum biochemical indices (e.g., myoglobin, creatine kinase, creatinine, and blood urea nitrogen) did not differ between the groups. Total (P = 0.011) and daily hospitalization costs (P = 0.002) were higher in the CVVHDF + SMT group than in the SMT group. After 53 months of follow-up, no patient developed increased serum creatinine, except for 1 CVVHDF + SMT-group patient who died of acute myocardial infarction. In the CVVHDF + SMT group, myoglobin levels significantly differed before and after the first CVVHDF treatment (P = 0.008), and serum myoglobin, serum creatinine, and blood urea nitrogen decreased significantly at different time points after CVVHDF. CONCLUSIONS: Although CVVHDF facilitated myoglobin elimination, its addition to SMT did not improve biochemical indices like serum myoglobin, serum creatine kinase, creatinine, blood urea nitrogen, and lactate dehydrogenase or the long-term renal prognosis. Despite similar hospitalization durations, both total and daily hospitalization costs were higher in the CVVHDF + SMT group.

HPV16 E6/E7 -based mRNA vaccine is therapeutic in mice bearing aggressive HPV-positive lesions.

HPV (Human papillomavirus) affects 600,000 people worldwide each year. Almost all cervical cancers are associated with a past HPV infection. In particular, the positivity to the high-risk type HPV16 is detected in most of the invasive cervical cancers. FDA has approved prophylactic vaccines that protect against new HPV16 infections, but do not induce immunity in those patients with established infections or neoplasms. To date, no therapeutic vaccine targeting HPV16-associated lesions has been authorized. We have developed an mRNA-based vaccine against the HPV16 late oncoproteins E6 and E7, which are abundantly and exclusively expressed in high-grade squamous intraepithelial lesions (HSILs), a stage of the cervical disease that precedes the progression to carcinoma. Our in vitro and in vivo studies demonstrated that the translated mRNA is functional and elicits an antigen-specific adaptive immune response. Upon immunization with the vaccine, mice with HPV16+ lesions exhibited tumor growth inhibition, extension of lifespan, and development of a protective immune memory. In light of these results and the remarkable clinical success of mRNA vaccines against SARS-CoV2, we believe that our mRNA-based therapeutic vaccine has the potential to offer a non-invasive treatment alternative to the current standard of care for HPV16+ HSILs.

Inherent structures of water using fully ab initio simulations.

Using fully ab initio molecular dynamics simulations based on the SCAN functional, we study the inherent structure of water and its temperature dependence. Our results show three types of translational ordering of the second oxygen coordination shell. With this as a criterion, the local structures in water are classified into three types, here named structures I, II, and III. In structure I, the second shell loses its translational ordering, while in structures II and III it presents a translational ordering similar to that in ice II (or ice V) and ice III, respectively. However, the tetrahedral orientational ordering distribution and bond-angle distribution in structures II and III are different from those in ice II (or ice V) and ice III. This indicates that the local atomic structures of liquid water and crystalline ice are not identical, although they have similar translational ordering. The temperature dependence of the inherent structure suggests that the density maximum of water originates from the competition not only between structures I and III, but also between structures II and III. These results provide fully ab initio evidence for the mixture model of water.

Mechanism of inulin in colic and gut microbiota of captive Asian elephant.

BACKGROUND: Gut microbiota have a complex role on the survivability, digestive physiology, production, and growth performance in animals. Recent studies have emphasized the effects of prebiotics therapy on the gut disease, but the relationship between elephant gut-related diseases and prebiotics remains elusive. Here, a case study was undertaken to evaluate the mechanism of inulin treatment in colic in Asian elephant (Elephas maximus Linnaeus). METHODS: Fecal samples were collected from a sick elephant and four healthy elephants. Analysis of microbial profile was carried out by 16S rRNA sequencing, and the short chain fatty acids were tested by gas chromatography. The physiological function of "inulin-microbiota" of elephant was verified in mice by fecal microbial transplantation (FMT). The expression of related proteins was determined by Western blotting and qPCR. RESULTS: (1) Eating inulin can cure gut colic of the sick elephant and changed gut microbiota. (2) It was found that "inulin microbiota" from the post-treatment elephants can promote the proliferation of intestinal cells, increase the utilization of short chain fatty acids (SCFAs), maintain intestinal barrier, and reduce the inflammation in mice. (3) The mechanism was inulin-gut microbiota-SCFAs-immune barrier. CONCLUSIONS: Inulin contributed to rehabilitate the gut microbiota and gut immune barrier of the elephant with colic. This provides reasonable verification for using prebiotics to treat the colic in captive elephants. Prebiotics will foresure play an increasingly important role in disease prevention and treatment of captive animals in the future. Video Abstract.