Insights into the formulation of lipid nanoparticles for the optimization of mRNA therapeutics.

mRNA-based therapeutics increasingly demonstrate significant potential in treating various diseases, including infectious diseases, cancers, and genetic disorders. Effective delivery systems are crucial for advancing mRNA therapeutics. Lipid nanoparticles (LNPs) serve as an excellent carrier, widely validated for their safety and tolerability in commercially available mRNA vaccines. Standard LNPs typically consist of four components: ionizable lipids (ILs), helper lipids, cholesterol, and polyethylene glycol-lipids (PEG-lipids), with the structural design of ILs gradually becoming a focal point of research interest. The chemical structures and formulations of the other components also significantly affect the delivery efficiency, targeting specificity, and stability of LNPs. The complex formulations of LNPs may hinder the clinical transformation of mRNA therapeutics and have raised widespread concerns about their safety. This review aims to summarize the progress of LNPs-based mRNA therapeutics in clinical trials, focusing on adverse effects that occurred during these trials. It also discusses representative innovations in LNP components, highlighting challenges and potential ways in this research field. We firmly believe this review will promote further improvements and designs of LNP compositions to optimize mRNA therapeutics. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Lipid-Based Structures.

Glutamine synthetase accelerates re-endothelialization of vascular grafts by mitigating endothelial cell dysfunction in a rat model.

Endothelial cell (EC) dysfunction within the aorta has long been recognized as a prominent contributor to the progression of atherosclerosis and the subsequent failure of vascular graft transplantation. However, the direct relationship between EC dysfunction and vascular remodeling remains to be investigated. In this study, we sought to address this knowledge gap by employing a strategy involving the release of glutamine synthetase (GS), which effectively activated endothelial metabolism and mitigates EC dysfunction. To achieve this, we developed GS-loaded small-diameter vascular grafts (GSVG) through the electrospinning technique, utilizing dual-component solutions consisting of photo-crosslinkable hyaluronic acid and polycaprolactone. Through an in vitro model of oxidized low-density lipoprotein-induced injury in human umbilical vein endothelial cells (HUVECs), we provided compelling evidence that the GSVG promoted the restoration of motility, angiogenic sprouting, and proliferation in dysfunctional HUVECs by enhancing cellular metabolism. Furthermore, the sequencing results indicated that these effects were mediated by miR-122-5p-related signaling pathways. Remarkably, the GSVG also exhibited regulatory capabilities in shifting vascular smooth muscle cells towards a contractile phenotype, mitigating inflammatory responses and thereby preventing vascular calcification. Finally, our data demonstrated that GS incorporation significantly enhanced re-endothelialization of vascular grafts in a ferric chloride-injured rat model. Collectively, our results offer insights into the promotion of re-endothelialization in vascular grafts by restoring dysfunctional ECs through the augmentation of cellular metabolism.

Total bile acid as a preoperative risk factor for post-hepatectomy liver failure in patients with hepatocellular carcinoma and normal bilirubin.

BACKGROUND AND AIMS: Total bile acid (TBA) is associated with portal hypertension, a risk factor for post-hepatectomy liver failure (PHLF). We conducted this study to clarify whether TBA is also associated with PHLF in patients with hepatocellular carcinoma (HCC). METHODS: We recruited patients with HCC and Child-Pugh class A, who underwent liver resection, and applied multivariate analyses to identify risk factors for PHLF. RESULTS: We analyzed data from 154 patients. The prevalence of PHLF was 14.3%. The median maximum tumor diameter was 5.1 cm (2.9-6.9 cm). The proportions of patients with elevated TBA levels (P = 0.001), severe albumin-bilirubin (AIBL) grades (P = 0.033), and low platelet counts (P = 0.031) were significantly higher within the subgroup of patients with PHLF than in the subgroup without PHLF. The multivariate analysis results suggest that TBA level (OR, 1.08; 951.03-1.14; P = 0.003) and MRI tumor diameter (OR, 1.17; 95% CI, 1.01-1.35; P = 0.038) are independent preoperative risk factors for PHLF. The TBA levels correlated with the indocyanine green retention rate at 15 minutes (P = 0.001) and the effective hepatic blood flow (P < 0.001), two markers of portal hypertension. However, TBA levels did not correlate with tumor diameter (P = 0.536). CONCLUSIONS: Compared to ICG R15 and AIBL score, preoperative TBA was risk factor for PHLF in Chinese patients with HCC, and it may impact PHLF through its potential role as a marker of portal hypertension.

Molecular identification and biological characterization of Eimeria columbarum from domestic pigeons (Columba livia domestica) in Guangdong, China.

Pigeon coccidiosis caused by Eimeria spp. is an important veterinary disease with a significant economic impact on the pigeon industry. Preventive measures for Eimeria columbarum in pigeons have been hampered by the lack of extensive genetic, morphological, and biological data on the oocysts. In this study, we examined the prevalence and identity of Eimeria spp. in domestic pigeons from seven cities in Guangdong Province, China. Data show that coccidiosis was prevalent in domestic pigeons in Guangdong Province, with an overall Eimeria spp. detection rate of 73.4%. Five Eimeria species were identified, including E. columbarum (73.4%), Eimeria kapotei (25.6%), Eimeria labbeana (19.6%), Eimeria duculai (19.6%), and Eimeria tropicalis (6.7%). We obtained single oocyst-derived lines of the dominant E. columbarum from fecal specimens. E. columbarum oocysts measured 20.06 ± 0.69 µm × 18.63 ± 1.03 µm, and sporocysts measured 10.29 ± 0.82 µm × 85.38 ± 0.46 µm. In infection experiment using obtained E. columbarum isolates, 60-day-old coccidia-free pigeons exhibited a prepatent period of 105 h and patent period of 9-10 days followed by severe diarrhea, depression, anorexia, and emaciation. Endogenous development of the parasite was observed mainly in the cytoplasm of epithelial cells in the duodenum, jejunum, ileum, and rectum. Two generations of meronts developed on days 3 and 4 after infection, respectively, while gamont and gamete developed on day 5 after infection. The morphological, genetic, and biological data are expected to be useful in elucidating the biological characterization of pigeon coccidiosis to develop measures against the treatment and containment of this disease.

Application of earthworm can enhance biological power generation and accelerate sulfamethoxazole removal in agricultural soils.

Microbial degradation plays a crucial role in removing sulfonamides from soil, enhancing sulfamethoxazole (SMX) remediation. To further augment SMX removal efficiency and mitigate the transmission risk associated with antibiotic resistance genes (ARGs), this study proposes a novel approach that integrates micro-animals, microorganisms, and microbial fuel cell (MFC) technology. The results showed that earthworm-MFC synergy substantially reduces SMX content and ARGs abundance in soil. The introduction of earthworms enhances humus content, facilitating electron transfer within MFC and consequently improving current generation. Furthermore, electrical stimulation applied to earthworms led to increased protein secretion and enhanced antioxidant system activity, thereby accelerating SMX degradation. Earthworms also foster MFC-associated bacterial growth and SMX-degrading bacteria proliferation, augmenting MFC treatment efficacy. This synergistic effect significantly augmented the overall efficacy of MFC treatment for antibiotics. Overall, integrating earthworm activity with MFC technology effectively optimizes electricity generation and enhances pollutant removal.

Causality investigation among gut microbiota, immune cells, and prostate diseases: a Mendelian randomization study.

Background: The gut microbiota has been demonstrated to have a significant role in the pathogenesis and progression of a variety of diseases, including prostate cancer, prostatitis, and benign prostatic hyperplasia. Potential links between prostate diseases, immune cells and the gut microbiota have not been adequately investigated. Methods: MR studies were conducted to estimate the effects of instrumental variables obtained from genome-wide association studies (GWASs) of 196 gut microbial taxa and 731 immune cells on the risk of prostate diseases. The primary method for analysing causal relationships was inverse variance-weighted (IVW) analysis, and the MR results were validated through various sensitivity analyses. Results: MR analysis revealed that 28 gut microbiome taxa and 75 immune cell types were significantly associated with prostate diseases. Furthermore, reverse MR analysis did not support a causal relationship between prostate diseases and the intestinal microbiota or immune cells. Finally, the results of the mediation analysis indicated that Secreting Treg % CD4 Treg, Activated & resting Treg % CD4 Treg, and Mo MDSC AC inhibited the role of the class Mollicutes in reducing the risk of PCa. In prostatitis, CD8+ T cells on EM CD8br hinder the increased risk associated with the genus Eubacterium nodatum group. Interestingly, in BPH, CD28- CD25++CD8br AC and CD16-CD56 on HLA DR+ NK promoted the role of the genus Dorea in reducing the risk of BPH. Conclusion: This study highlights the complex relationships among the gut microbiota, immune cells and prostate diseases. The involvement of the gut microbiota in regulating immune cells to impact prostate diseases could provide novel methods and concepts for its therapy and management.

Feasibility and effectiveness of cardiac telerehabilitation for older adults with coronary heart disease: A pilot randomized controlled trial.

Background: Cardiac rehabilitation is a beneficial multidisciplinary treatment of exercise promotion, patient education, risk factor management, and psychosocial counseling for people with coronary heart disease (CHD) that is underutilized due to substantial disparities in access, referral, and participation. Empirical studies suggest that cardiac telerehabilitation (CTR) have safety and efficacy comparable to traditional in-person cardiac rehabilitation, however, older adults are under-reported with effectiveness, feasibility, and usability remains unclear. Methods: The study randomized 43 older adults (84 % males) to the 12-week CTR intervention or standard of care. Guided by Social Cognitive Theory, participants received individualized in-person assessment and e-coaching sessions, followed by CTR usage at home. Data were collected at baseline (T0), six-week (T1), and 12-week (T2). Results: Participants in the CTR intervention group showed significant improvement in daily steps (T1: ß = 4126.58, p = 0.001; T2: ß = 5285, p = 0.01) and health-promoting lifestyle profile (T1: ß = 23.26, p < 0.001; T2: ß = 12.18, p = 0.008) across study endpoints. Twenty participants completed the intervention, with 40 % used the website for data-uploading or experiential learning, 90 % used the pedometer for tele-monitoring. Improving awareness of rehabilitation and an action focus were considered key facilitators while physical discomforts and difficulties in using the technology were described as the main barriers. Conclusions: The CTR is feasible, safe and effective in improving physical activity and healthy behaviors in older adults with CHD. Considering the variation in individual cardiovascular risk factors, full-scale RCT with a larger sample is needed to determine the effect of CTR on psychological symptoms, body weight and blood pressure, and quality of life.

Trends in under-five mortality rate in China, 1996-2020: a Joinpoint regression and correlation analysis.

OBJECTIVES: To analyse annual trends of the under-five mortality rate (U5MR) and main cause-specific U5MR in China from 1996 to 2020 and to assess the potential correlation of the healthcare system and health expenditure with the U5MR in China. DESIGN: A retrospective observational study using national data from 1996 to 2020. Joinpoint regression was employed to model U5MR trends and Pearson correlation analysis was conducted to examine the relationship between healthcare system factors, health expenditure and U5MR. SETTING: Nationwide study covering both rural and urban populations across China over a 25-year period. RESULTS: The U5MR in China experienced a three-stage decline from 1996 to 2020 with an average annual percentage rate change (AAPC) of -7.27 (p<0.001). The AAPC of the rural U5MR (-7.07, p<0.001) was higher than that in urban areas (-5.57, p<0.001). Among the five main causes, the decrease in pneumonia-caused U5MR was the fastest while the decreases in congenital heart disease and accidental asphyxia were relatively slow. The rates of hospital delivery (r=-0.981, p<0.001), neonatal visits (r=-0.848, p<0.001) and systematic health management (r=-0.893, p<0.001) correlated negatively with U5MR. The proportion of government health expenditure in the total health expenditure (THE) correlated negatively with the national U5MR (r=-0.892, p<0.001) while the proportion of out-of-pocket health expenditure in THE correlated positively (r=0.902, p<0.001). CONCLUSION: China made significant advances in reducing U5MR from 1996 to 2020. The rural-urban gap in U5MR has narrowed, though rural areas remain a key concern. To further reduce U5MR, China should focus on rural areas, pay more attention to congenital heart disease and accidental asphyxia, further improve its health policies, and continue to increase the government health expenditure.

A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.

Nirmatrelvir was the first protease inhibitor specifically developed against the SARS-CoV-2 main protease (3CLpro/Mpro) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir. To safely generate Mpro resistance mutations, we passaged a previously developed, chimeric vesicular stomatitis virus (VSV-Mpro) with increasing, yet suboptimal concentrations of nirmatrelvir. Using Wuhan-1 and Omicron Mpro variants, we selected a large set of mutants. Some mutations are frequently present in GISAID, suggesting their relevance in SARS-CoV-2. The resistance phenotype of a subset of mutations was characterized against clinically available protease inhibitors (nirmatrelvir and ensitrelvir) with cell-based, biochemical and SARS-CoV-2 replicon assays. Moreover, we showed the putative molecular mechanism of resistance based on in silico molecular modelling. These findings have implications on the development of future generation Mpro inhibitors, will help to understand SARS-CoV-2 protease inhibitor resistance mechanisms and show the relevance of specific mutations, thereby informing treatment decisions.

Mendelian randomization supports causal effects of inflammatory biomarkers on myopic refractive errors.

AIMS: To determine whether inflammatory biomarkers are causal risk factors for more myopic refractive errors. METHODS: Northern Sweden Population Health Study (NSPHS), providing inflammatory biomarkers data; UK Biobank, providing refractive errors data. 95,619 European men and women aged 40 to 69 years with available information of refractive errors and inflammatory biomakers. Inflammatory biomarkers including ADA, CCL23, CCL25, CD6, CD40, CDCP-1, CST5, CXCL-5, CXCL-6, CXCL-10, IL-10RB, IL-12B, IL-15RA, IL-18R1, MCP-2, MMP-1, TGF-ß1, TNF-ß, TWEAK and VEGF-A were exposures, and spherical equivalent (SE) using the formula SE = sphere + (cylinder/2) was outcome. RESULTS: Mendelian randomization analyses showed that each unit increase in VEGF-A, CD6, MCP-2 were causally related to a more myopic refractive errors of 0.040 D/pg.mL-1 (95% confidence interval 0.019 to 0.062; P = 2.031 × 10-4), 0.042 D/pg.mL-1 (0.027 to 0.057; P = 7.361 × 10-8) and 0.016 D/pg.mL-1 (0.004 to 0.028; P = 0.009), and each unit increase in TWEAK was causally related to a less myopic refractive errors of 0.104 D/pg.mL-1 (-0.152 to -0.055; P = 2.878 × 10-5). Tested by the MR-Egger, weighted median, MR-PRESSO, Leave-one-out methods, our results were robust to horizontal pleiotropy and heterogeneity in VEGF-A, MCP-2, CD6, but not in TWEAK. CONCLUSIONS: Our Mendelian Randomization analysis supported the causal effects of VEGF-A, MCP-2, CD6 and TWEAK on myopic refractive errors. These findings are important for providing new indicators for early intervention of myopia to make myopic eyesight threatening consequences less inevitable.

Hb A2-Guangxi [δ79 (EF3) Asp→Asn, HBD: C.238G > A] and polyA + 70 (HBD: C.*200G > A): Two Novel δ-Globin Gene Mutations Identified in a Chinese Family.

We report the molecular and hematological identifications of two novel δ-globin gene mutations found in Guangxi Zhuang Autonomous Region, China. Capillary electrophoresis of the proband showed 1.3% Hb A2, accompanied by a minor unknown peak (0.7%) within the Z1 zone. High-performance liquid chromatography also revealed the presence of 1.5% Hb A2 and a 0.6% unknown peak. Routine genetic testing (Gap-PCR and reverse dot-blot hybridization) for common α-thalassemia was performed, and no mutations were observed. Sanger sequencing identified a heterozygous mutation for GAC > AAC at codon 79 (HBD:c.238G > A) and G > A at polyA + 70 (HBD:c.*200G > A) of the δ-globin gene. This variant was named Hb A2-Guangxi [δ79 (EF3) Asp→Asn, HBD:c.238G > A] after the geographic origin of the proband.

A 3-component module maintains sepal flatness in Arabidopsis.

As in origami, morphogenesis in living systems heavily relies on tissue curving and folding through the interplay between biochemical and biomechanical cues. By contrast, certain organs maintain their flat posture over several days. Here, we identified a pathway that is required for the maintenance of organ flatness, taking the sepal, the outermost floral organ, in Arabidopsis as a model system. Through genetic, cellular, and mechanical approaches, our results demonstrate that the global gene expression regulator VERNALIZATION INDEPENDENCE 4 (VIP4) fine-tunes the mechanical properties of sepal cell walls and maintains balanced growth on both sides of the sepals, mainly by orchestrating the distribution pattern of AUXIN RESPONSE FACTOR 3 (ARF3). vip4 mutation results in softer cell walls and faster cell growth on the adaxial sepal side, which eventually cause sepals to bend outward. Downstream of VIP4, ARF3 works through modulating auxin to downregulate pectin methylesterase VANGUARD1, resulting in decreased cell wall stiffness. Thus, our work unravels a 3-component module that relates hormonal patterns to organ curvature and actively maintains sepal flatness during its growth.

Effects of Tibetan Sheep-Derived Compound Probiotics on Growth Performance, Immune Function, Intestinal Tissue Morphology, and Intestinal Microbiota in Mice.

Probiotics play an important role in animal growth, immunity, and gut microbial balance and are now widely used in agriculture, food, and medicine. This study analysed the effects of different concentrations of Tibetan sheep compound probiotics on the immunity, tissue morphology, and intestinal microbiota of mice using histological, molecular, and 16S rRNA techniques. The results showed that the composite probiotics sourced from Tibetan sheep improved the growth performance of mice, increased the length of small intestinal villi and mucosal thickness, and enhanced the intestinal barrier function of mice. DZ-L and DZ-M significantly increased the mRNA expression levels of ZO-1, Occludin, and Claudin-1 mRNA. They also up-regulated IL-10 and TNF-ß, and down-regulated TNF-α, IL-1ß, and IL-8. The immune function of mice was enhanced, with DZ-M treatment having an extremely significant effect, while the effect of DZ-H treatment was slightly lower compared to DZ-L and DZ-M. In addition, the composition and diversity of the intestinal microbiota were modulated, and at the phylum level, the relative abundance of Firmicutes was higher in the DZ-M group, the relative abundance of Desulfobacterota, Actinobacteriota, and Patescibacteria was reduced in the probiotic complex group, and the relative abundance of Verrucomicrobiota was higher. At the genus level, the relative abundance of Muribaculaceae was higher in the DZ-L and DZ-M groups, and the relative abundance of Lachnospiraceae_NK4A136_group in the DZ-H group; and the relative abundance of Bacteroides and Roseburia in the composite probiotic group. This study can improve the reference for the development of new green feed additives instead of antibiotics, which will also further promote the development of the livestock industry.

Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones.

Previous studies of hematopoietic stem cells (HSCs) primarily focused on single cell-based niche models, yielding fruitful but conflicting findings 1-5 . Here we report our investigation on the fetal liver (FL) as the primary fetal hematopoietic site using spatial transcriptomics. Our study reveals two distinct niches: the portal-vessel (PV) niche and the sinusoidal niche. The PV niche, composing N-cadherin (N-cad) Hi Pdgfrα + mesenchymal stromal cells (MSCs), endothelial cells (ECs), and N-cad Lo Albumin + hepatoblasts, maintains quiescent and multipotential FL-HSCs. Conversely, the sinusoidal niche, comprising ECs, hepatoblasts and hepatocytes, as well as potential macrophages and megakaryocytes, supports proliferative FL-HSCs biased towards myeloid lineages. Unlike prior reports on the role of Cxcl12, with its depletion from vessel-associated stromal cells leading to 80% of HSCs' reduction in the adult bone marrow (BM) 6,7 , depletion of Cxcl12 via Cdh2 CreERT (encoding N-cad) induces altered localization of HSCs from the PV to the sinusoidal niches, resulting in an increase of HSC number but with myeloid-bias. Similarly, we discovered that adult BM encompasses two niches within different zones, each composed of multi-cellular components: trabecular bone area (TBA, or metaphysis) supporting deep-quiescent HSCs, and central marrow (CM, or diaphysis) fostering heterogenous proliferative HSCs. This study transforms our understanding of niches by shifting from single cell-based to multicellular components within distinct zones, illuminating the intricate regulation of HSCs tailored to their different cycling states.

Social network strategies to distribute HIV self-testing kits: a global systematic review and network meta-analysis.

INTRODUCTION: Social network strategies, in which social networks are utilized to influence individuals or communities, are increasingly being used to deliver human immunodeficiency virus (HIV) interventions to key populations. We summarized and critically assessed existing research on the effectiveness of social network strategies in promoting HIV self-testing (HIVST). METHODS: Using search terms related to social network interventions and HIVST, we searched five databases for trials published between 1st January 2010 and 30th June 2023. Outcomes included uptake of HIV testing, HIV prevalence and linkage to antiretroviral therapy (ART) or HIV care. We used network meta-analysis to assess the uptake of HIV testing through social network strategies compared with control methods. A pairwise meta-analysis of studies with a comparison arm that reported outcomes was performed to assess relative risks (RR) and their corresponding 95% confidence intervals (CI). RESULTS: Among the 4496 manuscripts identified, 39 studies fulfilled the inclusion criteria, including one quasi-experimental study, 22 randomized controlled trials and 16 observational studies. Networks HIVST testing was organized by peers (distributed to known peers, 15 studies), partners (distributed to their sexual partners, 16 studies) and peer educators (distributed to unknown peers, 8 studies). Among social networks, simulating the possibilities of ranking position, peer distribution had the highest uptake of HIV testing (84% probability), followed by partner distribution (80% probability) and peer educator distribution (74% probability). Pairwise meta-analysis showed that peer distribution (RR 2.29, 95% CI 1.54-3.39, 5 studies) and partner distribution (RR 1.76, 95% CI 1.50-2.07, 10 studies) also increased the probability of detecting HIV reactivity during testing within the key population when compared to the control. DISCUSSION: All of the three social network distribution strategies enhanced the uptake of HIV testing compared to standard facility-based testing. Linkage to ART or HIV care remained comparable to facility-based testing across the three HIVST distribution strategies. CONCLUSIONS: Network-based HIVST distribution is considered effective in augmenting HIV testing rates and reaching marginalized populations compared to facility-based testing. These strategies can be integrated with the existing HIV care services, to fill the testing gap among key populations globally. PROSPERO NUMBER: CRD42022361782.

Dietary silymarin improves performance by altering hepatic lipid metabolism and cecal microbiota function and its metabolites in late laying hens.

BACKGROUND: Liver lipid dysregulation is one of the major factors in the decline of production performance in late-stage laying hens. Silymarin (SIL), a natural flavonolignan extracted from milk thistle, is known for its hepatoprotective and lipid-lowering properties in humans. This study evaluates whether SIL can provide similar benefits to late-stage laying hens. A total of 480 68-week-old Lohmann Pink laying hens were randomly assigned into 5 groups, each group consisting of 6 replicates with 16 hens each. The birds received a basal diet either without silymarin (control) or supplemented with silymarin at concentrations of 250, 500, 750, or 1,000 mg/kg (SIL250, SIL500, SIL750, SIL1000) over a 12-week period. RESULTS: The CON group exhibited a significant decline in laying rates from weeks 9 to 12 compared to the initial 4 weeks (P = 0.042), while SIL supplementation maintained consistent laying rates throughout the study (P > 0.05). Notably, the SIL500 and SIL750 groups showed higher average egg weight than the CON group during weeks 5 to 8 (P = 0.049). The SIL750 group had a significantly higher average daily feed intake across the study period (P < 0.05), and the SIL500 group saw a marked decrease in the feed-to-egg ratio from weeks 5 to 8 (P = 0.003). Furthermore, the SIL500 group demonstrated significant reductions in serum ALT and AST levels (P < 0.05) and a significant decrease in serum triglycerides and total cholesterol at week 12 with increasing doses of SIL (P < 0.05). SIL also positively influenced liver enzyme expression (FASN, ACC, Apo-VLDL II, FXR, and CYP7A1; P < 0.05) and altered the cecal microbiota composition, enhancing species linked to secondary bile acid synthesis. Targeted metabolomics identified 9 metabolites predominantly involved in thiamin metabolism that were significantly different in the SIL groups (P < 0.05). CONCLUSIONS: Our study demonstrated that dietary SIL supplementation could ameliorate egg production rate in late stage laying hens, mechanistically, this effect was via improving hepatic lipid metabolism and cecal microbiota function to achieve. Revealed the potentially of SIL as a feed supplementation to regulate hepatic lipid metabolism dysregulation. Overall, dietary 500 mg/kg SIL had the best effects.

Impact of discrepant accumulations strategy on collective cooperation in multilayer networks.

Understanding large-scale cooperation among related individuals has been one of the largest challenges. Since humans are in multiple social networks, the theoretical framework of multilayer networks is perfectly suited for studying this fascinating aspect of our biology. To that effect, we here study the cooperation in evolutionary game on interdependent networks. Importantly, a part of players are set to adopt Discrepant Accumulations Strategy. Players employing this mechanism not only use their payoffs in the multilayer network as the basis for the updating process as in previous experiments, but also take into account the similarities and differences in strategies across different layers. Monte Carlo simulations demonstrate that considering the similarities and differences in strategies across layers when calculating fitness can significantly enhance the cooperation level in the system. By examining the behavior of different pairing modes within cooperators and defectors, the equilibrium state can be attributed to the evolution of correlated pairing modes between interdependent networks. Our results provide a theoretical analysis of the group cooperation induced by the Discrepant Accumulations Strategy. And we also discuss potential implications of these findings for future human experiments concerning the cooperation on multilayer networks.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.