CRISPRimmunity: an interactive web server for CRISPR-associated Important Molecular events and Modulators Used in geNome edIting Tool identifYing.

The CRISPR-Cas system is a highly adaptive and RNA-guided immune system found in bacteria and archaea, which has applications as a genome editing tool and is a valuable system for studying the co-evolutionary dynamics of bacteriophage interactions. Here introduces CRISPRimmunity, a new web server designed for Acr prediction, identification of novel class 2 CRISPR-Cas loci, and dissection of key CRISPR-associated molecular events. CRISPRimmunity is built on a suite of CRISPR-oriented databases providing a comprehensive co-evolutionary perspective of the CRISPR-Cas and anti-CRISPR systems. The platform achieved a high prediction accuracy of 0.997 for Acr prediction when tested on a dataset of 99 experimentally validated Acrs and 676 non-Acrs, outperforming other existing prediction tools. Some of the newly identified class 2 CRISPR-Cas loci using CRISPRimmunity have been experimentally validated for cleavage activity in vitro. CRISPRimmunity offers the catalogues of pre-identified CRISPR systems to browse and query, the collected resources or databases to download, a well-designed graphical interface, a detailed tutorial, multi-faceted information, and exportable results in machine-readable formats, making it easy to use and facilitating future experimental design and further data mining. The platform is available at http://www.microbiome-bigdata.com/CRISPRimmunity. Moreover, the source code for batch analysis are published on Github (https://github.com/HIT-ImmunologyLab/CRISPRimmunity).

Association between small dense low-density lipoprotein cholesterol and neuroimaging markers of cerebral small vessel disease in middle-aged and elderly Chinese populations.

BACKGROUND: Cerebral small vascular disease (CSVD) is one of the leading causes of death in the aged population and is closely related to abnormalities in low-density lipoprotein cholesterol (LDL-C). Our study aims to clarify the relationship between small and dense low-density lipoprotein cholesterol (sdLDL-C) (a subcomponent of LDL-C) and neuroimaging markers of CSVD. METHODS: In total, 1211 Chinese adults aged ≥45 years with cranial magnetic resonance imaging (MRI) were recruited in this retrospective study from January 2018 to May 2021. Serum lipids and other baseline characteristics were investigated in relation to the occurrence of CSVD. A logistic regression model was performed to analyze the relationships between LDL subtypes and CSVD risk, and the Pearson correlation coefficient was used to analyze the correlation between clinical characteristics and CSVD risk. ROC curves and AUCs were created and depicted to predict the best cutoff value of LDL-C subtypes for CSVD risk. Based on these data, we performed comprehensive analyses to investigate the risk factors for CSVD. RESULTS: Ultimately, 623 eligible patients were included in the present study. Of the 623 eligible patients, 487 were included in the CSVD group, and 136 were included in the group without CSVD (control group). We adjusted for confounders in the multivariate logistic regression model, and LDL-C3 was still higher in the CSVD patients than in the group of those without CSVD (OR (95% CI), 1.22(1.08-1.38), P < 0.05). Pearson correlation showed that there was a positive correlation between the levels of LDL-C3, LDL-C4, LDL-C5, glucose, age, hypertension, previous ischemic stroke and CSVD risk (r > 0.15, P < 0.01). Moreover, the best cutoff value of LDL-C3 to predict CSVD was 9.5 mg/dL with 68.4% sensitivity and 72.8% specificity, and the best cutoff value of LDL-C4 to predict CSVD was 5.5 mg/dL with 50.5% sensitivity and 90.4% specificity. CONCLUSION: The results indicate that LDL-C3 is an independent risk factor for CSVD. A new prediction model based on LDL-C3 and LDL-C4 can help clinicians identify high-risk CSVD, even in people with normal LDL-C levels. The levels of sdLDL-C should be considered in the assessment and management of CSVD.

Design and fabrication of dual-layer PCL nanofibrous scaffolds with inductive influence on vascular cell responses.

Confronted with the profound threat of cardiovascular diseases to health, vascular tissue engineering presents potential beyond the limitations of autologous and allogeneic grafts, offering a promising solution. This study undertakes an initial exploration into the impact of a natural active protein, elastin, on vascular cell behavior, by incorporating with polycaprolactone to prepare fibrous tissue engineering scaffold. The results reveal that elastin serves to foster endothelial cell adhesion and proliferation, suppress smooth muscle cell proliferation, and induce macrophage polarization. Furthermore, the incorporation of elastin contributes to heightened scaffold strength, compliance, and elongation, concomitantly lowering the elastic modulus. Subsequently, a bilayer oriented polycaprolactone (PCL) scaffold infused with elastin is proposed. This design draws inspiration from the cellular arrangement of native blood vessels, leveraging oriented fibers to guide cell orientation. The resulting fiber scaffold exhibits commendable mechanical properties and cell infiltration capacity, imparting valuable insights for the rapid endothelialization of vascular scaffolds.

Dysfunction of the triple-network model is associated with cognitive impairment in patients with cerebral small vessel disease.

Purpose: This study aimed to demonstrate the correlations between the altered functional connectivity patterns in the triple-network model and cognitive impairment in patients with cerebral small vascular disease (CSVD). Methods: Resting-state functional magnetic resonance imaging data were obtained from 22 patients with CSVD and 20 healthy controls. The resting-state data were analyzed using independent component analysis and functional network connectivity (FNC) analysis to explore the functional alterations in the intrinsic triple-network model including the salience network (SN), default mode network (DMN), and central executive network (CEN), and their correlations with the cognitive deficits and clinical observations in the patients with CSVD. Results: Compared to the healthy controls, the patients with CSVD exhibited increased connectivity patterns in the CEN-DMN and decreased connectivity patterns in the DMN-SN, CEN-SN, intra-SN, and intra-DMN. Significant negative correlations were detected between the intra-DMN connectivity pattern and the Montreal Cognitive Assessment (MoCA) total scores (r = -0.460, p = 0.048) and MoCA abstraction scores (r = -0.565, p = 0.012), and a positive correlation was determined between the intra-SN connectivity pattern and the MoCA abstraction scores (r = 0.491, p = 0.033). Conclusions: Our study findings suggest that the functional alterations in the triple-network model are associated with the cognitive deficits in patients with CSVD and shed light on the importance of the triple-network model in the pathogenesis of CSVD.

Ythdf2-mediated STK11 mRNA decay supports myogenesis by inhibiting the AMPK/mTOR pathway.

An emerging research focus is the role of m6A modifications in mediating the post-transcriptional regulation of mRNA during mammalian development. Recent evidence suggests that m6A methyltransferases and demethylases play critical roles in skeletal muscle development. Ythdf2 is a m6A "reader" protein that mediates mRNA degradation in an m6A-dependent manner. However, the specific function of Ythdf2 in skeletal muscle development and the underlying mechanisms remain unclear. Here, we observed that Ythdf2 expression was significantly upregulated during myogenic differentiation, whereas Ythdf2 knockdown markedly inhibited myoblast proliferation and differentiation. Combined analysis of high-throughput sequencing, Co-IP, and RIP assay revealed that Ythdf2 could bind to m6A sites in STK11 mRNA and form an Ago2 silencing complex to promote its degradation, thereby regulating its expression and consequently, the AMPK/mTOR pathway. Furthermore, STK11 downregulation partially rescued Ythdf2 knockdown-induced impairment of proliferation and myogenic differentiation by inhibiting the AMPK/mTOR pathway. Collectively, our results indicate that Ythdf2 mediates the decay of STK11 mRNA, an AMPK activator, in an Ago2 system-dependent manner, thereby driving skeletal myogenesis by suppressing the AMPK/mTOR pathway. These findings further enhance our understanding of the molecular mechanisms underlying RNA methylation in the regulation of myogenesis and provide valuable insights for conducting in-depth studies on myogenesis.

HDL-C/LDL-C and Risk of Cerebral White Matter Hyperintensities: A Cross-Sectional Study.

Background and Purpose: At present, there is still a lack of metabolic indices to predict white matter hyperintensities. This study aimed to explore the correlations of the high-density lipoprotein cholesterol (HDL-C)/low-density lipoprotein cholesterol (LDL-C) ratio with the risk of white matter hyperintensities. Methods: Hospitalized patients who underwent inpatient treatment or physical examination due to various chronic diseases between January 18, 2018, and March 20, 2023, were enrolled. Fazekas scores were used to assess the severity of white matter hyperintensities. Logistic regression analysis was used to adjust for possible confounders. Results: Of the 1162 enrolled patients, 770 (66.27%) patients were classified as having no or mild WMHs, and 392 (33.73%) were classified as having moderate or severe WMHs. After adjusting for covariates, the logistic regression analysis indicated that the ratio of HDL-C to LDL-C was related to the severity of WMHs (Model 1, OR = 0.23, 95% CI: 0.07-0.73, P=0.012; Model 2, OR = 2.03, 95% CI: 1.12-3.67, P=0.019). Conclusion: Our findings suggest that the ratio of HDL-C to LDL-C is related to the severity of WMHs and that a high ratio of HDL-C to LDL-C is a protective factor against WMHs. This suggests that the ratio of HDL-C to LDL-C could be used as a metabolic prediction index of WMH severity.

Investigation of Catalytic Co-Pyrolysis Characteristics and Synergistic Effect of Oily Sludge and Walnut Shell.

The co-pyrolysis of oily sludge and walnut shell is a reliable method for solid waste treatment and waste recycling. In this paper, a thermogravimetric analysis was used to study the thermodynamics and synergy effect of oily sludge (OS) and walnut shell (WS) at four heating rates (10, 20, 30, and 40 °C/min) in the temperature range from 50-850 °C. Two model-free methods (FWO and KAS) were used to calculate the activation energy. The results showed that the heating rate had no significant effect on the pyrolysis process. The addition of walnut shell improved the pyrolysis process of the samples. Mixture 1OS3WS had a synergy effect, while other blends showed an inhibitory effect. The synergy effect of co-pyrolysis was strongest when the mass ratio of oily sludge was 25%. The activation energy of the Zn-ZSM-5/25 catalyst was the lowest, and the residual substances were the least, indicating that the Zn-ZSM-5/25 was beneficial to the co-pyrolysis of oily sludge and walnut shell. The analysis of catalytic pyrolysis products by Py-GC/MS found that co-pyrolysis was beneficial to the generation of aromatic hydrocarbons. This study provided a method for the resource utilization of hazardous waste and biomass waste, which was conducive to the production of aromatic chemicals with added value while reducing environmental pollution.

Ketone Body ß-Hydroxybutyric Acid Ameliorates Dopaminergic Neuron Injury Through Modulating Zinc Finger Protein 36/Acyl-CoA Synthetase Long-Chain Family Member Four Signaling Axis-Mediated Ferroptosis.

ß-hydroxybutyrate (BHB) is one of main component of ketone body, which plays an important protective role in various tissues and organs. Whereas, its exact regulatory roles and mechanisms in Parkinson's disease (PD) have not been full elucidated. In this study, SN4741 cells and C57BL/6 mice were treated with 1-methyl-4-phenylpyridinium ion (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish the PD model in vitro and in vivo. Cell viability and damage to dopaminergic neurons were measured by cell counting kit 8, Calcein-AM/PI staining, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and hematoxylin & eosin staining. Corresponding assay kits and BODIPY 581/591 C11 probe evaluated oxidative stress and intracellular iron levels. Western blot examined the ferroptosis-related proteins. MPTP/MPP+-treatment reduced cell viability but triggered oxidative stress and ferroptosis in SNA4741 cells and brain tissues of mice. However, these effects were dramatically reversed by BHB and Fer-1 treatment. Mechanistically, Zinc finger protein 36 (ZFP36) was a target of BHB, and its depletion could reverse the anti-oxidative stress and anti-ferroptosis roles of BHB. Moreover, ZFP36 could directly bound to acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA to decay its expression, thus negatively modulating ACSL4-mediated oxidative stress and ferroptosis. Summary, BHB alleviated oxidative stress and ferroptosis of dopaminergic neurons in PD via modulating ZFP36/ACSL4 axis, which provided some new understanding for PD prevention and treatment.

Comparison of the Effects of Yucca saponin, Yucca schidigera, and Quillaja saponaria on Growth Performance, Immunity, Antioxidant Capability, and Intestinal Flora in Broilers.

The purpose of this study is to investigate the effects of Yucca saponin (YSa), Yucca schidigera (YS), and Quillaja Saponaria (QS) on growth performance, nitrogen metabolism, immune ability, antioxidant capability, and intestinal flora of yellow-feather broilers. This study randomly divided a total of 480 1-day yellow-feather broilers into 4 treatment groups. Factors in the 4 groups included CON group (basic diet), YSa group (basic diet mixed with 500 mg/kg YSa), YS group (basic diet mixed with 500 mg/kg YS), and QS group (basic diet mixed with 500 mg/kg QS). Throughout the 56-day study period, YSa, YS, and QS groups had higher average daily gain in broilers than the CON group (p < 0.01). The YS group had a lower feed gain ratio (F: G) in broilers than the CON group (p < 0.05). YSa, YS, and QS showed increased serum immunoglobin A (IgA), immunoglobin Y (IgY), immunoglobin M (IgM), and total antioxidant capacity (T-AOC) levels; enhanced acetic acid, butyric acid, and valeric acid levels of cecal content; and reduced contents of ammonia nitrogen, urea nitrogen, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA) in serum in broilers (p < 0.05). The relative abundance of Lachnoclostridium in the QS group was decreased compared with that in the CON group (p < 0.05). Higher IgA and IgY sera contents were observed in the YS group compared to the YSa and QS groups (p < 0.05). In contrast with the QS group, the serum IL-6 concentration of the YS group was reduced (p < 0.05). In conclusion, YSa, YS, and QS promoted growth performance, nitrogen metabolism, immunity, antioxidant capability, and intestinal flora in broilers. Through the comparison of YSa, YS, and QS, it was found that YS is more suitable as a feed additive to ameliorate the healthy growth of broilers.

Protective effects of Bacillus licheniformis on growth performance, gut barrier functions, immunity and serum metabolome in lipopolysaccharide-challenged weaned piglets.

Bacillus licheniformis (B. licheniformis) is a well-accepted probiotic that has many benefits on both humans and animals. This study explored the effects of B. licheniformis on growth performance, intestinal mucosal barrier functions, immunity as well as serum metabolome in the weaned piglets exposed to lipopolysaccharide (LPS). One hundred and twenty piglets weaned at four weeks of age were separated into two groups that received a basal diet (the control group, CON), and a basal diet complemented with B. licheniformis (500 mg/kg, the BL group, BL). Twenty-four piglets were chosen from the above two groups and 12 piglets were injected with LPS intraperitoneally at a concentration of 100 µg/kg and the others were injected with sterile saline solution of the same volume. All the piglets were sacrificed 4 h after LPS challenge. Results showed that B. licheniformis enhanced the ADG and final body weight and lowered the F/G and diarrhea rate. Pre-treatment with B. licheniformis markedly attenuated intestinal mucosal damage induced by LPS challenge. Supplementation with B. licheniformis strengthened immune function and suppressed inflammatory response by elevating the concentrations of serum immunoglobulin (Ig) A and jejunum mucosal IgA and IgG and decreasing serum IL-6 and jejunum mucosal IL-1ß. In addition, B. licheniformis pretreatment prevented LPS-induced intestinal injury by regulating the NLRP3 inflammasome. Furthermore, pretreatment with B. licheniformis tended to reverse the reduction of acetate and propionic acids in the colonic contents that occurred due to LPS stress. B. licheniformis markedly modulated the metabolites of saccharopine and allantoin from lysine and purine metabolic pathways, respectively. Overall, these data emphasize the potentiality of B. licheniformis as a dietary supplement to overcome the challenge of bacterial LPS in the animal and to enhance the food safety.

Can Patients with Asymptomatic/Mild Illness and Moderate Illness COVID-19 Have White Matter Damage?

Background and Purpose: Studies have shown that severe coronavirus pandemic 2019 infection could lead to white matter hyperintensities, but the relationship between asymptomatic/mild illness and moderate illness coronavirus pandemic 2019 and white matter hyperintensities remains largely unknown. This study aimed to investigate the relationship between asymptomatic/mild illness and moderate illness coronavirus pandemic 2019 and the risk of white matter hyperintensities. Methods: Hospitalized patients who were confirmed to have coronavirus pandemic 2019 for the first time were enrolled. Fazekas scores were used for assessment of the severity of white matter hyperintensities. We also rated the 90-day functional outcome after discharge. Results: Of the 157 enrolled patients, 124 (78.98%) coronavirus pandemic 2019 patients were classified as having asymptomatic or mild illness, and 33 (21.02%) were classified as having moderate illness. The results showed that the Fazekas scale scores at baseline (periventricular white matter hyperintensities, 1.31±1.16 vs 2.06±1.20; Deep white matter hyperintensities, 1.04±0.97 vs 1.73±1.13 P <0.01) and at follow-up (periventricular white matter hyperintensities, 1.38±1.21 vs 2.09±1.21; Deep white matter hyperintensities, 1.13±1.04 vs 1.79±1.14 P <0.01) were lower in patients with symptomatic or mild illness than in those with moderate illness. Moreover, no significant difference (7.26% vs 3.03%; P =0.377) was observed between the two divided groups in terms of white matter hyperintensities progression. Conclusion: Our findings suggest that moderate COVID-19 is related to severe white matter hyperintensities compared with asymptomatic/mild illness but not to the progression of white matter hyperintensities.

Can hyperuricemia predict the progression risk of cerebral small vessel disease?

AIMS: Uric acid (UA) may play a crucial role in the process of cerebral small vessel disease (SVD), but few follow-up studies have focused on the effect of UA in the progression of SVD. The present study aimed to ascertain whether serum UA levels are associated with the risk of SVD progression. METHODS: We performed an observational clinical study in adults older than 45 years with cranial magnetic resonance imaging (MRI) from 30 October 2015, to 28 January 2021. The patients were divided into two groups according to whether their total burden of SVD scores increased or not during the follow-up: SVD progression (increased by at least one point) and without SVD progression (increased 0 points). Cox regression and Kaplan-Meier survival analyses were used for univariate analysis between groups to identify the risk factors for SVD progression. RESULTS: Ultimately, 261 eligible patients were included in the final analysis. Of the 261 eligible patients, 73 were included in the SVD progression group, and 188 were included in the group without SVD progression. Correlation analysis found that the levels of UA and the ratio of hyperuricemia (HUA) showed statistically significant correlations with SVD progression risk (r = 0.197 and Crammer's V = 0.213, respectively, P < 0.01). Cox regression and Kaplan-Meier survival analyses showed that after adjustment for covariates, HUA was an independent risk factor for the incidence of SVD progression. The risk of SVD progression in patients with HUA was higher than that in those without HUA (HR (95% CI), 1.77 (1.03-3.05), P < 0.05). CONCLUSIONS: High serum UA levels are independently related to the risk of SVD progression, thus highlighting not only the influence of traditional risk factors such as hypertension and age on SVD but also the UA levels of patients for individualized treatment.

Effects of Bacillus licheniformis on Growth Performance, Diarrhea Incidence, Antioxidant Capacity, Immune Function, and Fecal Microflora in Weaned Piglets.

Bacillus licheniformis (B. licheniformis) is a safe probiotic that can promote animal growth and inhibit pathogenic bacteria. This study aimed to assess the effects of B. licheniformis, one green feed additive, on growth performance, diarrhea incidence, immune function, fecal volatile fatty acids, and microflora structure in weaned piglets. Weaned piglets (n = 180) were randomly divided into three treatment groups and fed a basal diet and a basal diet supplemented with 500 mg B. licheniformis per kg and 1000 mg B. licheniformis per kg, respectively. The dietary 500 mg/kg B. licheniformis inclusion improved the average daily gain, reduced diarrhea incidence, and strengthened antioxidant capacity. Piglets supplemented with B. licheniformis presented increased serum immunoglobulins (IgA, IgM) compared to the CON group. Meanwhile, the expression of anti-inflammation factors was increased, and the levels of pro-inflammation factors were reduced after B. licheniformis administration. Moreover, the levels of volatile fatty acids, including acetic acid, propionic acid, butyric acid, isobutyric acid, and isovaleric acid, in the BL500 and BL1000 groups were increased compared with the CON group, and the concentration of valeric acid was higher in the BL500 group. Furthermore, piglets in the 500 mg/kg B. licheniformis addition group significantly altered fecal microbiota by increasing Clostridium_sensu_stricto_1 and Oscillospira. In conclusion, dietary B. licheniformis relieved diarrhea, enhanced antioxidant capacity, immunity function, and fecal microflora structure in weaned pigs.

Cerebral small vessel disease combined with cerebral collaterals to predict the prognosis of patients with acute large artery atherosclerotic stroke.

Background and purpose: Besides cerebral collaterals, few studies have examined other additional factors affecting the prognosis of patients with large artery atherosclerotic (LAA) stroke. Our study aims to explore the effect of the cerebral small vessel disease (SVD) and the effects of its interaction with cerebral collaterals on the prognosis of patients with acute LAA stroke. Method: Patients aged 18 years or older with LAA stroke within 24 h after stroke onset were consecutively enrolled. The functional outcome was determined using the modified Rankin Scale (mRS) at 3 months after stroke onset. Logistic multivariate analyses were used to identify the risk factors for stroke prognosis. Receiver operating characteristic (ROC) curves were constructed to compare the effects of cerebral collaterals and SVD on predicting the prognosis. Results: Of the 274 enrolled patients, 174 (63.50%) were identified as having a favorable prognosis, and 100 (36.50%) were identified as having an unfavorable prognosis. After adjusting for covariates, the logistic regression analysis identified that unfavorable prognosis was related to the total SVD score (Model 1, adjusted odds ratio = 1.73, 95% CI: 1.15-2.61, P < 0.01; Model 2, adjusted odds ratio = 1.85, 95% CI: 1.23-2.79, P < 0.01) and Tan score (Model 1, adjusted odds ratio = 0.38, 95% CI: 0.23-0.64, P < 0.01; Model 2, adjusted odds ratio = 0.52, 95% CI: 0.33-0.82, P < 0.01). Compared with cerebral collaterals (AUC = 0.59; 95% CI: 0.52-0.67; P < 0.01) or SVD (AUC = 0.62; 95% CI: 0.56-0.69; P < 0.01) alone, the combination of collaterals and SVD (AUC = 0.66; 95% CI: 0.59-0.73; P < 0.01) had higher diagnostic value for an unfavorable prognosis, and the optimal sensitivity and specificity were 77.01 and 53.00%, respectively. Conclusions: The total SVD burden was related to the prognosis of patients with LAA stroke. Compared with cerebral collaterals or SVD alone, cerebral collaterals combined with total SVD burden are better at predicting the prognosis of patients with acute LAA stroke.

Association Between White Matter Hyperintensities and Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Objectives: Previous studies of the associations between white matter hyperintensities (WMH) and chronic kidney disease (CKD) were still conflicting; therefore, our study aimed to conduct a systematic review of all of the available research on this topic and a meta-analysis of the association between WMH and CKD among observational studies. Setting and Design: Systematic review and meta-analysis. Outcome Measures: Severity of WMH. Methods and Participants: All relevant studies in public databases were examined until 15 November 2020. Two independent reviewers assessed all the included studies using the Cross-Sectional/Prevalence Study Quality (CSSQ) scale, and then literature review and meta-analyses were undertaken. Results: We pooled the odds ratio (OR) for the presence of WMH, periventricular hyperintensities (PVH), and deep subcortical white matter hyperintensities (DWMH) of patients with CKD vs. non-CKD patients by subgroup analysis, and the results obtained were WMH OR 2.07, 95% CI [1.58, 2.70], PVH OR 2.41, 95% CI [1.90, 3.05], and DWMH OR 2.11, 95% CI [1.60, 2.80], respectively. The main outcome showed that patients with CKD were more likely to have WMH in the brain compared to the normal controls. Another meta-analysis showed a statistically significant decline in renal function in patients with moderate to severe WMH compared with those with no to mild WMH. Conclusions: The findings indicated that patients with CKD were more likely to experience WMH than demographically matched controls. On the other hand, patients with moderate to severe WMH in the brain had poor renal function more frequently than those with no to mild WMH.

Comprehensive Analysis of the Carcinogenic Process, Tumor Microenvironment, and Drug Response in HPV-Positive Cancers.

Human papillomavirus (HPV) is a common virus, and about 5% of all cancers worldwide is caused by persistent high-risk HPV infections. Here, we reported a comprehensive analysis of the molecular features for HPV-related cancer types using TCGA (The Cancer Genome Atlas) data with HPV status. We found that the HPV-positive cancer patients had a unique oncogenic process, tumor microenvironment, and drug response compared with HPV-negative patients. In addition, HPV improved overall survival for the four cancer types, namely, cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC). The stronger activity of cell-cycle pathways and lower driver gene mutation rates were observed in HPV-positive patients, which implied the different carcinogenic processes between HPV-positive and HPV-negative groups. The increased activities of immune cells and differences in metabolic pathways helped explain the heterogeneity of prognosis between the two groups. Furthermore, we constructed HPV prediction models for different cancers by the virus infection score (VIS) which was linearly correlated with HPV load and found that VIS was associated with drug response. Altogether, our study reveals that HPV-positive cancer patients have unique molecular characteristics which help the development of precision medicine in HPV-positive cancers.

Inulin and isomalto-oligosaccharide alleviate constipation and improve reproductive performance by modulating motility-related hormones, short-chain fatty acids, and feces microflora in pregnant sows.

Constipation in gestating and lactating sows is common and the inclusion of dietary fiber may help to alleviate this problem. We investigated the effects of inulin (INU) and isomalto-oligosaccharide (IMO), two sources of soluble dietary fiber, on gastrointestinal motility-related hormones, short-chain fatty acids (SCFA), fecal microflora, and reproductive performance in pregnant sows. On day 64 of gestation, 30 sows were randomly divided into three groups and fed as follows: a basal diet, a basal diet with 0.5% INU, and a basal diet with 0.5% IMO. We found that INU and IMO significantly modulated the levels of gastrointestinal motility-related hormones, as evidenced by an increase in substance P (P < 0.05), and a decrease in the vasoactive intestinal peptide concentrations (P < 0.05), indicating the capacity of INU and IMO to alleviate constipation. Furthermore, IMO enhanced the concentrations of acetic, propionic, isobutyric, butyric, isovaleric, and valeric acids in the feces (P < 0.05). High-throughput sequencing showed that IMO and INU increased the fecal microflora α- and ß-diversity (P < 0.05). Methanobrevibacter was more abundant (P < 0.05), whereas the richness of Turicibacter was lower in the INU and IMO groups than in the control group (P < 0.05). In addition, IMO significantly increased litter size (P < 0.05). Overall, our findings indicate that INU and IMO can relieve constipation, optimize intestinal flora, and promote reproductive performance in pregnant sows.

Effects of Rhamnolipids on Growth Performance, Immune Function, and Cecal Microflora in Linnan Yellow Broilers Challenged with Lipopolysaccharides.

This present study aimed to investigate the effects of rhamnolipids (RLS) on the growth performance, intestinal morphology, immune function, short-chain fatty acid content, and microflora community in broiler chickens challenged with lipopolysaccharides (LPS). A total of 450 broiler chickens were randomly allocated into three groups: basal diet with no supplement (NCO), basal diet with bacitracin (ANT), and basal diet with rhamnolipids (RLS). After 56 d of feeding, 20 healthy broilers were selected from each group, with half being intraperitoneally injected with lipopolysaccharides (LPS) and the other half with normal saline. Treatments with LPS were labelled LPS-NCO, LPS-ANT, and LPS-RLS, whereas treatments with normal saline were labelled NS-NCO, NS-ANT, and NS-RLS. LPS-challenged birds had lower jejunal villus height and higher crypt depth than unchallenged birds. LPS-RLS broilers had increased jejunal villus height and villus height/crypt depth ratio (V/C) but lower crypt depth than LPS-NCO. Dietary supplementation with RLS reduced the LPS-induced immunological stress. Compared with LPS-NCO, birds in LPS-RLS had lower concentrations of IL-1ß, IL-6, and TNF-α. In LPS-challenged broilers, RLS and ANT increased the concentrations of IgA, IgM, and IgY compared with LPS-NCO. In LPS treatments, RLS enhanced the contents of acetic acid, butyrate, isobutyric acid, isovalerate, and valerate more than LPS-NCO birds. High-throughput sequencing indicated that RLS supplementation led to changes in the cecal microbial community of broilers. At the species level, Clostridium-sp-Marseille-p3244 was more abundant in NS-RLS than in NS-NCO broilers. In summary, RLS improved the growth performance and relative abundance of cecal microbiota and reduced the LPS-induced immunological stress in broiler chickens.

Targeting IL-17alpha to promote anti-PD-1 therapy effect by screening the tumor immune microenvironment in a mouse oral carcinogenesis model.

BACKGROUND: Resistance to PD-1 blocking agents is not uncommon, limiting their wide clinical success. Certain tumor-infiltrating immune cells (e.g., TILs/CTLs) have emerged as biomarkers of response, and absence of such immune cells contributes to resistance. OBJECTIVE: We deconvoluted the dynamic immune microenvironment in a mouse model of oral carcinogenesis for augmenting the resistance to PD-1 blocking agents by combination. METHODS: Bioinformatics methods and routine biological experiments were adopted such as morphological analysis and ELISA in the 4NQO-treated mice model. RESULTS: Our findings revealed that dysplastic tongue tissues from 4NQO-treated mice were characterized by an immunosuppressive tumor microenvironment. Tongue tissues from mice treated with 4NQO for 12 weeks had higher levels of Th2 cells and Tregs compared to tissues taken from control mice or mice treated with 4NQO for 28 weeks; these results suggested a potential therapeutic benefit of anti-PD-1 in the oral cancer. The IL-17 pathway was significantly upregulated during progression from normal mucosa to hyperplasia and tumor formation in mice. Inhibition of IL-17α combined with PD-1 blockade delayed the development of 4NQO-induced precancerous and cancerous lesions and prolonged the survival of 4NQO-treated mice. CONCLUSIONS: Our data suggested a strong rationale of IL-17α blockade as a potential approach to augment the tumor-eliminating effects of anti-PD-1 therapy.

The Functional Characterization of Epigenetically Related lncRNAs Involved in Dysregulated CeRNA-CeRNA Networks Across Eight Cancer Types.

Numerous studies have demonstrated that lncRNAs could compete with other RNAs to bind miRNAs, as competing endogenous RNAs (ceRNAs), to regulate each other. On the other hand, ceRNAs were found to be recurrently dysregulated in cancer status. However, limited studies considered the upstream epigenetic regulatory factors that disrupted the normal competing mechanism. In the present study, we constructed the lncRNA-associated dysregulated ceRNA networks across eight cancer types. lncRNAs in the individual dysregulated network and pan-cancer core dysregulated ceRNA subnetwork were found to play more important roles than mRNAs. Integrating lncRNA methylation profiles, we identified 49 epigenetically related (ER) lncRNAs involved in the dysregulated ceRNA networks, including 18 epigenetically activated (EA) lncRNAs, 18 epigenetically silenced (ES) lncRNAs, and 13 rewired ER lncRNAs across eight cancer types. Furthermore, we evaluated the epigenetic regulating patterns of these lncRNAs and screened nine pan-cancer ER lncRNAs (six EA and three ES lncRNAs). The nine lncRNAs were found to regulate the cancer hallmarks by competing with mRNAs. Moreover, we found that integrating the expression and methylation profiles of the nine lncRNAs could predict cancer incidence in eight cancer types robustly and the cancer outcome of several cancer types. These results provide an improved understanding of methylation regulation to ceRNA and offer novel potential molecular therapeutic targets for the diagnosis and prognosis across different cancer types.