Nanomaterials-mediated lysosomal regulation: a robust protein-clearance approach for the treatment of Alzheimer's disease.

Alzheimer's disease is a debilitating, progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins, including amyloid plaques and intracellular tau tangles, primarily within the brain. Lysosomes, crucial intracellular organelles responsible for protein degradation, play a key role in maintaining cellular homeostasis. Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer's disease. Currently, the efficacy of drugs in treating Alzheimer's disease is limited, with major challenges in drug delivery efficiency and targeting. Recently, nanomaterials have gained widespread use in Alzheimer's disease drug research owing to their favorable physical and chemical properties. This review aims to provide a comprehensive overview of recent advances in using nanomaterials (polymeric nanomaterials, nanoemulsions, and carbon-based nanomaterials) to enhance lysosomal function in treating Alzheimer's disease. This review also explores new concepts and potential therapeutic strategies for Alzheimer's disease through the integration of nanomaterials and modulation of lysosomal function. In conclusion, this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer's disease. The application of nanotechnology to the development of Alzheimer's disease drugs brings new ideas and approaches for future treatment of this disease.

Relationships of serum MMP-7 and clinical characteristics in choledochal cyst children.

BACKGROUND: Matrix metalloproteinase-7 (MMP-7) is associated with biliary injury. This study aimed to evaluate the relationships of serum MMP-7 with clinical characteristics in choledochal cysts (CDC) children. METHODS: Between June 2020 and July 2022, we conducted a prospective study of CDCs who underwent one-stage definitive operation at our center. Serum MMP-7 was measured using an enzyme-linked immunosorbent assay. We evaluated the relationships between serum MMP-7 and age, laboratory tests, imaging examinations, liver fibrosis, MMP-7 expression, and perforation. RESULTS: A total of 328 CDCs were enrolled in the study, with a median serum MMP-7 of 7.67 ng/mL. Higher serum MMP-7 was correlated with younger age at diagnosis (p < 0.001), larger cyst sizes (p < 0.001), higher liver fibrosis stages (p < 0.001), and higher incidence of perforation (p < 0.01). Liver MMP-7 was mainly expressed in intrahepatic and extrahepatic biliary epithelial cells. The area under the receiver operating characteristic curve (AUROC) was 0.630 (p < 0.001) for serum MMP-7 in predicting perforation. When serum MMP-7 was combined with γ-glutamyl transferase (GGT), the AUROC increased to 0.706 (p < 0.001). CONCLUSIONS: Serum MMP-7 was associated with biliary obstruction in CDCs. Patients with high serum MMP-7 were more likely to have severe liver damage and biliary injury, with higher incidences of liver fibrosis and perforation.

Association of CHAT Gene Polymorphism rs3793790 and rs2177370 with Donepezil Response and the Risk of Alzheimer's Disease Continuum.

Background: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC). Objective: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC. Material and Methods: According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid ß-protein positive (Aß+) and negative (Aß-) patients were recruited according to the Aß-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aß+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aß+ and 73 Aß- patients using a logistic regression analysis. Results: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95). Conclusion: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.

Platelet-derived circFAM13B associated with anti-platelet responsiveness of ticagrelor in patients with acute coronary syndrome.

BACKGROUND: Platelet is enriched with Circular RNAs (circRNAs), with circFAM13B rank among the 10 most abundant circRNAs in platelets. The aim of the present study was to evaluate the predictive value of platelet-derived circFAM13B for the antiplatelet responsiveness and efficacy of ticagrelor in patients with acute coronary syndrome (ACS). METHODS: Consecutive ACS patients treated with ticagrelor were enrolled, and the antiplatelet responsiveness of 3 days of ticagrelor maintenance treatment was assessed by measuring the adenosine diphosphate (ADP)-induced platelet inhibition rate (ADP%) using thromboelastography. The expression of circFAM13B in the patients' platelets was analyzed by quantitative real-time polymerase chain reaction. The correlation between circFAM13B expression and ticagrelor antiplatelet responsiveness, as well as the independent contribution of circFAM13B to the composite of adverse ischemic events during a follow-up period of at least 12 months was evaluated. RESULTS: A total of 129 eligible ACS patients treated with ticagrelor were enrolled in the study. A negative correlation was found between the expression of circFAM13B and the ADP% value (r = -0.41, P < 0.001). Patients with ADP% ≥ 76% had a significantly lower level of circFAM13B compared to those with ADP% < 76% (adjusted P = 0.009). Receiver operating characteristic curve analysis demonstrated that combining circFAM13B expression > 1.05 with clinical risk factors could effectively predict the risk of adverse ischemic events (AUC = 0.81, 95% CI: 0.69 to 0.92, P < 0.001). Kaplan-Meier survival analysis showed that patients with circFAM13B > 1.05 had a significantly higher risk of adverse ischemic events compared to those with circFAM13B ≤ 1.05 (P = 0.003). Multivariate logistic hazard analysis identified circFAM13B > 1.05 as an independent risk factor for adverse ischemic events in in ticagrelor-treated ACS patients (adjusted OR: 5.60, 95% CI: 1.69-18.50; P = 0.005). CONCLUSIONS: Platelet-derived circFAM13B could be utilized for predicting the antiplatelet responsiveness and efficacy of ticagrelor in patients with ACS.

Expansion of effector memory Vδ2neg γδ T cells associates with cytomegalovirus reactivation in allogeneic stem cell transplant recipients.

Background: Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited. Methods: This study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation. Results: CMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2neg γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2neg γδ T cells following CMV reactivation, while Vδ2pos T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2neg γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2neg γδ T cell-mediated anti-CMV cytotoxicity. Conclusion: This study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2neg γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.

Chinese patent medicine combined with calcium channel blockers in the treatment of essential hypertension:a Bayes network meta-analysis and systematic review.

Backgroud: The co-administration of Chinese patent medicine with calcium channel blockers (CCBs) is a prevalent practice in China for treating essential hypertension (EH). However, robust evidence supporting the efficacy and safety of tailored combinations of different Chinese patent medicines with CCBs, according to individual patient conditions, is still limited. This study sought to elucidate the efficacy and safety of these combinations using a systematic review and network meta-analysis. Materials and methods: Relevant studies were sourced from established databases, incorporating randomized controlled trials published up to 1 February 2023. The ROB2 tool from the Cochrane Collaborative Network was employed to independently assess and cross-verify the quality of the included literature. A network meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 and PRISMA-Network Meta-Analyses (PRISMA-NMA) guidelines. A Bayesian network meta-analysis was utilized to gauge the efficacy and safety of distinct integrations of Chinese patent medicine and CCBs. Primary outcomes were interpreted using a paired fixed-effect meta-analysis. Publication bias was appraised through Egger's test and represented with funnel plots. All statistical analyses were executed within the R statistical framework. Results: Following rigorous selection, data extraction, and bias evaluation, 36 articles were incorporated. Tianma Gouteng Granule, when combined with CCBs, displayed superior efficacy in reducing systolic blood pressure (SBP). In terms of diastolic blood pressure (DBP) reduction, Songling Xuemaikang Capsule combined with CCBs emerged as the most effective. Regarding enhancement of antihypertensive effective rates, Qinggan Jiangya Capsule paired with CCBs demonstrated optimal results. For diminishing Traditional Chinese Medicine syndrome scores, the Qiangli Dingxuan Tablet and CCBs combination proved most beneficial. When aiming to reduce total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, Tianma Gouteng Granule and CCBs showcased superior results. In contrast, the combination of Songling Xuemaikang Capsule and CCBs was more effective in reducing LDL-C, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Conclusion: This study underscores variability in outcomes from combining Chinese patent medicine and CCBs for hypertension, emphasizing the importance of personalized medicinal combinations, especially Tianma Gouteng Granule and Songling Xuemaikang Capsule. The results offer robust evidence to inform clinical guidelines for essential hypertention and significantly aid clinician in seleting appropriate Chinese patent medicines for treatment.

SSK1-Loaded Neurotransmitter-Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells.

Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging-associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti-AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by ß-gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of ß-gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1-loaded neurotransmitter -derived lipid nanoparticles are herein developed (SSK1-NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1-NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid-beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1-NPs, a novel nanomedicine displaying potent anti-AD activity and excellent safety profile, provides a promising strategy for AD therapy.

Elucidating the anti-hypertensive mechanisms of Uncaria rhynchophylla-Alisma plantago-aquatica L: an integrated network pharmacology, cluster analysis, and molecular docking approach.

Background: With the increasing global prevalence of hypertension, a condition that can severely affect multiple organs, there is a growing need for effective treatment options. Uncaria rhynchophylla-Alisma plantago-aquatica L. (UR-AP) is a traditional drug pair used for treating hypertension based on the liver-kidney synergy concept. However, the detailed molecular mechanisms underlying its efficacy remain unclear. Methods: This study utilized an integrative approach combining network pharmacology, cluster analysis, and molecular docking to uncover the bioactive components and targets of UR-AP in the treatment of hypertension. Initially, we extracted data from public databases to identify these components and targets. A Protein-Protein Interaction (PPI) network was constructed, followed by enrichment analysis to pinpoint the bioactive components, core targets, and pivotal pathways. Cluster analysis helped in identifying key sub-networks and hypothesizing primary targets. Furthermore, molecular docking was conducted to validate the interaction between the core targets and major bioactive components, thus confirming their potential efficacy in hypertension treatment. Results: Network pharmacological analysis identified 58 bioactive compounds in UR-AP, notably quercetin, kaempferol, beta-sitosterol (from Uncaria rhynchophylla), and Alisol B, alisol B 23-acetate (from Alisma plantago-aquatica L.), as pivotal bioactives. We pinpointed 143 targets common to both UR-AP and hypertension, highlighting MAPK1, IL6, AKT1, VEGFA, EGFR, and TP53 as central targets involved in key pathways like diastolic and endothelial function, anti-atherosclerosis, AGE-RAGE signaling, and calcium signaling. Cluster analysis emphasized IL6, TNF, AKT1, and VEGFA's roles in atherosclerosis and inflammation. Molecular docking confirmed strong interactions between these targets and UR-AP's main bioactives, underscoring their therapeutic potential. Conclusion: This research delineates UR-AP's pharmacological profile in hypertension treatment, linking traditional medicine with modern pharmacology. It highlights key bioactive components and their interactions with principal targets, suggesting UR-AP's potential as a novel therapeutic option for hypertension. The evidence from molecular docking studies supports these interactions, indicating the relevance of these components in affecting hypertension pathways. However, the study acknowledges its limitations, including the reliance on in silico analyses and the need for in vivo validation. These findings pave the way for future clinical research, aiming to integrate traditional medicine insights with contemporary scientific approaches for developing innovative hypertension therapies.

Dairy consumption and liver cancer risk: A meta­analysis of observational studies.

The connection between the consumption of dairy products and the risk of developing primary liver cancer (PLC) remains unclear. The present study performed a comprehensive meta-analysis with the aim of providing evidence for any connection between the risk of developing PLC and the consumption of dairy products. For this purpose, eligible studies were screened from the PubMed, Cochrane Library and Embase databases before December 2022. A total of 10 cohort studies and 8 case-control studies were included, making a total of 18 studies with 6,562,714 participants and 7,970 PLC cases. The relative risks (RRs) for milk and yogurt were 1.38 [95% confidence interval (CI), 1.07-1.77] and 0.49 (95% CI, 0.27-0.91), which revealed a positive and negative association, respectively, with the risk of developing PLC. There was no association between total dairy (RR, 1.04; 95% CI, 0.84-1.30) or cheese and curd (RR, 1.05; 95% CI, 0.87-1.27) consumption and the risk of developing PLC. On the whole, the findings of the present study demonstrated that high milk consumption was associated with a higher risk of developing PLC, while by contrast, yogurt consumption was associated with a lower risk of developing PLC. Consequently, further studies are required to further examine this association.

Genetic evaluations and genome-wide association studies for specific digital dermatitis diagnoses in dairy cows considering genotype × housing system interactions.

The present study aimed to use detailed phenotyping for the claw disorder digital dermatitis (DD) considering specific DD stages in 2 housing systems (conventional cubicle barns [CON] and compost-bedded pack barns [CBPB]) to infer possible genotype × housing system interactions. The DD stages included 2,980 observations for the 3 traits DD-sick, DD-acute, and DD-chronic from 1,311 Holstein-Friesian and 399 Fleckvieh-Simmental cows. Selection of the 5 CBPB and 5 CON herds was based on a specific protocol to achieve a high level of herd similarity with regard to climate, feeding, milking system, and location, but with pronounced housing-system differences. Five other farms had a "mixed system" with 2 subherds, one representing CBPB and the other one CON. The CBPB system was represented by 899 cows (1,530 observations), and 811 cows (1,450 observations) represented the CON system. The average disease prevalence was 20.47% for DD-sick, 13.88% for DD-acute, and 5.34% for DD-chronic, with a higher prevalence in CON than in CBPB. After quality control of 50K genotypes, 38,495 SNPs from 926 cows remained for the ongoing genomic analyses. Genetic parameters for DD-sick, DD-acute, and DD-chronic were estimated by applying single-step approaches for single-trait repeatability animal models considering the whole dataset, and separately for the CON and CBPB subsets. Genetic correlations between same DD traits from different housing systems, and between DD-sick, DD-chronic, and DD-acute, were estimated via bivariate animal models. Heritabilities based on the whole dataset were 0.16 for DD-sick, 0.14 for DD-acute, and 0.11 for DD-chronic. A slight increase of heritabilities and genetic variances was observed in CON compared with the "well-being" CBPB system, indicating a stronger genetic differentiation of diseases in a more challenging environment. Genetic correlations between same DD traits recorded in CON or CBPB were close to 0.80, disproving obvious genotype × housing system interactions. Genetic correlations among DD-sick, DD-acute and DD-chronic ranged from 0.58 to 0.81. SNP main effects and SNP × housing system interaction effects were estimated simultaneously via GWAS, considering only the phenotypes from genotyped cows. Ongoing annotations of potential candidate genes focused on chromosomal segments 100 kb upstream and downstream from the significantly associated candidate SNP. GWAS for main effects indicated heterogeneous Manhattan plots especially for DD-acute and DD-chronic, indicating particularities in disease pathogenesis. Nevertheless, a few shared annotated potential candidate genes, that is, METTL25, AFF3, PRKG1, and TENM4 for DD-sick and DD-acute, were identified. These genes have direct or indirect effects on disease resistance or immunology. For the SNP × housing system interaction, the annotated genes ASXL1 and NOL4L on BTA 13 were relevant for DD-sick and DD-acute. Overall, the very similar genetic parameters for the same traits in different environments and negligible genotype × housing system interactions indicate only minor effects on genetic evaluations for DD due to housing-system particularities.

Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.

Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.

Early T-cell reconstitution predicts risk of EBV reactivation after allogeneic hematopoietic stem cell transplantation.

The quality of immune reconstitution (IR) is crucial for the outcome of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is closely connected with infection, relapse and graft-versus-host disease (GvHD) which are the most important causes for transplantation failure. However, the IR pattern in the early stage after allo-HSCT, particularly haploidentical (HID) HSCT, remains unclear. In this retrospective study, we examined the T cell reconstitution of patients within the initial 30 days (n = 173) and 100 days (n = 122) after allo-HSCT with myeloablative condition (MAC), of which > 70% were HID HSCT, to assess the influence of IR on the transplant outcomes. By comparing 78 patients with good IR (GIR) to 44 patients with poor IR (PIR), we observed that GIR was associated with lower risk for Epstein-Barr virus (EBV) reactivation and cytomegalovirus (CMV) reactivation, but had no significant impacts on the survival outcomes (i.e., overall survival, event-free survival) and cumulative incidences of GvHD. Importantly, we found lymphocyte reconstitution pattern at day 30 after allo-HSCT would be a surrogate for IR evaluated at day 100. In the Cox proportional hazard model, early reconstitution of CD4+, CD4+CD25+, CD4+CD45RO+, CD4+CD25+CD27low, and CD8+ T cells at day 30 was reversely correlated with risk of EBV reactivation. Finally, we constructed a predictive model for EBV reactivation with CD8+ and CD4+CD45RO+ T cell proportions of the training cohort (n = 102), which was validated with a validation cohort (n = 37). In summary, our study found that the quality of IR at day 30 had a predictive value for the risk of EBV reactivation, and might provide guidance for close monitoring for EBV reactivation.

Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia.

The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research. Though an altered microenvironment is a general cancer hallmark, how APL blasts shape their plasma composition is poorly understood. Here, we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters, proteomes, and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy. Our study revealed the two prominent features of the APL plasma, suggesting a possible involvement of APL blasts in modulating plasma composition. One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts, and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA. Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

Biomembrane-Derived Nanoparticles in Alzheimer's Disease Therapy: A Comprehensive Review of Synthetic Lipid Nanoparticles and Natural Cell-Derived Vesicles.

Current therapies for Alzheimer's disease used in the clinic predominantly focus on reducing symptoms with limited capability to control disease progression; thus, novel drugs are urgently needed. While nanoparticles (liposomes, high-density lipoprotein-based nanoparticles) constructed with synthetic biomembranes have shown great potential in AD therapy due to their excellent biocompatibility, multifunctionality and ability to penetrate the BBB, nanoparticles derived from natural biomembranes (extracellular vesicles, cell membrane-based nanoparticles) display inherent biocompatibility, stability, homing ability and ability to penetrate the BBB, which may present a safer and more effective treatment for AD. In this paper, we reviewed the synthetic and natural biomembrane-derived nanoparticles that are used in AD therapy. The challenges associated with the clinical translation of biomembrane-derived nanoparticles and future perspectives are also discussed.

Diagnosis, Treatment, and Management for Chronic Coronary Syndrome: A Systematic Review of Clinical Practice Guidelines and Consensus Statements.

Objectives: Management of chronic coronary syndrome (CCS) encompasses a broad spectrum of practices, posing considerable complexity and variability. While guidelines have been established to augment the management quality of CCS, notable disparities persist across their recommendations. This study strives to scrutinize, compare, and reconcile these guideline recommendations pertaining to the diagnosis, treatment, and management of CCS patients. Our goal is to align these recommendations with contemporary clinical practices, thus laying a robust foundation for their pragmatic application in clinical settings. Methods: A comprehensive systematic search was conducted across multiple databases, including PubMed, EMBASE, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database, Chinese Biomedical Literature Service System, Chinese Science and Technology Periodical Database, and Chinese Biological Medicine Database. The timeframe for this search spanned from their inception up to May 30, 2022, aiming to collate all published guidelines relevant to CCS. Subsequently, two independent reviewers undertook the task of appraising the quality of these guidelines by utilizing the Appraisal of Guidelines for Research and Evaluation II instrument. Results: The search yielded a total of 10,699 citations. Following a thorough evaluation, fourteen clinical practice guidelines and four consensus statements, each offering specific recommendations for CCS, were selected. The quality of these guidelines showcased a broad spectrum of variation. The domain of "presentation clarity" received the highest accolades, while "applicability" languished at the lower end of the scoring spectrum. On average, the guidelines attained a quality score denoting sufficiency. Furthermore, recommendations across different guidelines for the diagnosis, treatment, and management of CCS displayed a striking level of divergence. Conclusion: The landscape of published CCS guidelines is marked by extensive variations in scope, quality, and recommendations. Hence, there is a compelling need for collaborative efforts amongst multidisciplinary professionals to forge comprehensive, higher-quality evidence-based guidelines; such a concerted approach is paramount to enhance treatment efficacy and health outcomes for patients grappling with CCS.

Unraveling the Genomic Association for Milk Production Traits and Signatures of Selection of Cattle in a Harsh Tropical Environment.

A study was designed to identify the genomic regions associated with milk production traits in a dairy cattle population reared by smallholder farmers in the harsh and challenging tropical savanna climate of Bengaluru, India. This study is a first-of-its-kind attempt to identify the selection sweeps for the dairy cattle breeds reared in such an environment. Two hundred forty lactating dairy cows reared by 68 farmers across the rural-urban transiting regions of Bengaluru were selected for this study. A genome-wide association study (GWAS) was performed to identify candidate genes for test-day milk yield, solids-not-fat (SNF), milk lactose, milk density and clinical mastitis. Furthermore, the cross-population extended haplotype homozygosity (XP-EHH) methodology was adopted to scan the dairy cattle breeds (Holstein Friesian, Jersey and Crossbred) in Bengaluru. Two SNPs, rs109340659 and rs41571523, were observed to be significantly associated with test-day milk yield. No significant SNPs were observed for the remaining production traits. The GWAS for milk lactose revealed one SNP (rs41634101) that was very close to the threshold limit, though not significant. The potential candidate genes fibrosin-like 1 (FBRSL) and calcium voltage-gated channel auxiliary subunit gamma 3 (CACN) were identified to be in close proximity to the SNP identified for test-day milk yield. These genes were observed to be associated with milk production traits based on previous reports. Furthermore, the selection signature analysis revealed a number of regions under selection for the breed-group comparisons (Crossbred-HF, Crossbred-J and HF-J). Functional analysis of these annotated genes under selection indicated pathways and mechanisms involving ubiquitination, cell signaling and immune response. These findings point towards the probable selection of dairy cows in Bengaluru for thermotolerance.

Selective Sweeps in Cattle Genomes in Response to the Influence of Urbanization and Environmental Contamination.

A genomic study was conducted to identify the effects of urbanization and environmental contaminants with heavy metals on selection footprints in dairy cattle populations reared in the megacity of Bengaluru, South India. Dairy cattle reared along the rural-urban interface of Bengaluru with/without access to roughage from public lakeshores were selected. The genotyped animals were subjected to the cross-population-extended haplotype homozygosity (XP-EHH) methodology to infer selection sweeps caused by urbanization (rural, mixed, and urban) and environmental contamination with cadmium and lead. We postulated that social-ecological challenges contribute to mechanisms of natural selection. A number of selection sweeps were identified when comparing the genomes of cattle located in rural, mixed, or urban regions. The largest effects were identified on BTA21, displaying pronounced peaks for selection sweeps for all three urbanization levels (urban_vs_rural, urban_vs_mixed and rural_vs_mixed). Selection sweeps are located in chromosomal segments in close proximity to the genes lrand rab interactor 3 (RIN3), solute carrier family 24 member 4 (SLC24A4), tetraspanin 3 (TSPAN3), and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1). Functional enrichment analyses of the selection sweeps for all three comparisons revealed a number of gene ontology (GO) and KEGG terms, which were associated with reproduction, metabolism, and cell signaling-related functional mechanisms. Likewise, a number of the chromosomal segments under selection were observed when creating cattle groups according to cadmium and lead contaminations. Stronger and more intense positive selection sweeps were observed for the cadmium contaminated group, i.e., signals of selection on BTA 16 and BTA19 in close proximity to genes regulating the somatotropic axis (growth factor receptor bound protein 2 (GRB2) and cell ion exchange (chloride voltage-gated channel 6 (CLCN6)). A few novel, so far uncharacterized genes, mostly with effects on immune physiology, were identified. The lead contaminated group revealed sweeps which were annotated with genes involved in carcass traits (TNNC2, SLC12A5, and GABRA4), milk yield (HTR1D, SLCO3A1, TEK, and OPCML), reproduction (GABRA4), hypoxia/stress response (OPRD1 and KDR), cell adhesion (PCDHGC3), inflammatory response (ADORA2A), and immune defense mechanism (ALCAM). Thus, the findings from this study provide a deeper insight into the genomic regions under selection under the effects of urbanization and environmental contamination.

Inferring Causalities of Environmental and Genetic Factors for Differential Somatic Cell Count and Mastitis Pathogens in Dairy Cows Using Structural Equation Modelling.

The aim of this study was to establish and evaluate a structural equation model to infer causal relationships among environmental and genetic factors on udder health. For this purpose, 537 Holstein Friesian cows were genotyped, and milk samples were analyzed for novel traits including differential somatic cell counts and specific mastitis pathogens. In the structural model, four latent variables (intramammary infection (IMI), production, time and genetics) were defined, which were explained using manifest measurable variables. The measurable variables included udder pathogens and somatic differential cell counts, milk composition, as well as significant SNP markers from previous genome-wide associations for major and minor pathogens. The housing system effect (i.e., compost-bedded pack barns versus cubicle barns) indicated a small influence on IMI with a path coefficient of -0.05. However, housing system significantly affected production (0.37), with ongoing causal effects on IMI (0.17). Thus, indirect associations between housing and udder health could be inferred via structural equation modeling. Furthermore, genotype by environment interactions on IMI can be represented, i.e., the detection of specific latent variables such as significant SNP markers only for specific housing systems. For the latent variable genetics, especially one SNP is of primary interest. This SNP is located in the EVA1A gene, which plays a fundamental role in the MAPK1 signaling pathway. Other identified genes (e.g., CTNNA3 and CHL1) support results from previous studies, and this gene also contributes to mechanisms of the MAPK1 signaling pathway.

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis.

Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

ß1-blockers in the reduction of bleeding risk in patients prescribed with potent dual antiplatelet therapy after acute coronary syndrome or percutaneous coronary intervention.

BACKGROUND: ß1-blockers could improve clinical outcomes in patients with coronary artery disease by lowering the heart rate, blood pressure, and myocardial contractility. Moreover, recent studies have suggested that ß1-blockers may also have the potential to reduce bleeding risk. OBJECTIVES: This study aimed to evaluate the association between ß1-blockers and bleeding risk in the patients prescribed with potent dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). METHODS: Patients with ACS or undergoing PCI treated by DAPT of ticagrelor and aspirin were consecutively recruited. Follow-up for all eligible patients was conducted for 1 year. Major bleeding outcomes were defined as events that were type ≥2 based on the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: A total of 1,113 eligible ticagrelor-treated patients were recruited. During the 1-year follow-up interval, 142 (12.6%) patients experienced BARC ≥2 bleedings including 23 patients (2.1%) suffering BARC ≥3 bleedings, with the most common site of bleeding located in the gastrointestinal tract. ß1-blockers treatment was associated with a lower risk of BARC ≥2 bleedings (11.2% vs. 23.3%, adjusted HR: 0.42, 95% CI: 0.28-0.62, P < 0.01). Moreover, metoprolol (11.1% vs. 23.3%, adjusted HR: 0.56, 95% CI: 0.37-0.83, P < 0.01) and bisoprolol (11.3% vs. 23.3%, adjusted HR: 0.56, 95% CI: 0.33-0.96, P = 0.04) had similar effects on the reduction of bleeding risk. CONCLUSION: ß1-blockers might be beneficial for the reduction of bleeding risk in potent dual antiplatelet therapy patients with ACS or undergoing PCI.