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Traditional transcriptomic studies often overlook the complex heterogeneity of skeletal muscle, as they typically isolate RNA from mixed muscle fibre and cell populations, resulting in an averaged transcriptomic profile that obscures fibre type-specific differences. This study assessed the potential of the recently developed Xenium platform for high-resolution spatial transcriptomic analysis of human skeletal muscle histological sections. Human vastus lateralis muscle samples from two individuals were analysed using the Xenium platform and Human Multi-Tissue and Cancer Panel targeting 377 genes complemented by staining of successive sections for Myosin Heavy Chain isoforms to differentiate between type 1 and type 2 muscle fibres. Manual segmentation of muscle fibres allowed accurate comparisons of transcript densities across fibre types and subcellular regions, overcoming limitations in the platform's automated segmentation. The analysis revealed higher transcript density in type 1 fibres, particularly in nuclear and perinuclear areas, and identified 191 out of 377 genes with differential expression between muscle fibres and perimysium. Genes such as PROX1, S100A1, LGR5, ACTA2, and LPL exhibited higher expression in type 1 fibres, whereas PEBP4, CAVIN1, GATM, and PVALB in type 2 fibres. We demonstrated that the Xenium platform is capable of high-resolution spatial in situ transcriptomic analysis of skeletal muscle histological sections. This study demonstrates that, with manual segmentation, the Xenium platform effectively performs fibre type-specific transcriptomic analysis, providing new insights into skeletal muscle biology. Show less

Dementia is a comprehensive term that refers to illnesses characterized by a decline in cognitive memory and other cognitive functions, affecting a person's overall ability to operate. The exact causes of dementia are unknown to this day. The heterogeneity of Alzheimer's indicates the contribution of genetic polymorphism to this disease. This disease is the most prevalent and damaging illness. Studies indicate that the global prevalence of Alzheimer's disease (AD) exceeds 26 million individuals. Investigation of variations in many genes indicates that these variations may be linked to the susceptibility to AD. Additional genetic factors could potentially influence AD. Analysis of several single-nucleotide polymorphisms in this context reveals a correlation between certain variants and AD. Regardless, Alzheimer's disease is always influenced by a particular APOE gene allele. The study's findings indicate that risk of Alzheimer's disease (AD) is linked to polymorphisms in the following genes: BDNF, presenilin-1 (PS-1), presenilin-2 (PS-2), LRP, APP, CTSD,5-6HT, TREM2, TNF-α, LPL, Clusterin (CLU), SORL1 (Sortilin-Related Receptor), PICALM, Complement Receptor 1 (CR1), and APOE genes. Show less

Inflammation is a complex factor in the pathogenesis of intracranial aneurysms (IA), but its specific cellular inflammatory factors remain uncertain. We collected two cohorts and measured the representation of vascular inflammation-related proteins using the Olink CVD II Vascular Inflammation Panel. We subsequently validated our findings using ELISA and RT-qPCR. Our proteomic analysis identified 11 vascular inflammation-related markers that were significantly differentially represented between the IA and control groups. These markers were implicated in leukocyte migration, immune response, triglyceride and lipoprotein metabolism, acute phase response, T cell regulation, and several key biological pathways, including PPAR, HIF-1, cytokine-cytokine interactions, and PI3K-AKT signaling. Further validation with ELISA and RT-qPCR confirmed the differential representation of IL6, PTX3, LPL, and OLR1 between the two groups. Notably, a combination marker incorporating these four factors demonstrated high diagnostic potential for the early detection of IA. Our study has identified a set of informative biomarkers (IL6, PTX3, LPL, and OLR1) that could be valuable for the early diagnosis of IA. Importantly, this is the first report of significantly elevated OLR1 representation in the plasma of IA patients. Further investigation into the role of OLR1 in the pathogenesis of IA is warranted. SIGNIFICANCE: This study significantly advances our understanding of the molecular mechanisms underlying intracranial aneurysm (IA) pathogenesis. By identifying a panel of novel biomarkers, including the previously unreported elevated expression of OLR1 in IA patients, we provide crucial insights into the inflammatory processes involved in aneurysm formation and development. These findings have important clinical implications, as the identified biomarkers could serve as valuable tools for early diagnosis and potentially targeted therapeutic interventions. Furthermore, the study highlights the complex interplay of inflammatory pathways in IA, suggesting that a multi-faceted approach may be necessary for effective management. Show less

Regulating strategies for long persistent luminescence (LPL) are always in high demand. Herein, a series of coordination polymers (CPs) (SUST-Z1-Z4) are fabricated using 1,10-phenanthroline derivatives involving different substituents (─H, ─CH Show less

The diagnosis of lymphoplasmacytic lymphoma (LPL) in the bone marrow (BM) is challenged by aberrant phenotypes and by overlapping histological features with marginal zone lymphoma (MZL). To address these issues, we (i) assessed LPL immunophenotype on a large series of BM samples, (ii) drew possible correlations between LPL phenotype and clinical/molecular data and (iii) investigated the role of new phenotypical markers in the differential diagnosis between LPL and MZL. The study retrospectively considered 81 clinically annotated LPL diagnosed at Padua University Hospital (Padua, Italy) during a 5-year period. BM findings were correlated with clinical laboratory findings and with MYD88 and CXCR4 mutational status. The obtained results were compared with a series of 77 MZL in the BM, including 46 splenic MZL (SMZL), 14 nodal MZL (NMZL) and 17 extra-nodal MZL (EMZL). The LPL cohort included 52 males and 29 females (median age at diagnosis = 71 years). Aberrant CD10 and CD5 positivity was documented in 3 of 81 (3.7%) and 13 of 81 (16.1%) cases, respectively. CD23 positivity occurred in 56 of 81 (69.1%) cases, being usually partial/focal. CD23 expression did not correlate with any specific clinical-pathological parameter. Comparison with SMZL, NMZL and EMZL highlighted less frequent splenomegaly, higher serum paraprotein, higher CD23 expression and fewer follicular dendritic cell networks in LPL. A combined clinical-pathological score supported the differential diagnosis between LPL and MZL of any type. The highest diagnostic yield was obtained for the differential diagnosis between LPL and SMZL. Partial positivity for CD23 is a common feature of LPL in the BM. Together with other clinical and histological parameters, CD23 expression supports the differential diagnosis between LPL and MZL. Show less

This study aims to investigate the current evidence regarding long-term outcomes using laparoscopic peritoneal lavage (LPL) versus primary bowel resection (PR) in Hinchey III diverticulitis. A systematic review was undertaken based upon articles published between January 1, 2000, and March 1, 2024. Databases Pubmed, Scopus, and Embase were used employing the key search terms "Diverticulitis" and "Peritoneal Lavage." Articles were selected according to the PRISMA guidelines and statistical analysis was undertaken. Cumulative analysis of diverticulitis recurrence and secondary outcomes of disease-related mortality, serious adverse events, stoma incidence, reoperation, and readmission rates were performed. An initial search identified 506 articles for review. A total of 294 patients were included for final analysis from 3 prospective randomized controlled trials. There was no significant difference in disease-related mortality or serious adverse events between LPL and PR. There was significantly decreased likelihood of having a stoma in the LPL group; however, there was also a significantly increased likelihood of having recurrent diverticulitis. There was heterogenicity across all trials. There is a paucity of level 1 evidence available regarding the long-term outcomes of Hinchey III diverticulitis managed with LPL. At 3-year follow-up, there is a significantly decreased likelihood of having a stoma, tempered by the fact that there is a significantly increased likelihood of having recurrent diverticulitis. Further homogenous high-quality randomized studies are required to clarify whether LPL shows long-term benefit over PR. Show less

The surgical management of complicated diverticulitis varies across Europe. EAES members prioritized this topic to be addressed by a clinical practice guideline through an online questionnaire. To develop evidence-informed clinical practice recommendations for key stakeholders involved in the treatment of complicated diverticulitis; to improve operative and perioperative outcomes, patient experience and quality of life through a systematic evidence-to-decision approach by a diverse, multidisciplinary panel. Informed by a linked individual participant data network meta-analysis of resection and primary anastomosis (PRA) versus Hartmann's resection (HR) versus laparoscopic lavage (LPL), a panel of general and colorectal surgeons, patient partners, trialists, and fellows appraised the certainty of the evidence using GRADE and CINeMA. The panel discussed the evidence using the evidence-to-decision framework during a synchronous consensus meeting. An asynchronous modified Delphi survey was used to establish consensus. The panel suggests that patients with complicated diverticulitis without sepsis receive PRA over HR or LPL when there is availability of a surgeon with skills and experience in colorectal surgery. HR is suggested over PRA or LPL in the subgroups of septic, frail, as well as immunocompromised patients. These recommendations apply to patients with an indication for surgery. Surgeons and patients should first consider conditionally recommended interventions, then conditionally recommended against. Based on the evidence, the key benefit of PRA was a higher likelihood of not having a stoma at 1 year, with similar risks across comparisons. Conditional recommendations call for shared decision-making when considering management options. The full guideline with user-friendly decision aids is available in https://app.magicapp.org/#/guideline/7490 . This clinical practice guideline provides evidence-informed recommendations on the management of patients with complicated diverticulitis in accordance with the highest methodological standards through a structured framework informed by an international, multidisciplinary panel of stakeholders. Show less

We performed a systematic review and network meta-analysis (NMA) of individualized patient data (IPD) to inform the development of evidence-informed clinical practice recommendations. We searched MEDLINE, Embase, and Cochrane Central in October 2023 to identify RCTs comparing Hartmann's resection (HR), primary resection and anastomosis (PRA), or laparoscopic peritoneal lavage (LPL) among patients with class Ib-IV Hinchey diverticulitis. Outcomes of interest were prioritized by an international, multidisciplinary panel including two patient partners. Article screening, data extraction for IPD, and risk of bias appraisal were performed by two reviewers. We used a random-effects NMA to synthesize direct and indirect evidence. Heterogeneity was evaluated using the I Fourteen reports of seven RCTs were derived from 4,659 articles. IPD data were available for 595/678 patients (88.8%) across trials. Patients had a mean age ± SD of 64.61 ± 13.64 years and a mean BMI ± SD of 26.12 ± 5.20 kg/m PRA likely confers a lower stoma rate at 1 year compared to HR, while there may be no difference in 30-day/in-hospital mortality. LPL likely confers a higher in-hospital/30-day mortality rate compared to HR and PRA. Show less

Metal-organic frameworks (MOFs) with long persistent luminescence (LPL) have attracted extensive research attention due to their potential applications in information encryption, anticounterfeiting technology, and security logic. The strategic combinations of organic phosphor linkers and metal ions lead to tremendous frameworks, which could unveil many undiscovered properties of organics. Here, the synthesis and characterization of a three-dimensional MOF (Cd-MOF) is reported, which demonstrates enhanced blue photoluminescence and a phosphorescent lifetime of 124 ms as compared to the pristine linker (H Show less

Studies showed that contaminants adhered to the surface of nano-polystyrene microplastics (NPs) have a toxicological effect. Juveniles tilapia were dispersed into four groups: the control group A, 75 nm NPs exposed group B, 5 ng·L Show less

There are many options for the surgical management of complicated diverticulitis, and standards vary widely despite international practice recommendations. We conducted a survey to capture the variation in practice across Europe. An online questionnaire was distributed to fellow and surgeon members of the European Association of Endoscopic Surgery (EAES) via email using the Opinio survey platform. Participants shared their demographic details. We asked members to rank the most likely intervention for patients with both stable and unstable Hinchey Class III, as well as Hinchey Class IV diverticulitis based on practice standards in their country. We used descriptive statistics, including counts and percentages, to characterize survey results. We created a heatmap to visualize the percentage of votes received for each intervention. We received 233 responses from surgeons and fellows across Europe from various countries, including Italy (35.6%), Greece (11.2%), and the United Kingdom (9.9%). Most members (79.4%) self-reported having expertise in colorectal surgery. For patients with stable Hinchey III diverticulitis, surgeons offered Hartmann's resection (HR) (41.6%), primary resection and anastomosis (PRA) (18.5%), laparoscopic peritonea lavage (LPL) prior to HR (16.9%), or LPL prior to PRA (15.5%), or LPL only (8.6%). In total, 31.4% of respondents offered LPL prior to sigmoid resection (HR + PRA). For patients with unstable Hinchey III diverticulitis, respondents offered HR (73.9%), PRA (3.85%), LPL only (6.84%), or LPL followed by sigmoid resection (15.4%). For patients with stable Hinchey IV diverticulitis, surgeons offered HR (71.7%), PRA (4.7%), LPL only (1.3%), or LPL then sigmoid resection (22.3%). Finally, for patients with unstable Hinchey IV diverticulitis, surgeons offered HR (83.1%), PRA (1.3%), LPL only (3.5%), or LPL followed by sigmoid resection (12.1%). Significant variation exists in the surgical management of complicated diverticulitis across Europe. Efforts must be made to increase the awareness and uptake of surgical guideline recommendations in clinical practice. Show less

There has been remarkable progress over the past 80 years since Jan Waldenstrom first described patients with a hyperviscosity syndrome related to IgM paraprotein in 1944. The definition of Waldenstrom macroglobulinemia (WM) has evolved from a clinical syndrome to a distinct clinicopathologic entity with characteristic morphology, immunophenotype and molecular features. The landmark discovery of MYD88 mutation among most WM cases in 2012 marked the dawning of an era of molecular genomic exploration that led to a paradigm shift in clinical practice. In the current World Health Organization (WHO) classification of hematologic neoplasms, WM is included in the category of lymphoplasmacytic lymphoma (LPL) of which WM represents over 90% of cases. LPL/WM is also better defined, resolving ambiguity in many cases that would have been classified as "low-grade B-cell lymphoma with plasmacytic differentiation" a decade before. Nevertheless, challenges still face pathologists because criteria for distinguishing LPL/WM from other types of low-grade B-cell lymphoma, particularly marginal zone lymphoma (MZL), remain imperfect. In this review, we highlight the current understanding of LPL and WM brought to light by new discoveries, which in turn are increasingly translated to improved diagnosis and personalized therapy. Key concepts in the diagnosis and their clinical implications are emphasized. Controversies and challenges are also discussed. Show less

Gestational diabetes mellitus (GDM) is defined as glucose intolerance during pregnancy. We aimed to investigate the potential effects of betatrophin and ApoC2 in GDM, focusing on their roles in LPL (lipoprotein lipase) regulation and their relationship with hPL to elucidate the possible impact of hPL on lipid metabolism and its potential contribution to the development of GDM. Thirty pregnant women with normal glucose tolerance and 29 with gestational diabetes mellitus (diagnosed by 75g OGTT between 24 and 28 weeks) were included in the study. Serum betatrophin, hPL, and ApoC2 were measured by Elisa and HOMA-IR was calculated. In the GDM group, hPL levels correlated with betatrophin and ApoC2 (r = 0.552, p < 0.05; r = 0.588, p < 0.05 respectively) while betatrophin correlated with the ApoC2 (r = 0.584, p < 0.05). A linear relationship between hPL and betatropin and also between hPL and ApoC2 values in the control group (r = 0.454, p < 0.05; r = 0.779, p < 0.01 respectively) were observed. ApoC2 levels in the GDM group (n = 20) with HOMA-IR cut-off >2.5 were significantly higher than the control group (n = 10) (p < 0.05). There was also a positive relationship between betatrophin and ApoC2 (r = 0.591) (p < 0.05). GDM patients may have impaired LPL enzyme regulation in addition to insulin resistance, with hPL potentially contributing to this disruption. Impaired lipoprotein lipase activity and its dysregulation secondary to genetic disorders may play a role in the etiopathogenesis of GDM. Further investigation into the correlation between betatrophin, ApoC2, and other LPL modulators in patients with various forms of diabetes could be beneficial for understanding this interaction more comprehensively. Show less

Lysophospholipids (LPLs) and host defense peptides (HDPs) are naturally occurring membrane-active agents that disrupt key membrane properties, including the hydrocarbon thickness, intrinsic curvature, and molecular packing. Although the membrane activity of these agents has been widely examined separately, their combined effects are largely unexplored. Here, we use experimental and computational tools to investigate how lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), an LPL of lower positive spontaneous curvature, influence the membrane activity of piscidin 1 (P1), an α-helical HDP from fish. Four membrane systems are probed: 75:25 C16:0-C18:1 PC (POPC)/C16:0-C18:1 phosphoglycerol (POPG), 50:25:25 POPC/POPG/16:0 LPC, 75:25 C16:0-C18:1 PE (POPE)/POPG, and 50:25:25 POPE/POPG/14:0 LPE. Dye leakage, circular dichroism, and NMR experiments demonstrate that while the presence of LPLs alone does not induce leakage-proficient defects, it boosts the permeabilization capability of P1, resulting in an efficacy order of POPC/POPG/16:0 LPC > POPE/POPG/14:0 LPE > POPC/POPG > POPE/POPG. This enhancement occurs without altering the membrane affinity and conformation of P1. Molecular dynamics simulations feature two types of asymmetric membranes to represent the imbalanced ("area stressed") and balanced ("area relaxed") distribution of lipids and peptides in the two leaflets. The simulations capture the membrane thinning effects of P1, LPC, and LPE, and the positive curvature strain imposed by both LPLs is reflected in the lateral pressure profiles. They also reveal a higher number of membrane defects for the P1/LPC than P1/LPE combination, congruent with the permeabilization experiments. Altogether, these results show that P1 and LPLs disrupt membranes in a concerted fashion, with LPC, the more disruptive LPL, boosting the permeabilization of P1 more than LPE. This mechanistic knowledge is relevant to understanding biological processes where multiple membrane-active agents such as HDPs and LPLs are involved. Show less

Speech and co-speech gestures always go hand in hand. Whether we find the precursors of these co-speech gestures in infants before they master their native language still remains an open question. Except for deictic gestures, there is little agreement on the existence of iconic, non-referential and conventional gestures before children start producing their first words. Here, we bridge this knowledge gap by leveraging an ethological method already established for describing speech independent gestures in nonhuman primates, to analyze the spontaneous gestures produced by infants when interacting with their caregivers. We manually annotated video recordings of infant-caregiver interactions (26 h) from the CHILDES platform, to describe the gesture forms, types and functions in six infants from 12 to 15 months of age. We describe 62 gesture forms in the preverbal repertoire. These were categorized into deictic, iconic, non-referential and conventional gesture types, similar to co-speech gesture types. We also find that the type-function relation of preverbal gestures map similarly to type-meaning relation of co-speech gestures. Taken together, our results illustrate linguistic properties of infant gestures in the absence of speech, suggesting them to be precursors of co-speech gestures. Show less

In the context of global warming, heat stress poses a threat to aquatic organisms. In the present study, a comprehensive analysis in hepatopancreas from Procambarus clarkii was conducted to examine the histology, physiological changes, and transcriptome alterations after exposed at 32 and 37 ℃ for 24 and 72 h, respectively, with 26 ℃ as the control group. The results demonstrated that the survival rate of P. clarkii decreased significantly with the stress time and the temperature increased, with a corresponding damage to its hepatopancreas. Significant fluctuations were observed in the malondialdehyde (MDA) content, reactive oxygen species (ROS) production, total antioxidant capacity (T-AOC), and activities of pyruvate kinase (PK), hexokinase (HK), alkaline phosphatase (ALP), lysozyme (LYS), acid phosphatase (ACP), fatty acid synthase (FAS), as well as lipoprotein lipase (LPL) in response to different stress conditions (P < 0.05). Heat stress notably altered the expression of genes related to glucose, lipid, and protein metabolism, as well as oxidative phosphorylation pathways. The expression of genes related to protein processing and degradation pathways in the endoplasmic reticulum was up-regulation. On the contrary, the expression of genes related to ER autophagy was suppressed. Simultaneously, the differentially expressed genes (DEGs) were significantly enriched in lysosomal and phagosomal pathways. In summary, heat stress induced oxidative damage, disrupted metabolic pathways, impacted protein processing, and compromised immune defense mechanisms, ultimately resulting in decreased survival rates of P. clarkii. These findings contribute to a deeper understanding of aquatic organisms respond to heat stress. Show less

The aim of this study was to investigate the ameliorative effects of pterostilbene (PTE), a polyphenolic compound, on stress-induced lipid metabolic disorders in the liver of broiler chickens. Six hundred healthy, 1-day-old Arbor Acres with similar weight were randomly assigned to five groups, each consisting of eight replicates with 15 broilers per replicate. The groups included: a control group (fed a basal diet), and four groups treated with corticosterone (CORT) at varying dietary levels of PTE supplementation: CORT (0 mg/kg PTE), CORT-PT200 (200 mg/kg PTE), CORT-PT400 (400 mg/kg PTE), and CORT-PT600 (600 mg/kg PTE). The results indicated that PTE administration to corticosterone (CORT)-injected broilers significantly improved weight gain, reduced liver index, and lowered the elevation of serum aspartate aminotransferase, gamma-glutamyl transferase, glucose, total cholesterol, triglycerides, and lipoprotein cholesterol concentrations induced by CORT injection (P<.05), but had no significant effect on serum CORT concentration (P>.05). PTE also significantly reduced the increased rate of abdominal fat deposition induced by CORT, decreased the average size of adipocytes, and downregulated the expression of the FAS gene (P<.05). It reversed the increase in liver total cholesterol, triglycerides, lipoprotein cholesterol, and non-esterified fatty acids content induced by CORT (P<.05). PTE had no significant effect on the expression of the glucocorticoid receptor (P>.05), but significantly upregulated the protein expression of Sirt1 and p-AMPK (P<.05), promoted the expression of lipid autophagy genes MAP1LC3B and lipolytic genes LPL, but inhibited the expression of fatty acid synthesis genes SREBP-1c, ACC, and SCD (P<.05). The addition of PTE to the diet alleviated CORT-induced oxidative stress and inflammation by enhancing T-SOD and GSH-Px activities, reducing MDA content, inhibiting p-NF-κB p65 and NLRP3 expression and the release of TNF-α and IL-1β in the serum, and increasing IL-4 content (P<.05). Overall, dietary PTE effectively regulates lipid metabolism and antioxidant status, offering a potential strategy to mitigate stress-induced metabolic disruptions in broilers. Show less

This study explores the impact of visually similar flanking stimuli on central target words using the Flanking Letter Lexical Decision (FLLD) task. Specifically, we investigated whether visual similarity effects can explain orthographic relatedness effects observed in previous FLLD tasks. By employing non-reversal mirror letters as visual flankers, we compared their influence on response times to traditional orthographic-related and orthographic-unrelated conditions. Results confirmed the known facilitative effect of orthographic-related flankers on response times (ROCK ROCK ROCK). However, mirror-related conditions showed no facilitative effect ([Formula: see text] ROCK [Formula: see text]), as evidenced by a Bayesian analysis indicating no significant differences between mirror-related and mirror-unrelated ([Formula: see text] ROCK [Formula: see text]). These findings suggest that low-level visual information in the parafovea does not contribute to the processing of the foveal word in tasks requiring specific word identification. The study concludes that only parafoveal information with relevant linguistic content is spatially pooled across target and flankers during word identification tasks. This research highlights the need to consider task-specific attentional demands and the linguistic relevance of parafoveal information in understanding visual and orthographic processing in reading. Show less

The aim of this study was to obtain goat CRTC2 gene sequence and elucidate its biological properties, and further study the impact of overexpression and interference of CRTC2 on the cell differentiation of goat subcutaneous precursor adipocytes. The sequence of goat CRTC2 was cloned by reverse transcription (RT)-polymerase chain reaction (PCR) and its molecular characterization was analyzed. The expression of CRTC2 gene in goat tissues and subcutaneous precursor adipocytes differentiated from 0 to 120 h was examined by quantitative real-time PCR (qRT-PCR). The effects of CRTC2 on the subcutaneous precursor adipocyte differentiation were investigated by using liposome transfection, Bodipy, Oil Red O staining and qPCR. The results showed that the cloned goat CRTC2 gene was 2363 bp long (coding sequence [CDS] 2082 bp), encoding 693 amino acids. The relative expression levels of CRTC2 gene were highest in liver and then in kidney (p<0.05). During differentiation, the highest expression of CRTC2 in subcutaneous precursor adipocytes was observed at 120 of differentiating (p<0.01). In addition, we found that overexpression of CRTC2 significantly increased the expression of lipid metabolism-related genes (C/EBPα, C/EBPβ, PPARγ, DGAT1, DGAT2, ACC, FASN, SREBP1, AP2, LPL, ATGL) and promoted lipid accumulation. We then chemically synthesized goat CRTC2 small interfering RNA and transfected it into goat subcutaneous precursor adipocytes. The results revealed that SiRNA-mediated interference with CRTC2 significantly inhibited its differentiation and suppressed lipid droplet aggregation. So, this study indicates that CRTC2 is a positive regulator that promoting cell differentiation of subcutaneous adipocyte in goats, which lays the foundation for an in-depth study of the role of CRTC2 in lipid deposition in goats. Show less

To investigate the mechanism of liraglutide affecting lipid metabolism by regulating lipolysis and lipogenesis in cells and ob/ob mice. 3 T3-L1 cells were treated with liraglutide in vitro, and differentially expressed genes were screened by RNA sequencing. Gene Ontology (GO) and KEGG (Kvoto Encyclopedia of Genes and Genomes) enrichment analyses identified target genes for lipid regulation of liraglutide. 3 T3-L1 preadipocytes were induced to differentiate into adipocytes using a "cocktail method". Western blot and immunofluorescence were used to detect the expression of target genes and the lipid regulatory effect of liraglutide. 3 T3-L1 preadipocytes were transfected with lentivirus overexpressing Zbtb20 to study its role in adipogenesis, and gene expression was analyzed by RT-qPCR and Western blot. In vivo, ob/ob mice were subcutaneously injected with liraglutide or saline for 4 weeks. Blood lipids, adipose tissue volume and adipocyte size were detected. Immunohistochemical analysis and RT-qPCR were used to detect the expression of target genes in adipose tissue. Liraglutide reduced lipid droplets and TG levels and altered the expression of genes related to fatty acid metabolism, lipogenesis, fatty acid oxidation, and adipocyte browning. The results of PCR, Western blot and immunofluorescence confirmed that liraglutide could regulate the adipogenesis by downregulating the transcriptional suppressor ZBTB20, and overexpression of Zbtb20 inhibited the expression of LPL, the key enzyme for lipohydrolysis. Liraglutide regulates lipid metabolism through ZBTB20-LPL pathway to reveal its molecular mechanism. Show less

The length of ewe productive life (LPL), defined as the number of days between the first and last lambing, is a key indicator of ewe longevity and is directly related to the sustainability of the sheep industry. Therefore, the primary objective of this study was to investigate systematic effects influencing LPL in Katahdin sheep. The LPL of 10,474 Katahdin ewes (69.5% with uncensored and 30.5% with right-censored observations) born between 1992 and 2021 in 58 flocks located across the United States were analyzed. The Kaplan-Meier (K-M) and Cox proportional hazard (Cox PH) methods were used to estimate survival probability. Four Cox PH models were evaluated. Model 1 included contemporary group (CG; flock-year-season of ewe birth) as a random effect and the ewe's dam's age (EDA), ewe's own birth-rearing type (BR; 1/1, 2/1, 2/2, 3/2, 3/3, with the digit-3 including lamb counts ≥ 3), and age at first lambing (AFL) as fixed effects. Models 2 to 4 were an extension of model 1. Model 2 also included average lamb birth weight (ABW) per ewe lifetime, while model 3 included average lamb weaning weight (AWW) per ewe lifetime. Both ABW and AWW were fitted as fixed effects. Model 4 fitted all previous effects together. The factors CG, BR, ABW, and AWW affected LPL (P < 0.05) in all models in which these effects were fitted. The EDA effect only influenced LPL (P < 0.05) in model 1, while AFL had no effect (P > 0.05) in any model. The median LPL ranged from approximately 2 to 3 yr, depending on the risk factors analyzed. In general, Katahdin ewes themselves born in multiple litters, and that produced lambs weighing approximately 5 kg at lambing and 20 to 25 kg at weaning (over their lifespan) had better survival probability. Although the LPL of Katahdin sheep is relatively low, it appears to be a consequence of voluntary culling due to its association with both ABW and AWW. Future studies should quantify the rate of involuntary culling in Katahdin ewes to identify whether longevity indicator traits should be included in more comprehensive breeding objectives. Show less

Intracranial aneurysms (IAs) are the major cause of subarachnoid hemorrhage. Stent-assisted coiling, especially with the Neuroform Atlas stent (NAS), has proved more effective than coiling alone for treating these aneurysms. To perform a systematic review and meta-analysis to investigate the efficacy and safety of the NAS in treating IAs. A comprehensive literature search was conducted on PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from inception until June 2024. We included studies on ruptured and unruptured IAs treated with the NAS, covering experimental, observational, and case series across all age groups. The aneurysm occlusion rate was assessed by using the Raymond-Roy classification (RROC). The mRS and adverse events related to stent use were also recorded. The statistical analysis was conducted on R Version 4.3.2 by using the packages "meta" and "metasens." We reported our results as proportions with their corresponding CIs. Meta-regression, leave-one-out, and sensitivity analyses were conducted to confirm the robustness of our results. A total of 42 studies including 2434 participants with a mean age of 51 to 73 years were included. Among angiographic outcomes, the final RROC 1/RROC 2 was achieved in 95% of the patients, final RROC 1 in 82%, RROC 2 in 12%, and RROC 3 in 5% of the patients. Additionally, 93% of the patients showed mRS grade 0, 5% showed mRS grade 1, 3% showed mRS grade 2, 2% showed mRS grade 3, 0% showed mRS grade 4, 0% showed mRS grade 5, and 1% showed mRS grade 6. All adverse events had a ≤5% rate. Due to limited cause-specific data, we were unable to analyze mortality specific to the stent placement and complications. Despite the large number of studies included, comparative studies were still observed to be scarce. Although the generalizability of our findings is limited, this study demonstrates that the NAS is highly effective for treating IAs, with high occlusion rates and a low incidence of adverse events. The stent's performance, supported by comprehensive analysis, highlights its safety and efficacy in managing both ruptured and unruptured aneurysms. Show less

Dyslipidemia is described in several autoimmune conditions. Lipoprotein lipase (LPL) is responsible for triglyceride breakdown. Anti-LPL antibodies have been described. To review articles on anti-LPL antibodies in autoimmune and non-autoimmune diseases. Twenty-two articles were found: 9 case reports and 13 observational studies. In 5 of 9 case reports, hypertriglyceridemia normalized after immunosuppressive treatment. The observational studies showed the prevalence and associations of anti-LPL antibodies: systemic lupus erythematosus, found in 37.8 % to 71 % of patients and associated with nephritis, disease activity, and the presence of anti-dsDNA antibodies. In myositis, the prevalence ranged from 4 % to 43 % without any reported association. In scleroderma, they were found in 35 % to 42 % and associated with skin and lung fibrosis, heart involvement, and the presence of anti-topoisomerase-1 antibodies. In Sjögren's syndrome and rheumatoid arthritis, they were found in a minority of individuals. They were absent in Behçet's disease, antiphospholipid antibody syndrome, juvenile idiopathic arthritis, juvenile dermatomyositis, and Takayasu arteritis. Three studies were conducted on dyslipidemic patients without autoimmune conditions, and in one of them, anti-LPL antibodies were associated with necrosis in atherosclerotic plaques. Anti-LPL antibodies were detected in several autoimmune and non-autoimmune diseases, mainly connective tissue diseases, and were associated with increased triglyceride levels. These antibodies may contribute to the accelerated atherogenesis seen in these patients. Show less

Standard models of lexical production assume that speakers access representations of meaning, grammar, and different aspects of sound in a roughly sequential manner (whether or not they admit cascading or interactivity). In contrast, we review evidence for a parallel activation model in which these representations are accessed in parallel. According to this account, word learning involves the binding of the meaning, grammar, and sound of a word into a single representation. This representation is then activated as a whole during production, and so all linguistic components are available simultaneously. We then note that language comprehension involves extensive use of prediction and argue that comprehenders use production mechanisms to determine (roughly) what they would say next if they were speaking. So far, theories of prediction-by-production have assumed sequential lexical production. We therefore reinterpret such evidence in terms of parallel lexical production. Show less

Sneddon-Wilkinson (SW) disease is rare condition which typically occurs in the context of a monoclonal immunoglobulin and treatment options have not been well studied. Here we present a case of a 65-year-old female with SW with underlying, otherwise indolent, lymphoplasmacytic lymphoma (LPL) with an IgA paraprotein, who achieved a complete skin remission with the administration of the Bruton Tyrosine Kinase inhibitor (BTKi), acalabrutinib. Show less

Triglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n = 1,384). Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling and adjusted for age, sex, field centers, and principal components. GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based identity-by-descent estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (P = 1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds exceeding 3 on 3q28 (logarithm of the odds = 4.1). Using a subset of 25 linkage-enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2 [eukaryotic translation initiation factor 4A2]/ADIPOQ-rs114108468, p = 5e-6, minor allele frequency = 1.8%; TPRG1-rs16864075, p = 3e-6, minor allele frequency = 8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p = 7e-5)/ADIPOQ (P = 3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (P = 0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort observed modest effect of these loci on ΔTHR. Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance. Show less

The Weibull proportional hazards model was used to identify the nongenetic effects that affect length of productive life (LPL) of the Italian Mediterranean buffalo. Data were provided by the Italian National Association of Buffalo Breeders and included records of reproductive, productive, and linear type traits from 59,943 buffalo with first calving from 2002 to 2019. Data were divided into 4 geographical regions to determine whether the relationship between the investigated effects and LPL varied by region. Length of productive life was defined as the number of days from the first calving to culling for those buffaloes that were culled (uncensored) or to the date of the last test-day for those that are still alive (censored). The Weibull model included time-dependent effects of herd-year-season of calving, parity and stage of lactation, production as within-herd deviations, as well as time-independent effects of age at first calving, year of birth, type of reproduction (natural mating vs. AI), classifier, and ten linear type traits. The average duration of productive life was 1,604 days. Both year of birth and production level had a significant effect on culling risk. Moreover, culling risk decreased linearly across parities. The reference point for age at first calving relative to other classes was set at 35 months. A significant relationship between linear type traits and relative culling risk was also observed, being highest for buffaloes with the lowest linear scores. The results show that the Weibull model provides consistent and robust risk estimates. Therefore, this model would be recommended for future implementation of the first genetic evaluation of LPL in the Italian Mediterranean buffalo. Show less

Dysregulated lipid metabolism promotes the progression of various cancer types, including breast cancer. The present study aimed to explore the lipidomic profiles of patients with breast cancer, providing insights into the correlation between lipid compositions and tumor subtypes characterized by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Briefly, 30 patients with breast cancer were categorized into four groups based on their HR and HER2 status: HR+ no HER2 expression (HER2-0), HR+ HER2-low; HR+ HER2-positive (pos) and HR- HER2-pos. The lipidomic profiles of these patients were analyzed using high-throughput liquid chromatography-mass spectrometry. The data were processed through principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and random forest (RF) classification to assess the lipidomic variations and significant lipid features among these groups. The profiles of the lipids, particularly triglycerides (TG) such as TG(16:0-18:1-18:1)+NH Show less

Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. This study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings. Show less