Sex-biased gene content is associated with sex chromosome turnover in Danaini butterflies.

Sex chromosomes play an outsized role in adaptation and speciation, and thus deserve particular attention in evolutionary genomics. In particular, fusions between sex chromosomes and autosomes can produce neo-sex chromosomes, which offer important insights into the evolutionary dynamics of sex chromosomes. Here, we investigate the evolutionary origin of the previously reported Danaus neo-sex chromosome within the tribe Danaini. We assembled and annotated genomes of Tirumala septentrionis (subtribe Danaina), Ideopsis similis (Amaurina), Idea leuconoe (Euploeina) and Lycorea halia (Itunina) and identified their Z-linked scaffolds. We found that the Danaus neo-sex chromosome resulting from the fusion between a Z chromosome and an autosome corresponding to the Melitaea cinxia chromosome (McChr) 21 arose in a common ancestor of Danaina, Amaurina and Euploina. We also identified two additional fusions as the W chromosome further fused with the synteny block McChr31 in I. similis and independent fusion occurred between ancestral Z chromosome and McChr12 in L. halia. We further tested a possible role of sexually antagonistic selection in sex chromosome turnover by analysing the genomic distribution of sex-biased genes in I. leuconoe and L. halia. The autosomes corresponding to McChr21 and McChr31 involved in the fusions are significantly enriched in female- and male-biased genes, respectively, which could have hypothetically facilitated fixation of the neo-sex chromosomes. This suggests a role of sexual antagonism in sex chromosome turnover in Lepidoptera. The neo-Z chromosomes of both I. leuconoe and L. halia appear fully compensated in somatic tissues, but the extent of dosage compensation for the ancestral Z varies across tissues and species.

Fast satellite DNA evolution in Nothobranchius annual killifishes.

Satellite DNA (satDNA) is a rapidly evolving class of tandem repeats, with some monomers being involved in centromere organization and function. To identify repeats associated with (peri)centromeric regions, we investigated satDNA across Southern and Coastal clades of African annual killifishes of the genus Nothobranchius. Molecular cytogenetic and bioinformatic analyses revealed that two previously identified satellites, designated here as NkadSat01-77 and NfurSat01-348, are associated with (peri)centromeres only in one lineage of the Southern clade. NfurSat01-348 was, however, additionally detected outside centromeres in three members of the Coastal clade. We also identified a novel satDNA, NrubSat01-48, associated with (peri)centromeres in N. foerschi, N. guentheri, and N. rubripinnis. Our findings revealed fast turnover of satDNA associated with (peri)centromeres and different trends in their evolution in two clades of the genus Nothobranchius.

Expression of Elafin and CD200 as Immune Checkpoint Molecules Involved in Celiac Disease.

We comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules involved in celiac disease (CD). We have focused on the alteration of the CD200/CD200R pathway and Elafin expression in celiac disease and discussed their roles in regulating the immune response. There are limited data related to the expression or function of these molecules in celiac disease. This finding could significantly contribute to the understanding of the clinical manifestation of CD. CD200, CD200R and Elafin distributions were determined by ELISA and immunohistochemistry analyses in serum and biopsies of CD patients. Analyses of Th1 and Th17 cytokines were determined. PCR amplification of a fragment of the PI3 gene was carried out using genomic DNA isolated from whole blood samples of the study subjects. Different aliquots of the PCR reaction product were subjected to RFLP analysis for SNP genotyping and detection. We characterized the expression and function of the CD200-CD200R axis and PI3 in celiac disease. A significantly higher level of soluble CD200 and CD200R and lower expression of PI3 in serum of CD patients was observed compared to healthy controls. Consistent with our results, CD200 expression is regulated by IFN-gamma. Interaction of CD200/CD200R leads to production of type-Th1 and -Th17 cytokines. Regarding the PI3 genotype, the CT genotype proportion SNP rs1733103 and the GG genotype SNP rs41282752 were predominant in CD patients. SNP rs1733103 showed a significant association between the SNP variables and CD. In celiac disease the immune checkpoint is compromised or dysregulated, which can contribute to inflammation and the autoimmunity process. The study of these checkpoint points will lead to the development of targeted therapies aimed at restoring immunological balance in CD. Specific coding regions of the PI3 gene-splice variants predispose the Elafin protein, both at the transcriptional and post-translational levels, to modify its expression and function, resulting in reduced differential functional protein levels in patients with active celiac disease.

Holocentric repeat landscapes: From micro-evolutionary patterns to macro-evolutionary associations with karyotype evolution.

Repetitive elements can cause large-scale chromosomal rearrangements, for example through ectopic recombination, potentially promoting reproductive isolation and speciation. Species with holocentric chromosomes, that lack a localized centromere, might be more likely to retain chromosomal rearrangements that lead to karyotype changes such as fusions and fissions. This is because chromosome segregation during cell division should be less affected than in organisms with a localized centromere. The relationships between repetitive elements and chromosomal rearrangements and how they may translate to patterns of speciation in holocentric organisms are though poorly understood. Here, we use a reference-free approach based on low-coverage short-read sequencing data to characterize the repeat landscape of two independently evolved holocentric groups: Erebia butterflies and Carex sedges. We consider both micro- and macro-evolutionary scales to investigate the repeat landscape differentiation between Erebia populations and the association between repeats and karyotype changes in a phylogenetic framework for both Erebia and Carex. At a micro-evolutionary scale, we found population differentiation in repeat landscape that increases with overall intraspecific genetic differentiation among four Erebia species. At a macro-evolutionary scale, we found indications for an association between repetitive elements and karyotype changes along both Erebia and Carex phylogenies. Altogether, our results suggest that repetitive elements are associated with the level of population differentiation and chromosomal rearrangements in holocentric clades and therefore likely play a role in adaptation and potentially species diversification.

The spread of satellite DNAs in euchromatin and insights into the multiple sex chromosome evolution in Hemiptera revealed by repeatome analysis of the bug Oxycarenus hyalinipennis.

Satellite DNAs (satDNAs) are highly repeated tandem sequences primarily located in heterochromatin, although their occurrence in euchromatin has been reported. Here, our aim was to advance the understanding of satDNA and multiple sex chromosome evolution in heteropterans. We combined cytogenetic and genomic approaches to study, for the first time, the satDNA composition of the genome in an Oxycarenidae bug, Oxycarenus hyalinipennis. The species exhibits a male karyotype of 2n = 19 (14A + 2 m + X1 X2 Y), with a highly differentiated Y chromosome, as demonstrated by C-banding and comparative genomic hybridization, revealing an enrichment of repeats from the male genome. Additionally, comparative analysis between males and females revealed that the 26 identified satDNA families are significantly biased towards male genome, accumulating in discrete regions in the Y chromosome. Exceptionally, the OhyaSat04-125 family was found to be distributed virtually throughout the entire extension of the Y chromosome. This suggests an important role of satDNA in Y chromosome differentiation, in comparison of other repeats, which collectively shows similar abundance between sexes, about 50%. Furthermore, chromosomal mapping of all satDNA families revealed an unexpected high spread in euchromatic regions, covering the entire extension, irrespective of their abundance. Only discrete regions of heterochromatin on the Y chromosome and of the m-chromosomes (peculiar chromosomes commonly observed in heteropterans) were enriched with satDNAs. The putative causes of the intense enrichment of satDNAs in euchromatin are discussed, including the possible existence of burst cycles similar to transposable elements and as a result of holocentricity. These data challenge the classical notion that euchromatin is not enriched with satDNAs.

Tumour budding in cutaneous squamous cell carcinoma: A novel prognosis risk factor.

INTRODUCTION: Most cutaneous squamous cell carcinomas (cSCC) have a good prognosis, there is a small group where metastasis and death occur and the evaluation of this risk is still cause for controversy. Tumour budding is a pattern of histological invasion that is an emerging risk factor in other solid tumours. OBJECTIVE: To examine the association between tumour budding and other known high-risk predictors in cSCC. In addition, the impact of tumour budding on overall survival (OS) and disease-specific survival (DSS) was analysed. METHOD: Retrospective study. It included patients with a diagnosis of non-genital cSCC by excisional biopsy at a university hospital, between 2010 and 2020. A pathologist re-analysed their histological slides and evaluated budding. Univariate and multivariate analyses were made to study the associations. RESULTS: 156 cSCC biopsies were found, and positive tumour budding was found in 13.5%. This correlated with worse DSS and OS. On univariate analysis, budding was correlated with the diameter, thickness of the tumour, histological grade, level of invasion, perineural and lymphovascular invasion, previous radiotherapy, recurrent tumours and lymph node metastasis (LNM). Multivariate analysis: tumour budding was associated with poorly differentiated tumours, prior radiotherapy and LNM. CONCLUSION: An association was found between tumour budding and most known risk factors in cSCC. We found findings that indicate that the presence of tumour budding is associated with a worse prognosis in terms of LNM, OS and DSS. This supports the results of previous work which has suggested that budding could be related to high-risk cSCC.

Impact of the time interval between primary melanoma excision and sentinel node biopsy: A systematic review and meta-analysis.

BACKGROUND: Obtaining a sentinel lymph node biopsy (SLNB) specimen is a standard staging procedure in the management of cutaneous melanoma. However, there is no consensus on the safe time interval between the primary melanoma biopsy procedure and the SLNB procedure. OBJECTIVE: We evaluated the association between time from biopsy to SLNB and patients' outcomes for melanoma. METHODS: We performed this systematic review and meta-analysis based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Six retrospective studies were included. Nine thousand seven hundred five patients were identified, of which 4383 underwent a SNLB procedure at a time interval defined as early and 4574 at an interval defined as late. A combined hazard ratio of 1.25 (95% confidence interval [CI] 0.92-1.68) was determined, and there was high heterogeneity (I2 = 83%; P = .002) of the SLNB time interval on melanoma-specific survival. The combined HR for disease-free survival was 1.05 (95% CI 0.95-1.15), with low heterogeneity (I2 = 9%; P = .36). Regarding overall survival, a combined HR of 1.25 (95% CI 0.92-1.70) was found, with low heterogeneity (I2 = 37%; P = .2). LIMITATIONS: There is heterogeneity between some studies. CONCLUSION: There are no significant differences in patient outcome between a short interval versus a long interval between the primary biopsy procedure and obtaining a SNLB specimen.

Theoretical study of Aun clusters (n = 1-5) deposited on a rutile TiO2 (110) slab, concerning structure and stability.

The initial nucleation of gold clusters Aun (n = 1-5) on TiO2 rutile (110) reduced surface is studied using density functional theory and a full-potential augmented-plane-wave method implemented in the WIEN2k code. The first two gold atoms remained tied to the surface with a bond length similar to those belonging to other well-known related materials, while the other gold atoms do not spread over the surface; they preferred to form a new layer. The occurrence of relativistic effects produced a preferential triangle geometry for Au3 and a combination of triangular units for Au4 and Au5 . The Au-Au average distance increased from n = 2 to n = 5, indicating an expansion with a tendency to the bond distance found in the bulk. We are reporting an early 2D→3D transition of small folding, from Au3 →Au4 , followed by an Au4 →Au5 transition of evident 3D character.

EFFICACY AND SAFETY OF IGLARLIXI IN HISPANICS AND NON-HISPANIC WHITES WITH TYPE 2 DIABETES.

Objective: Type 2 diabetes (T2D) is more common in Hispanic than non-Hispanic white (NHW) populations worldwide, and ethnicity, among other factors, may affect response to therapy. The efficacy and safety of insulin glargine 100 units/mL (iGlar) and the fixed-ratio combination of iGlar and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi) was assessed in Hispanic and NHW patients with T2D from 25 countries. Methods: In this post hoc analysis, data from two 30-week randomized controlled trials comparing iGlar and iGlarLixi in patients with T2D uncontrolled on basal insulin ± oral antidiabetes drugs (OADs; LixiLan-L: NCT02058160) or uncontrolled on metformin ± OADs (LixiLan-O: NCT02058147) were evaluated. Results: Of the 1,512 patients included across trials, 301 were Hispanic and 1,211 NHW. Compared with iGlar, iGlarLixi resulted in greater reductions in glycated hemoglobin (A1C) and 2-hour postprandial glucose and a higher proportion of patients at target A1C <7.0% (<53 mmol/mol), regardless of ethnicity. Among NHWs from the LixiLan-L trial, documented symptomatic hypoglycemia (plasma glucose ≤70 mg/dL) rates were higher with iGlar compared with iGlarLixi (P = .06), whereas this trend was reversed among Hispanics (P = .07). Nevertheless, in both trials, a greater proportion of patients taking iGlarLixi than iGlar reached the composite efficacy endpoints of target A1C without hypoglycemia and target A1C without weight gain, regardless of ethnicity. Conclusion: These results indicate that iGlarLixi is a viable therapeutic option for both Hispanic and NHW patients with T2D, as it is efficacious without a significant increase in hypoglycemia, irrespective of ethnicity. Abbreviations: A1C = glycated hemoglobin; BMI = body mass index; FPG = fasting plasma glucose; FRC = fixed-ratio combination; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HDL-C = high-density-lipoprotein cholesterol; iGlar = insulin glargine; iGlarLixi = insulin glargine + lixisenatide; LDL-C = low-density-lipoprotein cholesterol; NHW = non-Hispanic white; OAD = oral antidiabetes drug; PPG = postprandial glucose; T2D = type 2 diabetes.

Optimizing mHealth Technologies in Real-World Clinical Practices.

IN BRIEF Therapeutic inertia and suboptimal treatment adherence remain the key drivers of chronic poor diabetes control. Advances in mHealth technologies have spurred the development of a new generation of blood glucose monitoring systems that enable individuals with diabetes to automatically transfer glucose data and other information from their smartphones to their health care providers for analysis and interpretation via diabetes data-management software. This report discusses key lessons learned from two investigations that assessed the effects of interventions using the Accu-Chek Connect diabetes-management system (Roche Diabetes Care, Indianapolis, Ind.) within diverse diabetes populations.

Comparative Analysis of Repetitive DNA between the Main Vectors of Chagas Disease: Triatoma infestans and Rhodnius prolixus.

Chagas disease or American trypanosomiasis affects six to seven million people worldwide, mostly in Latin America. This disease is transmitted by hematophagous insects known as "kissing bugs" (Hemiptera, Triatominae), with Triatoma infestans and Rhodnius prolixus being the two most important vector species. Despite the fact that both species present the same diploid chromosome number (2n = 22), they have remarkable differences in their total DNA content, chromosome structure and genome organization. Variations in the DNA genome size are expected to be due to differences in the amount of repetitive DNA sequences. The T. infestans genome-wide analysis revealed the existence of 42 satellite DNA families. BLAST searches of these sequences against the R. prolixus genome assembly revealed that only four of these satellite DNA families are shared between both species, suggesting a great differentiation between the Triatoma and Rhodnius genomes. Fluorescence in situ hybridization (FISH) location of these repetitive DNAs in both species showed that they are dispersed on the euchromatic regions of all autosomes and the X chromosome. Regarding the Y chromosome, these common satellite DNAs are absent in T. infestans but they are present in the R. prolixus Y chromosome. These results support a different origin and/or evolution in the Y chromosome of both species.

CARDIOVASCULAR OUTCOME TRIALS OF THE INCRETIN-BASED THERAPIES: WHAT DO WE KNOW SO FAR?

OBJECTIVE: Diabetes is a well-established pro-inflammatory state with an increased risk for cardiovascular (CV) diseases. In recent years, the number of different classes of agents for the treatment of type 2 diabetes has increased substantially, and while glycemic control is the major focus of these medications, CV safety has become of interest. Two incretin-based therapies are currently available: glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: The literature was reviewed for information regarding the incretin-based therapies and their effects on the CV system. RESULTS: Independent of their glucose-lowering action, incretin-based therapies may have incretin-dependent mechanisms that positively affect blood pressure, weight, and other markers of CV disease risk, and, in the case of DPP-4 inhibition, nonincretin-dependent actions such as improving endothelial function. Several CV outcomes trials (CVOTs) with incretin-based therapies have recently completed with no excess CV risk observed, and positive effects have been reported in at least 1 trial of GLP-1 RAs, with more studies ongoing. Results for the risk for heart failure with DPP-4 inhibitor use are mixed, but no increase has been demonstrated with GLP-1 RAs. CONCLUSION: Future CVOTs will need to be redesigned to help address these questions in the context of the emerging scope of the underlying mechanisms of cardio-metabolic disease in populations with diabetes. ABBREVIATIONS: A1C = hemoglobin A1C ACS = acute coronary syndrome CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVOT = Cardiovascular Outcome Trial DPP-4 = dipeptidyl peptidase 4 FDA = U.S. Food and Drug Administration GIP = glucose-dependent insulinotropic polypeptide GLP-1 = glucagon-like protein 1 GLP-1 RA = glucagon-like protein 1 receptor agonist HF = heart failure HR = hazard ratio LVEF = left ventricular ejection fraction MACE = major adverse cardiovascular events MI = myocardial infarction T2D = type 2 diabetes.

Prognostic Factors of Recurrence and Survival in Vulvar Melanoma: Subgroup Analysis of the VULvar CANcer Study.

OBJECTIVE: The aim of this study was to analyze the prognostic factors related to the recurrence rate and overall survival of vulval melanoma patients by means of a subgroup analysis of the VULvar CANcer study. METHODS: The international multicenter VULvar CANcer study involved 100 international centers, which contributed 2453 vulvar cancer cases. Of the 1727 patients finally included in the study, 42 were suffering from vulvar melanoma (2.4%). RESULTS: The mean follow-up for vulval melanoma patients was 44.1±35.7 months. Recurrence rate was 50%, and the mean recurrence-free survival was 43.5±6.6 months. For local recurrences, the mean recurrence-free interval was 63.3±8.6 months; for metastasis, 33.5±3.5 months. The 5-year recurrence-free survival rate was 28.6%. The mean overall survival for vulvar melanomas was 45.9±4 months and the 5-year overall survival rate was 78.6%. The only factor with prognostic significance regarding local recurrence of vulvar melanoma was tumor size (P = 0.003). American Joint Committee on Cancer staging was the only prognostic factor associated with metastatic disease at recurrence (P < 0.001). Finally, age of patient was significantly associated with overall survival (P < 0.001). CONCLUSIONS: Tumor size and American Joint Committee on Cancer stage were independent prognostic factors associated with local and distant recurrence, respectively. Patients' age was the only independent prognostic factor associated with overall survival.

EFFECTS OF LIRAGLUTIDE 3.0 MG ON WEIGHT AND RISK FACTORS IN HISPANIC VERSUS NON-HIPANIC POPULATIONS: SUBGROUP ANALYSIS FROM SCALE RANDOMIZED TRIALS.

OBJECTIVE: Scarce data exist on pharmacotherapy for obesity in Hispanic individuals. This post hoc analysis of pooled data from 4 phase 3a trials compared the efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to a reduced-calorie diet and physical activity, in Hispanic versus non-Hispanic subgroups. METHODS: We conducted the double-blind randomized, placebo-controlled trials in adults with a minimum body mass index (BMI) of 27 kg/m2 with at least 1 comorbidity, or a minimum BMI of 30 kg/m2, at clinical research sites worldwide. In this analysis, we investigated possible differences in treatment effects between 534 Hispanics (10.4% of the population) and 4,597 non-Hispanics (89.6%) through statistical tests of interaction between subgroups and treatment. Variables examined included mean and categorical weight change, cardiovascular risk markers, and safety data. RESULTS: Both subgroups achieved clinically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: Hispanics 7.0% versus 1.5%, treatment difference -5.1% (95% CI, -6.2 to -4.0); non-Hispanics 7.5% versus 2.3%, -5.2% (95% CI, -5.5 to -4.8). More individuals in both subgroups lost ≥5%, >10%, and >15% of their baseline weight with liraglutide 3.0 mg than with placebo. Efficacy endpoints generally did not vary with ethnicity (P>.05). Adverse events were comparable between ethnic subgroups, with more gastrointestinal disorders reported with liraglutide 3.0 mg than placebo. CONCLUSION: Efficacy and safety were largely similar between Hispanic and non-Hispanic subgroups. Results support that liraglutide 3.0 mg, used with a reduced-calorie diet and physical activity, can facilitate weight loss in Hispanic individuals. ABBREVIATIONS: A1c = glycated hemoglobin BMI = body mass index CI = confidence interval FPG = fasting plasma glucose GLP-1 = glucagon-like peptide-1 hsCRP = high-sensitivity C-reactive protein SCALE = Satiety and Clinical Adiposity - Liraglutide Evidence in individuals with and without diabetes T2DM = type 2 diabetes mellitus.

Acoustics from a rectangular supersonic nozzle exhausting over a flat surface.

A jet exhausting over a plate at different distances away from the nozzle was investigated to simulate jets exhausting over airframe surfaces and the jet-ground interaction during take-off and landing operations. A supersonic rectangular nozzle of 2:1 aspect ratio and 1.5 design Mach number was tested with and without the plate. Far-field acoustics from the cold and heated jets at over-expanded, design, and under-expanded conditions were measured at the reflected, sideline, and shielded azimuthal directions. When the plate starts at the nozzle exit, the "scrubbing" and "scattering" noise from the surface-jet interaction was observed at the low-end frequencies of the reflected and shielded measurements and increased as the plate approached the jet. In the sideline, the plate attached to the nozzle exit diminished the broadband shock-associated noise while the shadowgraph results showed a connection to weakening of the shock-cell structures. In the cold jet, screech was mitigated with the plate attached at the nozzle exit. When the plate was moved away from the nozzle, screech tones were intensified at the under-expanded condition. Crackle levels were significantly intensified in the sideline within a range of plate positions. Noise levels in the shielded region were considerably lower due to the shielding effect.