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In sum, the manuscripts within this issue discuss anatomical, paleontological, genetic, and behavioral evidence bearing on the antiquity of the domestic dog, the process of domestication, and the many ways in which dogs continue to affect human life.Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and rate-limiting step in the biosynthesis of melanin. Mutations in Tyr might result in non-functional Tyr protein and, consequently, loss of pigment production. This is a rare genetic condition, known as albinism, described for most animal species and one of the most obvious and simple phenotypes to investigate in model organisms. Mutations in the orthologous human TYR gene are associated with oculocutaneous albinism type 1 (OCA1). Over the last thirty years, the mouse Tyr locus has been studied as a paradigm for how genes and expression domains are organized and regulated in mammalian genomes. This review summarizes the major findings and experimental strategies used, from the production of conventional transgenic mice to the latest CRISPR-Cas9 genome-edited animals. The main conclusion inferred from all of these studies, which extends beyond the analysis of the mouse Tyr locus, is the relevance of analyzing non-coding regulatory DNA elements in their natural chromosomal environment, and not only as randomly inserted transgenes. Further, the identification of evolutionary conserved regulatory sequences might highlight new vulnerable sites in the human TYR gene, whose mutations could also be associated with albinism.Solar radiation exposure is recognised to be a significant contributor to the development of skin cancer. Monitoring the simultaneous and consecutive mechanisms of interaction could provide a greater understanding of the process of photocarcinogenesis. This work presents an analysis of the biochemical and morphological changes occurring to immortalised human epithelial keratinocyte (HaCaT) cell cultures exposed to simulated solar radiation (SSR). Cell viability was monitored with the aid of the Alamar Blue assay, morphological examination was done with haematoxylin and eosin staining (H&E) and changes to the biochemical constituents (nucleic acids and proteins) as a result of the radiation insult were demonstrated through a combination of Raman microspectroscopy and multivariate analysis of spectral patterns. The spectral results suggest that SSR induces changes to the conformational structure of DNA as an immediate result of the radiation, whereas alteration in the protein signature is mostly seen as a later response.

To study the relationship between hydroxychloroquine (HCQ) use and new onset atrial fibrillation in patients with systemic lupus erythematosus (SLE).

A retrospective cohort of adult SLE patients from Dec 1, 2014 to May 30, 2017 was constructed. Patients were categorized as either HCQ users or non-users. The primary outcome was incident atrial fibrillation; secondary outcomes included incident ventricular arrhythmias (composite of ventricular tachycardia (VT), ventricular fibrillation (VF), or torsades de pointes). Outcomes were adjudicated by review of the electronic health record. Statistical analyses included simple and multivariable logistic regression analyses to estimate the association between HCQ use and incident atrial fibrillation after adjusting for relevant confounders. Propensity score matching analysis was completed.

Our study included 1647 patients with SLE, of which 917 were HCQ users and 730 were non-users. A total of 23 atrial fibrillation events occurred, 3 in HCQ users and 20 in non-un. Further studies would be needed to confirm the anti-fibrillatory benefit of this relatively safe and low-cost medication.Germplasm from perennial ryegrass (Lolium perenne L.) natural populations is useful for breeding because of its adaptation to a wide range of climates. Climate-adaptive genes can be detected from associations between genotype, phenotype and climate but an integrated framework for the analysis of these three sources of information is lacking. We used two approaches to identify adaptive loci in perennial ryegrass and their effect on phenotypic traits. First, we combined Genome-Environment Association (GEA) and GWAS analyses. Then, we implemented a new test based on a Canonical Correlation Analysis (CANCOR) to detect adaptive loci. Furthermore, we improved the previous perennial ryegrass gene set by de novo gene prediction and functional annotation of 39,967 genes. GEA-GWAS revealed eight outlier loci associated with both environmental variables and phenotypic traits. CANCOR retrieved 633 outlier loci associated with two climatic gradients, characterized by cold-dry winter versus mild-wet winter and long rainy season versus long summer, and pointed out traits putatively conferring adaptation at the extremes of these gradients. Our CANCOR test also revealed the presence of both polygenic and oligogenic climatic adaptations. Our gene annotation revealed that 374 of the CANCOR outlier loci were positioned within or close to a gene. Co-association networks of outlier loci revealed a potential utility of CANCOR for investigating the interaction of genes involved in polygenic adaptations. The CANCOR test provides an integrated framework to analyse adaptive genomic diversity and phenotypic responses to environmental selection pressures that could be used to facilitate the adaptation of plant species to climate change.Randomized controlled trials (RCTs) are the gold standard for evaluation of the efficacy and safety of investigational interventions. If every patient in an RCT were to adhere to the randomized treatment, one could simply analyze the complete data to infer the treatment effect. However, intercurrent events (ICEs) including the use of concomitant medication for unsatisfactory efficacy, treatment discontinuation due to adverse events, or lack of efficacy may lead to interventions that deviate from the original treatment assignment. Therefore, defining the appropriate estimand (the appropriate parameter to be estimated) based on the primary objective of the study is critical prior to determining the statistical analysis method and analyzing the data. The International Council for Harmonisation (ICH) E9 (R1), adopted on November 20, 2019, provided five strategies to define the estimand treatment policy, hypothetical, composite variable, while on treatment, and principal stratum. In this article, we propose an estimand using a mix of strategies in handling ICEs. This estimand is an average of the "null" treatment difference for those with ICEs potentially related to safety and the treatment difference for the other patients if they would complete the assigned treatments. alphaNaphthoflavone Two examples from clinical trials evaluating antidiabetes treatments are provided to illustrate the estimation of this proposed estimand and to compare it with the estimates for estimands using hypothetical and treatment policy strategies in handling ICEs.LncRNA FOXD2-AS1 is abnormally expressed in many diseases. However, the molecular mechanisms whereby FOXD2-AS1 is involved in recurrent pterygium remain unknown. Here, qRT-PCR was performed to quantify FOXD2-AS1 expression, while CCK-8, flow cytometer and neoplasm xenograft assays were used to investigate its function. Dual-luciferase reporter, RIP and RNA pull-down assays were conducted to address the relationship between FOXD2-AS1, miR-205-5p and VEGF-A, while ChIP assays were used to detect H3K27 acetylation at the FOXD2-AS1 promoter. FOXD2-AS1 expression was up-regulated in recurrent pterygium tissues. Moreover, a high FOXD2-AS1 expression was associated with advanced stages, increased microvessel density and shorter recurrent-free survival. In addition, ROC analysis showed that FOXD2-AS1 is a valid predictor of recurrent pterygium. Furthermore, we show that FOXD2-AS1 induced proliferation and inhibited apoptosis in a cell line derived from recurrent pterygia (HPF-R) at least partially through the regulation of the miR-205-VEGF pathway. In addition, the up-regulation of FOXD2-AS1 was attributed to the H3K27 acetylation at the promoter region. In conclusion, FOXD2-AS1 is activated via its H3K27 acetylation and regulates VEGF-A expression by sponging miR-205-5p in recurrent pterygium. Our results may provide a basis for the development of new therapeutic targets and biomarkers for recurrent pterygium.DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti-PD-1/PD-L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti-PD-1/PD-L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum-based chemotherapy. DDR alterations (including ATM) were associated with a non-significantly higher ORR to PD-1/PD-L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non-significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20-1.38, p = 0.19). ATM alterations were associated with a non-significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65-19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD-1/PD-L1 blockade versus 24% ORR in patients with less then 3 DDR alterations. In summary, DDR alterations were associated with non-significantly higher ORR and longer OS for patients with advanced UC receiving anti-PD-1/PD-L1 agents. ATM alterations were associated with shorter OS.Osteogenesis imperfecta (OI) type VIII (OMIM 610915) is a rare autosomal recessive disorder characterized by white sclerae, severe growth deficiency, and bone fragility. This condition results from pathogenic variants of P3H1, a gene that codes for P3H1, an important protein involved in the prolyl-3-hydroxylation complex required for collagen type I folding. Here, we described a woman with OI type VIII due to a homozygous mutation of c.1914+1G>C (NM_001243246.1) in P3H1 and retinal detachment. We compared our case to five severe OI and retinal detachment cases reported in the literature. The only case previously reported with a molecular diagnosis had a similar mutation in P3H1 c.1914+1G>A and a giant retinal detachment. We suggest that individuals with OI type VIII should be submitted to careful fundoscopic examination.Skull surgery, also known as craniectomy, is done to treat trauma or brain diseases and may require the use of an implant to reestablish skull integrity. This study investigates the performance of 3D printed bone implants in a mouse model of craniectomy with the aim of making biodegradable porous implants that can ultimately be fitted to a patient's anatomy. A nonpolymeric thermoplastic bioink composed of fatty acids and β-tricalcium phosphate was used to 3D print the skull implants. Some of these were sintered to yield pure β-tricalcium phosphate implants. The performance of nonsintered and sintered implants was then compared in two semi-quantitative murine calvarial defect models using computed tomography, histology, and luciferase activity. Both types of implants were biocompatible, but only sintered implants promoted defect healing, with osseointegration to adjacent bone and the formation of new bone and bone marrow tissue in the implant pores. Luciferase scanning and histology showed that mesenchymal stem cells seeded onto the implants engraft and proliferate on the implants after implantation and contribute to forming bone.