We report 2 cases of melioidosis in women with diabetes admitted to an emergency department in the US Virgin Islands during October 2017. These cases emerged after Hurricanes Irma and Maria and did not have a definitively identified source. Poor outcomes were observed when septicemia and pulmonary involvement were present.

Thompson and Austin Moore prostheses have been commonly used in hemiarthroplasties for displaced femoral neck fractures. There has been considerable debate about which of these prostheses is preferred. The purpose of this meta-analysis was to compare historical data for clinical outcomes of cemented Thompson and uncemented Austin Moore hemiarthroplasty in displaced femoral neck fractures.

Recent revolutionary advancements in sequencing technologies have made it possible to obtain mass quantities of genome-scale sequence data in a cost-effective manner and have drastically altered molecular biological studies. To utilize these sequence data, genome-wide association studies (GWASs) have become increasingly important. Hence, there is an urgent need to develop a visualization tool that enables efficient data retrieval, integration of GWAS results with diverse information and rapid public release of such large-scale genotypic and phenotypic data. We developed a web-based genome browser TASUKE+ (https://tasuke.dna.affrc.go.jp/), which is equipped with the following functions: (i) interactive GWAS results visualization with genome resequencing data and annotation information, (ii) PCR primer design, (iii) phylogenetic tree reconstruction and (iv) data sharing via the web. GWAS results can be displayed in parallel with polymorphism data, read depths and annotation information in an interactive and scalable manner. Users can design PCR primers for polymorphic sites of interest. In addition, a molecular phylogenetic tree of any region can be reconstructed so that the overall relationship among the examined genomes can be understood intuitively at a glance. All functions are implemented through user-friendly web-based interfaces so that researchers can easily share data with collaborators in remote places without extensive bioinformatics knowledge.

Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.

Immune checkpoint inhibitors (ICIs) can elicit durable antitumor responses in patients with non-small cell lung cancer (NSCLC), but only 20% to 25% of patients respond to treatment. As important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. However, the prevalence of TP53 and ATM comutation and its association with response to ICIs are not fully understood.

Many disease resistance genes that have been transferred from wild relatives to cultivated wheat have played a significant role in wheat production worldwide. Ae. umbellulata is one of the species within the genus Aegilops that have been successfully used as sources of resistance genes to leaf rust, stem rust and powdery mildew. The objectives of the current work was to validate the map position of a major QTL that confers resistance to the stem rust pathogen races Ug99 (TTKSK) and TTTTF with an independent bi-parental mapping population and to refine the QTL region with a bulk segregant analysis approach. Two F2 bi-parental mapping populations were developed from stem rust resistant Ae. umbellulata accessions (PI 298905 and PI 5422375) and stem rust susceptible accessions (PI 542369 and PI 554395). Firstly, one of the two populations was used to map the chromosome location of the resistance gene. Later on, the 2nd population was used to validate the chromosome location in combination with a bulk segregant analysis approach. For the bulk segregant analysis, RNA was extracted from a bulk of leaf tissues of 12 homozygous resistant F3 families, and a separate bulk of 11 susceptible homozygous F3 families derived from the PI 5422375 and PI 554395 cross. The RNA samples of the two bulks and the two parents were sequenced for SNPs identification. Stem rust resistance QTL was validated on chromosome 2U of Ae. umbellulata in the same region in both populations. With bulk segregant analysis, the QTL position was delimited within 3.2 Mbp. Although there were a large number of genes in the orthologous region of the detected QTL on chromosome 2D of Ae. tauschii, we detected only two Ae. umbellulata NLR genes which can be considered as a potential candidate genes.

Dysregulation of the seven-transmembrane (7TM) receptor Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway contributes to the development of cancers including basal cell carcinoma (BCC) and medulloblastoma (MB). However, SMO-specific antagonists produced mixed results in clinical trials, marked by limited efficacy and high rate of acquired resistance in tumors. Here we discovered that Nilotinib, an approved inhibitor of several kinases, possesses an anti-Hh activity, at clinically achievable concentrations, due to direct binding to SMO and inhibition of SMO signaling. Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting growth of two Hh-dependent MB cell lines. It also reduced tumor growth in subcutaneous MB mouse xenograft model. These results indicate that in addition to its known activity against several tyrosine-kinase-mediated proliferative pathways, Nilotinib is a direct inhibitor of the Hh pathway. The newly discovered extension of Nilotinib's target profile holds promise for the treatment of Hh-dependent cancers.

To evaluate the association between alcohol intake and incident chronic kidney disease measures as well as the sex differences in this association, we analyzed health screening data of 14,190,878 adults who underwent health screening ≥3 times and had glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and normal proteinuria at baseline. eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration equation. Proteinuria was defined as ≥1+ dipstick proteinuria and low eGFR as <60 mL/min/1.73 m2. The risk of incident proteinuria and low eGFR was analyzed with an extended Cox model with alcohol intake level as a time-varying determinant and the annual change of eGFR with generalized linear model. A J-shape association of alcohol intake with the incident proteinuria was observed in men (adjusted hazard ratio [aHR], 0.961, 95% confidence interval [CI], 0.953-0.970 in men drinking alcohol <10 g/day; aHR 1.139, 95% CI, 1.123-1.154 in men drinking alcohol ≥40 g/day, compared with non-drinking men), and a positive association was seen in women (aHR, 1.034, 95% CI, 1.023-1.044 in women drinking alcohol <10 g/day; aHR, 1.094, 95% CI, 1.034-1.158 in women drinking alcohol ≥40 g/day, compared with non-drinking women). In both sexes, an inverse association of alcohol intake with the annual eGFR decline and incident low eGFR was observed. This study observed a beneficial effect of moderate alcohol intake on incident proteinuria in men and a protective effect of alcohol intake of any amount on the annual eGFR decline and incident low eGFR in both sexes. The long-term implications of these observations need to be elucidated with future studies.

Aeromonas bacteria can cause an infection characterized by septicemia and is one of the most common pathogens in tropical fish. This disease is responsible for high morbidity and mortality rates, causing considerable losses in aquaculture. Thus, the understanding of its pathophysiology is crucial to develop control strategies of this bacterial infection in farmed fish. This study aimed to characterize early pathological aspects of acute sepsis in pacu (Piaractus mesopotamicus) experimentally infected with Aeromonas hydrophila. A total of 160 juvenile pacus were inoculated intraperitoneally with A. hydrophila (1.78 x 109 CFU/mL) and at 0 (control), 1, 3, 6, and 9 hours post-inoculation (hpi), animals were anesthetized and samples were collected for microbiological, light microscopy and transmission electron microscopy (TEM) analyzes. The results showed the occurrence of hemodynamic alterations, such as hemorrhage and congestion, which were observed mainly after 6 and 9 hpi. It was possible to re-isolate Aeromonas at all sampling times except in control group. However, just after 9 hpi it was possible to find the bacteria in all fish and tissues. Light microscopy analyses revealed a degenerative process, necrosis and vascular damage mainly at 6 and 9 hpi. According to the ultrastructural examination, areas of cellular death were identified in all examined tissues, especially at 6 and 9 hpi. However, the most severe, related to necrosis, were observed after 6 and 9 hpi. The findings suggested that this bacterium spreads in the first hpi through the fish organs, mainly affecting spleen, liver and kidney, causing irreversible lesions at the molecular level.

Pigs are anatomically, genetically and physiologically comparable to humans and represent a natural host for influenza A virus (IAV) infections. Thus, pigs may represent a relevant biomedical model for human IAV infections. We set out to investigate the systemic as well as the local immune response in pigs upon two subsequent intranasal infections with IAV H1N1pdm09. We detected decreasing numbers of peripheral blood lymphocytes after the first infection. The simultaneous increase in the frequencies of proliferating cells correlated with an increase in infiltrating leukocytes in the lung. Enhanced perforin expression in αβ and γδ T cells in the respiratory tract indicated a cytotoxic T cell response restricted to the route of virus entry such as the nose, the lung and the bronchoalveolar lavage. Simultaneously, increasing frequencies of CD8αα expressing αβ T cells were observed rapidly after the first infection, which may have inhibited uncontrolled inflammation in the respiratory tract. Taking together, the results of this study demonstrate that experimental IAV infection in pigs mimics major characteristics of human seasonal IAV infections.

In studying the causative mechanisms behind migration and life history, the salmonids-salmon, trout, and charr-are an exemplary taxonomic group, as life history development is known to have a strong genetic component. A double inversion located on chromosome 5 in rainbow trout (Oncorhynchus mykiss) is associated with life history development in multiple populations, but the importance of this inversion has not been thoroughly tested in conjunction with other polymorphisms in the genome. To that end, we used a high-density SNP chip to genotype 192 F1 migratory and resident rainbow trout and focused our analyses to determine whether this inversion is important in life history development in a well-studied population of rainbow trout from Southeast Alaska. We identified 4,994 and 436 SNPs-predominantly outside of the inversion region-associated with life history development in the migrant and resident familial lines, respectively. Although F1 samples showed genomic patterns consistent with the double inversion on chromosome 5 (reduced observed and expected heterozygosity and an increase in linkage disequilibrium), we found no statistical association between the inversion and life history development. Progeny produced by crossing resident trout and progeny produced by crossing migrant trout both consisted of a mix of migrant and resident individuals, irrespective of the individuals' inversion haplotype on chromosome 5. This suggests that although the inversion is present at a low frequency, it is not strongly associated with migration as it is in populations of Oncorhynchus mykiss from lower latitudes.

The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development.

Previous studies suggest theory of mind (ToM) ability declines with age. However, prior tasks not only required ToM competence but also imposed high executive function (EF) demands, so decline in ToM ability could be caused by deterioration in ToM competence, EF, or both. It was predicted that if the elderly have intact ToM competence but compromised EF, then they should perform similarly to younger adults when using ToM tasks that lower executive demands, such as spontaneous-response tasks. Results showed that on tasks with reduced demands, older adults tracked belief to the same extent as younger adults, despite their declining EF. The findings support a model in which age-related decline in ToM ability is primarily caused by compromised EF, not ToM competence, suggesting that underlying ToM mechanisms are still intact in the elderly. We discuss implications of this work for competence-performance issues in ToM processing and the underlying sources of age-related deterioration of ToM.

Rezafungin is a novel echinocandin with excellent activity against common Candida species; however, limited data are available regarding rare Candida species.

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.

Laryngeal squamous cell carcinoma (LSCC) has been shown to respond to 17β-estradiol. However, the presence and characterization of estrogen receptors (ER) and other sex hormone receptors in LSCC are still being determined. Sex hormone receptors and the way sex hormones impact LSCC tumors are important for understanding which patients would benefit from hormone therapies, such as anti-estrogen therapies. This information also has prognostic value, as there may be a correlation between ER profiles and LSCC aggression. Recent work by our team and others has shown that the canonical ER, estrogen receptor α (ERα), and its splice variant ERα36, are important modulators of estrogen signaling in LSCC. This review describes some common 17β-estradiol signaling pathways, and explains how these signaling pathways might control LSCC tumor growth. We also show that loss of ERα, but not ERα36, imbues LSCC with enhanced aggression, a pattern which has previously only been observed in breast cancer. We make a case for using ERα as a tumorigenic modulator and pathogenic marker in LSCC on par with the use of ERα as a prognostic marker in breast cancer.

The aim of this study was to determine the role of microencapsulated olfactory ensheathing cells (MC-OECs) transplantation in rats with sciatic nerve injury-induced neuropathic pain, and its relationship with P2X4 receptor expression in the L4-5 spinal cord segment.

Prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and sustained increase of glucocorticoids have been evidenced in major depression and are related to changes involving neurotrophins and markers of oxidative stress in response to inflammation. This study aimed to evaluate central measures of brain-derived neurotrophic factor (BDNF), oxidative damage and total antioxidant capacity in rats submitted to chronic unpredictable mild stress (CUMS), as well as to investigate the relationship between BDNF levels and differentially processes. For this purpose, male Wistar rats were submitted to CUMS for six weeks. Based on a sucrose preference test (SPT), the animals were divided into anhedonic or non-anhedonic clusters. Afterwards, forced swim test (FST) and open field test (OFT) were performed, and the animals were euthanized. Brain tissue was collected, followed by quantification of oxidative damage, total antioxidant capacity and BDNF levels. Anhedonic behavior was evidenced in stress-susceptible animals through decreased sucrose preference. No differences were found in FST or OFT results. We observed increased BDNF levels in the hippocampus (HPC) of animals exposed to the CUMS protocol, accompanied by decreased total antioxidant capacity, despite the absence of oxidative damage to lipids and proteins. Moreover, we used a bioinformatics approach to identify proteins involved in oxidative stress and inflammation pathways, which were differentially expressed in anhedonic animals from other studies with similar experimental protocol. expressed proteins (DEP) involved in oxidative stress and inflammatory biological Anhedonic behavior was associated with peroxiredoxin-1 (PRDX-1) up-regulation and down-regulation of proteins involved with apoptotic and inflammation signaling (RELA, ASK-1 and TAK-1) in the HPC. Taken together, these data suggest that BDNF and PRDX-1 might be involved in initial stress response, playing a compensatory role by preventing oxidative damage to lipids and proteins through the modulation of antioxidant defense after CUMS in anhedonic animals.

The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and female AT2R knockout (KO) mice. When compared to the respective wild-type (WT) group, glycemia and insulinemia was unaltered in AT2RKO mice regardless of sex. However, female AT2RKO mice displayed decreased insulin sensitivity compared to their WT littermates. This was accompanied by a compensatory increase in adiponectinemia and with a specific attenuation of the activity of main insulin signaling components (insulin receptor, Akt and ERK1/2) in adipose tissue with no apparent alterations in insulin signaling in either liver or skeletal muscle. These parameters remained unaltered in male AT2RKO mice as compared to male WT mice. Present data show that the AT2R has a physiological role in the conservation of insulin action in female but not in male mice. Our results suggest a sexual dimorphism in the control of insulin action and glucose homeostasis by the AT2R and reinforce the notion that pharmacological modulation of the balance between the AT1R and AT2R receptor could be important for treatment of metabolic syndrome and type 2 diabetes.

Although conventional therapeutic approaches have brought remarkable advantages for the treatment of breast cancer (BC), drug-resistance still remains as a leading cause of tumor recurrence in this malignancy. In the present study, we designed experiments to evaluate the therapeutic value of PI3K inhibition in combination with Arsenic trioxide (ATO) in MCF-7 cells. The results of our study manifested that BKM120 sensitized MCF-7 cells to the lower concentrations of ATO. The significant anti-cancer effect of PI3K inhibition became even more evident when we found that BKM120, either as a single agent or in combination with ATO, reduced clonogenic ability of anoikis-resistant stem-like MCF-7 cells. Our findings also showed that BKM120 augmented ATO-induced anti-proliferative effects through inducing G1 arrest and reducing the incorporation of BrdU into the synthesized DNA of drugs-treated cells, which was coupled with c-Myc-mediated suppression of hTERT expression. Moreover, we found that in the presence of PI3K inhibitor, ATO is able to more profoundly induce apoptosis in MCF-7 cells, as revealed by the increment in the percentage of haplodiploid sub-G1 cells and the externalization of phosphatidylserine. Real-time PCR analysis also revealed that probably down-regulation of survivin coupled with up-regulation of forkhead family transcription factors is responsible for the enhancive effect of drugs in this cell line. Conclusively, this study shed lights on the effect of PI3K inhibition in chemo-sensitivity of MCF-7 cells, disclosing that combination of BKM120 and ATO could be a promising therapeutic approach in BC.