Testosterone has been found to play important roles in men's sexual function. However, the effects of testosterone can be modulated by androgen receptor (AR) CAG repeat polymorphism. It could also ...contribute to the risk of erectile dysfunction (ED). The aim of this study is to evaluate the interaction of serum testosterone levels and AR CAG repeat polymorphism on the risk of ED in aging Taiwanese men. This cross‐sectional data of Taiwanese men older than 40 years were collected from a free health screening held between August 2010 and August 2011 in Kaohsiung city, Taiwan. All participants completed a health questionnaires included five‐item version of the International Index of Erectile Function (IIEF‐5) and the International Prostate Symptoms Score, received a detailed physical examination and provided 20 cm3 whole blood samples for biochemical and genetic evaluation. The IIEF‐5 was used to evaluate ED. Serum albumin, total testosterone (TT), and sex hormone‐binding globulin levels were measured. Free testosterone level was calculated. AR gene CAG repeat polymorphism was determined by direct sequencing. Finally, 478 men with the mean age of 55.7 ± 4.8 years were included. When TT levels were above 330 ng/dL, the effect of testosterone level on erectile function seemed to reach a plateau and a significantly negative correlation between AR CAG repeat length and the score of IIEF‐5 was found (r = −0.119, p = 0.034). After adjusting for other covariates, the longer AR CAG repeat length was still an independent risk factor for ED in subjects with TT above 330 ng/dL (p = 0.006), but not in TT of 330 ng/dL or below. In conclusion, both serum testosterone levels and AR CAG repeat polymorphism can influence erectile function concomitantly. In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing ED.
Traditional agro‐pastoral practices are more beneficial for biodiversity than intensified agricultural systems. Promotion of the growth of natural herbaceous vegetation in pastoral fields can enhance ...rodent populations and consequently influence ecological aspects of carnivores with rodent‐based diets, like prey consumption in the European wildcat (Felis silvestris). In this article, we investigated the effects of pastoral field extent, season and prey abundance on wildcat consumption of several prey species in the Cantabrian Mountains (NW Spain). Prey consumption in areas with presence of pastoral fields (even in low proportions) was dominated by profitable field‐dwelling rodent species such as Arvicola monticola. Consumption of Arvicola was not correlated with its abundance and was higher during summer and autumn. Apodemus dominated the wildcat diet in areas with higher forest proportion and far from pastoral fields, particularly during spring. Our results suggest that varying habitat use and seasonal changes in prey accessibility may determine wildcat prey consumption in pastoral landscapes. Our results can contribute to highlight the potential benefits of traditional and sustainable pastoral activities for the conservation of the European wildcat across its distribution range.
Promotion of growth of natural herbaceous vegetation in pastoral fields can enhance rodent populations and consequently influence ecological aspects of carnivores with rodent‐based diets, like prey consumption in the European wildcat (Felis silvestris). Prey consumption in areas with presence of pastoral fields (even in low proportions) was dominated by profitable field‐dwelling rodent species such as Arvicola monticola particularly during summer and autumn, whereas Apodemus dominated wildcat diet in areas with higher forest proportion and far from pastoral fields particularly during spring. Our results suggest that varying habitat use and seasonal changes in prey accessibility may determine wildcat prey consumption in pastoral landscapes and can contribute to highlight the potential benefits of traditional and sustainable pastoral activities for the conservation of the European wildcat across its distribution range.
Toll-like receptor 4 (TLR4) plays an essential role in mediating organ injury in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Herein, we assess whether inhibiting TLR4 ...signaling can ameliorate liver failure and serve as a potential treatment.
Circulating TLR4 ligands and hepatic TLR4 expression were measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo (10 mg/kg intraperitoneally) in rodent models of ACLF (bile duct ligation + lipopolysaccharide LPS; carbon tetrachloride + LPS) and ALF (galactosamine + LPS) and in vitro on immortalized human monocytes (THP-1) and hepatocytes (HHL5). The in vivo therapeutic effect was assessed by coma-free survival, organ injury and cytokine release and in vitro by measuring IL-6, IL-1β or cell injury (TUNEL), respectively.
In patients with cirrhosis, hepatic TLR4 expression was upregulated and circulating TLR4 ligands were increased (p <0.001). ACLF in rodents was associated with a switch from apoptotic cell death in ALF to non-apoptotic forms of cell death. TAK-242 reduced LPS-induced cytokine secretion and cell death (p = 0.002) in hepatocytes and monocytes in vitro. In rodent models of ACLF, TAK-242 administration improved coma-free survival, reduced the degree of hepatocyte cell death in the liver (p <0.001) and kidneys (p = 0.048) and reduced circulating cytokine levels (IL-1β, p <0.001). In a rodent model of ALF, TAK-242 prevented organ injury (p <0.001) and systemic inflammation (IL-1β, p <0.001).
This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF; its inhibition reduces the severity of organ injury and improves outcome. TAK-242 may be of therapeutic relevance in patients with liver failure.
Toll-like receptor 4 (or TLR4) mediates endotoxin-induced tissue injury in liver failure and cirrhosis. This receptor sensitizes cells to endotoxins, which are produced by gram-negative bacteria. Thus, inhibiting TLR4 signaling with an inhibitor (TAK-242) ameliorates organ injury and systemic inflammation in rodent models of acute and acute-on-chronic liver failure.
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•Cirrhosis is associated with TLR4-related sensitization to endotoxins and a switch from apoptotic to necroptotic cell death.•Inhibition of TLR4 signaling by TAK-242 reduces immune cell responses and hepatocyte injury in response to LPS in vitro.•In models of acute and acute-on-chronic liver failure, TAK-242 mitigated LPS-driven systemic inflammation and organ injury.
Abstract We report first-time reverberation-mapping results for 14 active galactic nuclei (AGNs) from the ongoing Monitoring AGNs with H β Asymmetry campaign (MAHA). These results utilize optical ...spectra obtained with the Long Slit Spectrograph on the Wyoming Infrared 2.3 m Telescope between 2017 November and 2023 May. MAHA combines long-duration monitoring with high cadence. We report results from multiple observing seasons for nine of the 14 objects. These results include H β time lags, supermassive black hole masses, and velocity-resolved time lags. The velocity-resolved lags allow us to investigate the kinematics of the broad-line region.
Erythro-myeloid progenitors of the yolk sac that originates during early embryo development has been suggested to generate tissue-resident macrophage, mast cell, and even endothelial cell populations ...from fetal to adult stages. However, the heterogeneity of erythro-myeloid progenitors (EMPs) is not well characterized. Here, we adapt single-cell RNA sequencing to dissect the heterogeneity of EMPs and establish several fate-mapping tools for each EMP subset to trace the contributions of different EMP subsets. We identify two primitive and one definitive EMP subsets from the yolk sac. In addition, we find that primitive EMPs are decoupled from definitive EMPs. Furthermore, we confirm that primitive and definitive EMPs give rise to microglia and other tissue-resident macrophages, respectively. In contrast, only Kit+ Csf1r− primitive EMPs generate endothelial cells transiently during early embryo development. Overall, our results delineate the contribution of yolk sac EMPs more clearly based on the single-cell RNA sequencing (scRNA-seq)-guided fate-mapping toolkit.
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•scRNA-seq profiles of early yolk sac identify primitive and definitive subsets of EMPs•Csf1r− pEMPs generate Csf1r+ pEMPs•Only Csf1r− pEMPs contribute to ECs transiently during early embryogenesis•pEMPs and dEMPs give rise to different tissue-resident macrophages
Zhao et al. found that Csf1r− pEMPs can differentiate into Csf1r+ pEMPs, and only Csf1r− pEMPs are responsible for transiently contributing to endothelial cells during early embryogenesis, suggesting that pEMPs and dEMPs give rise to distinct populations of tissue-resident macrophages.
Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these ...cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
Src tyrosine kinase (Src) is implicated in the development of bone metastasis and castration resistance of prostate cancer. Src inhibitors are currently being tested in clinical trials for such ...diseases. Understanding the molecular and cellular actions of Src inhibitors holds the key to future improvement of this line of therapy. Here we describe the microRNA expression profiles modulated by two Src inhibitors and demonstrate that the miR-30 family members are the most prominently induced species. Consistent with its tumor suppressor role, miR-30 is downmodulated by oncogenic signals such as epidermal growth factor (EGF) and hepatocyte growth factor, and is generally underexpressed in prostate cancer specimens. A number of epithelial-to-mesenchymal transition (EMT)-associated genes are predicted targets of miR-30. Among these genes the Ets-related gene (ERG) is the most frequently overexpressed oncogene in prostate cancer activated by genomic fusion events between promoter upstream sequences of the TMPRSS2 and coding sequences of ERG. We showed by ERG 3' untranslated region reporter and mutagenesis assays that ERG is a direct target of miR-30. Overexpression of miR-30 in prostate cancer cells suppresses EMT phenotypes and inhibits cell migration and invasion. It also inhibits the in vitro and in vivo growth of VCaP cells, which depends on TMPRSS2-ERG for proliferation. TMPRSS2-ERG is generally regulated by androgen at the transcriptional level. Our finding reveals a new post-transcriptional mechanism of TMPRSS2-ERG regulation by Src and growth signals via miR-30 providing a rationale for targeting ERG-positive castration-resistant tumors with Src inhibitors.
Sexually selected infanticides (SSI) committed by male bears during the mating season has attracted a great research attention, although this type of behavior has been rarely observed in the wild. ...Here, we document a bear infanticide attempt in the Cantabrian Mountains in which the male killed the adult female during the fight and, subsequently, consumed the carcass for several days. Interestingly, in this case, the bear male tried to reach the cub with the apparent intention of killing it, even though the female was already dead. We complement this observation with data on documented cases of SSI events between 1996 and 2020 in the Cantabrian Mountains. We hypothesize that when females are unintentionally killed while defending their cubs in SSI events, males can benefit by feeding on the carcasses.
Anisakiasis is an emerging zoonosis caused by the fish parasitic nematode Anisakis. Spain appears to have the highest reported incidence in Europe and marinated anchovies are recognised as the main ...food vehicle. Using data on fishery landings, fish infection rates and consumption habits of the Spanish population from questionnaires, we developed a quantitative risk assessment (QRA) model for the anchovy value chain. Spaniards were estimated to consume on average 0.66 Anisakis per untreated (non-frozen) raw or marinated anchovy meal. A dose-response relationship was generated and the probability of anisakiasis was calculated to be 9.56 × 10
per meal, and the number of annual anisakiasis cases requiring medical attention was predicted between 7,700 and 8,320. Monte Carlo simulations estimated post-mortem migration of Anisakis from viscera to flesh increases the disease burden by >1000% whilst an education campaign to freeze anchovy before consumption may reduce cases by 80%. However, most of the questionnaire respondents who ate untreated meals knew how to prevent Anisakis infection. The QRA suggests that previously reported figures of 500 anisakiasis per year in Europe is a considerable underestimate. The QRA tool can be used by policy makers and informs industry, health professionals and consumers about this underdiagnosed zoonosis.
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