An understanding of the relationship between radio-loud active galaxies and their large-scale environments is essential for realistic modelling of radio-galaxy evolution and environmental impact, for ...understanding AGN triggering and life cycles, and for calibrating galaxy feedback in cosmological models. We use the LOFAR Two-Metre Sky Survey (LoTSS) Data Release 1 catalogues to investigate this relationship. We cross-matched a sample of 8745 radio-loud AGN with 0.08 < z < 0.4, selected from LoTSS, with two Sloan Digital Sky Survey (SDSS) cluster catalogues, and find that only 10 percent of LoTSS AGN in this redshift range have a high-probability association, so that the majority of low-redshift AGN (including a substantial fraction of the most radio-luminous objects) must inhabit haloes with M < 1014 M⊙. We find that the probability of a cluster association, and the richness of the associated cluster, is correlated with AGN radio luminosity, and we also find that, for the cluster population, the number of associated AGN and the radio luminosity of the brightest associated AGN is richness-dependent. We demonstrate that these relations are not driven solely by host-galaxy stellar mass, supporting models in which large-scale environment is influential in driving AGN jet activity in the local Universe. At the lowest radio luminosities we find that the minority of objects with a cluster association are located at larger mean cluster-centre distances than more luminous AGN, an effect that appears to be driven primarily by host-galaxy mass. Finally, we also find that FRI radio galaxies inhabit systematically richer environments than FRIIs, consistent with previous work. The work presented here demonstrates the potential of LoTSS for AGN environmental studies. In future, the full northern-sky LoTSS catalogue, together with the use of deeper optical/IR imaging data and spectroscopic follow-up with WEAVE-LOFAR, will provide opportunities to extend this type of work to much larger samples and higher redshifts.
Tail docking is a controversial practice in the dairy industry. Proponents claim that tail docking keeps the udder cleaner, and therefore improves milk quality and decreases somatic cell count. ...Opponents of tail docking cite that it causes unnecessary pain, backed by multiple studies that demonstrate no positive benefits of tail docking and that tail docking increases aggravation from flies. The objective of this study was to evaluate and compare cow cleanliness, fly population, and fly-avoidance behaviors among cows with docked, switch-trimmed, and switch-intact tails. A total of 206 cows from 3 Kentucky dairy herds were included in the longitudinal observational study. Each farm included previously docked cows, switch-intact cows, and cows whose switches were trimmed at the initial farm visit. Researchers visited each farm every 2 wk for 8 wk to record cow cleanliness, teat cleanliness, fly population, and fly-avoidance behavior scores. No significant differences were found in cow cleanliness scores, teat cleanliness scores, fly population scores, skin twitching, or foot stomping counts among docked, switch-trimmed, or switch-intact cows. Although the fly population scores did not differ, the amount of tail swings among docked, switch-intact, and switch-trimmed cows were significantly different. The odds of exhibiting tail swinging were 2.63 times greater for docked cows than for switch-trimmed cows and 1.92 times greater than for switch-intact cows. Overall, switch trimming resulted in similar outcomes to tail docking, although neither showed improvements over intact tails.
COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian ...study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time.
Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the Mann–Whitney U test for continuous variables.
A slight reduction (−6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop −12% versus −3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36).
Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.
•The COVID-19 outbreak had an impact on access to lung cancer (LC) diagnosis and treatment.•A slight reduction (−6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019.•Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease.•The Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.•A reverse migration from high-volume to low-volume cancer centers was noted during the pandemic.
Two central issues in polyglutamine-induced neurodegeneration are the influence of the normal function of the disease protein and modulation by protein quality control pathways. By using
Drosophila, ...we now directly link host protein function and disease pathogenesis to ubiquitin pathways in the polyglutamine disease spinocerebellar ataxia type 3 (SCA3). Normal human ataxin-3—a polyubiquitin binding protein with ubiquitin protease activity—is a striking suppressor of polyglutamine neurodegeneration in vivo. This suppressor activity requires ubiquitin-associated activities of the protein and is dependent upon proteasome function. Our results highlight the critical importance of host protein function in SCA3 disease and a potential therapeutic role of ataxin-3 activity for polyglutamine disorders.
Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body ...weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss.
Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central ...hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.
To determine whether longterm therapy (up to 1 year) with the weakly androgenic adrenal steroid dehydroepiandrosterone (DHEA) is feasible and beneficial in patients with mild to moderate systemic ...lupus erythematosus (SLE).
In a prospective, open label, uncontrolled longitudinal study 50 female patients (37 premenopausal, 13 postmenopausal) with mild to moderate SLE were treated with oral DHEA 50-200 mg/day.
DHEA therapy was associated with increases in the serum levels of DHEA, DHEA sulfate, and testosterone and, for those patients who continued DHEA, with decreasing disease activity measured by SLE Disease Activity Index score (p < 0.01), patient global assessment (p < 0.01), and physician global assessment (p < 0.05), compared to baseline. Concurrent prednisone doses were reduced (p < 0.05). These improvements were sustained over the entire treatment period. Thirty-four patients (68%) completed 6 months of treatment and 21 patients (42%) completed 12 months. Mild acneiform dermatitis was the most common adverse event (54%). Pre and postmenopausal women experienced similar efficacy and adverse effects from DHEA.
DHEA was well tolerated and appeared clinically beneficial, with the benefits sustained for at least one year in those patients who maintained therapy.
Acquired autoantibodies against coagulation factors (acquired haemophilia) frequently constitute a life-threatening bleeding situation requiring a prompt therapeutic intervention, including control ...of bleeding and secondarily an attempt of eradication of the inhibitor by prolonged immunosuppressive therapy. The combination of oral corticosteroids and cyplophosphamide seems to be effective to eradicate the autoantibody, but some patients may be resistant. Another therapeutic approach, recently described, observes treatment with the chimeric anti-CD20 monoclonal antibody rituximab. We report two consecutively treated patients whose acquired FVIII inhibitors did not respond to standard immunosuppressive regimens, and only when rituximab was added to therapy, complete response and prolonged remission were obtained.
Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a ...receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance.
In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m
every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety.
A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively.
Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.
The presence of 10 virulence genes was examined using polymerase chain reaction (PCR) in 365 European O157 and non-O157 Escherichia coli isolates associated with verotoxin production. Strain-specific ...PCR data were analysed using hierarchical clustering. The resulting dendrogram clearly separated O157 from non-O157 strains. The former clustered typical high-risk seropathotype (SPT) A strains from all regions, including Sweden and Spain, which were homogenous by Cramer's V statistic, and strains with less typical O157 features mostly from Hungary. The non-O157 strains divided into a high-risk SPTB harbouring O26, O111 and O103 strains, a group pathogenic to pigs, and a group with few virulence genes other than for verotoxin. The data demonstrate SPT designation and selected PCR separated verotoxigenic E. coli of high and low risk to humans; although more virulence genes or pulsed-field gel electrophoresis will need to be included to separate high-risk strains further for epidemiological tracing.
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