Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have ...been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.
From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.
LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018).
This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.
This cross-sectional study evaluated cow comfort measures in free stall dairies across the United States as part of the National Animal Health Monitoring System's Dairy 2007 study. The study was ...conducted in 17 states and evaluations were completed between March 5 and September 5, 2007. Assessors recorded hygiene and hock scores, number of cows housed in the pen, the number of cows standing with only the front feet in a stall, standing fully in a stall, and lying in a stall. Facility design measures included bedding type, bedding quantity, stall length and width, presence of a neck rail or brisket locator, and relevant distances from the rear and bed of the stall. Of the 491 operations that completed the cow comfort assessment, 297 had Holstein cows housed in free stalls and were included in this analysis. Negative binomial models were constructed to evaluate the following outcomes: the number of cows that were very dirty, had severe hock injuries, stood with front feet in the stall, stood with all feet in the stall, and were lying in the stall. Hygiene was better on farms that did not tail dock cows compared with those that did (5.7 vs. 8.8% were dirty) and on farms located in the study's west region compared with those located in the east region (5.2 vs. 9.7% were dirty). Severe hock injuries were less common on farms in the west than those in the east (0.5 vs. 4.1%). In addition, severe hock injuries were less common on farms that used dirt as a stall base or sand as bedding compared with farms that did not. A higher percentage of cows was standing with front feet in the stall at higher ambient temperatures (incidence rate ratio=1.016) and as time since feeding increased (incidence rate ratio=1.030). A lower percentage of cows were standing with front feet in the stall when the stalls were shorter and when there were fewer cows per stall. Standing fully in a stall was performed by a higher percentage of cows during the summer than during the spring (13.6 vs. 8.1%), when cows were provided free stalls with rubber mats or mattresses, and as the distance from the rear curb to neck rail increased. A higher percentage of cows were lying in a stall when sand bedding was used, when bedding was added more frequently, and during the spring months. Results of this national survey indicate that tail docking provides no benefit to cow hygiene and that stall base and bedding are key factors influencing hock injuries and stall usage on US free stall dairy farms.
ABSTRACT
We place statistical constraints on Type Ia supernova (SN Ia) progenitors using 227 nebular-phase spectra of 111 SNe Ia. We find no evidence of stripped companion emission in any of the ...nebular-phase spectra. Upper limits are placed on the amount of mass that could go undetected in each spectrum using recent hydrodynamic simulations. With these null detections, we place an observational 3σ upper limit on the fraction of SNe Ia that are produced through the classical H-rich non-degenerate companion scenario of $\lt 5.5 {{\ \rm per\ cent}}$. Additionally, we set a tentative 3σ upper limit otan He star progenitor scenarios of $\lt 6.4 {{\ \rm per\ cent}}$, although further theoretical modelling is required. These limits refer to our most representative sample including normal, 91bg-like, 91T-like, and ‘super-Chandrasekhar’ SNe Ia but excluding SNe Iax and SNe Ia-CSM. As part of our analysis, we also derive a Nebular Phase Phillips Relation, which approximates the brightness of an SN Ia from 150 to 500 d after maximum using the peak magnitude and decline rate parameter Δm15(B).
Young adults living with episodic disabilities face unpredictable disruptions to their employment and health. Our study aimed to examine the impact of employment and income support interventions on ...the health and well-being of young adults living with episodic disabilities.
We conducted a systematic review of peer-reviewed intervention studies published in 2001-2021 in industrialized contexts. Two independent reviewers screened titles, abstracts and full-texts. We undertook a narrative synthesis of eligible articles.
Our search yielded 15 269 published articles, of which only five studies were eligible for evidence synthesis. All articles were appraised as being of medium quality. Four interventions focused on young adults living with mental health conditions. Two were based in clinical settings; three were based in community-based settings. Each employment intervention exhibited improvements in health outcomes. Three studies examined the impact of supported employment interventions that were particularly beneficial to improving work and health outcomes.
Involvement in employment interventions could provide benefits for the health of young adults living with episodic disabilities. Our systematic review highlights the need for research to elaborate on the ways in which employment interventions can impact the health and well-being of young adults living with different episodic disabilities.
Over half of US dairy operations use tie-stalls, but these farming systems have received relatively little research attention in terms of stall design and management. The current study tested the ...effects of the amount of 2 bedding materials, straw and shavings, on dairy cattle lying behavior. The effects of 4 levels of shavings, 3, 9, 15, and 24kg/stall (experiment 1, n=12), and high and low levels of straw in 2 separate experiments: 1, 3, 5, and 7kg/stall (experiment 2, n=12) and 0.5, 1, 2, and 3kg/stall (experiment 3, n=12) were assessed. Treatments were compared using a crossover design with lactating cows housed in tie-stalls fitted with mattresses. Treatments were applied for 1 wk. Total lying time, number of lying bouts, and the length of each lying bout was recorded with data loggers. In experiment 1, cows spent 3min more lying down for each additional kilogram of shavings (11.0, 11.7, 11.6, and 12.1±0.24 h/d for 3, 9, 15, and 24kg/stall shavings, respectively). In experiment 2, cows increased lying time by 12min for every additional kilogram of straw (11.2, 12.0, 11.8, and 12.4±0.24 h/d for 1, 3, 5, and 7kg/stall of straw, respectively). There were no differences in lying behavior among the lower levels of straw tested in experiment 3 (11.7±0.32 h/d). These results indicated that additional bedding above a scant amount improves cow comfort, as measured by lying time, likely because a well-bedded surface is more compressible.
Abstract We collect a sample of 42 Type Ia supernovae (SNe Ia) with Swift UV photometry and well-measured early time light-curve rises and find that 2002es-like and 2003fg-like SNe Ia have different ...prepeak UV color evolutions compared to normal SNe Ia and other spectroscopic subtypes. Specifically, 2002es-like and 2003fg-like SNe Ia are cleanly separated from other SNe Ia subtypes by UVM 2 − UVW 1 ≳ 1.0 mag at t = − 10 days relative to B -band maximum. Furthermore, the SNe Ia that exhibit nonmonotonic bumps in their rising light curves, to date, consist solely of 2002es-like and 2003fg-like SNe Ia. We also find that SNe Ia with two-component power-law rises are more luminous than SNe Ia with single-component power-law rises at prepeak epochs. Given the similar UV colors, along with other observational similarities, we discuss a possible progenitor scenario that places 2002es-like and 2003fg-like SNe Ia along a continuum and may explain the unique UV colors, early time bumps, and other observational similarities between these objects. Ultimately, further observations of both subtypes, especially in the near-infrared, are critical for constraining models of these peculiar thermonuclear explosions.
ABSTRACT
We present the discovery of ASASSN-18jd (AT 2018bcb), a luminous optical/ultraviolet(UV)/X-ray transient located in the nucleus of the galaxy 2MASX J22434289–1659083 at z = 0.1192. Over the ...year after discovery, Swift UltraViolet and Optical Telescope (UVOT) photometry shows the UV spectral energy distribution of the transient to be well modelled by a slowly shrinking blackbody with temperature $T \sim 2.5 \times 10^{4} \, {\rm K}$, a maximum observed luminosity of $L_{\rm max} = 4.5^{+0.6}_{-0.3}\times 10^{44} \, {\rm erg \,s}^{-1}$, and a radiated energy of $E = 9.6^{+1.1}_{-0.6} \times 10^{51} \, {\rm erg}$. X-ray data from Swift X-Ray Telescope (XRT) and XMM–Newton show a transient, variable X-ray flux with blackbody and power-law components that fade by nearly an order of magnitude over the following year. Optical spectra show strong, roughly constant broad Balmer emission and transient features attributable to He ii, N iii–v, O iii, and coronal Fe. While ASASSN-18jd shares similarities with tidal disruption events (TDEs), it is also similar to the newly discovered nuclear transients seen in quiescent galaxies and faint active galactic nuclei (AGNs).
Melanoma etiology: where are we? Tucker, Margaret A; Goldstein, Alisa M
Oncogene,
05/2003, Letnik:
22, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Melanoma incidence rates are rising rapidly, particularly in older men. Older men are also more likely to have thick melanomas, which confer high mortality and morbidity. The reasons for the rate of ...increase are not known; increasing sun and UV exposure, however, is the major hypothesized explanation. In the past several years, two major susceptibility genes for melanoma, CDKN2A and CDK4, have been identified, but the two genes together account for a minority of familial melanoma. Other high-risk susceptibility genes are being sought actively. Genetic epidemiologic studies suggest that penetrance of each of the two identified genes is altered by other factors, either genetic or environmental. Epidemiologic studies have also identified other major host factors important in the development of melanoma. In European, North American, and Australian populations, the presence of clinically identified dysplastic nevi confers greatly increased risk of melanoma. A new measure of sun exposure, based on individual residential history, confers substantially increased risk of melanoma. Recent surveys of sun behavior in the US reveal extensive sunburning and use of tanning beds in adolescents and adults. Sun protective behaviors are not as prevalent as in Australia, where population rates of melanoma are stabilizing.
Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for generating the majority of cellular ATP. Complex III (ubiquinol-cytochrome c oxidoreductase) is the third of five OXPHOS complexes. ...Complex III assembly relies on the coordinated expression of the mitochondrial and nuclear genomes, with 10 subunits encoded by nuclear DNA and one by mitochondrial DNA (mtDNA). Complex III deficiency is a debilitating and often fatal disorder that can arise from mutations in complex III subunit genes or one of three known complex III assembly factors. The molecular cause for complex III deficiency in about half of cases, however, is unknown and there are likely many complex III assembly factors yet to be identified. Here, we used Massively Parallel Sequencing to identify a homozygous splicing mutation in the gene encoding Ubiquinol-Cytochrome c Reductase Complex Assembly Factor 2 (UQCC2) in a consanguineous Lebanese patient displaying complex III deficiency, severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction. We prove causality of the mutation via lentiviral correction studies in patient fibroblasts. Sequence-profile based orthology prediction shows UQCC2 is an ortholog of the Saccharomyces cerevisiae complex III assembly factor, Cbp6p, although its sequence has diverged substantially. Co-purification studies show that UQCC2 interacts with UQCC1, the predicted ortholog of the Cbp6p binding partner, Cbp3p. Fibroblasts from the patient with UQCC2 mutations have deficiency of UQCC1, while UQCC1-depleted cells have reduced levels of UQCC2 and complex III. We show that UQCC1 binds the newly synthesized mtDNA-encoded cytochrome b subunit of complex III and that UQCC2 patient fibroblasts have specific defects in the synthesis or stability of cytochrome b. This work reveals a new cause for complex III deficiency that can assist future patient diagnosis, and provides insight into human complex III assembly by establishing that UQCC1 and UQCC2 are complex III assembly factors participating in cytochrome b biogenesis.
Intestinal hyperpermeability and subsequent immune activation alters nutrient partitioning and thus, decreases productivity. Developing experimental models of intestinal barrier dysfunction in heathy ...cows is a prerequisite in identifying nutritional strategies to mitigate it. Six cannulated Holstein cows (mean ± standard deviation, 37 ± 10 kg/d milk yield; 219 ± 97 d in milk; 691 ± 70 kg body weight) were used in a replicated 3 × 3 Latin square design experiment with 21-d periods (16-d wash-out and 5-d challenge) to evaluate either feed restriction or hindgut acidosis as potential models for inducing intestinal hyperpermeability. Cows were randomly assigned to treatment sequence within square and treatment sequences were balanced for carryover effects. Treatments during the challenge were (1) control (CTR; ad libitum feeding); (2) feed restriction (FR; total mixed ration fed at 50% of ad libitum feed intake); and (3) resistant starch (RS; 500 g of resistant starch infused in abomasum once a day as a pulse-dose 30 min before morning feeding). The RS (ActiStar RT 75330, Cargill Inc.) was tapioca starch that was expected to be resistant to enzymatic digestion in the small intestine and highly fermentable in the hindgut. Blood samples were collected 4 h after feeding on d 13 and 14 of the wash-out periods (baseline data used as covariate), and on d 1, 3, and 5 of the challenge periods. Fecal samples were collected 4 and 8 h after the morning feeding on d 14 of the wash-out periods and d 5 of the challenge periods. By design, FR decreased dry matter intake (48%) relative to CTR and RS, and this resulted in marked reductions in milk and 3.5% FCM yields over time, with the most pronounced decrease occurring on d 5 of the challenge (34 and 27%, respectively). Further, FR increased somatic cell count by 115% on d 5 of the challenge relative to CTR and RS. Overall, FR increased nonesterified fatty acids (159 vs. 79 mEq/L) and decreased BHB (8.5 vs. 11.2 mg/dL), but did not change circulating glucose relative to CTR. However, RS had no effect on production or metabolism metrics. Resistant starch decreased fecal pH 8 h after the morning feeding (6.26 vs. 6.81) relative to CTR and FR. Further, RS increased circulating lipopolysaccharide binding protein (4.26 vs. 2.74 µg/mL) compared with FR only on d 1 of the challenge. Resistant starch also increased Hp (1.52 vs. 0.48 µg/mL) compared with CTR, but only on d 5 of the challenge. However, neither RS or FR affected concentrations of serum amyloid A, IL1β, or circulating endotoxin compared with CTR. The lack of consistent responses in inflammatory biomarkers suggests that FR and RS did not meaningfully affect intestinal barrier function. Thus, future research evaluating the effects of hindgut acidosis and FR using more intense insults and direct metrics of intestinal barrier function is warranted.
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