Impacts of Stocking Density on Development and Puberty Attainment of Replacement Beef Heifers

The following experiment presented herein compared growth, physical activity, stress-related responses, and puberty attainment in heifers reared on high- (HIDENS) or low-stocking densities (LOWDENS). Sixty Angus x Hereford heifers were ranked by age and BW (210 ± 2 d and 220 ± 2 kg, respectively) on d 0, and assigned to: a) 1 of 3 drylot pens (10 × 14 m pens; 10 heifers/pen) resulting in a stocking density of 14 m²/heifer (HIDENS; n = 3), or b) 1 of 3 pastures (25-ha pastures; 10 heifers/pasture), resulting in a stocking density of 25,000 m²/heifer (LOWDENS; n = 3). Pastures utilized herein were harvested for hay prior to the beginning of this experiment, and negligible forage was available for grazing to LOWDENS heifers throughout the experimental period (d 0 to 182). Heifers received the same limit-fed diet during the experiment, which averaged (DM basis) 4.0 kg/heifer daily of alfalfa-grass hay and 3.0 kg/heifer daily of a corn-based concentrate. Heifer shrunk BW was recorded after 16 h of feed and water withdrawal on d -3 and d 183 for ADG calculation. On d 0, heifers were fitted with a pedometer fixed behind their right shoulder. Each week during the experiment, pedometer results were recorded and blood samples were collected for puberty evaluation via plasma progesterone. Plasma samples collected on d 0, 28, 56, 84, 112, 140, 161, and 182 were also analyzed for concentrations of cortisol and IGF-I. On d 28, 102, and 175, blood samples were also collected for RNA isolation and analysis of heat shock protein (HSP) 70 and HSP72 mRNA expression. On d 0, 49, 98, 147, and 182, hair samples were collected from the tail switch for analysis of hair cortisol concentrations. No treatment effects were detected (P = 0.66) for heifer BW or ADG. Heifers from LOWDENS had more (P < 0.01) steps/week compared with HIDENS. Heifers from LOWDENS had greater (P = 0.05) mRNA expression of HSP72, and tended (P = 0.10) to have greater mRNA expression of HSP70 compared with HIDENS. Plasma concentrations of cortisol and IGF-I were often greater (P ≤ 0.05) in LOWDENS vs. HIDENS heifers (treatment × day interaction; P < 0.01). Hair cortisol concentrations were greater (P < 0.01) for HIDENS vs. LOWDENS heifers beginning on d 98 (treatment × day interaction; P < 0.01). Heifers from HIDENS experienced delayed puberty attainment and had a lower (P < 0.01) proportion of pubertal heifers on d 182 compared with LOWDENS (treatment × day interaction; P < 0.01). In summary, HIDENS negatively impacted heifer stress-related and physiological responses, and delayed puberty attainment compared with LOWDENS

The impact of coronavirus disease 2019 on genitourinary and prostate cancer care and clinical trials: a qualitative exploration of the Australian and New Zealand experience.

Abstract: Purpose: This qualitative study aimed to understand the impact of the coronavirus disease 2019 pandemic from March to November 2020 on healthcare delivery and clinical trials for genitourinary (GU) cancers in Australia. Methods: Annually a pre‐conference workshop is hosted by the Australian New Zealand Urogenital and Prostate Cancer Trials Group for supportive care health professionals. In November 2020, those that selected to attend were invited to participate in a focus group. Workshop and focus group discussions were recorded and transcripts were analyzed thematically. Results: Seventy‐two individuals involved in GU cancer care and clinical trials took part. Participants described negative changes to GU cancer care and clinical trials from the pandemic due to reduced clinical services and increased wait times. Trial recruitment was paused temporarily during lockdowns, and standard treatment protocols were used to limit hospital visits. Trial process changes included electronic capture of informed consent, home delivery of oral medications, and delegations of assessments. These changes increased administrative activity for clinical trial teams and Human Research Ethics Committees. A transition to telehealth enabled continuity of service delivery and trials but reduced the opportunity for face‐to‐face patient consultations with increasing concern about the failure to detect supportive care needs. Conclusion: The pandemic has prompted a critical review of service delivery and clinical trials for people with GU cancers

Imbalance-Aware Machine Learning for Predicting Rare and Common Disease-Associated Non-Coding Variants

Disease and trait-associated variants represent a tiny minority of all known genetic variation, and therefore there is necessarily an imbalance between the small set of available disease-associated and the much larger set of non-deleterious genomic variation, especially in non-coding regulatory regions of human genome. Machine Learning (ML) methods for predicting disease-associated non-coding variants are faced with a chicken and egg problem - such variants cannot be easily found without ML, but ML cannot begin to be effective until a sufficient number of instances have been found. Most of state-of-the-art ML-based methods do not adopt specific imbalance-aware learning techniques to deal with imbalanced data that naturally arise in several genome-wide variant scoring problems, thus resulting in a significant reduction of sensitivity and precision. We present a novel method that adopts imbalance-aware learning strategies based on resampling techniques and a hyper-ensemble approach that outperforms state-of-the-art methods in two different contexts: the prediction of non-coding variants associated with Mendelian and with complex diseases. We show that imbalance-aware ML is a key issue for the design of robust and accurate prediction algorithms and we provide a method and an easy-to-use software tool that can be effectively applied to this challenging prediction task

Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility

Release of cytokines, growth factors and other life-essential molecules from precursors by a-disintegrin-and-metalloproteases (ADAMs) is regulated with high substrate-specificity. We hypothesized that this is achieved by cleavage-regulatory intracellular-domain (ICD)-modifications of the precursors. We show here that cleavage-stimuli-induced specific ICD-modifications cause structural substrate changes that enhance ectodomain sensitivity of neuregulin-1 (NRG1; epidermal-growth-factor) or CD44 (receptor-tyrosine-kinase (RTK) co-receptor) to chymotrypsin/trypsin or soluble ADAM. This inside-out signal transfer required substrate homodimerization and was prevented by cleavage-inhibitory ICD-mutations. In chimeras, regulation could be conferred to a foreign ectodomain, suggesting a common higher-order structure. We predict that substrate-specific protease-accessibility-regulation controls release of numerous ADAM substrates

Viability and Burden of Leishmania in Extralesional Sites during Human Dermal Leishmaniasis

Understanding of the dynamics and distribution of Leishmania in the human host is fundamental to the targeting of control measures and their evaluation. Amplification of parasite gene sequences in clinical samples from cutaneous leishmaniasis patients has provided evidence of Leishmania in blood, other tissues and sites distinct from the lesion and of persistence of infection after clinical resolution of disease. However, there is uncertainty about the interpretation of the presence of Leishmania DNA as indicative of viable parasites. Because RNA is short-lived and labile, its presence provides an indicator of viability. We amplified Leishmania 7SLRNA, a molecule involved in intracellular protein translocation, to establish viability and estimate parasite load in blood monocytes, tonsil swab samples, and tissue fluid from healthy skin of patients with dermal leishmaniasis. Results showed that during active dermal leishmaniasis, viable Leishmania are present in blood monocytes, tonsils and normal skin in quantities similar to that in lesions, demonstrating widespread dissemination of infection and subclinical involvement of tissues beyond the lesion site. Leishmania 7SLRNA will be useful in deciphering the role of human infection in transmission

Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders

Context Many different inherited and acquired conditions can result in premature bone fragility / low bone mass disorders (LBMD). Objective We aimed at elucidating the impact of genetic testing on differential diagnosis of adult LBMD and at defining clinical criteria for predicting monogenic forms. Methods Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score 2), and a high normal BMI. In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD, e.g. in LRP5, were overrepresented. Conclusion The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield