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The objective was to examine the effects of metabolizable protein (MP) and ruminal-protected methionine supplementation on growth performance of Holstein steer calves during the initial feedlot growing phase (112 d). One hundred eighty Holstein steer calves (122 ± 7 kg) were blocked by weight and assigned to 30 pens (6 steers per pen). Five treatments were applied: 1) control, a diet based on steam-flaked corn containing urea and dry distillers grains plus solubles as supplemental N sources with no amino acid addition; 2) control diet plus blood meal supplementation; 3) diet from treatment 2, with 0.064% Smartamine M (70% methionine; Adisseo, Alpharetta, GA) supplementation; 4) diet from treatment 2 with 0.096% Smartamine M supplementation; 5) diet from treatment 2 with 0.128% Smartamine M supplementation. All diets were formulated to exceed the estimated MP requirements. The estimated metabolizable lysine, as well as methionine, was deficient in the control diet. Blood meal was added to the control diet to meet estimated lysine requirements (diet 2), the other diets had increasing concentrations of supplemental methionine. Supplemental MP enhanced (10%, P  < 0.02) interim and overall 112-d average daily gain (ADG). Additional effects of supplemental methionine on ADG were not appreciable ( P  > 0.10). Supplemental MP did not affect ( P  > 0.10) dry matter intake (DMI) during the first 56-d period; however, it tended to increase ( P  = 0.08) DMI during the subsequent 56-d period. Overall, supplemental MP or methionine had no appreciable effect (P > 0.10) on DMI. Supplemental MP improved ( P  < 0.01) gain efficiency and estimated dietary net energy (NE) values during the initial 56-d period (11 and 7%, respectively) and overall (7 and 4%, respectively). Supplemental MP did not affect ( P  > 0.10) gain efficiency during the second 56-d period, although it tended to enhance ( P  = 0.08) estimated dietary NE. Supplemental methionine did not appreciably affect ( P  > 0.10) gain efficiency or estimated dietary NE. Therefore, adding MP to cover the estimated limiting amino acid supply in diets may enhance the gain efficiency and dietary energetics of growing Holstein calves. However, amino acid addition supplementation beyond the requirements may not produce extra productive performance of steer calves., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Biomarkers that provide insight into drivers of aging are needed for people with human immunodeficiency virus (PWH). The study objective was to determine if epigenetic age acceleration (EAA) markers are associated with physiologic frailty measured by the Veterans Aging Cohort Study (VACS) Index and predict all-cause mortality for PWH., Methods: Epigenome-wide DNA methylation was profiled in VACS total white blood cell samples collected during 2005-2007 from 531 PWH to generate 6 established markers of EAA. The association of each EAA marker was tested with VACS Index 2.0. All-cause mortality was assessed over 10 years. For each EAA marker, the hazard ratio per increased year was determined using Cox regression. To evaluate mortality discrimination, C-statistics were derived., Results: Participants were mostly men (98.5%) and non-Hispanic Black (84.4%), with a mean age of 52.4 years (standard deviation [SD], 7.8 years). Mean VACS Index score was 59.3 (SD, 16.4) and 136 deaths occurred over a median follow-up of 8.7 years. Grim age acceleration (AA), PhenoAA, HannumAA, and extrinsic epigenetic AA were associated with the VACS Index and mortality. HorvathAA and intrinsic epigenetic AA were not associated with either outcome. GrimAA had the greatest mortality discrimination among EAA markers and predicted mortality independently of the VACS Index. One-year increase in GrimAA was associated with a 1-point increase in VACS Index and a 10% increased hazard for mortality., Conclusions: The observed associations between EAA markers with physiologic frailty and mortality support future research to provide mechanistic insight into the accelerated aging process and inform interventions tailored to PWH for promoting increased healthspan., Competing Interests: Potential conflicts of interest. V. C. M. has received investigator-initiated research grants (paid to institution) and consulting fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences, and ViiV; grants or contracts from Gilead (for ACTT2, ACTT3, and ACTT4), ViiV (for DISCO and ASPIRE), and the Centers for Disease Control and Prevention, NIH, and Department of Veterans Affairs (other studies); honorarium in 2019 and support for attending meeting and/or travel from Eli Lilly (Ground Transportation 2019); participation on a data and safety monitoring board (DSMB) for IL-1b inhibitor study sponsored by the NIH and Novartis; and was the Study Section Chair for NIH. K. K. O. is the DSMB chair (1R01AG066562 from NIH, payment in-kind). K. S. reports grants or contracts from NIH. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery., Methods: We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan., Results: Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90., Conclusions: Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions., Clinical Trials Registration: NCT03011957.

Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and cardiovascular risk. We thus investigated the effects of testosterone administration on blood viscosity and erythrocyte deformability using mouse models. Blood viscosity, erythrocyte deformability, and hematocrits were measured in normal male and female mice, as well as in females and castrated males after short-term (2 wk) and long-term (5-7 mo) testosterone intervention (50 mg/kg, weekly). Castrated males for long-term intervention were studied in parallel with the normal males to assess the effect of long-term testosterone deprivation. An additional short-term intervention study was conducted in females with a lower testosterone dose (5 mg/kg). Our results indicate no rheological difference among normal males, females, and castrated males at steady-state. Short-term high-dose testosterone increased hematocrit and whole-blood viscosity in both females and castrated males. This effect diminished after long-term treatment, in association with increased erythrocyte deformability in the testosterone-treated mice, suggesting the presence of adaptive mechanism. Considering that cardiovascular events in human trials are seen early after intervention, rheological changes as potential mediator of vascular events warrant further investigation.

Objectives: To evaluate the correlations of the combination of undetectable HIV-DNA (<10 copies/10(6) peripheral blood mononuclear cells) and HIV-RNA (<1 copy/mL of plasma) levels and a CD4 cell count of >500 cells/mm(3) (defined as the treatment goal) in a group of 420 antiretroviral treatment (ART) responder patients., Methods: A cross-sectional, open-label, multicentre trial was conducted in a cohort of 420 HIV-infected ART-treated subjects with viral loads persistently <50 copies/mL for a median observation time of 28.8 months. HIV-DNA and residual viraemia values and demographic, virological and immunological data were collected for each subject., Results: Undetectable HIV-DNA was found in 16.6% (70/420) of patients and was significantly correlated with undetectable (<1 copy/mL) plasma viraemia (P = 0.0001). Higher CD4 cell count nadir (P < 0.001), a lower HIV-RNA viraemia at the start of treatment (P = 0.0016) and nevirapine use (P < 0.001) were correlated with an undetectable value of HIV-RNA. Twenty-six out of 420 patients (6.2%) reached the treatment goal. In multivariate analysis, higher nadir CD4 cell count (OR 3.86, 95% CI 1.47-10.16, P = 0.006), the duration of therapy (OR 1.07, 95% CI 1.02-1.12, P = 0.004) and the use of nevirapine (OR 2.59, 95% CI 1.07-6.28, P = 0.034) were independently related to this condition., Conclusions: Only 6.2% of ART-responder patients presented the combination of three laboratory markers that identified them as full responders. These results indicate the high variability of the ART-responding population and lead us to suggest caution in the selection of patients for possible simplification regimens.

The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. We report the capacity for HIV reactivation by a selective small molecule inhibitor of BET family bromodomains, JQ1, a promising therapeutic agent with antioncogenic properties. JQ1 reactivated HIV transcription in models of latent T cell infection and latent monocyte infection. We also tested the effect of exposure to JQ1 to allow recovery of replication-competent HIV from pools of resting CD4(+) T cells isolated from HIV-infected, ART-treated patients. In one of three patients, JQ1 allowed recovery of virus at a frequency above unstimulated conditions. JQ1 potently suppressed T cell proliferation with minimal cytotoxic effect. Transcriptional profiling of T cells with JQ1 showed potent down-regulation of T cell activation genes, including CD3, CD28, and CXCR4, similar to HDAC inhibitors, but JQ1 also showed potent up-regulation of chromatin modification genes, including SIRT1, HDAC6, and multiple lysine demethylases (KDMs). Thus, JQ1 reactivates HIV-1 while suppressing T cell activation genes and up-regulating histone modification genes predicted to favor increased Tat activity. Thus, JQ1 may be useful in studies of potentially novel mechanisms for transcriptional control as well as in translational efforts to identify therapeutic molecules to achieve viral eradication.

Background: Infants of human immunodeficiency virus (HIV)-infected women have high mortality, but the immunologic integrity and protection afforded by the breast milk of HIV-infected women is unknown., Methods: We determined morbidity and mortality by 24 months among breast-fed infants of 588 HIV-infected and 137 HIV-uninfected women followed-up in a clinical trial in Botswana. A matched case-control study compared clinical, behavioral, and breast milk immunologic parameters among 120 HIV-infected women by infant outcome. Breast milk factors were also compared between HIV-infected and HIV-uninfected women., Results: Twenty-four-month mortality was 29.5% among HIV-infected infants, 6.7% among HIV-exposed uninfected infants, and 1.6% among HIV-unexposed infants. No differences were detected in breast milk immunologic profiles of HIV-infected women whose infants were either ill or well. Discontinuation of breast-feeding was the strongest predictor of illness (P<.001). Levels in breast milk of pathogen-specific immunoglobulin (Ig) G and IgA to Haemophilus influenzae, Campylobacter jejuni, Helicobacter pylori, Streptococcus pneumoniae, and innate immune factors were not lower among HIV-infected women than among HIV-uninfected women., Conclusions: Mortality was higher among HIV-infected and HIV-exposed infants than among HIV-unexposed infants. However, the immunologic profiles of breast milk among HIV-infected women were intact, and discontinuation of breast-feeding was the primary risk for infant morbidity. Thus, the breast milk of HIV-infected women may confer protection against common infant pathogens., Trial Registration: (ClinicalTrials.Gov) identifiers: NCT00197691 and NCT00197652.

Context: HIV-associated wasting and weight loss remain clinically significant concerns even in the era of potent antiretroviral therapy. Although androgen treatment increases muscle mass, the cell-intrinsic mechanisms engaged remain poorly understood., Objective: This study was an unbiased approach to identify expression profiles associated with testosterone treatment using genome-wide microarray analysis of skeletal muscle biopsies., Design, Setting, and Participants: Forty-four HIV-positive men with weight loss were randomized to receive either 300 mg testosterone enanthate or placebo injections im weekly for 16 wk. Muscle biopsies were obtained at baseline and on treatment d 14. A subset of specimens was chosen for microarray analysis, with changes in selected genes confirmed by real-time PCR, Western blot analysis, and in vitro culture of muscle precursor cells., Results: Significantly greater gains in body mass (+2.05 and -1.07 kg, respectively; P = 0.003) and lean body mass by dual-energy x-ray absorptiometry (2.93 vs. 0.35 kg, respectively; P = 0.003) were observed in subjects treated with testosterone compared with placebo. Microarray analysis revealed up-regulation in genes involved in myogenesis and muscle protein synthesis, immune regulation, metabolic pathways, and chromatin remodeling. Representative genes were confirmed by real-time PCR and protein expression studies. In an independent analysis, gene networks that differentiate healthy young men from older men with sarcopenia had substantial overlap with those activated by testosterone treatment., Conclusions: These data provide new insights into the mechanisms of androgen action and have implications for both development of muscle biomarkers and anabolic therapies for wasting and sarcopenia.

Maternal plasma human immunodeficiency virus (HIV) type 1 RNA load has a role in perinatal transmission, but significant overlap in the range of plasma virus loads among transmitters and nontransmitters is often observed, which makes it difficult to predict transmission outcome. We measured several virus markers in a drug-naive population of HIV-1-infected mothers in Botswana. Maternal plasma HIV-1 RNA load, peripheral blood mononuclear cell-associated blood HIV-1 DNA load, and cervicovaginal fluid (CVF) HIV-1 DNA load were determined using quantitative real-time polymerase chain reaction. The overall rate of transmission among these mother-infant pairs was 35.7%. Median infant age was 2.5 months. An association between increased plasma HIV-1 RNA load and perinatal transmission was observed (odds ratio [OR], 2.20/1-log virus load; 95% confidence interval [CI], 1.15-4.18). However, the association between increased blood HIV-1 DNA load and perinatal transmission was stronger (OR, 10.30; 95% CI, 2.11-50.38). When blood HIV-1 DNA load was combined with CVF HIV-1 DNA load, the association with transmission increased (OR, 25.0; 95% CI 2.73-228.60).

The human immunodeficiency virus type 1 (HIV-1) epidemic within southern Africa is predominantly associated with the HIV-1C subtype. Functional analysis of the enhancer region within the long terminal repeat (LTR) indicates that HIV-1C isolates have >/=3 NF-kappaB binding sites, unlike other subtypes, which have only 1 or 2 sites. A correlation was shown between NF-kappaB enhancer configuration and responsiveness to the proinflammatory cytokine tumor necrosis factor (TNF)-alpha within the context of naturally occurring subtype LTRs, subtype-specific NF-kappaB enhancer regions cloned upstream of an isogenic HXB2 core promoter or a heterologous SV40 minimal promoter, and full-genome subtype clones. In all cases, TNF-alpha activation was correlated with the subtype configuration of the NF-kappaB enhancer. Whether the naturally occurring gain-of-function in the NF-kappaB enhancer of HIV-1C observed in this study can provide a selective advantage for the virus in vivo remains to be determined and warrants further study.

At least 10 different genetic human immunodeficiency virus type 1 (HIV-1) subtypes (A-J) are responsible for the AIDS pandemic. Much of the understanding of HIV-1 disease progression derives from studies in the developed world where HIV infection is almost exclusively subtype B. This has led many to question whether the properties and consequences of HIV-1 infection can be generalized across subtypes that afflict the majority of infected persons in the developing world. From 1985 to 1997, a prospective study of registered female sex workers in Senegal tracked the introduction and spread of HIV-1 subtypes A, C, D, and G. In clinical follow-up, the AIDS-free survival curves differed by HIV-1 subtype. Women infected with a non-A subtype were 8 times more likely to develop AIDS than were those infected with subtype A (hazard ratio=8.23; P=. 009), the predominant subtype in the study. These data suggest that HIV-1 subtypes may differ in rates of progression to AIDS.

Circulating estradiol is assumed not to contribute to sexual differentiation of the brain or other estrogen target tissues. The only estradiol available for binding to estrogen receptors is thought to be produced within brain cells by the aromatization of testosterone to estradiol as part of the action of androgen in the brain. However, we report that the concentration of free, biologically active serum estradiol (the concentration not bound to plasma proteins) was 0.54-2.17 pg/ml during the fetal and early neonatal period of sexual differentiation. These values were within the same concentration range for free estradiol observed in adult female rats throughout the estrous cycle (diestrus = 0.53 pg/ml; proestrus = 2.26 pg/ml), and estradiol clearly has physiological effects during diestrus as well as proestrus in adult females. When a stable, physiological blood concentration of [3H]estradiol of 49 pg/ml total (0.61 pg/ml free) was achieved with Silastic capsules in 2-day-old female pups, [3H]estradiol was recovered specifically bound to brain cell nuclei at approximately 2.7 fmol per pup brain or 12.4 fmol/mg DNA. The finding of brain uptake of circulating estradiol is contrary to current hypotheses. These findings suggest that estradiol in the fetal and neonatal circulation may be able to interact with testosterone and its metabolites to regulate sexual differentiation of the brain and other estrogen target tissues.