Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within ...resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
Awareness of Human Immunodeficiency Virus (HIV) status improves health outcomes in children living with HIV, yet caregivers often delay disclosure. This qualitative investigation explored, through ...observation, how 30 caregivers responded to a HIV Disclosure study conducted between 2017 and 2020 at Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. Caregivers were assisted in disclosing to their children, aged 7-13 years; followed by a sub-sample of caregivers providing in-depth interviews to elaborate on findings.1) Barriers to disclosure included: caregivers being ill equipped, the fear of negative consequences and children considered lacking emotional or cognitive readiness. 2) Deflecting diagnosis from their children and the need for medication, motivated caregivers to disclosure. 3) Apprehension was evident during disclosure; however, overall disclosure was a positive experience with the support of the healthcare providers. These results highlight the significant role healthcare providers' play in supporting caregivers through the disclosure process.
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency ...have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage-gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory protein collapsin response mediator protein 2 (CRMP2) regulates activity of these channels, and also binds to the targeted C-terminus of neurofibromin in a tripartite complex, suggesting a possible mechanism underlying NF1 pain. Prevention of CRMP2 phosphorylation with (S)-lacosamide resulted in normalization of channel current densities, excitability, as well as of hyperalgesia following CRISPR/Cas9 truncation of neurofibromin. These studies reveal the protein partners that drive NF1 pain and suggest that CRMP2 is a key target for therapeutic intervention.
Purpose: To report the 1-year results of a multicenter study of peripheral artery disease (PAD) treatment with a variety of endovascular treatment strategies employed in routine practice. Materials ...and Methods: The LIBERTY trial (ClinicalTrials.gov identifier NCT01855412) is a prospective, observational, core laboratory–assessed, multicenter study of endovascular device intervention in 1204 subjects (mean age 69.8±10.7 years; 770 men) stratified by Rutherford category (RC): claudicants (RC2,3; n=501) and critical limb ischemia (CLI) with no/minimal tissue loss (RC4,5; n=603) or significant tissue loss (RC6; n=100). Key outcomes included quality of life (QoL) measures (VascuQol and EuroQol) and freedom from major adverse events (MAE), defined as death (within 30 days), major amputation, and target vessel revascularization based on Kaplan-Meier analysis. Results: Successful revascularization was beneficial, with RC improvement noted across all groups. Thirty-day freedom from MAE estimates were high across all groups: 99.2% in RC2,3, 96.1% in RC4,5, and 90.8% in RC6. At 12 months, the freedom from MAE was 82.6% in RC2,3, 73.2% in RC4,5, and 59.3% in RC6 patients. Estimates for freedom from major amputation at 12 months were 99.3%, 96.0%, and 81.7%, respectively. QoL scores improved significantly across all domains in all groups with 12-month VascuQol total scores of 5.3, 5.0, and 4.8 for RC2,3, RC4,5, and RC6, respectively. Conclusion: The results indicate that peripheral endovascular intervention is a viable treatment option for RC2,3, RC4,5, and RC6 patients as evidenced by the high freedom from major amputation, as well as the improvement in QoL and the RC at 12 months. Furthermore, primary unplanned amputation is often not necessary in RC6.
HIV type 1 (HIV-1) persists within resting CD4⁺ T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a ...mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10⁻⁴) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4⁺ T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4⁺ T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4⁺ T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.
In this study, raw grinded groundnut shell (RGGNS) was used as a fine aggregate in the brick industry to reuse agricultural waste in building materials. In this study, an experimental approach was ...used to examine a new cement brick with raw groundnut shells integrated with compressive strength, water absorption and dry density optimization utilizing response surface methodology (RSM). The raw ground-nut shell content improved the fine aggregate performance of the 40%, 50%, and 60% samples. The 28-day high compressive strength with the raw ground-nut shell was 6.1 N/mm
maximum, as needed by the technical standard. Samples made from 40%, 50%, and 60% raw groundnut shells yielded densities of 1.7, 2.2, and 1.9 kg/cm
for groundnut shell (GNS) brick, respectively. A product's mechanical properties meet the IS code standard's minimum requirements. RSM was then utilized to develop a model for the addition of raw groundnut shell to concrete. R-square and Adeq precision values indicated that the results are highly significant, and equations for predicting compressive strength, water absorption, and dry density have been developed. In addition, optimization was performed on the RSM findings to determine the efficiency optimization of the model. Following the optimization results, experiments were conducted to determine the applicability of the optimized model.
In pursuit of cleaner energy, this study explored the role of support materials in NiO's desulfurization capacity and selectivity in diesel fuel, thereby offering insight into sustainable fuel ...production. Nickel oxide (NiO) was loaded on different supports (activated carbon (AC), SiO
2
, Al
2
O
3
, and TiO
2
) for desulfurization. The adsorbent system was characterized using various techniques including FTIR, XRD, SEM, TPD-pyridine, TGA, and BET. At a low loading of approximately 5%NiO/support, the addition of NiO enhanced the adsorbent activity for all four supports at 30°C. However, increased NiO loading led to decreased adsorption activity due to agglomeration. The loading of NiO affected the selectivity of the adsorbents toward high molecular weight sulfur compounds differently. There was a decrease in selectivity for AC and Al
2
O
3
, a positive effect on SiO
2
, and no effect on TiO
2
. The positive effect on SiO
2
resulted from NiO-SiO
2
synergy. Additionally, NiO loading on SiO
2
reduced hydrocarbon adsorption, thereby improving overall relative selectivity. When real diesel was used, the addition of 5%NiO on SiO
2
and AC at a higher temperature (60°C) increased adsorption activity. This higher activity at elevated temperatures was attributed to poor adsorption of polyaromatic hydrocarbons and increased involvement of chemical-bonds. Lastly, all adsorption reactions were exothermic.
In The Nature-Study Idea, Liberty Hyde Bailey articulated the essence of a social movement, led by ordinary public-school teachers, that lifted education out of the classroom and placed it into ...firsthand contact with the natural world. The aim was simple but revolutionary: sympathy with nature to increase the joy of living and foster stewardship of the earth. With this definitive edition, John Linstrom reintroducesThe Nature-Study Idea as an environmental classic for our time. It provides historical context through a wealth of related writings, and introductory essays relate Bailey's vision to current work in education and the intersection of climate change and culture. In this period of planetary turmoil, Bailey's ambition to cultivate wonder (in adults as well as children) and lead readers back into the natural world is more important than ever.
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