Peroxidases are a group of heterogeneous family of enzyme that plays diverse biological functions. Ascorbate peroxidase is a redox enzyme that is reduced by trypanothione, which plays a central role in the redox defence system of Leishmania. In view of developing new and novel therapeutics, we have performed in silico studies in order to search for ligand library and identification of new drug candidates and its physiological role against promastigotes and intracellular amastigotes of Leishmania donovani. Our results demonstrated that the selected inhibitor ZINC96021026 has significant anti-leishmanial effect and effectively killed both free and intracellular forms of the parasite. ZINC96021026 was found to be identical to ML-240, a selective inhibitor of Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family which was derived from the scaffold of DBeQ, targeting the D2-ATPase domain of the enzyme. ZINC96021026 (ML-240) thus have broad range of cellular functions, thought to be derived from its ability to unfold proteins or disassemble protein complexes besides inhibiting the ascorbate peroxidase activity. ML-240 may inhibits the parasite's ascorbate peroxidase leading to extensive apoptosis and inducing generation of reactive oxygen species. Taken together, our results demonstrated that ML-240 could be an attractive therapeutic option for treatment against leishmaniasis.

CYP450 enzymes are involved in biotransformation of chloroquine (CQ), but the role of the different metabolism profiles of this drug has not been properly investigated in relation to P. vivax recurrences. To investigate the influence of CYPs genotypes associated with CQ-metabolism on early recurrence rates of P. vivax, a case-control study was carried out. Cases included patients presenting an early recurrence (CQ-recurrent), defined as recurrence during the first 28 days after initial infection, plasma concentrations of CQ plus desethylchloroquine (DCQ, the major CQ metabolite) higher than 100 ng/mL. A control (CQ-responsive) with no parasite recurrence over the follow-up was also included. CQ and DCQ plasma levels were measured on Day 28. CQ CYPs (CYP2C8, CYP3A4 and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify CQ and DCQ efficacy in P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and controls for CYP2C8 (OR=1.45, 95% CI=0.51-4.14, p=0.570), CYP3A4 (OR=2.38, 95% CI=0.92-6.19, p=0.105) and CYP3A5 (OR=4.17, 95% CI=0.79-22.04, p=1.038) genes. DCQ levels were higher than CQ, regardless of the genotype. Regarding the DCQ/CQ rate, there was no difference between groups or between those patients who had a normal or mutant genotype. DCQ and CQ showed similar efficacy ex vivo. CYPs genotypes had no influence on early recurrence rates. Similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite presence of alleles associated with slow metabolism.

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

Google has made it easier to join the company's Advanced Protection Program, which is designed to stop the most sophisticated hackers from breaking into your Gmail account. Before you needed two security keys to enroll. Now you just need a smartphone.

The local bourse had managed to open firmer following a rally in Asian stocks in earlier trading.

On the currency market, the rand traded softer against the greenback as it slipped to a session low of R18.77/$.

BACKGROUND:

Mexican-origin women breastfeed at similar rates as white women in the United States, yet they usually breastfeed for less time. In our study, we seek to identify differences in Mexican-origin women’s breastfeeding intentions, initiation, continuation, and supplementation across nativity and country-of-education groups.

BACKGROUND AND OBJECTIVES:

Children with medical complexity (CMC) comprise only 6% of the pediatric population, account for ~40% of pediatric health care spending, and provide an important opportunity for cost saving. Savings in this group can have an important impact on pediatric health care costs. The objective of this study was to assess the impact of a multicenter care management program on spending and use in CMC.

BACKGROUND AND OBJECTIVES:

Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing.

BACKGROUND:

In the United States, transgender youth are at especially high risk for HIV infection. Literature regarding HIV prevention strategies for this vulnerable, often-hidden population is scant. Before effective, population-based HIV prevention strategies may be adequately developed, it is necessary to first enhance the contextual understanding of transgender youth HIV risk and experiences with HIV preventive services.

Wix Stores has a smooth offering that's strongly geared toward beginners who just want to get off the ground quickly. More advanced users or those who need more in-depth customizability, however, will need to look elsewhere.

The Samsung Galaxy Note 10+ is a big, powerful phone that's good for artists and note-takers.

The Whistle GO Explore pet tracker improves on the previous generation in nearly every while, while adding a few new tricks in the process.

Rosario, Argentina :: Church members from a vulnerable community learn about human trafficking and experience care and respect.

For years, Gustavo, an architect from Central America, felt drawn to working in the Arabian Peninsula. Then, on a short-term trip, he saw what it could be like to use his profession overseas.

God uses Janet to reach people through one-on-one encounters at a bookshop in a closed country.

The Penn State Smeal College of Business Center for the Business of Sustainability recently hosted the first in a series of virtual fireside discussions titled “The Impact of Coronavirus on Sustainability and Social Impact,” to explore how recent momentum in sustainability efforts has been altered.

Using their unique skills and experiences, three LaunchBox grant recipients are providing a variety of COVID-19 relief efforts.

Reducing indebtedness and improving savings in South Africa is a major socio-economic challenge, warns an industry expert.

Today you can save $120 on the Lenovo Flex 14 2-in-1 laptop. Also, the 24-inch Dell S2419HGF 1080p monitor dropped is now just $149.99. Finally, the new Nintendo Switch, featuring improved battery life, is now available.

Remittances from overseas are a lifeline for many South Africans, says Richard Ambrose, CEO of Azimo.

Africa can be a challenging place to do business and property investment is not exempt from some, often unique, challenges, says a Nedbank expert.

Fin24 asked financial experts how they would grow R10 000 in the new year. Here's what they said.

Interest in Section 12J has grown each year, with the current financial year being no different, says Jonty Sacks, a partner at Jaltech.

Many investors do not fully understand the tax incentive and structure of a Section 12J venture capital investment, according to a managing director involved in this sector.

By the end of February, most taxpayers are looking for every opportunity to reduce their tax liabilities.

Instability in local and international stock markets – mainly due to concerns over the impact of the coronavirus – might have you concerned about preserving your retirement savings.

The UEFA Futsal EURO is being enhanced, and will soon be joined by two new futsal competitions – the UEFA Women's Futsal EURO and the UEFA European Under-19 Futsal Championship.

Rosario, Argentina :: Church members from a vulnerable community learn about human trafficking and experience care and respect.

For years, Gustavo, an architect from Central America, felt drawn to working in the Arabian Peninsula. Then, on a short-term trip, he saw what it could be like to use his profession overseas.

God uses Janet to reach people through one-on-one encounters at a bookshop in a closed country.

Effective immediately and for the foreseeable future, the Entrepreneurship and Assistance Clinic is expanding its scope and service offerings to small Pennsylvania businesses, in response to the COVID-19 pandemic.

When the novel coronavirus pandemic prompted the transition to remote learning at Penn State, faculty and administrators in the Department of Mechanical Engineering were prepared for the challenge.

Computer fans can get pretty noisy, but there are a few things you can do to reduce the din. Here's how to quiet disruptive PC equipment.

Getting started is as easy as picking a show and pressing play. However, there are a few tricks you can use to get the most out of your viewing experience, like killing autoplay trailers.

A new high-res audio player looks like a wooden flask and has a tie-up with Tidal.

The Velocity Micro Raptor Z55a is a clean, straightforward gaming desktop with excellent performance. It's a bit pricey, though, and doesn't do a lot to differentiate itself from its rivals.

Amazon is offering up to 30 percent off Acer laptops, desktops, and monitors. Plus, you can save $930 on the 65-inch Vizio P-Series Quantum X 4K TV.

CyberPower's Gamer Xtreme midtower packs fluid 1080p gaming performance into a quality package, although it's not quite the top value in its class.

Comixology Unlimited lets you dive into more than 20,000 digital comics for just $5.99 per month. Make the most of your subscription by starting with these 10 titles.

Today you can save up to 30 percent on select laptops, networking devices, and storage drives at Amazon. Also, the highly anticipated game Cyberpunk 2077 is $10 off when you pre-order it.

Google Docs, Sheets, and Slides can already be saved and edited offline using the web app, but Google is expanding offline access to all file types, as long as you're using Chrome.

The 256GB Samsung EVO Select microSDXC card is back at just $39.99, the Echo Dot is half off, and the MacBook Air is $150 off.

Snag the Samsung EVO Select 512GB microSDXC card for $88, one of its lowest prices ever. Also, the 75-inch Samsung QLED 4K TV is more than $1,000 off and a Dell XPS 15 is $300 off.

Capacities range from 2TB right up to 12TB, with the P50 Game Drive boasting a 'first-to-industry' USB 3.2 gen 2x2 connection and 2,000MB/s read speeds.

The start of November has brought a ton of great deals, with some matching last year's Black Friday prices. The 512GB Samsung EVO Select microSDXC card is only $78.

In our review, we called this TV 'among the brightest we've tested.' It comes in five different sizes, all of which are currently between 18 and 39 percent off at Amazon.

The 55-inch Vizio M-Series 4K TV is just $358, $40 less than its Black Friday price. Plus, Dell's XPS 15 laptop is $350 off and the Roborock S5 robot vacuum is $200 off.