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Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. ClinicalTrials.gov NCT00592124.

This review discusses the history, fundamentals, and applications of different fuel cell technologies, including proton exchange membrane fuel cells (PEMFCs), direct methanol fuel cells, solid oxide fuel cells (SOFCs), phosphoric acid fuel cells (PAFCs), alkaline fuel cells (AFCs), and molten carbonate fuel cells (MCFCs). Recent advances in fuel cell technologies have led to potential applications in aerospace, transportation, and portable and stationary power generation due to high efficiency and low emissions. Fuel cell types are also compared based on efficiency, operating temperature, lifetime, energy/power density, and cost. It was noticed that PEMFCs have the highest mass power density, reaching 1,000 W/kg compared to less than 100 W/kg for SOFCs, which makes them suitable for portable applications such as aircraft. PEMFCs and AFCs are suitable for low‐temperature applications and are highly efficient. SOFCs and MCFCs are better for high‐temperature operations. SOFCs are robust and suitable for high‐power demands, while MCFCs are advantageous for high‐power output. Hydrogen fuel cells promise to decarbonize transportation and aviation sectors with the advantages of lower weight, compactness, and quick startup times. However, challenges remain around renewable hydrogen production/infrastructure and aircraft integration, besides hydrogen storage, water management inside fuel cells, and operational robustness under varying pressures. Generally, for all fuel cell types, more focus should be given to enhancing the stability and efficiency of fuel cell materials and reducing their cost.

Background Long-term tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) is associated with sustained viral suppression and regression of fibrosis and cirrhosis at year 5 (240 weeks) and no TDF resistance through 6 years (288 weeks). Aim We assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients. Methods Patients who completed 1 year (48 weeks) of randomized treatment with TDF or adefovir dipivoxil were eligible to receive open-label TDF for a total duration of 8 years (384 weeks). Results Of 641 patients initially randomized, 585 (91.3 %) entered the open-label phase; 437/585 (74.7 %) remained on study at year 7. For patients on treatment at year 7, 99.3 % maintained viral suppression (HBV DNA < 69 IU/mL), 80.0 % achieved serum alanine aminotransferase normalization, and in HBeAg-positive patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved HBeAg and HBsAg loss, respectively. One/375 (0.3 %) HBeAg-negative patients achieved HBsAg loss. No resistance to TDF was detected through 7 years. During the open-label phase, grade 3/4 drug-related adverse events were uncommon (1.0 %); ten (1.7 %) patients had elevation of serum creatinine ≥0.5 mg/dL above baseline. No significant change in bone mineral density was observed from year 4 to year 7 (week 192 to week 336). Conclusions Long-term TDF treatment was associated with sustained virologic, biochemical, and serologic responses, without resistance. TDF treatment was well tolerated, with a low incidence of renal and bone events. These data confirm the safety and efficacy of long-term TDF for CHB.

The emergence of RNA viruses driven by global population growth and international trade highlights the urgent need for effective antiviral agents that can inhibit viral replication. Nucleoside analogs, which mimic natural nucleotides, have shown promise in targeting RNA-dependent RNA polymerases (RdRps). Starting from protected 5-iodouridine, we report the synthesis of hitherto unknown C5-substituted-(1,3-diyne)-uridines nucleosides and their phosphoramidate prodrugs. The modifications at C5 include 4-(trifluoromethyl)benzene (a), 4-pentyl-benzene (b), 3,5-dimethoxy-benzene (c), 4-(trifluoromethoxy)benzene (d), 3-aniline (e), 4-pyridine (f), 3-thiophene (g), C6H13 (h), 2-pyrimidine (i), cyclopropyl (j), and phenyl (k) groups. These compounds were synthesized using Sonogashira palladium-catalyzed reactions and nickel–copper-catalyzed C-H activation between various alkynes, yielding between 25% and 67%. The antiviral activities of obtained compounds were measured through HTS against RNA viruses including influenza H1N1 and H3N2, human respiratory syncytial virus (RSV), SARS-CoV-2, Zika, hepatitis C virus (HCV), Hepatitis E virus (HEV), as well as against coronavirus (HCoV-229E). Unfortunately, none of them showed promising antiviral activity, with less than 85% inhibition observed in the cell viability screening of infected cells.

Treatment of HIV-1 infection in sub-Saharan Africa has many challenges. In this report, the safety and efficacy of three different regimens are assessed in HIV-1–infected persons in South Africa: tenofovir alafenamide fumarate (TAF)–emtricitabine (FTC)–dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)–FTC–DTG, and the local standard-of-care regimen (TDF–FTC–efavirenz).

In recent years, there has been an increase in the incidence of urinary stones, including infection urinary stones, especially in highly developed countries. One of the areas where the cause of the increased morbidity in these countries can be found is food products and their ingredients, which are not as common in other countries. Very often, attention is drawn to the greater consumption of highly processed food, the production of which uses flavour enhancers and various preservatives. One of the substances used in the food industry as an acidity regulator or antioxidant is phosphoric acid. It is used in the production of many products from food, sweets, beers to soft drinks, e. g. Coca‐Cola. In this paper, we present the results of research on the effect of phosphoric acid (H3PO4) on the mineralization and growth of carbonate apatite Ca10(PO4)6CO3 (CA) and hydroxyapatite Ca10(PO4)6(OH)2 (HAP), which are one of the main components of infection urinary stones, next to struvite. The research was conducted in an artificial urine environment in two ways: in the presence of Proteus mirabilis bacteria and without them. In the latter case, bacterial urease activity was simulated by adding an aqueous ammonia solution. The results obtained, both in the presence of bacteria and without them, indicate that phosphoric acid present in artificial urine causes a shift in the mineralization of CA and HAP towards a lower pH, which means that these components mineralize earlier in artificial urine compared to the control sample. On the other hand, the amount of solid phases formed is smaller, the higher the concentration of phosphoric acid. The effect of phosphoric acid on the mineralization of CA and HAP was explained on the basis of theoretical speciation analysis of chemical complexes formed in urine in the presence of the tested acid. This analysis indicates that the experimentally observed shift in the formation of solid phases towards a lower pH with increasing phosphoric acid concentration is related to the earlier appearance of C10(PO4)6(OH)2 complexes, forming HAP, and not to C10(PO4)6CO3 complexes, forming CA. It should be remembered that the described effect of this acid on the formation of CA and HAP is possible only when the urinary tract is infected with urease‐positive bacteria. In the absence of infection, phosphoric acid will not cause the formation of solid phases characteristic of infection urinary stones. Phosphoric acid is used in various products like food, sweets, beers, and soft drinks. Higher phosphoric acid concentration in urine accelerates the formation of carbonate apatite and hydroxyapatite, which are key components of infection urinary stones, a negative effect. However, the amount of these solid phases is smaller, which is beneficial. These effects occur when the urinary tract is infected with urease‐positive bacteria.

Feruloyl esterase (FAE) is a critical enzyme in bio-extraction of ferulic acid (FA) from plant cell wall. A new FAE (EpFAE1) encoding gene was isolated from Eupenicillium parvum and heterologously expressed in Pichia pastoris cells. Based on phylogenetic tree analysis, the protein EpFAE1 belongs to type A of the seventh FAE subfamily. Using methyl ferulate as substrate, the optimum temperature and pH for the catalytic activity of EpFAE1 were 50 °C and 5.5, respectively. The enzyme exhibited high stability at 50 °C, in a wide pH range (3.0–11.0), or in the presence of 2 M of NaCl. Together with the endo-xylanase EpXYN1, EpFAE1 released 72.32% and 4.00% of the alkali-extractable FA from de-starched wheat bran (DSWB) or de-starched corn bran (DSCB), respectively. Meanwhile, the substrates were pretreated with 1.75% (for DSWB) or 1.0% (for DSCB) of phosphoric acid (PA) at 90 °C for 12 h, followed by enzymatic hydrolysis of the soluble and insoluble fractions. The release efficiencies of FA were up to 84.64% for DSWB and 66.73% for DSCB. Combined dilute PA pretreatment with enzymatic hydrolysis is a low-cost and highly efficient method for the extraction of FA from cereal brans.

Life is an out-of-equilibrium system sustained by a continuous supply of energy. In extant biology, the generation of the primary energy currency, adenosine 5′-triphosphate and its use in the synthesis of biomolecules require enzymes. Before their emergence, alternative energy sources, perhaps assisted by simple catalysts, must have mediated the activation of carboxylates and phosphates for condensation reactions. Here, we show that the chemical energy inherent to isonitriles can be harnessed to activate nucleoside phosphates and carboxylic acids through catalysis by acid and 4,5-dicyanoimidazole under mild aqueous conditions. Simultaneous activation of carboxylates and phosphates provides multiple pathways for the generation of reactive intermediates, including mixed carboxylic acid–phosphoric acid anhydrides, for the synthesis of peptidyl–RNAs, peptides, RNA oligomers and primordial phospholipids. Our results indicate that unified prebiotic activation chemistry could have enabled the joining of building blocks in aqueous solution from a common pool and enabled the progression of a system towards higher complexity, foreshadowing today’s encapsulated peptide–nucleic acid system.Life requires a constant supply of energy, but the energy sources that drove the transition from prebiotic chemistry to biochemistry on the early Earth are unknown. Now, a potentially prebiotic chemical activating reagent has been shown to enable the synthesis, in aqueous conditions and catalysed by small molecules, of peptides, peptidyl–RNAs, RNA oligomers and primordial phospholipids.

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5′-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5′-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5′-monophosphate, which is further transformed to the active 5′-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan’s research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.

To reduce the time of postoperative recovery and to prevent post-surgical complications, biocompatible synthetic materials with osteoconductive and osteoinductive properties are used as bone substitutes in large bone defect management. A simplified biomimetic approach to similar materials is based on the use of an inorganic filler, a polymer matrix, and a compatibilizer, mimicking the composition of the natural bone. Based on plate-like micro-sized carbonated hydroxyapatite (pCAp), we prepared compression-molded samples optionally containing an additional polyester component (poly(ε-caprolactone) PCL, poly(L-lactide) PLLA, or poly(L-methylglycolide) PLMG); syntheticblock copolymers comprising fragments of the corresponding polyester and poly(ethylene phosphoric acid) (PEPA) were also prepared and studied asa ‘two-in-one’ polymer matrix/compatibilizer. Bone regeneration experiments involving a three-month rat tibial defect model were conducted with 250–500 μm granules of the composites. Comparative studies of the introduction of the polyester-b-PEPA copolymer into composites revealed a positive effect, which manifests itself in accelerated bone regeneration, which further intensified for pCAp/PEPA-b-PLMG. The latter composite formulation was used to study the results of the introduction of cerium into the filler. One-month experiments with pCAp, CePO4-doped pCAp, and composites of these inorganic fillers with PEPA-b-PLMG were conducted. For the first time, a positive synergistic effect of the presence of cerium and PEPA in the composite, which appeared in substitution of the implant material by two-thirds of newly formed partly matured bone, was observed four weeks after surgery.