Prospective de novo drug design with deep interactome learning.

De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning.

Efficacy of the combination of monoclonal antibodies against the SARS-CoV-2 Beta and Delta variants.

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the biggest healthcare issue worldwide. This study aimed to develop a monoclonal antibody against SARS-CoV-2 from B cells of recovered COVID-19 patients, which might have beneficial therapeutic purposes for COVID-19 patients. We successfully generated human monoclonal antibodies (hmAbs) against the receptor binding domain (RBD) protein of SARS-CoV-2 using developed hybridoma technology.

Telehealth for Pediatric Disorders of Gut-Brain Interaction During the COVID-19 Pandemic.

A retrospective chart review was completed to examine psychological treatment duration and response among pediatric patients with a disorder of gut-brain interaction including functional abdominal pain and irritable bowel syndrome. Cognitive behavioral therapy (CBT) was delivered via telehealth with a licensed psychologist or supervised psychology trainee embedded in a pediatric gastroenterology clinic. Participants were 22 youth (mean age = 14.

Impact of Dentistry Materials on Chemical Remineralisation/Infiltration versus Salivary Remineralisation of Enamel-In Vitro Study.

The aim of this study is to evaluate salivary remineralisation versus chemical remineralisation/infiltration of enamel, using different dentistry materials. The enamel changes were studied using confocal laser scanning microscopy (CLSM), and the depth of lesions and demineralisation/remineralisation/infiltration percentage were calculated. Additionally, the macro elemental composition of the teeth was performed using atomic absorption spectroscopy (AAS).

Variations on a theme: crystal forms of the amino-acid transporter MhsT.

The bacterial amino-acid transporter MhsT from the SLC6A family has been crystallized in complex with different substrates in order to understand the determinants of the substrate specificity of the transporter. Surprisingly, crystals of the different MhsT-substrate complexes showed interrelated but different crystal-packing arrangements. Space-group assignment and structure determination of these different crystal forms present challenging combinations of pseudosymmetry, twinning and translational noncrystallographic symmetry.

Utilization of Pediatric Psychology Services in Outpatient Pediatric Gastroenterology Within a Rural Health System.

Increased utilization of pediatric psychology services has been demonstrated following integration into urban pediatric gastroenterology clinics; however, examination within rural health systems is lacking. Utilization of pediatric psychology services was assessed through a retrospective analysis of Electronic Health Record data contrasting referrals occurring six months pre- and post-integration of pediatric psychology in an outpatient pediatric gastroenterology clinic within a rural setting. Significant increases in the number of referrals to pediatric psychology and number of billed initial visits were observed after integration, as was a significant decrease in time to be seen.

New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens.

The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal.

A non-helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition.

MhsT of Bacillus halodurans is a transporter of hydrophobic amino acids and a homologue of the eukaryotic SLC6 family of Na -dependent symporters for amino acids, neurotransmitters, osmolytes, or creatine. The broad range of transported amino acids by MhsT prompted the investigation of the substrate recognition mechanism. Here, we report six new substrate-bound structures of MhsT, which, in conjunction with functional studies, reveal how the flexibility of a Gly-Met-Gly (GMG) motif in the unwound region of transmembrane segment 6 (TM6) is central for the recognition of substrates of different size by tailoring the binding site shape and volume.

Rational design of balanced dual-targeting antibiotics with limited resistance.

Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins.

Improved Model of Proton Pump Crystal Structure Obtained by Interactive Molecular Dynamics Flexible Fitting Expands the Mechanistic Model for Proton Translocation in P-Type ATPases.

The plasma membrane H-ATPase is a proton pump of the P-type ATPase family and essential in plants and fungi. It extrudes protons to regulate pH and maintains a strong proton-motive force that energizes e.g.

Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase.

Excessive activity of NADPH oxidase (Nox) is considered to be of importance for the progress of diabetic nephropathy. The aim of the study was to elucidate the effect of melatonin, known for its nephroprotective properties, on Nox activity under diabetic conditions. The experiments were performed on three groups of animals: (i) untreated lean (?/+) Zucker diabetic fatty (ZDF) rats; (ii) untreated obese diabetic (fa/fa) ZDF rats; and (iii) ZDF fa/fa rats treated with melatonin (20 mg/L) in drinking water.

ERK1/2 pathway is involved in renal gluconeogenesis inhibition under conditions of lowered NADPH oxidase activity.

The aim of this study was to elucidate the mechanisms involved in the inhibition of renal gluconeogenesis occurring under conditions of lowered activity of NADPH oxidase (Nox), the enzyme considered to be one of the main sources of reactive oxygen species in kidneys. The in vitro experiments were performed on primary cultures of rat renal proximal tubules, with the use of apocynin, a selective Nox inhibitor, and TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), a potent superoxide radical scavenger. In the in vivo experiments, Zucker diabetic fatty (ZDF) rats, a well established model of diabetes type 2, were treated with apocynin solution in drinking water.

NADPH oxidase inhibitor, apocynin, improves renal glutathione status in Zucker diabetic fatty rats: a comparison with melatonin.

Apocynin (4'-hydroxy-3'-methoxyacetophenone) is the most commonly used NADPH oxidase (Nox) inhibitor. However, its application raises serious controversies, as the compound has been reported to reveal some prooxidative effects. The aim of this study was to elucidate apocynin action on glutathione, the main intracellular antioxidant, metabolism in kidneys of Zucker diabetic fatty (ZDF) rat, a well established model of diabetes type 2.

Total and acylated ghrelin levels in children with poor growth.

Ghrelin, an enteric hormone with potent appetite stimulating effects, also stimulates growth hormone release. We hypothesized that altered levels of total ghrelin (TG) or acylated ghrelin (AG) could affect growth by altering growth hormone secretion, subsequently affecting insulin-like growth factor-1 (IGF-1) generation or by altering appetite and food intake. After institutional review board approval, 52 children presenting for evaluation of chronic gastrointestinal symptoms (group 1), poor weight gain (group 2), or poor linear growth (group 3) were evaluated for fasting TG and AG levels in addition to their regular evaluation.

Measurement of the thickness and volume of adherent cells using transmission-through-dye microscopy.

Cell volume is one of the basic characteristics of a cell and is being extensively studied in relationship to a variety of processes, such as proliferation, apoptosis, fertility, or locomotion. At the same time, its measurement under a microscope has not been well developed. The method we propose uses negative transmission contrast rendered to cells by a strongly absorbing dye present in the extracellular medium.

Variability in the management of childhood constipation.

To assist primary care providers, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) published clinical practice guidelines for management of childhood constipation. A cross-sectional survey of pediatricians from across the United States was conducted to assess pediatricians' constipation management strategies, whether pediatricians are familiar with the NASPGHAN constipation guidelines, and reasons pediatricians refer constipated patients to a pediatric gastroenterologist. Overall, 75% of pediatricians used polyethylene glycol without electrolytes to treat childhood constipation, 8% of pediatricians were aware NASPGHAN had published constipation guidelines, and parental pressure was just one reason pediatricians referred constipated patients to a pediatric gastroenterologist.

The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart).

Objective: To determine if application of duct tape is as effective as cryotherapy in the treatment of common warts.

Design: A prospective, randomized controlled trial with 2 treatment arms for warts in children.

Setting: The general pediatric and adolescent clinics at a military medical center.

The use of mutants to discern the degradation pathway of 3,4'-dichlorobiphenyl in Pseudomonas acidovorans M3GY.

Abstract Pseudomonas acidovorans strain M3GY is a recombinant bacterium with the novel ability to utilize 3,4'-dichlorobiphenyl (3,4'-DCBP) as a growth substrate. This strain was previously shown to oxidize the 3'-ring and produce 4-chlorobenzoate (4-CBa) through the standard biphenyl pathway. Although 4-CBa was metabolized through the meta-fission pathway, the genes encoding the ortho-chlorocatechol pathway were retained.

Simultaneous bilateral testing: validation of a new protocol to detect insincere effort during grip and pinch strength testing.

The detection of feigned weakness in hand grip strength assessment is difficult. The authors review several proposed methods and their weaknesses. A comparison of unilateral testing and simultaneous bilateral testing with the Jamar dynamometer and the Baseline pinch gauge is demonstrated as a solution.

Methyl tert-butyl ether (MTBE) degradation by a microbial consortium.

The widespread use of methyl tert-butyl ether (MTBE) as a gasoline additive has resulted in a large number of cases of groundwater contamination. Bioremediation is often proposed as the most promising alternative after treatment. However, MTBE biodegradation appears to be quite different from the biodegradation of usual gasoline contaminants such as benzene, toluene, ethyl benzene and xylene (BTEX).

Transformation of 1,1-dichloro-2,2-(4-chlorophenyl)ethane (DDD) by Ralstonia eutropha strain A5.

Evidence is presented demonstrating the ability of Ralstonia eutropha A5 to degrade 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (DDD) aerobically. Strain A5 was able to effect significant transformation of [(14)C]DDD: the hexane extractable radioactivity decreased to approximately 50% of the controls while more than 25% of the total radioactivity became associated with the acidified culture supernatant. There was also an increase in the amount of radioactivity associated with the cell pellet when compared to the biotic control.