lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.

Cryptosporidiosis is a diarrheal disease caused by infection with spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population.

SophosQM: Accurate Binding Affinity Prediction in Compound Optimization.

The optimization of compounds' binding affinity for a biological target is a crucial aspect of the drug development process. Being able to accurately predict binding energies in advance of synthesizing compounds would have a massive impact on the speed of the drug discovery process. The ideal binding affinity prediction method should combine accuracy, reliability, and speed.

Sorption of cefdinir, memantine, praziquantel and trimethoprim in sediment and soil samples.

The everyday use of various pharmaceuticals to treat humans or animals means that they are increasingly found in the environment. Contamination of the soil can cause the active ingredients to be strongly sorbed to the soil or sediment. In the worst case, they can also be expected to occur in the aquatic environment due to their different polarity.

DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis.

Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases.

Benzil Photoperoxidations in Polymer Films and Crosslinking by the Resultant Benzoyl Peroxides in Polystyrene and Other Polymers.

Benzil () can be converted almost quantitatively to benzoyl peroxide () in aerated polymer films upon irradiation at >400 nm (i.e., the long-wavelength edge of the → absorption band of , where does not absorb).

Ligand binding: evaluating the contribution of the water molecules network using the Fragment Molecular Orbital method.

Water molecules play a crucial role in protein-ligand binding, and many tools exist that aim to predict the position and relative energies of these important, but challenging participants of biomolecular recognition. The available tools are, in general, capable of predicting the location of water molecules. However, predicting the effects of their displacement is still very challenging.

Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis.

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 () as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with efficacy, which was hampered by poor solubility and genotoxicity.

Mapping Ligand-Shape Space for Protein-Ligand Systems: Distinguishing Key-in-Lock and Hand-in-Glove Proteins.

Many of the recently developed methods to study the shape of molecules permit one conformation of one molecule to be compared to another conformation of the same or a different molecule: a relative shape. Other methods provide an absolute description of the shape of a conformation that does not rely on comparisons or overlays. Any absolute description of shape can be used to generate a self-organizing map (shape map) that places all molecular shapes relative to one another; in the studies reported here, the shape fingerprint and ultrafast shape recognition methods are employed to create such maps.

Preparation of TiO/WO/C/N Composite Nanofibers by Electrospinning Using Precursors Soluble in Water and Their Photocatalytic Activity in Visible Light.

Extending the absorption range of TiO nanofibers to visible light is a great improvement of the photocatalytic property of TiO. In this study, TiO/WO/C/N nanofibers were prepared by electrospinning using precursors soluble in water then annealing in argon. Titanium(IV) bis(ammonium lactato)dihydroxide (TiBALDH) and ammonium metatungstate (AMT) were used as the precursor for TiO and WO respectively.

Utilisation patterns of group O red blood cell transfusion by ABO and D non-identical recipients in large academic hospital.

Objectives: Several studies have raised concerns that transfusion of O red blood cells (RBCs) to ABO and D non-identical recipients can intensify group O inventory shortages. The aim of this study was to retrospectively analyse particular clinical indications and polices responsible for O RBCs use by ABO and D non-identical recipients, as well as to assess the impact of this practice on the overall utilisation of O RBCs.

Material And Methods: Data of all transfused RBCs from 2014 to 2018 were extracted from the comprehensive database of transfusion service.

Predicting protein-ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A.

Accurately computing the geometry and energy of host-guest and protein-ligand interactions requires a physically accurate description of the forces in action. Quantum mechanics can provide this accuracy but the calculations can require a prohibitive quantity of computational resources. The size of the calculations can be reduced by including only the atoms of the receptor that are in close proximity to the ligand.

Hypothermic treatment after computer-controlled compression in minipig: A preliminary report on the effect of epidural vs. direct spinal cord cooling.

The aim of the present study was to investigate the therapeutic efficacy of local hypothermia (beginning 30 min post-injury persisting for 5 h) on tissue preservation along the rostro-caudal axis of the spinal cord (3 cm cranially and caudally from the lesion site), and the prevention of injury-induced functional loss in a newly developed computer-controlled compression model in minipig (force of impact 18N at L3 level), which mimics severe spinal cord injury (SCI). Minipigs underwent SCI with two post-injury modifications (durotomy vs. intact dura mater) followed by hypothermia through a perfusion chamber with cold (epidural t≈15°C) saline, DMEM/F12 or enriched DMEM/F12 (SCI/durotomy group) and with room temperature (t≈24°C) saline (SCI-only group).

Neuroprotective effect of local hypothermia in a computer-controlled compression model in minipig: Correlation of tissue sparing along the rostro-caudal axis with neurological outcome.

This study investigated the neuroprotective efficacy of local hypothermia in a minipig model of spinal cord injury (SCI) induced by a computer-controlled impactor device. The tissue integrity observed at the injury epicenter, and up to 3 cm cranially and caudally from the lesion site correlated with motor function. A computer-controlled device produced contusion lesions at L3 level with two different degrees of tissue sparing, depending upon pre-set impact parameters (8N- and 15N-force impact).

Turbocharging Matched Molecular Pair Analysis: Optimizing the Identification and Analysis of Pairs.

We have applied the two most commonly used methods for automatic matched pair identification, obtained the optimum settings, and discovered that the two methods are synergistic. A turbocharging approach to matched pair analysis is advocated in which a first round (a conservative categorical approach that uses an analogy with coin flips, heads corresponding to an increase in a measured property, tails to a decrease, and a biased coin to a structural change that reliably causes a change in that property) provides the settings for a second round (which uses the magnitude of the change in properties). Increased chemical specificity allows reliable knowledge to be extracted from smaller sets of pairs, and an assay-specific upper limit can be placed on the number of pairs required before adequate sampling of variability has been achieved.

Designing Hydroxamates and Reversed Hydroxamates to Inhibit Zinc-containing Proteases but not Cytochrome P450s: Insights from Quantum Mechanics and Protein-ligand Crystal Structures.

The Hydroxamate is a useful functional group that binds to metals in a range of enzymes, notably zinc in matrix metalloproteases and histone deacetylases. The group is also able to form interactions with iron leading to inhibition of the cytochromes P450, particularly the 3A4 isoform. We have studied the available crystal structures of zinc-containing proteins bound to hydroxamates and compared the observed geometries with those found by quantum mechanical calculations.

Resistant hypertension and chronotherapy.

Resistant hypertension is defined as blood pressure that remains above 140/90 mmHg in spite of the continuous use of three antihypertensive agents in optimal dose, including diuretic, and lifestyle changes. According to data from United States of America and Europe, the prevalence ranges from 10 up to 30% in patients with hypertension. Numerous biological and lifestyle factors can contribute to the development of resistant hypertension: medications, volume overload, obesity, diabetes mellitus, older age, renal parenchymal and renovascular disease, primary aldosteronism, obstructive sleep apnea, pheochormocytoma, Cushing's syndrome, thyroid diseases, aortic coarctation.

Structural basis of protein oxidation resistance: a lysozyme study.

Accumulation of oxidative damage in proteins correlates with aging since it can cause irreversible and progressive degeneration of almost all cellular functions. Apparently, native protein structures have evolved intrinsic resistance to oxidation since perfectly folded proteins are, by large most robust. Here we explore the structural basis of protein resistance to radiation-induced oxidation using chicken egg white lysozyme in the native and misfolded form.

Synthesis and photooxidation of styrene copolymer bearing camphorquinone pendant groups.

(±)-10-Methacryloyloxycamphorquinone (MCQ) was synthesized from (±)-10-camphorsulfonic acid either by a known seven-step synthetic route or by a novel, shorter five-step synthetic route. MCQ was copolymerized with styrene (S) and the photochemical behavior of the copolymer MCQ/S was compared with that of a formerly studied copolymer of styrene with monomers containing the benzil (BZ) moiety (another 1,2-dicarbonyl). Irradiation (λ > 380 nm) of aerated films of styrene copolymers with monomers containing the BZ moiety leads to the insertion of two oxygen atoms between the carbonyl groups of BZ and to the formation of benzoyl peroxide (BP) as pendant groups on the polymer backbone.

[Syndroma caudae equinae of rare etiology].

The results of treatment patients suffering from syndroma caudae equinae (SCE) are not generally satisfactory. The authors decided to evaluate occurrence according to etiology and permanent consequences after treatment in patients that were treated at the Department of Neurosurgery P. J.

Photo-crosslinking of polyethylene by mono- and diacetophenone derivatives and their precursors.

The efficiency of photochemical crosslinking of low-density polyethylene (PE) films by molecules containing one or two acetophenone groups and their precursors have been correlated with the relative rates of carbonyl group depletion under equivalent irradiation conditions. The acetophenone derivatives are found to be equally or more efficient than benzophenone as crosslinkers of PE. Because some additives are not thermodynamically equilibrated in the PE matrices and crystallize on standing at 30 degrees C, doped films were irradiated usually as soon as possible after their preparation.

Doppler sonography in diagnosis of the acute scrotum.

Doppler sonography has been reported to be a reliable technique for diagnosing acute scrotum significantly decreasing the number of unnecessary surgeries. The aim of this paper was to demonstrate the superiority and validity of Doppler sonography over conventional sonography for differential diagnosis of the acute scrotum. In the period from 2002-2004, 300 patients underwent ultrasound examination of the testicles at the Institute of Radiology in Novi Sad.

Carbon tetrachloride as a thermoporometry liquid probe to study the cross-linking of styrene copolymer networks.

Mesh size distributions (MSDs) of swollen cross-linked styrene copolymer networks have been measured by thermoporometry using CCl(4) as a probe liquid. All numerical relationships required for the calculation of the MSD were established for both the liquid-to-solid and the solid-to-solid thermal transitions of CCl(4) and successfully validated on test samples. It was found that the polymer network, for both thermally and photo-cross-linked materials, was completely built in about 4 h of exposure.

[Diagnosis of ureteral calculi using ultrasonography, intravenous urography and unenhanced helical computed tomography].

Introduction: The pain in the loins is usually the consequence of renal colic caused by small ureteral calculi.

Ultrasonography: Ultrasonography is an efficient tool in the detection of calculi in the pyelocalyx system, but it may not be sufficient for the area of renal pelvis and ureter, as wll as for the ureter and the ureterovesical junction.

Intravenous Urography: Radiolucent stones, dilatation of the ureter and of the pyelocalyx system were identified on the urogram, which are common signs of ureter calculosis.