Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses.

Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, -(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (), borne from our previously reported hit-to-lead effort.

Effect of low-temperature oxidation and heat treatment under vacuum on the Al-Be interdiffusion process.

The oxidation of the Be/Al and Al/Be bilayer thin film systems deposited by magnetron sputtering have been studied by photoelectron spectroscopy and transmission electron microscopy. Both systems are oxidized according to the Cabrera-Mott model in the air. A Be/BeO/Al/AlO structure is formed, with aluminium represented as localized nanocrystals.

Trace Organic Contaminant Removal from Municipal Wastewater by Styrenic β-Cyclodextrin Polymers.

Trace organic contaminants (TrOCs) present major removal challenges for wastewater treatment. TrOCs, such as perfluoroalkyl and polyfluoroalkyl substances (PFAS), are associated with chronic toxicity at ng L exposure levels and should be removed from wastewater to enable safe reuse and release of treated effluents. Established adsorbents, such as granular activated carbon (GAC), exhibit variable TrOC removal and fouling by wastewater constituents.

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.

TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term antiretroviral therapy (ART). We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal.

Discovery of Highly Potent Serotonin 5-HT Receptor Agonists Inspired by Heteroyohimbine Natural Products.

The serotonin 5-HT receptors are important pharmaceutical targets involved in signaling pathways underlying various neurological, psychiatric, and cardiac functions and dysfunctions. As such, numerous ligands for the investigation of these receptors' activity and downstream effects have been developed synthetically or discovered in nature. For example, the heteroyohimbine natural product alstonine exhibits antispychotic activity mediated by 5-HT agonism.

Effect of annealing on the interface formation in Mo/Be multilayer structures without/with a barrier layer.

In the present paper, the formation of an interface region in the multilayer periodic Mo/Be structure with/without a BC or Si barrier layer depending on the annealing conditions was studied using X-ray photoelectron spectroscopy. The formation of different beryllides at the interfaces Be-on-Mo and Mo-on-Be was explained by the impact of the deposition-induced exchange caused by ballistic collisions and surface free energy. The influence of the high temperatures on the thermal stability of Mo/Be multilayer systems without/with a barrier layer was studied.

Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs.

Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations.

Inhibition of chemical interaction of molybdenum and silicon in a Mo/Si multilayer structure by the formation of intermediate compounds.

In the present study, the formation of intermediate compounds in the Mo/Si multilayer was realized by the introduction of barrier layers at the interfaces. Their impact on the interdiffusion of Mo and Si was analyzed via X-ray photoelectron spectroscopy. It was established that the insertion of a thin Be barrier layer led to the formation of beryllide MoBe12 at the interface Si-on-Mo, which prevented the formation of molybdenum disilicide and improved the interface.

Angle resolved photoelectron spectroscopy as applied to X-ray mirrors: an in depth study of Mo/Si multilayer systems.

We present an approach adapted to study the interface (composition and extension) of X-ray multilayer mirrors using angle resolved photoelectron spectroscopy (ARXPS). In the approach we rely on the concept of the average effective attenuation length (EAL) of the photoelectron and not on the inelastic mean free path (IMPF), which allows us to take into account the contribution of elastically scattered electrons and to increase the accuracy of the determined thickness of the layers. We apply the developed approach to study the formation of interfaces in a multilayer periodic Mo/Si mirror.

Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors.

Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2.

[Hygienic characteristics of the quality OF underground drinking water in oil-producing areas].

The purpose of the research was the assessment and the disclosure of the features of the pollution of groundwater at the oil-producing areas of the Republic of Bashkortostan and the elaboration of hygienic recommendations for environmentally sound water management. According to results of the studies performed there is presented the characteristic of main reasons leading to the pollution of groundwater in the location of oil and gas producing regions There was suggested the complex of hygienic recommendations and management decisions on the improvement of the water supply in areas with advanced oil production.

Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.

The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties.

Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth.

Ovarian cancer is the most lethal gynecological malignancy among US women. Paclitaxel/carboplatin is the current drug therapy used to treat ovarian cancer, but most women develop drug resistance and recurrence of the disease, necessitating alternative strategies for treatment. A possible molecular target for cancer therapy is glycogen synthase kinase 3β (GSK3β), a downstream kinase in the Wnt signaling pathway that is overexpressed in serous ovarian cancer.

[Monitoring public health state in solving ecologic problems of cities].

The article covers morbidity and demographic changes in inhabitants of territories subjected to high geochemical load, exemplified by Ust-Kamenogorsk of East Kazakhstan region over 2005-2009. The authors revealed some unfavorable trends in medical and social processes in the region. The most sensitive to anthropogenic pollution are: infant mortality, general morbidity among adolescents and children, primary morbidity among children and adults, when compared to the reference area (Shiutchinsk).

[Complex treatment of vertebrogenic pain syndrome in women during pregnancy].

The proposed system of non-pharmacological treatment has been tried in 325 pregnant women with pain syndrome associated with spinal lesions (osteochondrosis, scoliosis, malformations, sequela of compression vertebral fractures, spondylolisthesis). The treatment combined orthopedic aids, relaxing massage, muscular relaxation, mobilization of functional blocks of intervertebral joints and pelvic junctions, therapeutic exercises. The above non-pharmacological system relieved vertebral pain syndrome partially or completely in 82% of the treated pregnant women.

[The analysis of urinary steroids using capillary gas-liquid chromatography].

Impaired steroid hormone secretion and metabolism may become the cause of symptomatic hypertension. Currently gas chromatography technique is employed for analysis of urinary steroids, that permits detection of the majority of components. To detect the important components present in but trace amounts gas chromatographic mass spectrometry is necessary.

Epidermolysis bullosa dystrophica polydysplastica. A case of anesthetic management in oral surgery.

Epidermolysis bullosa dystrophica is a rare disease that affects the skin and mucous membranes. Manifest at birth, it is characterized by poor dentition, esophageal strictures, syndactyly, and severe chronic anemia. Our 12-year-old patient required extensive dental treatment which necessitated overcoming problems of anesthesia as well as developing a technique of management that provided maximum safety and a minimum of discomfort.