Optimization of diarylazines as anti-HIV agents with dramatically

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

VAESim: A probabilistic approach for self-supervised prototype discovery

In medical image datasets, discrete labels are often used to describe a continuous spectrum of conditions, making unsupervised image stratification a challenging task. In this work, we propose VAESim, an architecture for image stratification based on a conditional variational autoencoder. VAESim learns a set of prototypical vectors during training, each associated with a cluster in a continuous latent space. We perform a soft assignment of each data sample to the clusters and reconstruct the sample based on a similarity measure between the sample embedding and the prototypical vectors. to update the prototypical embeddings, we use an exponential moving average of the most similar representations between actual prototypes and samples in the batch size. We test our approach on the MNIST handwritten digit dataset and the pneumoniaMNIST medical benchmark dataset, where we show that our method outperforms baselines in terms of kNN accuracy (up to +15% improvement in performance) and performs at par with classification models trained in a fully supervised way. our model also outperforms current end-to-end models for unsupervised stratification

EFFECTIVENESS OF “POLYKATAN” GEL IN CASE OF TRAUMATIC STOMATITIS

Traumatic stomatitis oforalmucosa in rabbits has been studied. Stimulatory effect ofmagnesium-containing "Polykatan” gel on thermal burn in comparison with "Polykatan" solution has been revealed. "Polykatan" solution based on solution of clean bischofite mineral is used in the therapeutic dentistry

Electrostatic effects in coupled quantum dot-point contact-single electron transistor devices

We study the operation of a system where quantum dot (QD) and point contact (PC) defined in a two-dimensional electron gas of a high-mobility GaAs/AlGaAs heterostructure are capacitively coupled to each other and to metallic single electron transistor (SET). The charge state of the quantum dot can be probed by the point contact or single electron transistor. These can be used for sensitive detection of terahertz radiation. In this work, we explore an electrostatic model of the system. From the model, we determine the sensitivity of the point contact and the single electron transistor to the charge excitation of the quantum dot. Nearly periodic oscillations of the point contact conductance are observed in the vicinity of pinch-off voltage. They can be attributed to Coulomb blockade effect in a quasi-1D channel because of unintentional formation of small quantum dot. The latter can be a result of fluctuations in GaAs quantum well thickness

Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase

Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Gray, William T.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gallardo Macias, Ricardo. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Extension into the entrance channel of HIV-1 reverse transcriptase—Crystallography and enhanced solubility

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Frey, Kathleen M.. University of Yale. School of Medicine; Estados UnidosFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale. School of Medicine; Estados UnidosFil: Das, Kalyan. Rutgers University; Estados UnidosFil: Bauman, Joseph D.. Rutgers University; Estados UnidosFil: Arnold, Eddy. Rutgers University; Estados UnidosFil: Anderson, Karen S.. University of Yale. School of Medicine; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

UBVRI observations of the flickering of RS Ophiuchi at Quiescence

We report observations of the flickering variability of the recurrent nova RS Oph at quiescence on the basis of simultaneous observations in 5 bands (UBVRI). RS Oph has flickering source with (U-B)_0=-0.62 \pm 0.07, (B-V)_0=0.15 \pm 0.10, (V-R)_0=0.25 \pm 0.05. We find for the flickering source a temperature T_fl = 9500 \pm 500 K, and luminosity L_fl = 50 - 150 L_sun (using a distance of d=1.6kpc). We also find that on a (U-B) vs (B-V) diagram the flickering of the symbiotic stars differs from that of the cataclysmic variables. The possible source of the flickering is discussed. The data are available upon request from the authors and on the web www.astro.bas.bg/~rz/RSOph.UBVRI.2010.MNRAS.tar.gz.Comment: 7 pages, MNRAS (accepted

Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase

Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Bertoletti, Nicole. University of Yale; Estados UnidosFil: Chan, Albert H.. University of Yale; Estados UnidosFil: Ippolito, Joseph A.. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Potent inhibitors active against HIV reverse transcriptase with K101P, a mutation conferring rilpivirine resistance

Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.Fil: Gray, William T.. University of Yale; Estados UnidosFil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Laskey, Sarah B.. University Johns Hopkins; Estados UnidosFil: Mislak, Andrea C.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Lee, Won Gil. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados UnidosFil: Siliciano, Robert F.. University Johns Hopkins; Estados Unidos. Howard Hughes Medial Institute; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

CLOSTRIDIUM DIFFICILE ASSOCIATED DIARRHEA IN MULTIDISCIPLINARY HOSPITAL

Currently, Clostridium difficile is the main reason of a nosocomial diarrhea, caused by uncontrolled antibacterial treatment. This problem is not paid, enough attention in our country. We analyzed. 536 cases of antibiotic associated infections using new immunochromotographical assay for express detection of Clostridium difficile. Since 2008 to 2011 evaluated rate of the positive tests was 28,7 % among the hospital patients. The first line therapy of this infection is vancomycine and metronidazole. We also observed increased incidence of mycosis, which accompanying the antibiotic associated diarrheas. During the same period the rate of Candida spp. infection was 50,8 % among the same patients. We used fluconazole and. amphotericine for the mycosis treatment. We also recommended to manage disbiosis during one year after discontinue of the treatment, and. we supposed reasonable to be managed by infectionist for this group of patients