Recovering actives in multi-antitarget and target design of analogs of the myosin II inhibitor blebbistatin

In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs a large number of targets, or in using in silica methods for understanding and reliably predicting these pharmacological outcomes In this paper, we have evaluated the potential of several in silica approaches to predict the target, antitarget and physicochemical profile of (S)-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof Standard and augmented structure-based design techniques could not recover the observed activity profiles A ligand-based method using molecular fingerprints was, however, able to select actives for myosin II inhibition Using further ligand- and structure-based methods, we also evaluated toxicity through androgen receptor binding, affinity for an array of antitargets and the ADME profile (including assay-interfering compounds) of the series In conclusion, in the search for (S)-blebbistatin analogs, the dissimilarity distance of molecular fingerprints to known actives and the computed antitarget and physicochemical profile of the molecules can be used for compound design for molecules with potential as tools for modulating myosin II and motility-related diseases

Distribution and ecology of wild lettuces Lactuca serriola L. and Lactuca virosa L. in central Chile

Wild lettuces (Lactuca L.) may provide valuable genetic resources for crop breeding, but are also significant invasive weeds. Monitoring populations of these species is important, therefore, both to inform genetic resource conservation efforts as well as for non-native plant species control. We explored the occurrences, distributions, and characteristics of populations of wild Lactuca species in central Chile through field surveys in 2016 and 2017, significantly adding to the available information on these species in the region. We documented two species - prickly lettuce (Lactuca serriola L.) and opium (bitter) lettuce (Lactuca virosa L.) in 204 localities. Occurrence only of L. serriola was recorded at 166 sites, only L. virosa at 21 sites, and both at 17 sites. Prickly lettuce was observed equally in urban areas and along transport corridors outside cities. Population sizes varied from a few plants to hundreds of individuals. Opium lettuce was recorded most frequently along roads outside cities, with population sizes of several individuals to a dozen. Species succession in different elevational gradients was observed along three roads: R 60 (Los Andes – Portillo), G-27 (Cajón Maipú), and 115 (Lago Colbún – Lago del Maule). These observations indicate that: i) both allochthonous (Euroasian) wild Lactuca species occur and are able to regenerate in central Chile; ii) L. serriola forms dense populations in urbanized areas; iii) both species can expand along transport corridors to high elevations; iv) the spread of L. virosa and persistence of dense populations in elevations above 2,000 m a.s.l. prove the invasiveness of this species in extreme climates; v) both species should be monitored (and treated) both in urbanized and agricultural areas, as well as in unique local mountainous areas

Brain status modeling with non-negative projective dictionary learning

Accurate prediction of individuals’ brain age is critical to establish a baseline for normal brain development. This study proposes to model brain development with a novel non-negative projective dictionary learning (NPDL) approach, which learns a discriminative representation of multi-modal neuroimaging data for predicting brain age. Our approach encodes the variability of subjects in different age groups using separate dictionaries, projecting features into a low-dimensional manifold such that information is preserved only for the corresponding age group. The proposed framework improves upon previous discriminative dictionary learning methods by inc

Seroincidence and phylogeny of human immunodeficiency virus infections in a cohort of commercial sex workers in Montevideo, Uruguay

Fil: Viñoles, Jose. HIV/AIDS National Control Program, and Department of Laboratories of Public Health, Ministry of Health, Montevideo; Uruguay.Fil: Serra, Margarita. HIV/AIDS National Control Program, and Department of Laboratories of Public Health, Ministry of Health, Montevideo; Uruguay.Fil: Russi, J. Ministerio de Salud Pública. Departamento de Laboratorios; Uruguay.Fil: Ruchansky, Dora. Servicio de Virología Molecular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.Fil: Sosa-Estani, Sergio. ANLIS Dr.C.G.Malbrán. Centro Nacional de Diagnóstico e Investigación en Endemo-Epidemias; Argentina.Fil: Montano, Silvia M. US Naval Medical Research Center Detachment-Lima; Peru.Fil: Carrion, Gladys. US Naval Medical Research Center Detachment (NMRCD). Unit 3800, APO-AA 34031-3800, Lima; Peru.Fil: Eyzaguirre, Lindsay. Department of Epidemiology, Institute of Human Virology, University of Maryland Biotechnology Institute, 725 West Lombard Street, Baltimore; Estados Unidos.Fil: Carr, Jean K. US Military HIV Research Program and Henry M. Jackson Foundation, Rockville, MD; Estados Unidos.Fil: Olson, James G. US Naval Medical Research Center Detachment-Lima; Peru.Fil: Bautista, Christian T. US Military HIV Research Program at the Walter Reed Army Institute of Research, Division of Retrovirology, the Henry M Jackson Foundation for the Advancement Military Medicine, Inc, Rockville, MD; Estados Unidos.Fil: Sanchez, Jose L. US Military HIV Research Program and Henry M. Jackson Foundation, Rockville, MD; Estados Unidos.Fil: Weissenbacher, Mercedes. Centro Nacional de Referencia de SIDA, Universidad de Buenos Aires; Argentina.A cohort study involving 60 human immunodeficiency virus (HIV)-negative male transvestite commercial sex workers (CSWs) was conducted in Montevideo, Uruguay in 1999-2001. Serum samples were tested for HIV by an enzyme-linked immunosorbent assay screening with immunoblot confirmation. Six participants seroconverted for an incidence-density rate of 6.03 (95% confidence interval = 2.21-13.12) per 100 person-years. Inconsistent condom use during client sex (adjusted hazard ratio [AHR] = 6.7), during oral sex (AHR = 5.6), and at the last sexual encounter (AHR = 7.8), and use of marihuana (AHR = 5.4) were marginally associated with HIV seroconversion. Five samples were genotyped in the protease and reverse transcriptase regions; three were subtypes B and two were BF recombinants. Full genome analysis of four samples confirmed all three subtype B samples and one of the two BF recombinants. Male transvestite CSWs sustained a high rate of HIV infection. Larger prospective studies are required to better define subtypes and associated sexual and drug-related risk factors

Bibliometric analysis of academic journal recommendations and requirements for surgical and anesthesiologic adverse events reporting.

BACKGROUND Standards for reporting surgical adverse events vary widely within the scientific literature. Failure to adequately capture adverse events hinders efforts to measure the safety of healthcare delivery and improve the quality of care. The aim of the present study is to assess the prevalence and typology of perioperative adverse event reporting guidelines among surgery and anesthesiology journals. MATERIALS AND METHODS In November 2021, three independent reviewers queried journal lists from the SCImago Journal & Country Rank (SJR) portal (www.scimagojr.com), a bibliometric indicator database for surgery and anesthesiology academic journals. Journal characteristics were summarized using SCImago, a bibliometric indicator database extracted from Scopus journal data. Quartile 1 (Q1) was considered the top quartile and Q4 bottom quartile based on the journal impact factor. Journal author guidelines were collected to determine whether adverse event reporting recommendations were included and, if so, the preferred reporting procedures. RESULTS Of 1,409 journals queried, 655 (46.5%) recommended surgical adverse event reporting. Journals most likely to recommend adverse event reporting were: 1) by category surgery (59.1%), urology (53.3%), and anesthesia (52.3%); 2) in top SJR quartiles (i.e. more influential); 3) by region, based in Western Europe (49.8%), North America (49.3%), and the Middle East (48.3%). CONCLUSIONS Surgery and anesthesiology journals do not consistently require or provide recommendations on perioperative adverse event reporting. Journal guidelines regarding adverse event reporting should be standardized and are needed to improve the quality of surgical adverse event reporting with the ultimate goal of improving patient morbidity and mortality

Recent results from Fermilab E690

Partial wave analysis results of centrally produced mesons in the reaction pp {yields} P{sub slow}(X)P{sub fast}, with 800 GeV/c protons incident on a liquid hydrogen target are presented. In the reactions considered in this paper the (X) system decays into: a) K{sup 0}{sub s}K{sup {+-}}{pi}{sup {-+}}, b) K{sub s}K{sub s}, and c) {pi}{sup +}{pi}{sup -}

MAP1B Regulates Axonal Development by Modulating Rho-GTPase Rac1 Activity

This article shows a novel function for the MAP1B protein, related to the control of actin dynamics through interaction with Tiam1

Bayesian Comparison of Neurovascular Coupling Models Using EEG-fMRI

Functional magnetic resonance imaging (fMRI), with blood oxygenation level-dependent (BOLD) contrast, is a widely used technique for studying the human brain. However, it is an indirect measure of underlying neuronal activity and the processes that link this activity to BOLD signals are still a topic of much debate. In order to relate findings from fMRI research to other measures of neuronal activity it is vital to understand the underlying neurovascular coupling mechanism. Currently, there is no consensus on the relative roles of synaptic and spiking activity in the generation of the BOLD response. Here we designed a modelling framework to investigate different neurovascular coupling mechanisms. We use Electroencephalographic (EEG) and fMRI data from a visual stimulation task together with biophysically informed mathematical models describing how neuronal activity generates the BOLD signals. These models allow us to non-invasively infer the degree of local synaptic and spiking activity in the healthy human brain. In addition, we use Bayesian model comparison to decide between neurovascular coupling mechanisms. We show that the BOLD signal is dependent upon both the synaptic and spiking activity but that the relative contributions of these two inputs are dependent upon the underlying neuronal firing rate. When the underlying neuronal firing is low then the BOLD response is best explained by synaptic activity. However, when the neuronal firing rate is high then both synaptic and spiking activity are required to explain the BOLD signal

New approaches to the study of human brain networks underlying spatial attention and related processes

Cognitive processes, such as spatial attention, are thought to rely on extended networks in the human brain. Both clinical data from lesioned patients and fMRI data acquired when healthy subjects perform particular cognitive tasks typically implicate a wide expanse of potentially contributing areas, rather than just a single brain area. Conversely, evidence from more targeted interventions, such as transcranial magnetic stimulation (TMS) or invasive microstimulation of the brain, or selective study of patients with highly focal brain damage, can sometimes indicate that a single brain area may make a key contribution to a particular cognitive process. But this in turn raises questions about how such a brain area may interface with other interconnected areas within a more extended network to support cognitive processes. Here, we provide a brief overview of new approaches that seek to characterise the causal role of particular brain areas within networks of several interacting areas, by measuring the effects of manipulations for a targeted area on function in remote interconnected areas. In human participants, these approaches include concurrent TMS-fMRI and TMS-EEG, as well as combination of the focal lesion method in selected patients with fMRI and/or EEG measures of the functional impact from the lesion on interconnected intact brain areas. Such approaches shed new light on how frontal cortex and parietal cortex modulate sensory areas in the service of attention and cognition, for the normal and damaged human brain