Refractive Development in the “ROP Rat”

Although retinopathy of prematurity (ROP) is clinically characterized by abnormal retinal vessels at the posterior pole of the eye, it is also commonly characterized by vascular abnormalities in the anterior segment, visual dysfunction which is based in retinal dysfunction, and, most commonly of all, arrested eye growth and high refractive error, particularly (and paradoxically) myopia. The oxygen-induced retinopathy rat model of ROP presents neurovascular outcomes similar to the human disease, although it is not yet known if the “ROP rat” also models the small-eyed myopia characteristic of ROP. In this study, magnetic resonance images (MRIs) of albino (Sprague-Dawley) and pigmented (Long-Evans) ROP rat eyes, and age- and strain-matched room-air-reared (RAR) controls, were examined. The positions and curvatures of the various optical media were measured and the refractive state (℞) of each eye estimated based on a previously published model. Even in adulthood (postnatal day 50), Sprague-Dawley and Long-Evans ROP rats were significantly myopic compared to strain-matched controls. The myopia in the Long-Evans ROP rats was more severe than in the Sprague-Dawley ROP rats, which also had significantly shorter axial lengths. These data reveal the ROP rat to be a novel and potentially informative approach to investigating physiological mechanisms in myopia in general and the myopia peculiar to ROP in particular

Examining the reversibility of long-term behavioral disruptions in progeny of maternal SSRI exposure

Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6(+/-) mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy

BBMS + + – basic bioinformatics meta-searcher

In this paper we present a Basic Bioinformatics Meta-searcher (BBMS), a web-based service aiming to simplify and integrate biological data searching through selected biological databases. BBMS facilitates biological data searching enabling multiple sources transparently, increasing research productivity as it avoids time consuming learning and parameterization of different search engines. As a complementary service, BBMS provides insight and links to common online bioinformatics tools. Users’ feedback when evaluating BBMS in terms of usability, usefulness and efficiency was very positive

Tuning supersymmetric models at the LHC: A comparative analysis at two-loop level

We provide a comparative study of the fine tuning amount (Delta) at the two-loop leading log level in supersymmetric models commonly used in SUSY searches at the LHC. These are the constrained MSSM (CMSSM), non-universal Higgs masses models (NUHM1, NUHM2), non-universal gaugino masses model (NUGM) and GUT related gaugino masses models (NUGMd). Two definitions of the fine tuning are used, the first (Delta_{max}) measures maximal fine-tuning wrt individual parameters while the second (Delta_q) adds their contribution in "quadrature". As a direct result of two theoretical constraints (the EW minimum conditions), fine tuning (Delta_q) emerges as a suppressing factor (effective prior) of the averaged likelihood (under the priors), under the integral of the global probability of measuring the data (Bayesian evidence p(D)). For each model, there is little difference between Delta_q, Delta_{max} in the region allowed by the data, with similar behaviour as functions of the Higgs, gluino, stop mass or SUSY scale (m_{susy}=(m_{\tilde t_1} m_{\tilde t_2})^{1/2}) or dark matter and g-2 constraints. The analysis has the advantage that by replacing any of these mass scales or constraints by their latest bounds one easily infers for each model the value of Delta_q, Delta_{max} or vice versa. For all models, minimal fine tuning is achieved for M_{higgs} near 115 GeV with a Delta_q\approx Delta_{max}\approx 10 to 100 depending on the model, and in the CMSSM this is actually a global minimum. Due to a strong ($\approx$ exponential) dependence of Delta on M_{higgs}, for a Higgs mass near 125 GeV, the above values of Delta_q\approx Delta_{max} increase to between 500 and 1000. Possible corrections to these values are briefly discussed.Comment: 23 pages, 46 figures; references added; some clarifications (section 2

Properties of 125 GeV Higgs boson in non-decoupling MSSM scenarios

Tantalizing hints of the Higgs boson of mass around 125 GeV have been reported at the LHC. We explore the MSSM parameter space in which the 125 GeV state is identified as the heavier of the CP even Higgs bosons, and study two scenarios where the two photon production rate can be significantly larger than the standard model (SM). In one scenario, $\Gamma(H\to \gamma\gamma)$ is enhanced by a light stau contribution, while the $WW^{\ast}$ ($ZZ^{\ast}$) rate stays around the SM rate. In the other scenario, $\Gamma(H\to b\bar{b})$ is suppressed and not only the $\gamma\gamma$ but also the $WW^{\ast}$ ($ZZ^{\ast}$) rates should be enhanced. The $\tau\bar{\tau}$ rate can be significantly larger or smaller than the SM rate in both scenarios. Other common features of the scenarios include top quark decays into charged Higgs boson, single and pair production of all Higgs bosons in $e^+e^-$ collisions at $\sqrt{s}\lesssim 300$ GeV.Comment: 20 pages, 5 figures, accepted version for publication in JHE

Point Prevalence Surveys of Antimicrobial Use among Hospitalized Children in Six Hospitals in India in 2016.

The prevalence of antimicrobial resistance in India is among the highest in the world. Antimicrobial use in inpatient settings is an important driver of resistance, but is poorly characterized, particularly in hospitalized children. In this study, conducted as part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) project, we examined the prevalence of and indications of antimicrobial use, as well as antimicrobial agents used among hospitalized children by conducting four point prevalence surveys in six hospitals between February 2016 and February 2017. A total of 681 children were hospitalized in six hospitals across all survey days, and 419 (61.5%) were prescribed one or more antimicrobials (antibacterials, antivirals, antifungals). Antibacterial agents accounted for 90.8% (547/602) of the total antimicrobial prescriptions, of which third-generation cephalosporins (3GCs) accounted for 38.9% (213/547) and penicillin plus enzyme inhibitor combinations accounted for 14.4% (79/547). Lower respiratory tract infection (LRTI) was the most common indication for prescribing antimicrobials (149 prescriptions; 24.8%). Although national guidelines recommend the use of penicillin and combinations as first-line agents for LRTI, 3GCs were the most commonly prescribed antibacterial agents (55/149 LRTI prescriptions; 36.9%). In conclusion, 61.5% of hospitalized children were on at least one antimicrobial agent, with excessive use of 3GCs. Hence there is an opportunity to limit their inappropriate use

R-parity Conservation via the Stueckelberg Mechanism: LHC and Dark Matter Signals

We investigate the connection between the conservation of R-parity in supersymmetry and the Stueckelberg mechanism for the mass generation of the B-L vector gauge boson. It is shown that with universal boundary conditions for soft terms of sfermions in each family at the high scale and with the Stueckelberg mechanism for generating mass for the B-L gauge boson present in the theory, electric charge conservation guarantees the conservation of R-parity in the minimal B-L extended supersymmetric standard model. We also discuss non-minimal extensions. This includes extensions where the gauge symmetries arise with an additional U(1)_{B-L} x U(1)_X, where U(1)_X is a hidden sector gauge group. In this case the presence of the additional U(1)_X allows for a Z' gauge boson mass with B-L interactions to lie in the sub-TeV region overcoming the multi-TeV LEP constraints. The possible tests of the models at colliders and in dark matter experiments are analyzed including signals of a low mass Z' resonance and the production of spin zero bosons and their decays into two photons. In this model two types of dark matter candidates emerge which are Majorana and Dirac particles. Predictions are made for a possible simultaneous observation of new physics events in dark matter experiments and at the LHC.Comment: 38 pages, 7 fig

Effects of the Mutant TP53 Reactivator APR-246 on Therapeutic Sensitivity of Pancreatic Cancer Cells in the Presence and Absence of WT-TP53

The TP53 tumor suppressor is mutated in ~75% of pancreatic cancers. The mutant TP53 protein in pancreatic ductal adenocarcinomas (PDAC) promotes tumor growth and metastasis. Attempts have been made to develop molecules that restore at least some of the properties of wildtype (WT) TP53. APR-246 is one such molecule, and it is referred to as a mutant TP53 reactivator. To understand the potential of APR-246 to sensitize PDAC cells to chemotherapy, we introduced a vector encoding WT-TP53 into two PDAC cell lines, one lacking the expression of TP53 (PANC-28) and one with a gain-of-function (GOF) mutant TP53 (MIA-PaCa-2). APR-246 increased drug sensitivity in the cells containing either a WT or mutant TP53 protein with GOF activity, but not in cells that lacked TP53. The introduction of WT-T53 into PANC-28 cells increased their sensitivity to the TP53 reactivator, chemotherapeutic drugs, and signal transduction inhibitors. The addition of WT-TP53 to PDAC cells with GOF TP53 also increased their sensitivity to the drugs and therapeutics, indicating that APR-246 could function in cells with WT-TP53 and GOF TP53. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function through the reactivation of TP53

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/\u3b2-catenin signaling and \u3b2-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-\u3baB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth