bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing Immunization Strategies in Patients with IBD
Authors: Caldera Freddy , Ley Dana , Hayney Mary S , Farraye Francis A
Published: March 2020

Recent advances in the treatment of inflammatory bowel disease (IBD) include the use of immune modifiers and monoclonal antibodies, such as tumor necrosis factor (TNF) alpha inhibitors, anti-integrin agents, janus kinase inhibitors, and interleukin-12/23 inhibitors. These agents achieve higher rates of clinical remission and mucosal healing than conventional therapy. However, these therapies increase the risk of infections, including some vaccine-preventable diseases. Infections are one of the most common adverse event of immunosuppressive therapy. Thus, providers should optimize immunization strategies to reduce the risk of vaccine-preventable infections in patients with IBD. There are several newly licensed vaccines recommended for adults by the US Advisory Committee on Immunization Practices. This review will focus on how gastroenterology providers can implement the adult immunization schedule approved by ACIP for patients with IBD.
Blood and Lymph Node Dissemination of Clonal Genome-Intact Human Immunodeficiency Virus 1 DNA Sequences During Suppressive Antiretroviral Therapy
Authors: Kuo Hsiao-Hsuan , Banga Riddhima , Lee Guinevere Q , Gao Ce , Cavassini Matthias , Corpataux Jean-Marc , Blackmer Jane E , zur Wiesch Schulze , Yu Xu G , Pantaleo Giuseppe , Perreau Matthieu , Lichterfeld Mathias
Published: March 2020

The majority of cells with latent human immunodeficiency virus 1 infection are located in lymphoid tissues that are difficult to access. In the current study, we used single-genome near-full-length proviral sequencing to evaluate intact and defective proviruses in blood and lymph node CD4 T cells enriched for specific functional polarizations. We observed minor variations between the frequencies of proviral sequences within individual CD4 T-cell subsets and across tissue compartments. However, we noted multiple clonal clusters of identical intact or defective proviral sequences from distinct compartments and CD4 T-cell subpopulations, suggesting frequent interchanges between viral reservoir cells in blood and tissues.
Why is the Mass Public Not More Supportive of Free Trade? Evidence from the United States
Authors: Bearce David H , Moya Samantha L
Published: March 2020

This article explores why citizens favor protection despite the economic case for free trade. It argues that due to a lack of training and in an environment of stable prices, many individuals are not aware of the consumption benefits. Even when they are aware, citizens tend to discount these benefits due to media coverage of the employment costs and loss aversion. The article presents survey evidence from an American sample, showing that a belief in lost jobs is more strongly associated with trade preferences than a belief in lower prices. Given that the former pushes citizens toward less favorable trade attitudes, it also presents evidence from a priming experiment, testing if attitudes can be moved in a more favorable direction with positive information. Factual information about the consumer benefits has no effect, but information about the employment effects shifts attitudes positively. In the present environment, it thus appears more effective to prime pro-trade attitudes by appealing to jobs than to prices.
Role of low-level quinolone resistance in generating tolerance in Escherichia coli under therapeutic concentrations of ciprofloxacin
Authors: Ortiz-Padilla M , Diaz-Diaz S , Machuca J , Tejada-Gonzalez A , Recacha E , Docobo-Pérez F , Pascual A , Rodríguez-Martínez J M
Published: March 2020

Background

Tolerance (including persistence) and resistance result in increased survival under antibiotic pressure.

Objectives

We evaluated the interplay between resistance and tolerance to ciprofloxacin under therapeutic and killing conditions to determine the contribution of low-level quinolone resistance (LLQR) mechanisms to tolerance. We also determined how the interaction between resistance (LLQR phenotypes) and tolerance was modified under SOS response suppression.

Methods

Twelve isogenic Escherichia coli strains harbouring quinolone resistance mechanisms combined with SOS response deficiency and six clinical E. coli isolates (LLQR or non-LLQR) were evaluated. Survival (tolerance or persistence) assays were used to measure surviving bacteria after a short period (up to 4 h) of bactericidal antibiotic treatment under therapeutic and killing concentrations of ciprofloxacin [1 mg/L, EUCAST/CLSI breakpoint for resistance; and 2.5 mg/L, peak serum concentration (Cmax) of this drug].

Results

QRDR substitutions (S83L in GyrA alone or combined with S80R in ParC) significantly increased the fraction of tolerant bacteria (2–4 log10 cfu/mL) after exposure to ciprofloxacin at clinically relevant concentrations. The impact on tolerant bacteria due to SOS response suppression (including persistence mediated by the tisB gene) was reversed by LLQR mechanisms at therapeutic concentrations. Furthermore, no reduction in the fraction of tolerant bacteria due to SOS response suppression was observed when S83L in GyrA plus S80R in ParC were combined.

Conclusions

Tolerance and quinolone resistance mutations interact synergistically, giving LLQR mechanisms an additional role in allowing bacterial survival and evasion of therapeutic antimicrobial conditions by a combination of the two strategies. At clinically relevant concentrations, LLQR mechanisms reverse further impact of SOS response suppression in reducing bacterial tolerance.
Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease
Authors: Avataneo Valeria , de Nicolò Amedeo , Cusato Jessica , Antonucci Miriam , Manca Alessandra , Palermiti Alice , Waitt Catriona , Walimbwa Stephen , Lamorde Mohammed , di Perri Giovanni , D’Avolio Antonio
Published: March 2020

Background

Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.

Objectives

The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.

Methods

Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.

Results

Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.

Conclusions

This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.
Screening of OXA-244 producers, a difficult-to-detect and emerging OXA-48 variant?
Authors: Emeraud Cecile , Biez Laura , Girlich Delphine , Jousset Agnès B , Naas Thierry , Bonnin Rémy A , Dortet Laurent
Published: March 2020

Background

OXA-244, a single amino acid variant of OXA-48, demonstrates weaker hydrolytic activity towards carbapenems and temocillin compared with OXA-48. Of note, these antimicrobials are present in high concentrations in several carbapenemase-producing Enterobacterales (CPE) screening media. As a result, some screening media fail to grow OXA-244-producing isolates, while the prevalence of OXA-244 producers is constantly increasing in France.

Methods

Here, we evaluate the performance of three commercially available CPE screening media [ChromID® CARBA SMART (bioMérieux), Brilliance™ CRE (Thermo Fisher) and mSuperCARBA™ (MAST Diagnostic)] for their ability to detect OXA-244 producers (n = 101). As OXA-244 producers may also express an ESBL, two additional ESBL screening media were tested (Brilliance™ ESBL and ChromID® BLSE). MICs of temocillin and imipenem were determined by broth microdilution. The clonality of OXA-244-producing Escherichia coli isolates (n = 97) was assessed by MLST.

Results

Overall, the sensitivity of the ChromID® CARBA SMART, Brilliance™ CRE and mSuperCARBA™ media were 14% (95% CI = 8.1%–22.5%), 54% (95% CI = 43.3%–63.4%) and 99% (95% CI = 93.8%–100%), respectively, for the detection of OXA-244 producers. Among the 101 OXA-244-producing isolates, 96% were E. coli and 77%–78% grew on ESBL screening media. MLST analysis identified five main STs among OXA-244-producing E. coli isolates: ST38 (n = 37), ST361 (n = 17), ST69 (n = 12), ST167 (n = 11) and ST10 (n = 8).

Conclusions

Our results demonstrated that the mSuperCARBA™ medium is very efficient in the detection of OXA-244 producers, unlike the ChromID® CARBA SMART medium. The high prevalence of ESBLs among OXA-244 producers allowed detection of 77%–78% of them using ESBL-specific screening media.
Gene disruption of medaka (Oryzias latipes) orthologue for mammalian tissue-type transglutaminase (TG2) causes movement retardation
Authors: Watanabe Yuko , Okuya Kazuho , Takada Yuki , Kinoshita Masato , Yokoi Saori , Chisada Shinichi , Kamei Yasuhiro , Tatsukawa Hideki , Yamamoto Naoyuki , Abe Hideki , Hashimoto Hisashi , Hitomi Kiyotaka
Published: March 2020

Transglutaminases are an enzyme family that catalyses protein cross-linking essential for several biological functions. In the previous studies, we characterized the orthologues of the mammalian transglutaminase family in medaka (Oryzias latipes), an established fish model. Among the human isozymes, tissue-type transglutaminase (TG2) has multiple functions that are involved in several biological phenomena. In this study, we established medaka mutants deficient for the orthologue of human TG2 using the CRISPR/Cas9 and transcription activator-like effector nucleases systems. Although apparent morphological changes in the phenotype were not observed, movement retardation was found in the mutant fish when evaluated by a tank-diving test. Furthermore, comparative immunohistochemistry analysis using in this fish model revealed that orthologue of human TG2 was expressed at the periventricular layer of the optic tectum. Our findings provide novel insight for the relationship between tissue-type transglutaminase and the nervous system and the associated behaviour.
Make It Hot? How Food Temperature (Mis)Guides Product Judgments
Authors: Yamim Amanda P , Mai Robert , Werle Carolina O C
Published: March 2020

Despite being a basic food property, food temperature has been largely neglected by consumer research thus far. This research proposes that consumers spontaneously infer that warm foods contain more calories, an unexplored lay belief we named the “warm is calorie-rich” intuition. Eight studies reveal that this deep-seated intuition has powerful implications in terms of guiding (and often biasing) product judgments and consumption decisions. Temperature-induced calorie inferences are rooted in perceptions that warm foods are more filling and tastier than cold ones, which enhance warm foods’ desirability and affect consumer choices. The preference for warm products is mitigated when food energy does not provide utility to consumers though, such as when consumers have a health goal active, and it reverses when consumers purposefully aim to reduce their calorie intake. The “warm is calorie-rich” intuition is important for marketers and managers because warm food temperatures can increase willingness to pay (by 25%) and amount served (+27%), as well as influence consumer preferences. This intuition also has important public policy implications: consumers tend to underestimate the nutritional value of cold foods, resulting in increased consumption of calories (+31%) and fat (+37%).
Heparan Sulfate Proteoglycans Undergo Differential Expression Alterations in Alzheimer Disease Brains
Authors: Lorente-Gea Laura , García Beatriz , Martín Carla , Ordiales Helena , García-Suárez Olivia , Piña-Batista Kelvin M , Merayo-Lloves Jesús , Quirós Luís M , Fernández-Vega Iván
Published: March 2020

Previous studies have reported that heparan sulfate proteoglycans (HSPGs) promote amyloid-beta peptide and tau fibrillization in Alzheimer disease (AD) and provide resistance against proteolytic breakdown. We compared the expression levels of 17 HSPG core proteins in 18 AD cases and 6 controls. RT-PCR was used to analyze transcription levels. Immunohistochemistry was performed to localize HSPGs in the brain tissue. We detected expression of all HSPG genes investigated. SDC1, GPC3, and CD44v3 showed the lowest levels of expression, while SDC3 and GPC1 showed the highest. Remarkably, SDC4 and SRGN were overexpressed in most of the areas analyzed. Immunohistochemistry revealed the presence of both SDC4 and SRGN mostly associated with tau and amyloid-β pathology throughout the AD brains. In conclusion, in view of the involvement of HSPGs in AD pathology, especially SDC4 and SRGN, there would seem to be a relationship between the regulation of core protein expression and the pathological features suggesting HSPGs are potential inducers of the disease.
Identification of client iron–sulfur proteins of the chloroplastic NFU2 transfer protein in Arabidopsis thaliana
Authors: Berger Nathalie , Vignols Florence , Przybyla-Toscano Jonathan , Roland Mélanie , Rofidal Valérie , Touraine Brigitte , Zienkiewicz Krzysztof , Couturier Jérémy , Feussner Ivo , Santoni Véronique , Rouhier Nicolas , Gaymard Frédéric , Dubos Christian
Published: March 2020

Iron–sulfur (Fe-S) proteins have critical functions in plastids, notably participating in photosynthetic electron transfer, sulfur and nitrogen assimilation, chlorophyll metabolism, and vitamin or amino acid biosynthesis. Their maturation relies on the so-called SUF (sulfur mobilization) assembly machinery. Fe-S clusters are synthesized de novo on a scaffold protein complex and then delivered to client proteins via several transfer proteins. However, the maturation pathways of most client proteins and their specificities for transfer proteins are mostly unknown. In order to decipher the proteins interacting with the Fe-S cluster transfer protein NFU2, one of the three plastidial representatives found in Arabidopsis thaliana, we performed a quantitative proteomic analysis of shoots, roots, and seedlings of nfu2 plants, combined with NFU2 co-immunoprecipitation and binary yeast two-hybrid experiments. We identified 14 new targets, among which nine were validated in planta using a binary bimolecular fluorescence complementation assay. These analyses also revealed a possible role for NFU2 in the plant response to desiccation. Altogether, this study better delineates the maturation pathways of many chloroplast Fe-S proteins, considerably extending the number of NFU2 clients. It also helps to clarify the respective roles of the three NFU paralogs NFU1, NFU2, and NFU3.
Massive discs around low-mass stars
Authors: Haworth Thomas J , Cadman James , Meru Farzana , Hall Cassandra , Albertini Emma , Forgan Duncan , Rice Ken , Owen James E
Published: March 2020

We use a suite of smoothed particle hydrodynamic simulations to investigate the susceptibility of protoplanetary discs to the effects of self-gravity as a function of star–disc properties. We also include passive irradiation from the host star using different models for the stellar luminosities. The critical disc-to-star mass ratio for axisymmetry (for which we produce criteria) increases significantly for low-mass stars. This could have important consequences for increasing the potential mass reservoir in a proto Trappist-1 system, since even the efficient Ormel et al. formation model will be influenced by processes like external photoevaporation, which can rapidly and dramatically deplete the dust reservoir. The aforementioned scaling of the critical Md/M* for axisymmetry occurs in part because the Toomre Q parameter has a linear dependence on surface density (which promotes instability) and only an $M_*^{1/2}$ dependence on shear (which reduces instability), but also occurs because, for a given Md/M*, the thermal evolution depends on the host star mass. The early phase stellar irradiation of the disc (for which the luminosity is much higher than at the zero age main sequence, particularly at low stellar masses) can also play a key role in significantly reducing the role of self-gravity, meaning that even solar mass stars could support axisymmetric discs a factor two higher in mass than usually considered possible. We apply our criteria to the DSHARP discs with spirals, finding that self-gravity can explain the observed spirals so long as the discs are optically thick to the host star irradiation.
Euclid: the selection of quiescent and star-forming galaxies using observed colours
Authors: Bisigello L , Kuchner U , Conselice C J , Andreon S , Bolzonella M , Duc P-A , Garilli B , Humphrey A , Maraston C , Moresco M , Pozzetti L , Tortora C , Zamorani G , Auricchio N , Brinchmann J , Capobianco V , Carretero J , Castander F J , Castellano M , Cavuoti S , Cimatti A , Cledassou R , Congedo G , Conversi L , Corcione L , Cropper M S , Dusini S , Frailis M , Franceschi E , Franzetti P , Fumana M , Hormuth F , Israel H , Jahnke K , Kermiche S , Kitching T , Kohley R , Kubik B , Kunz M , Le Fèvre O , Ligori S , Lilje P B , Lloro I , Maiorano E , Marggraf O , Massey R , Masters D C , Mei S , Mellier Y , Meylan G , Padilla C , Paltani S , Pasian F , Pettorino V , Pires S , Polenta G , Poncet M , Raison F , Rhodes J , Roncarelli M , Rossetti E , Saglia R , Sauvage M , Schneider P , Secroun A , Serrano S , Sureau F , Taylor A N , Tereno I , Toledo-Moreo R , Valenziano L , Wang Y , Wetzstein M , Zoubian J
Published: March 2020

The Euclid mission will observe well over a billion galaxies out to z ∼ 6 and beyond. This will offer an unrivalled opportunity to investigate several key questions for understanding galaxy formation and evolution. The first step for many of these studies will be the selection of a sample of quiescent and star-forming galaxies, as is often done in the literature by using well-known colour techniques such as the ‘UVJ’ diagram. However, given the limited number of filters available for the Euclid telescope, the recovery of such rest-frame colours will be challenging. We therefore investigate the use of observed Euclid colours, on their own and together with ground-based u-band observations, for selecting quiescent and star-forming galaxies. The most efficient colour combination, among the ones tested in this work, consists of the (u − VIS) and (VIS − J) colours. We find that this combination allows users to select a sample of quiescent galaxies complete to above $\sim 70{{\ \rm per\ cent}}$ and with less than 15${{\ \rm per\ cent}}$ contamination at redshifts in the range 0.75 < z < 1. For galaxies at high-z or without the u-band complementary observations, the (VIS − Y) and (J − H) colours represent a valid alternative, with $\gt 65{{\ \rm per\ cent}}$ completeness level and contamination below 20${{\ \rm per\ cent}}$ at 1 < z < 2 for finding quiescent galaxies. In comparison, the sample of quiescent galaxies selected with the traditional UVJ technique is only $\sim 20{{\ \rm per\ cent}}$ complete at z < 3, when recovering the rest-frame colours using mock Euclid observations. This shows that our new methodology is the most suitable one when only Euclid bands, along with u-band imaging, are available.
On the unusually large spatial extent of the TeV nebula HESS J1825−137: implication from the energy-dependent morphology
Authors: Liu Ruo-Yu , Yan Huirong
Published: March 2020

Deep observation of the High Energy Stereoscopic System (HESS) on the most extended pulsar wind nebula HESS J1825−137 reveals an enhanced energy-dependent morphology, providing useful information on the particle transport mechanism in the nebula. We find that the energy-dependent morphology is consistent with a diffusion-dominated transport of electrons/positrons. It provides an alternative possible interpretation for the unusually large spatial extent (i.e. ${\gtrsim} 100$ pc) of the nebula, which could then be attributed to the diffusion of escaping electrons/positrons from a compact plerion. The influence of various model parameters on the energy-dependent extent of the nebula is studied in the diffusion-dominated scenario. We also show that the energy-dependent morphology of the nebula may also be used to study the spin-down history of the pulsar.
The ancient main-sequence solar proxy HIP 102152 unveils the activity and rotational fate of our Sun
Authors: Lorenzo-Oliveira Diego , Meléndez Jorge , Ponte Geisa , Yana Galarza Jhon
Published: March 2020

We present a detailed analysis of the possible future Sun’s rotational evolution scenario based on the 8-Gyr-old solar twin HIP 102152. Using HARPS high-cadence observations (and TESS light curves), we analysed the modulation of a variety of activity proxies (Ca ii , H i Balmer, and Na i lines), finding a strong rotational signal of 35.7 ± 1.4 d (log Bfactor ∼ 70, in the case of Ca ii K line). This value matches with the theoretical expectations regarding the smooth rotational evolution of the Sun towards the end of the main sequence, validating the use of gyrochronology after solar age.
The initial maturation status of marmoset testicular tissues has an impact on germ cell maintenance and somatic cell response in tissue fragment culture
Authors: Heckmann L , Langenstroth-Röwer D , Wistuba J , Portela J M D , van Pelt A M M , Redmann K , Stukenborg J B , Schlatt S , Neuhaus N
Published: March 2020

Successful in vitro spermatogenesis was reported using immature mouse testicular tissues in a fragment culture approach, raising hopes that this method could also be applied for fertility preservation in humans. Although maintaining immature human testicular tissue fragments in culture is feasible for an extended period, it remains unknown whether germ cell survival and the somatic cell response depend on the differentiation status of tissue. Employing the marmoset monkey (Callithrix jacchus), we aimed to assess whether the maturation status of prepubertal and peri-/pubertal testicular tissues influence the outcome of testis fragment culture. Testicular tissue fragments from 4- and 8-month-old (n = 3, each) marmosets were cultured and evaluated after 0, 7, 14, 28 and 42 days. Immunohistochemistry was performed for identification and quantification of germ cells (melanoma-associated antigen 4) and Sertoli cell maturation status (anti-Müllerian hormone: AMH). During testis fragment culture, spermatogonial numbers were significantly reduced (P < 0.05) in the 4- but not 8-month-old monkeys, at Day 0 versus Day 42 of culture. Moreover, while Sertoli cells from 4-month-old monkeys maintained an immature phenotype (i.e. AMH expression) during culture, AMH expression was regained in two of the 8-month-old monkeys. Interestingly, progression of differentiation to later meiotic stage was solely observed in one 8-month-old marmoset, which was at an intermediate state regarding germ cell content, with gonocytes as well as spermatocytes present, as well as Sertoli cell maturation status. Although species-specific differences might influence the outcome of testis fragment experiments in vitro, our study demonstrated that the developmental status of the testicular tissues needs to be considered as it seems to be decisive for germ cell maintenance, somatic cell response and possibly the differentiation potential.
A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1–associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study
Authors: Ullrich Nicole J , Prabhu Sanjay P , Reddy Alyssa T , Fisher Michael J , Packer Roger , Goldman Stewart , Robison Nathan J , Gutmann David H , Viskochil David H , Allen Jeffrey C , Korf Bruce , Cantor Alan , Cutter Gary , Thomas Coretta , Perentesis John P , Mizuno Tomoyuki , Vinks Alexander A , Manley Peter E , Chi Susan N , Kieran Mark W
Published: March 2020

Background

Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.

Methods

Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.

Results

Twenty-three participants (median age, 9.4 y; range, 3.2–21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.

Conclusion

Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.
Role of CX3CR1 signaling in malignant transformation of gliomas
Authors: Lee Sungho , Latha Khatri , Manyam Ganiraju , Yang Yuhui , Rao Arvind , Rao Ganesh
Published: March 2020

Background

Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs.

Methods

Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination.

Results

LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival.

Conclusions

CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.
Examining the Effect of Geographic Region of Residence on Childhood Malnutrition in Uganda
Authors: Amegbor Prince M , Yankey Ortis , Sabel Clive E
Published: March 2020

Objectives

In our study, we examine how geographic region of residence may predict childhood malnutrition, expressed as stunting, wasting and underweight, among children under the age of 5 years in Uganda.

Methods

Using data from the 2016 Uganda Demographic and Health Survey, we performed an incremental multivariate multilevel mixed-effect modelling to examine the effect of a child, parental and household factors on the association between region of residence and each indicator of childhood malnutrition.

Results

Approximately 28%, 3% and 9% of children under age 5 suffered from stunting, wasting and underweight, respectively. The bivariate result shows that the proportion of children suffering from stunting and underweight was relatively lower in the Kampala region compared with the other regions. With the exception of the Northern region (6.44%), wasting was higher (4.12%) among children in the Kampala region. Children in the other regions were more likely to experience stunting and underweight. When controlling for child, parent and household factors, children in the other regions were less likely to suffer from underweight and stunting, compared with those in Kampala region. Children in the other regions, except the Northern region, were less likely to be wasted compared with those in Kampala region.

Conclusion

Our finding suggests that child, parental and household characteristics have effects on the association between region of residence and childhood malnutrition. Addressing individual and household socioeconomic disparities may be vital in tackling regional differences in childhood malnutrition.
Identification of Leaf Rust Resistance Genes in Bread Wheat Cultivars from Ethiopia
Authors: Gebrewahid Takele Weldu , Zhang Pei-pei , Yao Zhan-jun , Li Zai-feng , Liu Da-qun
Published: March 2020

Wheat leaf rust, caused by Puccinia triticina (Pt), is a widespread disease of bread wheat worldwide. In the present study, 50 wheat cultivars from Ethiopia and 34 differential lines, mostly near-isogenic lines (NILs) in the background of Thatcher with known resistance genes to leaf rust (Lr), were tested with 14 Pt races in the greenhouse to postulate Lr genes at the seedling stage. Field experiments were also conducted to identify adult plant responses to leaf rust in Baoding in the 2017–2018 and 2018–2019 growing seasons and in Zhoukou in the 2018–2019 growing season. Thirteen Lr genes (Lr1, Lr18, Lr3ka, Lr15, Lr26, Lr20, Lr14a, Lr30, Lr2a, Lr11, Lr34, Lr46, and Lr68) either singly or in combination were found in 39 cultivars. Known Lr genes were not present in the remaining 11 cultivars. Lr1 and Lr46, each in 13 cultivars, and Lr34 in 12 cultivars were the most commonly identified resistance genes. Less frequently identified genes included Lr26 (five cultivars); Lr30 and Lr18 (each present in four cultivars); Lr15, Lr3ka, and Lr2a (each identified in three cultivars); and Lr68 (two cultivars). Evidence for the existence of Lr11, Lr20, and Lr14a (each in one cultivar) was also obtained. Twenty-one cultivars were found to have slow rusting resistance to leaf rust in the field tests. The results should be valuable for cultivar selection with combinations of effective Lr genes and used in breeding new cultivars with improved resistance to leaf rust in Ethiopia and China.
VdNPS, a Nonribosomal Peptide Synthetase, Is Involved in Regulating Virulence in Verticillium dahliae
Authors: Luo Xiumei , Tian Tingting , Tan Xue , Zheng Yixuan , Xie Chengjian , Xu Ya , Yang Xingyong
Published: March 2020

Nonribosomal peptide synthetases (NPS) are known for the biosynthesis of antibiotics, toxins, and siderophore production. They are also a virulence determinant in different phytopathogens. However, until now, the functional characterization of NPS in Verticillium dahliae has not been reported. Deletion of the NPS gene in V. dahliae led to the decrease of conidia, microsclerotia, and pathogenicity. ΔVdNPS strains were tolerant to H2O2, and the genes involved in H2O2 detoxification, iron/copper transport, and cytoskeleton were differentially expressed in ΔVdNPS. Interestingly, ΔVdNPS strains exhibited hypersensitivity to salicylic acid (SA), and the genes involved in SA hydroxylation were up-regulated in ΔVdNPS compared with wild-type V. dahliae under SA stress. Additionally, during infection, ΔVdNPS induced more pathogenesis-related gene expression, higher reactive oxygen species production, and stronger SA-mediated signaling transduction in host to overcome pathogen. Uncovering the function of VdNPS in pathogenicity could provide a reliable theoretical basis for the development of cultivars with durable resistance against V. dahliae-associated diseases.
Olanzapine for the Prevention of Postdischarge Nausea and Vomiting after Ambulatory Surgery
Authors: Hyman Jaime B. , Park Chang , Lin Hung-Mo , Cole Beatriz , Rosen Leigh , Fenske Suzanne S. , Barr Grzesh Rachel L. , Blank Stephanie V. , Polsky Sylvie B. , Hartnett Matthew , Taub Peter J. , Palvia Vijay , DeMaria Samuel , Ascher-Walsh Charles
Published: March 2020

Background

Postdischarge nausea and vomiting after ambulatory surgery is a common problem that is not adequately addressed in current practice. This prospective, randomized, double-blind, parallel-group, placebo-controlled study was designed to test the hypothesis that oral olanzapine is superior to placebo at preventing postdischarge nausea and vomiting.

Methods

In a single-center, double-blind, randomized, placebo-controlled trial, the authors compared a single preoperative dose of olanzapine 10 mg to placebo, in adult female patients 50 years old or less, undergoing ambulatory gynecologic or plastic surgery with general anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and ondansetron. The primary composite outcome was nausea and/or vomiting in the 24 h after discharge. Secondary outcomes included severe nausea, vomiting, and side effects.

Results

A total of 140 patients were randomized and evaluable. The primary outcome occurred in 26 of 69 patients (38%) in the placebo group and in 10 of 71 patients (14%) in the olanzapine group (relative risk, 0.37; 95% CI, 0.20 to 0.72; P = 0.003). Severe nausea occurred in 14 patients (20%) in the placebo group and 4 patients (6%) in the olanzapine group (relative risk, 0.28; 95% CI, 0.10 to 0.80). Vomiting occurred in eight patients (12%) in the placebo group and two patients (3%) in the olanzapine group (relative risk, 0.24; 95% CI, 0.05 to 1.10). The median score for sedation (scale 0 to 10, with 10 being highest) in the 24 h after discharge was 4 (interquartile range, 2 to 7) in the placebo group and 6 (interquartile range, 3 to 8) in the olanzapine group (P = 0.023).

Conclusions

When combined with ondansetron and dexamethasone, the addition of olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 h after discharge from ambulatory surgery by about 60% with a slight increase in reported sedation.

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What We Already Know about This Topic

What This Article Tells Us That Is New
Direct-acting antivirals and viral RNA targeting for hepatitis B cure
Authors: French Janine , Locarnini Stephen , Zoulim Fabien
Published: March 2020

Purpose of review

The current aim in the HBV landscape is to develop therapeutic strategies to achieve a functional cure of infection, characterized by a sustained loss of HBsAg off-treatment. Current treatment options, that is, nucleos(t)ide analogues and IFN are effective at viral suppression but very poor at achieving HBsAg loss. This article is designed to summarize the HBV life cycle in order to review the current treatment strategies and compounds targeting different points of the virus life cycle, which are either in preclinical or clinical phases.

Recent findings

Recently our developed understanding of the HBV life cycle has enabled the development of multiple novel treatment options, all aiming for functional cure.

It is likely that combinations of novel treatments will be needed to achieve a functional cure, including those that target the virus itself as well as those that target the immune system.
From Bimodal Hearing to Sequential Bilateral Cochlear Implantation in Children—A Within-Subject Comparison
Authors: Deep Nicholas L. , Green Janet E. , Chen Sophia , Shapiro William H. , McMenomey Sean O. , Thomas Roland J. , Waltzman Susan B.
Published: March 2020

Objective:

To evaluate the performance changes after sequential bilateral cochlear implantation in a pediatric population of bimodal cochlear implant (CI) users. To evaluate the factors which influence the parental and recipient decision to discontinue hearing aid use and seek a second implant.

Study Design:

Retrospective case review, within-subject comparison.

Setting:

Tertiary referral center.

Patients:

Thirty-one pediatric (<18 yr) bimodal CI users who underwent sequential bilateral CI.

Interventions:

Sequential bilateral CI.

Main Outcome Measures:

Parental and/or recipient's reasons for discontinuing their hearing aid and pursuing a second implant, device usage from datalogs, speech understanding in the bimodal and bilateral CI condition.

Results:

Parents/patients were motivated to pursue sequential bilateral CI based on their positive performance with CI1, the expectation of further improvement with a second CI, and the prospect of having a second independently functional ear. In the bimodal condition, mean word recognition score (WRS), sentence recognition in quiet (SIQ), and sentence recognition in noise (SIN) scores were 87.4, 97.3, and 92.9% respectively. At 1-year post-sequential bilateral CI, the mean WRS, SIQ, and SIN score were 92.7, 98.7, and 97.7%, respectively. The improvement in bilateral CI speech scores compared with bimodal scores was statistically significant for WRS (p = 0.015). A ceiling effect limited the ability to detect further meaningful differences on speech perception testing.

Conclusions:

The bilateral CI condition demonstrates equivalent or slightly superior performance compared with the bimodal condition. Several non-speech benefits were elicited from parents as reasons for pursuing a second implant. Close monitoring of the residual acoustic hearing, inquiring about the perceived benefits provided by the HA, and early counseling regarding the potential for sequential bilateral CI are important aspects in determining if and when a second implant is indicated.
Exploring the Relationship Between Schizotypal Traits and Dispositional Mindfulness From a Network Perspective
Authors: Bronchain Jonathan , Chabrol Henri
Published: March 2020

Schizotypy has been associated with impairment in social cognition (e.g., emotional processing, social perception, Theory of Mind). To our knowledge, no study has investigated these processes in terms of dispositional mindfulness. This study aimed to use network theory to explore the relationship between dispositional mindfulness dimensions and schizotypal traits. Participants were 1572 college students who completed the Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF) and the Schizotypal Personality Questionnaire-Brief (SPQ-B). We first estimated a Gaussian Graphical Model including the FFMQ-SF and the SPQ-B dimensions. We then computed centrality indices and predictability, and we finally conducted a bootstrapping procedure to assess the accuracy of edge weights and the stability of the centrality indices. Describing was strongly and negatively related to interpersonal schizotypy. Acting with awareness and nonjudgment shared negative edges with interpersonal schizotypy. These results provide potential keys to understand alexithymia, decreased sense of self-agency, and emotion regulation in schizotypy.
Factors affecting optic nerve head biomechanics in a rat model of glaucoma
Authors: Schwaner Stephen A. , Feola Andrew J. , Ethier C. Ross
Published: March 2020

Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells, which carry vision information from the retina to the brain. Although it is well accepted that biomechanics is an important part of the glaucomatous disease process, the mechanisms by which biomechanical insult, usually due to elevated intraocular pressure (IOP), leads to retinal ganglion cell death are not understood. Rat models of glaucoma afford an opportunity for learning more about these mechanisms, but the biomechanics of the rat optic nerve head (ONH), a primary region of damage in glaucoma, are only just beginning to be characterized. In a previous study, we built finite-element models with individual-specific rat ONH geometries. Here, we developed a parametrized model of the rat ONH and used it to perform a sensitivity study to determine the influence that six geometric parameters and 13 tissue material properties have on rat optic nerve biomechanical strains due to IOP elevation. Strain magnitudes and patterns in the parametrized model generally matched those from individual-specific models, suggesting that the parametrized model sufficiently approximated rat ONH anatomy. Similar to previous studies in human eyes, we found that scleral properties were highly influential: the six parameters with highest influence on optic nerve strains were optic nerve stiffness, IOP, scleral thickness, the degree of alignment of scleral collagen fibres, scleral ground substance stiffness and the scleral collagen fibre uncrimping coefficient. We conclude that a parametrized modelling strategy is an efficient approach that allows insight into rat ONH biomechanics. Further, scleral properties are important influences on rat ONH biomechanics, and additional efforts should be made to better characterize rat scleral collagen fibre organization.
Microbe Profile: Campylobacter jejuni – survival instincts
Authors: Gundogdu Ozan , Wren Brendan W.
Published: March 2020

Campylobacter jejuni

is considered to be the most common bacterial cause of human gastroenteritis worldwide.

C. jejuni

can cause bloody diarrhoea, fever and abdominal pain in humans along with post-infectious sequelae such as Guillain-Barré syndrome (a paralytic autoimmune complication).

C. jejuni

infections can be fatal, particularly among young children.

C. jejuni

are distributed in most warm-blooded animals, and therefore the main route of transmission is generally foodborne, via the consumption and handling of meat products (particularly poultry).

C. jejuni

is microaerophilic and oxygen-sensitive, although it appears to be omnipresent in the environment, one of the many contradictions of

Campylobacter

.
If Metformin Inhibited the Mitochondrial Glycerol Phosphate Dehydrogenase It Might Not Benefit Diabetes
Authors: MacDonald Michael J. , Ansari Israr-ul H. , Longacre Melissa J. , Stoker Scott W.
Published: March 2020

The mitochondrial glycerol phosphate dehydrogenase is the rate-limiting enzyme of the glycerol phosphate shuttle. It was recently claimed that metformin, a first line drug used worldwide for the treatment of type 2 diabetes, works by inhibiting the mitochondrial glycerol phosphate dehydrogenase 30-50% thus suppressing hepatic gluconeogenesis. This enzyme is 30-60 fold higher in the pancreatic islet than in liver. If metformin actually inhibited the enzyme, why would it not inhibit insulin secretion and exacerbate diabetes? Total body knockout of the mitochondrial glycerol phosphate dehydrogenase does not inhibit insulin secretion because insulin cells and liver cells possess the malate aspartate shuttle that is redundant to the action of the glycerol phosphate shuttle. In view of these and other apparent inconsistencies we reassessed the idea that metformin inhibited the mitochondrial glycerol phosphate dehydrogenase. We measured the enzyme’s activity in whole cell homogenates and mitochondria of insulin cells and liver cells using four different enzyme assays and were unable to show that metformin directly inhibits the enzyme. We conclude that metformin does not actually inhibit the enzyme. If it did, it might not be efficacious as a diabetes medicine.
Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
Authors: Smith Joan C. , Sausville Erin L. , Girish Vishruth , Yuan Monet Lou , John Kristen M. , Sheltzer Jason M.
Published: March 2020

The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive-feedback loops that increase ACE2 levels and facilitate viral dissemination.
Crystal structure of the SARS-CoV-2 non-structural protein 9, Nsp9
Authors: Littler D. R. , Gully B. S. , Colson R. N. , Rossjohn J
Published: March 2020

Many of the proteins produced by SARS-CoV-2 have related counterparts across the Severe Acute Respiratory Syndrome (SARS-CoV) family. One such protein is non-structural protein 9 (Nsp9), which is thought to mediate both viral replication and virulence. Current understanding suggests that Nsp9 is involved in viral genomic RNA reproduction. Nsp9 is thought to bind RNA via a fold that is unique to this class of betacoronoaviruses although the molecular basis for this remains ill-defined. We sought to better characterise the SARS-CoV-2 Nsp9 protein and subsequently solved its X-ray crystal structure, in an apo-form and, unexpectedly, in a peptide-bound form with a sequence originating from a rhinoviral 3C protease sequence (LEVL). The structure of the SARS-CoV-2 Nsp9 revealed the high level of structural conservation within the Nsp9 family. The exogenous peptide binding site is close to the dimer interface and impacted on the relative juxtaposition of the monomers within the homodimer. Together we have established a protocol for the production of SARS-CoV-2 Nsp9, determined its structure and identified a peptide-binding site that may warrant further study from the perspective of understanding Nsp9 function.