bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory effect of the compounds from the water extract of Curcuma longa on the production of PGE2 and NO in a macrophage cell line stimulated by LPS
Authors: Kawasaki Kengo , Okuda-Hanafusa Chinatsu , Aoyagi Morihiro , Taoka Koichi , Yamamoto Norio , Muroyama Koutarou , Murosaki Shinji , Yamamoto Yoshihiro
Published: August 2018

We wished to search for the compounds contributing to the anti-inflammatory effects of the water extract of Curcuma longa (WEC). WEC was fractioned and the fractions were evaluated with regard to their inhibitory effect on the production of nitric oxide (NO) from the macrophage cell line stimulated by lipopolysaccharide. Compounds in the active fractions were isolated and identified. One isolated compound was identified as new: (6S)-2-methyl-5-hydroxy-6-(3-hydroxy-4-methylphenyl)-2-heptene-4-one (1). Four isolated compounds were identified as known: (6S)-2-methyl-6-(4-hydroxyphenyl)-2-heptene-4-one (4), bisabolone-4-one (5), curcumenone (6), and turmeronol A (8). Three isolated compounds were not identified their stereostructures but their planar structures: 2-methyl-6-(4-hydroxymethyl-phenyl)-2-heptene-4-one (2), 2-methyl-6-(2,3-epoxy-4-methyl-4-cyclohexene)-2-heptene (3), and 4-methylene-5-hydroxybisabola-2,10-diene-9-one (7). Compounds 1, 4, 7 and 8 inhibited production of prostaglandin E2 and NO. Others inhibited NO production only. These results (at least in part) show the active compounds contributing to the anti-inflammatory effects of WEC, and may be useful for elucidating its various beneficial physiologic effects.
Learners’ views of (non)native speaker status, accent, and identity: an English as an international language perspective
Authors: Tamimi Sa’d Seyyed Hatam
Published: August 2018

The study examines perceptions of nonnative speakers (NNSs) of English toward accented speech and its relation with identity from the perspective of English as an international language (EIL). The data were collected from 51 Iranian EFL learners by means of questionnaires and interviews. The findings revealed the participants’ considerable uncertainty concerning the relationship between accent and socioeconomic and educational status as well as their reluctance to display their L1 identity through L1-accented speech. Furthermore, the results indicated that the participants are highly appreciative of NS accent, hold negative stereotypes of NNS accents and judge NNSs unfavorably. They exhibited a marked tendency to sound similar to NSs, regarding them as the best model of English accent to follow. The participants’ negative evaluations of NNSs’ accents of English are evidence of the dominance of Inner Circle speakers’ norms among the Expanding Circle speakers with implications for learning and teaching English as an international language.
Macropinosome formation by tent pole ruffling in macrophages
Authors: Condon Nicholas D. , Heddleston John M. , Chew Teng-Leong , Luo Lin , McPherson Peter S. , Ioannou Maria S. , Hodgson Louis , Stow Jennifer L. , Wall Adam A.
Published: August 2018

Pathogen-mediated activation of macrophages arms innate immune responses that include enhanced surface ruffling and macropinocytosis for environmental sampling and receptor internalization and signaling. Activation of macrophages with bacterial lipopolysaccharide (LPS) generates prominent dorsal ruffles, which are precursors for macropinosomes. Very rapid, high-resolution imaging of live macrophages with lattice light sheet microscopy (LLSM) reveals new features and actions of dorsal ruffles, which redefine the process of macropinosome formation and closure. We offer a new model in which ruffles are erected and supported by F-actin tent poles that cross over and twist to constrict the forming macropinosomes. This process allows for formation of large macropinosomes induced by LPS. We further describe the enrichment of active Rab13 on tent pole ruffles and show that CRISPR deletion of Rab13 results in aberrant tent pole ruffles and blocks the formation of large LPS-induced macropinosomes. Based on the exquisite temporal and spatial resolution of LLSM, we can redefine the ruffling and macropinosome processes that underpin innate immune responses.
Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors
Authors: Valverde Carlos A , Mazzocchi Gabriela , Di Carlo Mariano N , Ciocci Pardo Alejandro , Salas Nehuen , Ragone María Ines , Felice Juan I , Cely-Ortiz Alejandra , Consolini Alicia E , Portiansky Enrique , Mosca Susana , Kranias Evangelia G , Wehrens Xander H T , Mattiazzi Alicia
Published: August 2018

Aims

Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of RyR2 at Ser2814, has consistently been linked to arrhythmogenesis and ischaemia/reperfusion (I/R)-induced cell death. In contrast, the role played by SR Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation.

Methods and results

We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and phospholamban (PLN)-deficient-S2814D knock-in (SDKO) mice resulting from crossbreeding S2814D with phospholamban knockout deficient (PLNKO) mice. At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the strains were arrhythmic before ischaemia. Upon cardiac I/R, WT, and S2814D hearts exhibited abundant arrhythmias that were prevented by PLN ablation. In contrast, PLN ablation increased infarct size compared with WT and S2814D hearts. Mechanistically, the enhanced SR Ca2+ sequestration evoked by PLN ablation in SDKO hearts prevented arrhythmogenic events upon reperfusion by fragmenting SR Ca2+ waves into non-propagated and non-arrhythmogenic events (mini-waves). Conversely, the increase in SR Ca2+ sequestration did not reduce but rather exacerbated I/R-induced SR Ca2+ leak, as well as mitochondrial alterations, which were greatly avoided by inhibition of RyR2. These results indicate that the increase in SR Ca2+ uptake is ineffective in preventing the enhanced SR Ca2+ leak of PLN ablated myocytes from either entering into nearby mitochondria and/or activating additional CaMKII pathways, contributing to cardiac damage.

Conclusion

Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced SR Ca2+ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2+ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I/R cardiac injury.
Fractalis: a scalable open-source service for platform-independent interactive visual analysis of biomedical data
Authors: Herzinger Sascha , Grouès Valentin , Gu Wei , Satagopam Venkata , Banda Peter , Trefois Christophe , Schneider Reinhard
Published: August 2018

Background

Translational research platforms share the aim of promoting a deeper understanding of stored data by providing visualization and analysis tools for data exploration and hypothesis generation. However, such tools are usually platform bound and are not easily reusable by other systems. Furthermore, they rarely address access restriction issues when direct data transfer is not permitted. In this article, we present an analytical service that works in tandem with a visualization library to address these problems.

Findings

Using a combination of existing technologies and a platform-specific data abstraction layer, we developed a service that is capable of providing existing web-based data warehouses and repositories with platform-independent visual analytical capabilities. The design of this service also allows for federated data analysis by eliminating the need to move the data directly to the researcher. Instead, all operations are based on statistics and interactive charts without direct access to the dataset.

Conclusions

The software presented in this article has a potential to help translational researchers achieve a better understanding of a given dataset and quickly generate new hypotheses. Furthermore, it provides a framework that can be used to share and reuse explorative analysis tools within the community.
Pre-Strike Ballots and Collective Bargaining: The Impact of Quorum and Ballot Mode Requirements on Access to Lawful Industrial Action
Authors: Creighton Breen , Denvir Catrina , Johnstone Richard , McCrystal Shae , Orchiston Alice
Published: August 2018

In 2016, the UK Parliament passed the Trade Union Act 2016 (TU Act 2016), which introduced new quorum and approval requirements for pre-strike ballots. In Australia, mandatory pre-strike ballots, including a quorum requirement, were first introduced in 2006. This article explains the key features of the Australian pre-strike ballot system and reports on quantitative and qualitative empirical research findings on the operation of the ballots process to analyse the majority and quorum requirements, mode of ballot (postal, attendance or electronic) and choice of ballot agent. Quorum is the biggest obstacle to Australian unions authorising strike action under the pre-strike ballot rules, and postal ballots fail to reach quorum at significantly higher rates than do attendance ballots. By introducing quorums and retaining the requirement that all pre-strike ballots must be conducted by post, the TU Act 2016 endorsed the two factors under the Australian regime most likely to impede the authorisation of strike action in a pre-strike ballot.
Microtransplantation: clinical applications and mechanisms
Authors: Cai Bo , Guo Mei , Ai Huisheng
Published: August 2018

Purpose of review

Microtransplantation (MST) has been successfully used to manage patients with hematological malignancies, especially older patients with acute myeloid leukemia (AML). Recent clinical applications and mechanistic studies of MST are reviewed.

Recent findings

MST improves complete remission rates which have no significant difference among age groups in older patients with AML. Sufficient courses of postremission therapy lead to prolonged overall survival and reduced relapse rate. MST also benefits young patients with low-risk or intermediate-risk AML who lack a human leukocyte antigen-identical donor and shows therapeutic potential extending to other malignancies. Both donor and recipient-derived T cells contribute to the antileukemic effect. Novel methods to monitor donor microchimerism and donor–recipient immune cell interaction may further unveil mechanisms of MST.

MST shows therapeutic efficacy to several hematological malignancies, whereas mechanistic studies still need to be promoted, and its combination with other targeted therapies is warranted to further reduce relapse rate.
Eviction From Renter-occupied Households and Rates of Sexually Transmitted Infections: A County-level Ecological Analysis
Authors: Niccolai Linda M. , Blankenship Kim M. , Keene Danya E.
Published: August 2018

Background

Housing instability is linked to numerous health outcomes, but the specific impact of eviction from renter-occupied households, an event that has immediate implications for residential stability for low-income individuals, on sexually transmitted infections (STI) rates has not been adequately studied.

Methods

We examined county-level associations between eviction rates in 2014 and rates of chlamydia and gonorrhea in the following year using publicly available data sources (Eviction Lab National Database and AtlasPlus, respectively). Descriptive statistics compared medians and nonparametric distributions with Krusal-Wallis tests. Linear regression was used to compare tertile categories of eviction rates and STI rates while controlling for potential confounders.

Results

Median rates of chlamydia in counties with low, medium, and high rates of eviction were 229, 270, and 358 cases per 100,000 population, respectively (P < 0.001). The corresponding median rates of gonorrhea were 25, 37, and 75 cases per 100,000 population (P < 0.001). These associations remained statistically significant after controlling for all covariates in adjusted models. The beta coefficients and 95% confidence intervals (95% CI) for chlamydia and gonorrhea comparing high to low county-level eviction rates were 63.8 (95% CI, 45.1–82.5) and 20.4 (95% CI, 13.5–27.4), respectively. Similar associations were observed across levels of poverty and in both metropolitan and nonmetropolitan counties.

Conclusions

County-level eviction rates are associated with chlamydia and gonorrhea rates in a significant and robust way independent of other known predictors of STI. These results suggest that evictions result in residential instability in a way that may increase STI risk.
High Rates of Repeat Chlamydial Infections Among Young Women—Louisiana, 2000–2015
Authors: Cha Susan , Newman Daniel R. , Rahman Mohammad , Peterman Thomas A.
Published: August 2018

Background

Chlamydial infections are common among young women and can lead to serious reproductive health complications. We assessed the risk of reported repeat chlamydial infection among young women in Louisiana and time interval between infections by age and race/ethnicity.

Methods

We analyzed surveillance data on chlamydial infections reported among women in Louisiana from January 1, 2000, to December 31, 2015. Multiple reports for the same person were matched using unique codes. Chlamydial infections reported more than 30 days after a previous positive test were considered new infections. Women aged 15 to 34 years at first infection during 2000 to 2012 were censored after 3 years or after they had a repeat infection. Cumulative incidence and incidence rate of repeat chlamydial infection among women were determined by year of first infection. Race- and age-specific results were obtained using stratified analyses.

Results

One in 4 women diagnosed with a chlamydial infection at 15–34 years of age in Louisiana had a reported repeat infection in 3 years or less. Risk of repeat infection increased for younger women, racial/ethnic minorities, and women in more recent cohorts. Young black women aged 15 to 19 years in 2012 had the highest risk (44%). Black women also had shorter intervals between infections than white women.

Conclusions

Repeat chlamydial infections were common, especially among young black women. The true number is likely higher because surveillance data only count infections that were detected and reported. Comprehensive prevention strategies are needed to address high rates of repeat chlamydial infections among women.
The Effect of Hormonal Contraception and Menstrual Cycle Timing on Genital Herpes Simplex Virus-2 Shedding and Lesions
Authors: Micks Elizabeth , Son Hyunju , Magaret Amalia , Selke Stacy , Johnston Christine , Wald Anna
Published: August 2018

Background

The effect of female sex hormones on herpes simplex virus (HSV)-2 shedding and lesion frequency is poorly understood. Previous studies suggest that hormonal contraception may increase the frequency of HSV-2 shedding.

Methods

We studied HSV-2 seropositive women who performed daily genital swabbing for HSV DNA and completed diaries for genital lesions and menses. We used Poisson mixed effects models to determine if HSV detection varied throughout the menstrual cycle, or in response to hormonal contraception. We used the Wilcoxon signed-rank test and rank-sum test to determine if lesion frequency differed by cycle phase or hormonal contraceptive use.

Results

In 189 women aged 19 to 46 years who collected swabs on 10,715 days and were not using hormonal contraception, HSV-2 DNA was detected on 20.9% of days in the follicular phase and 17.8% of days in the luteal phase (rate ratio, 1.19; 95% confidence interval, 1.03–1.37, P = 0.02). Genital lesions did not differ in the follicular versus luteal phase (12.8% vs. 10.7%, P = 0.07). In analyses of hormonal contraception, including 244 women, HSV-2 DNA was detected on 19.0% of days for women not using hormonal contraception and 18.3% of days for those using hormonal contraception (P = 0.50). Lesions were present on 11.1% of days for women not using hormonal contraception, and 8.7% of days for those using hormonal contraception (P = 0.66).

Conclusions

In women with genital HSV-2 infection who are not using hormonal contraception, the follicular phase of the cycle may be associated with a higher frequency of HSV-2 shedding compared to the luteal phase. Lesion frequency is similar during the 2 menstrual phases. Hormonal contraception use was not observed to affect genital HSV-2 DNA detection or lesions.
Neural Correlates of Giving Social Support: Differences Between Giving Targeted Versus Untargeted Support
Authors: Inagaki Tristen K. , Ross Lauren P.
Published: August 2018

Objective

Giving support contributes to the link between social ties and health; however, the neural mechanisms are not known. Giving support in humans may rely on neural regions implicated in parental care in animals. The current studies, therefore, assess the contribution of parental care–related neural regions to giving support in humans and, as a further theoretical test, examine whether the benefits of giving targeted support to single, identifiable individuals in need extend to giving untargeted support to larger societal causes.

Methods

For study 1 (n = 45, M (SD) age = 21.98 (3.29), 69% females), participants completed a giving support task, followed by an emotional faces task in the functional magnetic resonance imaging scanner. For study 2 (n = 382, M (SD) age = 43.03 (7.28), 52% females), participants self-reported on their giving support behavior and completed an emotional faces task in the functional magnetic resonance imaging scanner.

Results

In study 1, giving targeted (versus untargeted) support resulted in greater feelings of social connection and support effectiveness. Furthermore, greater septal area activity, a region centrally involved in parental care in animals, to giving targeted support was associated with less right amygdala activity to an emotional faces task (r = −.297, 95% confidence interval = −.547 to −.043). Study 2 replicated and extended this association to show that self-reports of giving targeted support were associated with less amygdala activity to a different emotional faces task, even when adjusting for other social factors (r = −.105, 95% confidence interval = −.200 to −.011). Giving untargeted support was not related to amygdala activity in either study.

Conclusions

Results highlight the unique benefits of giving targeted support and elucidate neural pathways by which giving support may lead to health.
Platelet–lymphocyte Ratio After Granulocyte Colony Stimulating Factor Administration: an Early Prognostic Marker in Septic Shock Patients With Chemotherapy-Induced Febrile Neutropenia
Authors: Kim Youn-Jung , Kang Jihoon , Ryoo Seung Mok , Ahn Shin , Huh Jin Won , Kim Won Young
Published: August 2018

Introduction:

Chemotherapy-induced febrile neutropenia (FN) causes life-threatening complications, but little is known in septic shock patients with FN. The aim of this study was to investigate the prognostic value of inflammatory markers, including C-reactive protein level, immature granulocyte count, white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR), in septic shock patients with FN at admission and after granulocyte colony-stimulating factor (G-CSF) administration.

Methods:

Data on consecutive adult septic shock patients with FN treated with G-CSF between June 2012 and June 2017 were extracted from a prospectively compiled septic shock registry. Clinical and serial laboratory data at admission and <24 h after G-CSF administration were compared between nonsurvivor and 1-month survivor groups.

Results:

Of 1,671 septic shock patients, 158 FN patients were treated with G-CSF and 114 (72.2%) survived for 1 month. At admission, no clinical and serial laboratory data were significant to predict survival. After G-CSF administration, PLR and APACHE II were independent predictors for 1-month survival. PLR after administration of G-CSF >100 (adjusted odds ratio [aOR], 9.394; 95% CI, 2.821–31.285, P < 0.001) showed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 89.4%, 46.2%, 82.9%, and 60.0%, respectively, and APACHE II <28 (aOR, 6.944; 95% CI, 2.351–20.511, P < 0.001) showed sensitivity, specificity, PPV, and NPV of 86.8%, 63.6%, 86.1%, and 65.1%, respectively.

Conclusions:

After G-CSF administration in septic shock patients with chemotherapy-induced FN, PLR may be used as an early prognostic marker for mortality.
CIRP Induces Neutrophil Reverse Transendothelial Migration in Sepsis
Authors: Jin Hui , Aziz Monowar , Ode Yasumasa , Wang Ping
Published: August 2018

Extracellular cold-inducible RNA-binding protein (CIRP) exaggerates inflammation in sepsis. Neutrophil reverse transendothelial migration (rTEM) allows neutrophils to migrate from tissues into the circulation. The phenotype of neutrophils after reverse migration is CD54hiCXCR1lo. We hypothesize that CIRP induces neutrophil rTEM in sepsis. Sepsis was induced in male C57BL/6 mice by cecal ligation and puncture (CLP), and at 5, 10, or 20 h after CLP the frequencies of reversely migrated (RM) neutrophils were assessed in the blood by flow cytometry. As 20 h of CLP showed highest increase in the frequency of RM neutrophils, we further assessed RM neutrophils in the blood of WT and CIRP−/− mice at this time point. The effect of CIRP on neutrophil rTEM was determined by injecting mice with recombinant mouse CIRP (rmCIRP) intratracheally (i.t.) and assessed the frequencies of RM neutrophils. The expression of neutrophil elastase (NE) and junctional adhesion molecule-C (JAM-C) in the lungs was measured by Western blot. The mean frequency of RM neutrophils in sham mice was 0.4%, whereas the frequencies were significantly increased to 1%, 3%, and 7% at 5, 10, and 20 h of CLP, respectively. The mean frequency of RM neutrophils in the blood of CIRP−/− mice was significantly lower than that of WT mice at 20 h of CLP. The RM neutrophils in the blood was significantly increased after administration of rmCIRP i.t. into mice in a time- and dose-dependent manners. NE expression was upregulated, whereas JAM-C expression was downregulated in the lungs after CLP or rmCIRP administration. For the first time, we have showed that CIRP induces neutrophil rTEM in sepsis by increasing NE and decreasing JAM-C.
DNMT inhibitors increase methylation at subset of CpGs in colon, bladder, lymphoma, breast, and ovarian, cancer genome
Authors: Giri Anil K , Aittokallio Tero
Published: August 2018

Background

DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for acute myeloid leukemia and myelodysplastic syndrome. Identification of CpGs violating demethylaion due to DNMTi treatment may help to understand their resistance mechanisms.

Materials and Methods

To identify such CpGs, we analysed publicly available 450K methylation data of multiple cancer type cell lines.

Results

We identified 637 CpGs corresponding to genes enriched for p53 and olfactory receptor pathways with a transient increase in methylation (median Δβ = 0.12) after decitabine treatment in HCT116 cells. Azacytidine treatment also increased methylation of identified CpGs in 9 colon, 9 ovarian, 3 breast, and 1 lymphoma cancer cell lines.

Conclusion

DNMTi treatment increases methylation of subset of CpGs in cancer genome.
Laminar Segregation of Sensory Coding and Behavioral Readout in Macaque V4
Authors: Pettine Warren W. , Steinmetz Nicholas A. , Moore Tirin
Published: August 2018

Neurons in sensory areas of the neocortex are known to represent information both about sensory stimuli and behavioral state, but how these two disparate signals are integrated across cortical layers is poorly understood. To study this issue, we measured the coding of visual stimulus orientation and of behavioral state by neurons within superficial and deep layers of area V4 in monkeys while they covertly attended or prepared eye movements to visual stimuli. We show that single neurons and neuronal populations in superficial layers convey more information about the orientation of visual stimuli, whereas single neurons and neuronal populations in deep layers convey greater information about the behavioral relevance of those stimuli. In particular, deep layer neurons encode greater information about the direction of prepared eye movements. These results reveal a division of labor between laminae in the coding of visual input and visually guided behavior.
Restoration of visual function by transplantation of optogenetically engineered photoreceptors
Authors: Garita-Hernandez Marcela , Lampič Maruša , Chaffiol Antoine , Guibbal Laure , Routet Fiona , Santos-Ferreira Tiago , Gagliardi Giuliana , Reichman Sacha , Picaud Serge , Sahel José-Alain , Goureau Olivier , Ader Marius , Dalkara Deniz , Duebel Jens
Published: August 2018

A major challenge in the treatment of retinal degenerative diseases, with the transplantation of replacement photoreceptors, is the difficulty in inducing the grafted cells to grow and maintain light sensitive outer segments (OS) in the host retina, which depends on proper interaction with the underlying retinal pigment epithelium (RPE). For a RPE-independent treatment approach, we introduced a hyperpolarizing microbial opsin into photoreceptor precursors from new-born mice, and transplanted them into blind mice lacking the photoreceptor layer. These optogenetically transformed photoreceptors were light responsive and their transplantation lead to the recovery of visual function, as shown by ganglion cell recordings and behavioral tests. Subsequently, we generated cone photoreceptors from human induced pluripotent stem cells (hiPSCs), expressing the chloride pump Jaws. After transplantation into blind mice, we observed light-driven responses at the photoreceptor and ganglion cell level. These results demonstrate thatstructuralandfunctionalretinal repair is possible by combiningstem cell therapyandoptogenetics.
Perceptual inference employs intrinsic alpha frequency to resolve perceptual ambiguity
Authors: Shen Lu , Han Biao , Chen Lihan , Chen Qi
Published: August 2018

The brain uses its intrinsic dynamics to actively predict observed sensory inputs, especially under perceptual ambiguity. However, it remains unclear how this inference process is neurally implemented in biasing perception of ambiguous inputs towards the predicted percepts. Using electroencephalography and intracranial recordings, we first show that the alpha-band frequency defines a unified time window for perceptual grouping across both space and time: information segments, either spatially or temporally segregated, will be integrated if they fall within the same alpha cycle. Moreover, predictions employ this prior knowledge on intrinsic alpha frequency to shift perceptual inference towards the most possibly observed percepts. Multivariate decoding analysis showed that perceptual inference, based on variance in prestimulus alpha frequency (PAF), biases post-stimulus neural representations by inducing preactivation of the predicted percepts. fMRI results additionally showed that prestimulus activity and intrinsic organization status in the frontoparietal attentional network predict perceptual outcomes, probably by modulating occipitoparietal PAFs.
Evaluation of tuberculosis treatment response with serial C-reactive protein measurements
Authors: Wilson Douglas , S Moosa Mahomed-Yunus , Cohen Ted , Cudahy Patrick , Aldous Collen , Maartens Gary
Published: August 2018

Background

Novel biomarkers are needed to assess response to antituberculosis therapy in smear-negative patients.

Methods

To evaluate the utility of CRP in monitoring response to antituberculosis therapy we conducted a post-hoc analysis on a cohort of adults with symptoms of tuberculosis and negative sputum smears in a high tuberculosis and HIV prevalence setting in KwaZulu-Natal, South Africa. Serial changes in CRP, weight, and haemoglobin were evaluated over 8 weeks.

Results

421 participants with suspected smear-negative tuberculosis were enrolled and 33 excluded. 295 were treated for tuberculosis (137 confirmed, 158 possible), and 93 did not have tuberculosis. 185 of 215 (86%) participants who agreed to HIV testing were HIV-positive. At week 8, the on-treatment median CRP reduction in the tuberculosis group was 79.5% (IQR 25.4; 91.7), median weight gain 2.3% (IQR −1.0; 5.6), and median haemoglobin increase 7.0% (IQR 0.8; 18.9) (p-value <0.0001 for baseline to week 8 comparison of absolute median values). Only CRP changed significantly at week 2 (median reduction of 75.1% (IQR 46.9; 89.2) in the group with confirmed tuberculosis and 49.0% (IQR −0.4; 80.9) in the possible tuberculosis group. Failure of CRP to reduce to ≤55% of the baseline value at week 2 predicted hospitalization or death in both tuberculosis groups, with 99% negative predictive value.

Conclusion

Change in CRP may have utility in early evaluation of response to antituberculosis treatment and to identify those at increased risk of adverse outcomes.

Key points

C-reactive protein (CRP) falls by 80% after eight weeks of antituberculosis treatment. At two weeks sustained CRP elevation is associated with death or hospitalization.
Reverse engineering of an aspirin-responsive regulator in bacteria
Authors: Oliveira Monteiro Lummy Maria , Arruda Letícia Magalhães , Medeiros Ananda Sanches , Martins-Santana Leonardo , Fátima Alves Luana de , Guazzaroni María-Eugenia , Lorenzo Víctor de , Silva-Rocha Rafael
Published: August 2018

Bacterial transcriptional factors (TFs) and their target promoters are key devices for engineering of complex circuits in many biotechnological applications. Yet, there is a dearth of well characterized inducer-responsive TFs that could be used in the context of an animal or human host. In this work we have deciphered the inducer recognition mechanism of two AraC/XylS regulators from Pseudomonas putida (BenR and XylS) for creating a novel expression system responsive to acetyl salicylate (i.e. Aspirin). Using protein homology modeling and molecular docking with the cognate inducer benzoate and a suite of chemical analogues, we identified the conserved binding pocket of these two proteins. Using site directed mutagenesis, we identified a single amino acid position required for efficient inducer recognition and transcriptional activation. While modification of this position in BenR abolishes protein activity, its modification in XylS increases the response to several aromatic compounds, including acetyl salicylic acid to levels close to those achieved by the canonical inducer. Moreover, by constructing chimeric proteins with swapped N-terminal domains, we created novel regulators with mixed promoter and inducer recognition profiles. As a result, a collection of engineered TFs was generated with enhanced response to a well characterized and largely innocuous molecule with a potential for eliciting heterologous expression of bacterial genes in animal carriers.
Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas
Authors: Rello-Varona Santi , Fuentes-Guirado Miriam , López-Alemany Roser , Contreras-Pérez Aida , Mulet-Margalef Núria , García-Monclús Silvia , Tirado Oscar M. , García del Muro Xavier
Published: August 2018

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Bcl-xL showed a slower decay curve after protein synthesis disruption that in tolerant cell lines was enough to delay apoptosis, as its action cannot be countered by the relative low levels of pro-apoptotic BH3 proteins BIM and PUMA. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS.
Inferring the molecular mechanisms of noncoding Alzheimer’s disease-associated genetic variants
Authors: Amlie-Wolf Alexandre , Tang Mitchell , Way Jessica , Dombroski Beth , Jiang Ming , Vrettos Nicholas , Chou Yi-Fan , Zhao Yi , Kuzma Amanda , Mlynarski Elisabeth E. , Leung Yuk Yee , Brown Christopher D. , Wang Li-San , Schellenberg Gerard D.
Published: August 2018

Structured Abstract

INTRODUCTION

We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying noncoding late-onset Alzheimer’s Disease (LOAD)-associated genetic signals.

METHODS

We applied our INFERNO method to the IGAP genome-wide association study (GWAS) data, annotating all potentially causal variants with tissue-specific regulatory activity. Bayesian co-localization analysis of GWAS summary statistics and eQTL data was performed to identify tissue-specific target genes.

RESULTS

INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). We validated the allele-specific effects of several variants on enhancer function using luciferase expression assays.

DISCUSSION

Integrating functional genomics with GWAS signals yielded insights into the regulatory mechanisms, tissue contexts, and genes affected by noncoding genetic variation associated with LOAD risk.
EVR: Reconstruction of Bacterial Chromosome 3D Structure Using Error-Vector Resultant Algorithm
Authors: Hua Kang-Jian , Ma Bin-Guang
Published: August 2018

More and more 3C/Hi-C experiments on prokaryotes have been published. However, most of the published modeling tools for chromosome 3D structures are targeting at eukaryotes. How to transform prokaryotic experimental chromosome interaction data into spatial structures is an important task and in great need. We have developed a new reconstruction program for bacterial chromosome 3D structures called EVR that exploits a simple Error-Vector Resultant (EVR) algorithm. This software tool is particularly optimized for the closed-loop structural features of prokaryotic chromosomes. EVR can be used to reconstruct the bacterial 3D chromosome structure based on the contact frequency matrix derived from 3C/Hi-C experimental data quickly and precisely.
A novel DCL2-dependent miRNA pathway in tomato affects susceptibility to RNA viruses
Authors: Wang Zhengming , Hardcastle Thomas J. , Canto Pastor Alex , Yip Wing Hin , Tang Shuoya , Baulcombe David C.
Published: August 2018

Tomato Dicer-like2 (slDCL2) is a key component of resistance pathways against potato virus X (PVX) and tobacco mosaic virus (TMV). It is also required for production of endogenous small RNAs, including miR6026 and other noncanonical microRNAs (miRNAs). The slDCL2 mRNAs are targets of these slDCL2-dependent RNAs in a feedback loop that was disrupted by target mimic RNAs of miR6026. In lines expressing these RNAs, there was correspondingly enhanced resistance against PVX and TMV. These findings illustrate a novel miRNA pathway in plants and a crop protection strategy in which miRNA target mimicry elevates expression of defense-related mRNAs.
Contextual predictability influences word and morpheme duration in a morphologically complex language (Kaqchikel Mayan)
Authors: Tang Kevin , Bennett Ryan
Published: August 2018

The probability is one of the many factors which influence phonetic variation. Contextual probability, which describes how predictable a linguistic unit is in some local environment, has been consistently shown to modulate the phonetic salience of words and other linguistic units in speech production (the probabilistic reduction effect). In this paper the question of whether the probabilistic reduction effect, as previously observed for majority languages like English, is also found in a language (Kaqchikel Mayan) which has relatively rich morphology is explored. Specifically, whether the contextual predictability of words and morphemes influences their phonetic duration in Kaqchikel is examined. It is found that the contextual predictability of a word has a significant effect on its duration. The effect is manifested differently for lexical words and function words. It is also found that the contextual predictability of certain prefixes in Kaqchikel affects their duration, showing that contextual predictability may drive reduction effects at multiple levels of structure. While the findings are broadly consistent with many previous studies (primarily on English), some of the details of the results are different. These differences highlight the importance of examining the probabilistic reduction effect in languages beyond the majority, Indo-European languages most commonly investigated in experimental and corpus linguistics.
Genotyping and Quantifying Lyme Pathogen Strains by Deep Sequencing of the Outer Surface Protein C (ospC) Locus
Authors: Di Lia , Wan Zhenmao , Akther Saymon , Ying Chunxiao , Larracuente Amanda , Li Li , Di Chong , Nunez Roy , Cucura D. Moses , Goddard Noel L. , Krampis Konstantino , Qiu Wei-Gang
Published: August 2018

A mixed infection of a single tick or host by Lyme disease spirochetes is common and a unique challenge for the diagnosis, treatment, and surveillance of Lyme disease. Here, we describe a novel protocol for differentiating Lyme strains on the basis of deep sequencing of the hypervariable outer surface protein C locus (ospC).
Escherichia coli ST131-
H
22 as a Foodborne Uropathogen
Authors: Liu Cindy M. , Stegger Marc , Aziz Maliha , Johnson Timothy J. , Waits Kara , Nordstrom Lora , Gauld Lori , Weaver Brett , Rolland Diana , Statham Sally , Horwinski Joseph , Sariya Sanjeev , Davis Gregg S. , Sokurenko Evgeni , Keim Paul , Johnson James R. , Price Lance B.
Published: August 2018

E. coli
ST131 is an important extraintestinal pathogen that can colonize the gastrointestinal tracts of humans and food animals. Here, we combined detection of accessory traits associated with avian adaptation (ColV plasmids) with high-resolution phylogenetics to quantify the portion of human infections caused by ST131 strains of food animal origin. Our results suggest that one ST131 sublineage—ST131-
H
22—has become established in poultry populations around the world and that meat may serve as a vehicle for human exposure and infection. ST131-
H
22 is just one of many
E. coli
lineages that may be transmitted from food animals to humans. Additional studies that combine detection of host-associated accessory elements with phylogenetics may allow us to quantify the total fraction of human extraintestinal infections attributable to food animal
E. coli
strains.
Polygenic Analysis in Absence of Major EffectorATF1Unveils Novel Components in Yeast Flavor Ester Biosynthesis
Authors: Holt Sylvester , Trindade de Carvalho Bruna , Foulquié-Moreno María R. , Thevelein Johan M.
Published: August 2018

Basic research with laboratory strains of the yeastSaccharomyces cerevisiaehas identified the structural genes of most metabolic enzymes, as well as genes encoding major regulators of metabolism. On the other hand, more recent work on polygenic analysis of yeast biodiversity in natural and industrial yeast strains is revealing novel components of yeast metabolism. A major example is the metabolism of flavor compounds, a particularly important property of industrial yeast strains used for the production of alcoholic beverages. In this work, we have performed polygenic analysis of production of ethyl acetate, an important off-flavor compound in beer and other alcoholic beverages. To increase the chances of identifying novel components, we have used in parallel a wild-type strain and a strain with a deletion ofATF1encoding the main enzyme of acetate ester biosynthesis. This revealed a new structural gene,EAT1, encoding a putative mitochondrial enzyme, which was recently identified as an ethanol acetyl-CoA transferase in another yeast species. We also identified a novel regulatory gene,SNF8, which has not previously been linked to flavor production. Our results show that polygenic analysis of metabolic traits in the absence of major effector genes can reveal novel structural and regulatory genes. The mutant alleles identified can be used to affect the flavor profile in industrial yeast strains for production of alcoholic beverages in more subtle ways than by deletion or overexpression of the already known major effector genes and without significantly altering other industrially important traits. The effect of the novel variants was dependent on the genetic background, with a highly desirable outcome in the flavor profile of an ale brewing yeast.
NADPH Oxidase and Guanylate Binding Protein 5 Restrict Survival of Avirulent Type III Strains of Toxoplasma gondii in Naive Macrophages
Authors: Matta Sumit K. , Patten Kelley , Wang Quiling , Kim Bae-Hoon , MacMicking John D. , Sibley L. David
Published: August 2018

Toxoplasmainfections in humans and other mammals are largely controlled by IFN-γ produced by the activated adaptive immune system. However, we still do not completely understand the role of cell-intrinsic functions in controllingToxoplasmaor other apicomplexan infections. The present work identifies intrinsic activities in naive macrophages in counteractingT. gondiiinfection. Using an avirulent strain ofT. gondii, we highlight the importance of Nox complexes in conferring protection against parasite infection bothin vitroandin vivo. We also identify Gbp5 as a novel macrophage factor involved in limiting intracellular infection by avirulent strains ofT. gondii. The rarity of human infections caused by type III strains suggests that these mechanisms may also be important in controlling human toxoplasmosis. These findings further extend our understanding of host responses and defense mechanisms that act to control parasitic infections at the cellular level.
Signalment risk factors for cutaneous and renal glomerular vasculopathy (Alabama rot) in dogs in the UK
Authors: Stevens Kim B , O'Neill Dan , Jepson Rosanne , Holm Laura Phillipa , Walker David John , Cardwell Jacqueline Martina
Published: August 2018

Seasonal outbreaks of cutaneous and renal glomerular vasculopathy (CRGV) have been reported annually in UK dogs since 2012, yet the aetiology of the disease remains unknown. The objectives of this study were to explore whether any breeds had an increased or decreased risk of being diagnosed with CRGV, and to report on age and sex distributions of CRGV cases occurring in the UK. Multivariable logistic regression was used to compare 101 dogs diagnosed with CRGV between November 2012 and May 2017 with a denominator population of 446,453 dogs from the VetCompass database. Two Kennel Club breed groups—hounds (odds ratio (OR) 10.68) and gun dogs (OR 9.69)—had the highest risk of being diagnosed with CRGV compared with terriers, while toy dogs were absent from among CRGV cases. Females were more likely to be diagnosed with CRGV (OR 1.51) as were neutered dogs (OR 3.36). As well as helping veterinarians develop an index of suspicion for the disease, better understanding of the signalment risk factors may assist in the development of causal models for CRGV and help identify the aetiology of the disease.
Influence of composite flocculant FeCl3–APAM on vacuum drainage of river-dredged sludge
Authors: Wang Jun , Shi Wenjie , Wu Wenqing , Liu Feiyu , Fu Hongtao , Cai Yuanqiang , Hai Jun , Hu Xiuqing , Zhu Xiaoxiao
Published: August 2018

Sludge is an inevitable product of river dredging and is characterized by a high water content, high fluidity, and high heavy metal content. Its treatment requires consideration of the economic and environmental implications. In this study, a composite flocculant comprising anionic polyacrylamide (APAM) and FeCl3 was used in combination with vacuum preloading to conduct indoor tests on the treatment of dredged sludge. The monitored parameters included the water drainage rate and sludge settlement, and the water content and shear strength after testing. The addition of the composite flocculant was found to effectively enhance the flocculation of the soil and increase the soil particle size, resulting in accelerated water drainage, thus improving the treatment effect and the solidification of the contained heavy metals. The treatment was found to be optimized by an APAM:FeCl3 ratio of 1:5 in the composite flocculant, under which the moisture content of the sludge was reduced from 140% to 50%, and the solidification rate of the heavy metals exceeded 88%.
Phacidiaceae endophytes ofPicea rubensin Eastern Canada
Authors: Tanney Joey B. , Seifert Keith A.
Published: August 2018

More than 100 fungal endophyte strains belonging to the family Phacidiaceae were isolated from surface-sterilized Picea rubens Sarg. needles collected from the Acadian Forest Region in New Brunswick, Canada. The strains were characterized morphologically by their asexual states, and phylogenetic analyses were conducted using the nuclear internal transcribed spacer rDNA (ITS) marker and the second largest subunit of ribosomal polymerase II (RPB2). Morphological and phylogenetic data revealed seven species: Darkera cf. parca; Strasseria geniculata; two novel Phacidium species: Phacidium dicosmoanum and Phacidium faciforme; and three novel monotypic genera described to accommodate distinct species: Calvophomopsis rubenticola, Cornibusella ungulata, and Gloeopycnis protuberans. Further analyses of Darkera spp. were performed with ITS and partial translation elongation factor 1-α (TEF1α), and the results suggest that D. parca is a species complex. Phacidiaceae includes hundreds of known species that are unrepresented by sequence data; therefore, ITS sequences were generated from herbarium material including type specimens of Darkera parca, Phacidium lunatum, and specimens of Allantophomopsiella, Allantophomopsis, Bulgaria, Phacidium, and Pseudophacidium species. The description of novel species combined with morphological observations and reference sequences will facilitate the identification of conifer endophytes, both from specimens or cultures and in environmental sequence data, and improve our understanding of this large and mostly neglected family.