bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitigating Poverty through the Formation of Extended Family Households: Race and Ethnic Differences
Authors: Reyes Adriana M
Published: October 2019

In times of hardship, moving in with family is one strategy for alleviating economic deprivation and uncertainty. The ability of the family to buffer against poverty may vary by the resources available to and the economic needs of individuals. I assess how the formation of extended-family households is associated with a move into or out of poverty and how this association varies by race and ethnicity, since economic resources and norms around extended-family households differ. Using longitudinal data that span four years, I estimate linear fixed effects regression models to assess how changes in living arrangements are related to changes in poverty. I find that moving into an extended-family household reduces poverty, especially for the joining family unit. Most of this poverty reduction occurs through a family safety net, with a non-poor family taking in poor family units.
Negative Media Frames and Female Politicians: A Case Study of Jamaica’s First Female Prime Minister, Portia Simpson-Miller
Authors: Johnson-Myers Tracy-Ann
Published: October 2019

This study raises questions about how Jamaica’s first female prime minister, Portia Simpson-Miller, was portrayed in the media. This will be done through content analysis of editorial cartoons, covering the period in which Mrs Simpson-Miller occupied the highest public office in the country. An interesting finding from the study is that, unlike many female political leaders, media coverage of Simpson-Miller focused primarily on her performance as prime minister of Jamaica and less on her physical appearance and gender. The findings from this study will add to the wider discourse on the media’s portrayal of women in politics.
Functional and expressional analyses of appleFLC-like in relation to dormancy progress and flower bud development
Authors: Nishiyama Soichiro , Matsushita Miwako Cecile , Yamane Hisayo , Honda Chikako , Okada Kazuma , Tamada Yosuke , Moriya Shigeki , Tao Ryutaro
Published: October 2019

We previously identified the FLOWERING LOCUS C (FLC)-like gene, a MADS-box transcription factor gene that belongs to Arabidopsis thaliana L. FLC clade, in apple (Malus $\times$  domestica Borkh.), and its expression in dormant flower buds is positively correlated with cumulative cold exposure. To elucidate the role of the MdFLC-like in the dormancy process and flower development, we first characterized the phenotypes of MdFLC-like overexpressing lines with the Arabidopsis Columbia-0 background. The overexpression of MdFLC-like significantly delayed the bolting date and reduced the plant size, but it did not significantly affect the number of rosette leaves or flower organ formation. Thus, MdFLC-like may affect vegetative growth and development rather than flowering when expressed in Arabidopsis, which is not like Arabidopsis FLC that affects development of flowering. We compared seasonal expression patterns of MdFLC-like in low-chill ‘Anna’ and high-chill ‘Fuji’ and ‘Tsugaru’ apples collected from trees grown in a cold winter region in temperate zone and found an earlier upregulation in ‘Anna’ compared with ‘Fuji’ and ‘Tsugaru’. Expression patterns were also compared in relation to developmental changes in the flower primordia during the chilling accumulation period. Overall, MdFLC-like was progressively upregulated during flower primordia differentiation and development in autumn to early winter and reached a maximum expression level at around the same time as the genotype-dependent chilling requirements were fulfilled in high-chill cultivars. Thus, we hypothesize MdFLC-like may be upregulated in response to cold exposure and flower primordia development during the progress of endodormancy. Our study also suggests MdFLC-like may have a growth-inhibiting function during the end of endodormancy and ecodormancy when the temperature is low and unfavorable for rapid bud outgrowth.
Impact of the Sampling Site in the Result of Wet Mount Microscopy
Authors: Azevedo Sofia , Lima-Silva Joana , Vieira-Baptista Pedro
Published: October 2019

Objectives

Wet mount microscopy (WMM) is an ancillary test in the diagnosis of vulvovaginitis. However, there are little data about the impact of the sampling site. Our main objective was to determine the agreement between samples collected from different vaginal sites.

Materials and Methods

Five vaginal samples (one from each of the fornices and one from the lower third) were collected from 50 consecutive women and evaluated using phase-contrast WMM, including the following: lactobacillary grade, presence of other bacteria, clue cells, inflammation, and atrophy. Global percentage of agreement, κ index [poor (<0), slight (0.01–0.20), fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80), and almost perfect (0.81–1)], sensitivity and negative predictive value were calculated.

Results

Global percentage of agreement was high for all individual parameters (>75%), but low for the final diagnosis (57%). Agreement rate was substantial or almost perfect for the evaluation of normal versus abnormal flora, substantial for the presence of absence of bacteria other than lactobacilli and for the presence of clue cells, and moderate to almost perfect for the presence of dysbiosis and cytolysis. Agreement rates were worse for inflammation, atrophy, and the presence of Candida. The lower third of the vagina had the highest sensitivity for Candida (0.6, 95% CI = 0.41–0.86) and bacterial vaginosis (0.92, 95% CI = 0.73–1.00), whereas the anterior fornix performed better for cytolytic vaginosis (0.75, 95% CI = 0.43–0.93).

Conclusions

There is some variation in the results according to the sampling site, which may be overcome by collecting 2 samples (anterior fornix and lower third of the vagina).
Cervical, Vaginal, and Vulvar Cancer Costs Incurred by the Medicaid Program in Publicly Insured Patients in Texas
Authors: Fu Shuangshuang , Fokom Domgue Joel , Chan Wenyaw , Zhao Bo , Ramondetta Lois M. , Lairson David R.
Published: October 2019

Objectives

To determine from the perspective of the State of Texas, the direct medical care costs associated with cervical, vaginal, and vulvar cancers in Texas Medicaid enrollees.

Materials and Methods

We conducted a case-control study and searched Texas Medicaid databases between 2008 and 2012 for eligible cancer patients. A comparison group was selected for each cancer site using a 2-step 1:1 propensity score matching method. Patients were followed for 2 years after cancer diagnosis to estimate monthly and yearly direct medical costs. For each cancer site, the differential cost between patients and the matched comparison individuals was the estimated cost associated with cancer.

Results

The study included 583 cervical, 62 vaginal, and 137 vulvar cancer patients and equal numbers of cancer-free comparison individuals. Among the cases, 322 cervical cancer patients, 46 vaginal cancer patients, and 102 vulvar cancer patients were Medicaid-Medicare dual eligible enrollees. For Medicaid-only enrollees, the adjusted first- and second-year mean total differential costs were US $19,859 and $3,110 for cervical cancer, US $19,627 and $4,582 for vaginal cancer, and US $7,631 and $777 for vulvar cancer patients, respectively. For Medicaid-Medicare dual eligible enrollees, adjusted first- and second-year mean total differential costs incurred by Medicaid were US $2,565 and $792 for cervical cancer, US $1,293 and $181 for vaginal cancer, and US $1,774 and $1,049 for vulvar cancer patients, respectively.

Conclusions

The direct medical costs associated with cervical, vaginal, and vulvar cancers in Texas Medicaid were substantial in the first 2 years after cancer diagnosis, but dual eligibility for Medicare coverage attenuated Medicaid costs.
aer2vec: Distributed Representations of Adverse Event Reporting System Data as a Means to Identify Drug/Side-Effect Associations
Authors: Portanova Jake , Murray Nathan , Mower Justin , Subramanian Devika , Cohen Trevor
Published: October 2019

Adverse event report (AER) data are a key source of signal for post marketing drug surveillance. The standard methodology to analyze AER data applies disproportionality metrics, which estimate the strength of drug/side-effect associations from discrete counts of their occurrence at report level. However, in other domains, improvements in predictive modeling accuracy have been obtained through representation learning, where discrete features are replaced by distributed representations learned from unlabeled data. This paper describes aer2vec, a novel representational approach for AER data in which concept embeddings emerge from neural networks trained to predict drug/side-effect co-occurrence. Trained models are evaluated for their utility in identifying drug/side-effect relationships, with improvements over disproportionality metrics in most cases. In addition, we evaluate the utility of an otherwise-untapped resource in the Food and Drug Administration (FDA) AER system – reporter designations of suspected causality – and find that incorporating this information enhances performance of all models evaluated.
When will I get my paper back? A replication study of publication timelines for health professions education research
Authors: Maggio Lauren A. , Bynum William E. , Schreiber-Gregory Deanna N. , Durning Steven J. , Artino Anthony R.
Published: October 2019

Biomedical researchers have lamented the lengthy timelines from manuscript submission to publication and highlighted potential detrimental effects on scientific progress and scientists’ careers. In 2015, Himmelstein identified the mean time from manuscript submission to acceptance in biomedicine as approximately 100 days. The length of publication timelines in health professions education (HPE) is currently unknown.

This study replicates Himmelstein’s work with a sample of 14 HPE journals published between 2008-2018. Using PubMed, 19,182 article citations were retrieved. Open metadata for each was downloaded, including the date the article was received by the journal, the date the authors resubmitted revisions, the date the journal accepted the article, and date of entry into PubMed. Journals without publication history metadata were excluded.

Publication history data was available for 55% (n=8) of the journals sampled. The publication histories of 4,735 (25%) articles were analyzed. Mean time from: (1) author submission to journal acceptance was 180.93 days (SD=103.89), (2) author submission to posting on PubMed was 263.55 days (SD=157.61), and (3) journal acceptance to posting on PubMed was 83.15 days (SD=135.72).

This study presents publication metadata for journals that openly provide it—a first step towards understanding publication timelines in HPE. Findings confirm the replicability of the original study, and the limited data suggest that, in comparison to biomedical scientists broadly, medical educators may experience longer wait times for article acceptance and publication. Reasons for these delays are currently unknown and deserve further study; such work would be facilitated by increased public access to journal metadata.

What this article adds

Publication delays can negatively impact science and researchers’ careers. A previous study, in biomedicine, leveraged publicly available data to identify a 100-day waiting period between manuscript submission and acceptance. However, this study provides limited information on timelines for health professions education (HPE) articles. Thus, the current study replicates the original investigation with publication timeline data for eight HPE journals, which make their data publicly accessible, finding the mean time from submission to acceptance to be 181 days. Reasons for these delays are currently unknown and deserve further study; such work would be facilitated by increased public access to journal metadata.
A parametrized computational framework for description and design of genetic circuits of morphogenesis based on contact-dependent signaling and changes in cell-cell adhesion
Authors: Lam Calvin , Saluja Sajeev , Courcoubetis George , Courte Josquin , Yu Dottie , Chung Christian , Morsut Leonardo
Published: October 2019

Synthetic development is a nascent field of research that uses the tools of synthetic biology to design genetic programs directing cellular patterning and morphogenesis in higher eukaryotic cells, such as mammalian cells. One specific example of such synthetic genetic programs was based on cell-cell contact-dependent signaling using synthetic Notch pathways, and was shown to drive formation of multilayered spheroids by modulating cell-cell adhesion via differential expression of cadherin-family proteins. The design method for these genetic programs relied on trial and error, which limited the number of possible circuits and parameter ranges that could be explored. Here we build a parametrized computational framework that, given a cellcell communication network driving changes in cell adhesion and initial conditions as inputs, predicts developmental trajectories. We first built a general computational framework where contact-dependent cell-cell signaling networks and changes in cell-cell adhesion could be designed in a modular fashion. We then use a set of available in vitro results (that we call the “training set” in analogy to similar pipelines in the machine learning field) to parametrize the computational model with values for adhesion and signaling. We then show that this parametrized model can qualitatively predict experimental results from a “testing set” of available in vitro data that varied the genetic network in terms of adhesion combinations, initial number of cells and even changes to the network architecture. Finally, this parametrized model is used to recommend novel network implementation for the formation of a 4-layered structure that has not been reported previously. The framework that we develop here could function as a testing ground to identify the reachable space of morphologies that can be obtained by controlling contact-dependent cell-cell communications and adhesion. Additionally, we discuss how the model could be expanded to include other forms of communication or effectors for the computational design of the next generation of synthetic developmental trajectories.
An RNA-based system to study hepatitis B virus replication and select drug-resistance mutations
Authors: Yu Y. , Schneider W.M. , Michailidis E. , Acevedo A. , Ni Y. , Ambrose P. , Zou C. , Kabbani M. , Quirk C. , Jahan C. , Wu X. , Urban S. , Shlomai A. , de Jong Y.P. , Rice C.M.
Published: October 2019

Hepatitis B virus (HBV) chronically infects over 250 million people worldwide, increasing their risk of liver cirrhosis and hepatocellular carcinoma. There is a vaccine to prevent new infections, but no efficient cure for chronic infection. New insights into HBV biology are needed to improve cure rates for this widespread devastating disease. We describe a method to initiate replication of HBV, a DNA virus, using synthetic RNA. This approach has several advantages over existing systems: it eliminates contaminating background signal from input virus or plasmid DNA and can be easily adapted to multiple genotypes and mutants. Further, it can be applied to identify anti-HBV compounds, measure anti-HBV drug efficiency, study virus evolution, and, as we demonstrate, it can be uniquely applied to predict antiviral drug resistance.
The GTEx Consortium atlas of genetic regulatory effects across human tissues
Authors: Aguet François , Barbeira Alvaro N , Bonazzola Rodrigo , Brown Andrew , Castel Stephane E , Jo Brian , Kasela Silva , Kim-Hellmuth Sarah , Liang Yanyu , Oliva Meritxell , Parsana Princy E , Flynn Elise , Fresard Laure , Gaamzon Eric R , Hamel Andrew R , He Yuan , Hormozdiari Farhad , Mohammadi Pejman , Muñoz-Aguirre Manuel , Park YoSon , Saha Ashis , Segrć Ayellet V , Strober Benjamin J , Wen Xiaoquan , Wucher Valentin , Das Sayantan , Garrido-Martín Diego , Gay Nicole R , Handsaker Robert E , Hoffman Paul J , Kashin Seva , Kwong Alan , Li Xiao , MacArthur Daniel , Rouhana John M , Stephens Matthew , Todres Ellen , Viñuela Ana , Wang Gao , Zou Yuxin ,   The GTEx Consortium, Brown Christopher D , Cox Nancy , Dermitzakis Emmanouil , Engelhardt Barbara E , Getz Gad , Guigo Roderic , Montgomery Stephen B , Stranger Barbara E , Im Hae Kyung , Battle Alexis , Ardlie Kristin G , Lappalainen Tuuli
Published: October 2019

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
Heroin Choice Depends on Income Level and Economy Type
Authors: Gunawan Tommy , Hachiga Yosuke , Tripoli Christopher S. , Silberberg Alan , Kearns David N.
Published: October 2019

Rationale

In a previous study investigating choice between heroin and a non-drug alternative in animals, reductions in income (i.e., choices/day) caused the percentage of income spent on heroin to progressively decrease. In contrast, another study found that humans with opioid use disorder spent the majority of their income on heroin even though they had little income. Comparison of these two studies suggests that the seemingly conflicting results could be explained by differences in the underlying economy types of the choice alternatives.

Objective

The present experiment tested the hypothesis that the effect of income changes on choice between heroin and a non-drug alternative depends on economy type.

Methods

Rats chose between heroin and saccharin under three income levels. For the Closed group, the choice session was the only opportunity to obtain these reinforcers. For the Heroin Open group and the Saccharin Open group, choice sessions were followed by 3-h periods of unlimited access to heroin or saccharin, respectively.

Results

As income decreased, the Closed and Heroin Open groups, but not the Saccharin Open group, spent an increasingly greater percentage of income on saccharin than on heroin. The Saccharin Open group, compared to the other groups, spent a greater percentage of income on heroin as income decreased.

Conclusions

Results confirm that the effects of income and economy type can interact and this may explain the apparently discrepant results of earlier studies. More generally, findings suggest that situations where heroin choice has little consequence for consumption of non-drug alternatives may promote heroin use.
DeltaNeTS+: Elucidating the mechanism of drugs and diseases using gene expression and transcriptional regulatory networks
Authors: Noh Heeju , Hua Ziyi , Chrysinas Panagiotis , Shoemaker Jason E. , Gunawan Rudiyanto
Published: October 2019

Background

Knowledge on the molecular targets of diseases and drugs is crucial for elucidating disease pathogenesis and mechanism of action of drugs, and for driving drug discovery and treatment formulation. In this regard, high-throughput gene transcriptional profiling has become a leading technology, generating whole-genome data on the transcriptional alterations caused by diseases or drug compounds. However, identifying direct gene targets, especially in the background of indirect (downstream) effects, based on differential gene expressions is difficult due to the complexity of gene regulatory network governing the gene transcriptional processes.

Results

In this work, we developed a network analysis method, called DeltaNeTS+, for inferring direct gene targets of drugs and diseases from gene transcriptional profiles. DeltaNeTS+ relies on a gene regulatory network model to identify direct perturbations to the transcription of genes. Importantly, DeltaNeTS+ is able to combine both steady-state and time-course gene expression profiles, as well as to leverage information on the gene network structure that is increasingly becoming available for a multitude of organisms, including human. We demonstrated the power of DeltaNeTS+ in predicting gene targets using gene expression data in complex organisms, includingCaenorhabditis elegansand human cell lines (T-cell and Calu-3). More specifically, in an application to time-course gene expression profiles of influenza A H1N1 (swine flu) and H5N1 (avian flu) infection, DeltaNeTS+ shed light on the key differences of dynamic cellular perturbations caused by the two influenza strains.

Conclusion

DeltaNeTS+ is an enabling tool to infer gene transcriptional perturbations caused by diseases and drugs from gene transcriptional profiles. By incorporating available information on gene network structure, DeltaNeTS+ produces accurate predictions of direct gene targets from a small sample size (~10s). DeltaNeTS+ can freely downloaded fromhttp://www.github.com/cabsel/deltanetsplus.
Indian Wellderly exomes underscoreNRAProles in elderly hypertrophic cardiomyopathy
Authors: Chimata Prasanth , Ankit Sharma , Agrawal Radhika , Rao Vinay J , Koranchery Rakesh , Rajendran Ranjith , Mohanan Kurukkanparampil Sreedharan , Shenthar Jayaprakash , Bazrafshan Sholeh , Sadayappan Sakthivel , Ahamed Hisham , Dhandapany Perundurai S
Published: October 2019

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that affects people of all ages, with the elderly population being inadequately studied. It is primarily caused by gene variants that encode proteins involved in the structure and function of the heart muscle. The identification of genes associated with elderly HCM requires ethnic-specific genomic sequences from Wellderly individuals. Currently, no Indian Wellderly dataset is available. To address this, we collected and sequenced the Indian Wellderly population. We built a novel Indian database of healthy aging nucleotide sequences (named i-DHANS) and is newly accessible atIndiCardiome. Utilizing this database and Indian HCM cohort, we identified nebulin-related anchoring protein (NRAP) as a gene associated with elderly HCM. NRAP is crucial for the assembly of myofibrils and transmission of force from the sarcomere to the extracellular matrix. Our functional analysis showed that the identified NRAP variant had significantly reduced interactions with its interacting partners, such as Kelch-like protein 41 (KLHL41) and α-actinin, implying a loss of function. In summary, our findings indicate thatNRAPis a new elderly cardiomyopathy gene, and our Indian Wellderly database is a valuable resource for identifying ethnic-specific genes for various diseases.
Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274
Authors: Meckelmann Sven W. , Hawksworth Jade I. , White Daniel , Andrews Robert , Rodrigues Patricia , O’Connor Anne , Alvarez-Jarreta Jorge , Tyrrell Victoria J. , Hinz Christine , Zhou You , Williams Julie , Aldrovandi Maceler , Watkins William J , Engler Adam J , Slatter David A. , Allen Stuart M , Acharya Jay , Mitchell Jacquie , Cooper Jackie , Aoki Junken , Kano Kuniyuki , Humphries Steve E. , O’Donnell Valerie B.
Published: October 2019

Aims

Common chromosome 9p21 SNPs increase coronary heart disease (CHD) risk, independent of “traditional lipid risk factors”. However, lipids comprise large numbers of structurally-related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here we applied lipidomic and genomic approaches to three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer ∼30% elevated CHD risk associated with altered expression ofANRIL, a long ncRNA.

Methods and Results

Untargeted and targeted lipidomics was applied to plasma samples from Northwick Park Heart Study II (NPHSII) homozygotes for AA or GG in rs10757274. Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). Five other risk SNPs did not show this phenotype. Correlation and network analysis showed that lysoPL-lysoPA interconversion was uncoupled from ATX in GG, indicating metabolic dysregulation. To identify candidate genes, transcriptomic data from shRNA downregulation ofANRILin HEK293 cells was mined. Significantly-altered expression of several lysoPL/lysoPA metabolising enzymes was found (MBOAT2, PLA2G4C, LPCAT2, ACSL6, PNPLA2, PLBD1, PLPP1, PLPP2andPLPPR2). Next, vascular smooth muscle cells differentiated from iPSCs of individuals homozygous for Chr9p21 risk SNPs were examined. Here, the presence of risk alleles was associated with altered expression of several lysoPL/lysoPA enzymes. Importantly, for several, deletion of the risk locus fully or partially reversed their expression to non-risk haplotype levels:ACSL3, DGKA, PLA2G2A, LPCAT2, LPL, PLA2G3, PNPLA3, PLA2G12A LIPC, LCAT, PLA2G6, ACSL1, MBOAT2.

Conclusion

A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their enzymatic metabolism. Lipid metabolites and genomic pathways associated with CHD pathogenesis in Chr9p21 andANRIL-associated disease are demonstrated.

One sentence summary

Inflammatory phospholipid metabolism defines a cardiovascular disease SNP
Structure of KCNH2 cyclic nucleotide-binding homology domain reveals a functionally vital salt-bridge
Authors: Ben-Bassat Ariel , Giladi Moshe , Haitin Yoni
Published: October 2019

Human KCNH2 (hKCNH2, Ether-à-go-go (EAG)-Related Gene, hERG) are best known for their role in cardiac action potentials repolarization and have key roles in various pathologies. As other KCNH family members, hKCNH2 contains a unique intracellular complex crucial for channel function, consisting of an N-terminal eag domain and a C-terminal cyclic nucleotide-binding homology domain (CNBHD). Previous studies demonstrated that the CNBHD is occupied by an intrinsic ligand motif (ILM), in a self-liganded conformation, providing a structural mechanism for the lack of KCNH channels regulation by cyclic nucleotides. While significant advancements in structural and functional characterizations of the CNBHD of KCNH channels have been made, a high-resolution structure of the hKCNH2 intracellular complex was missing. Here, we report the 1.5 Å resolution structure of the hKCNH2 channel CNBHD. The structure reveals the canonical fold shared by other KCNH family members, where the spatial organization of the ILM is preserved within the β-roll region. Moreover, measurements of small-angle X-ray scattering profile in solution, as well as comparison with a recent nuclear magnetic resonance (NMR) analysis of hKCNH2, revealed high agreement with the structure, indicating an overall low flexibility in solution. Importantly, we identified a novel salt-bridge (E807-R863), which was not previously resolved in the NMR and cryogenic electron microscopy (cryo-EM) structures. Strikingly, electrophysiological analysis of charge reversal mutations revealed its crucial role for hKCNH2 function. Moreover, comparison with other KCNH members revealed the structural conservation of this salt-bridge, consistent with its functional significance. Together with the available structure of the mouse KCNH1 intracellular complex, and previous electrophysiological and spectroscopic studies of KCNH family members, we propose that this salt-bridge serves as a strategically positioned linchpin to support both the spatial organization of the ILM and the maintenance of the intracellular complex interface.

Human KCNH2 are key channels governing cardiac repolarization. Here, a 1.5 Å resolution structure of their cyclic nucleotide-binding homology domain is presented. Structural analysis and electrophysiological validation reveal a novel salt-bridge, playing an important role in hKCNH2 functional regulation.
Epigenetic regulation of protein translation in KMT2A-rearranged AML
Authors: Lenard Alexandra , Xie Hongbo Michael , Riedel Simone S. , Yuan Zuo-Fei , Zhu Nan , Neff Tobias , Bernt Kathrin M.
Published: October 2019

Inhibition of the histone methyl-transferase DOT1L (KMT4) has shown encouraging activity in preclinical models of KMT2A (MLL)-rearranged leukemia. The DOT1L inhibitor pinometostat (EPZ5676) was well tolerated in early phase clinical trials and showed modest clinical activity, including occasional complete responses (CRs) as single agent. These studies support the development of combinatorial therapies for KMT2A-rearranged leukemias. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination of a DOT1L inhibitor with the protein synthesis inhibitor homoharringtonine (HHR).

EZH2 is the catalytic histone methyltransferase in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has reported preclinical activity in KMT2A-rearranged leukemia. We found that the H3K79 and H3K27 methyl marks are not dependent on each other, and that DOT1L and EZH2 inhibition affect largely distinct gene expression programs. In particular, the KMT2A/DOT1L target HOXA9, which is commonly de-repressed as a consequence of PRC2 loss or inhibition in other contexts, was not re-activated upon dual DOT1L/EZH2 knockout or inhibition. Despite encouraging data in murine KMT2A-MLLT3 transformed cells suggesting synergy between DOT1L and EZH2 inhibition, we found both synergistic and antagonistic effects on a panel of human KMT2A rearranged cell lines. Combinatorial inhibition of DOT1L and EZH2 is thus not a promising strategy. We identified opposing effects on ribosomal gene transcription and protein translation by DOT1L and EZH2 as a mechanism that is partially responsible for observed antagonistic effects. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (HHR), supporting further preclinical/clinical development of this combination.
Stereo In-Line Holographic Digital Microscope
Authors: Zimmerman Thomas , Antipa Nick , Elnatan Daniel , Murru Alessio , Biswas Sujoy , Pastore Vito , Bonani Mayara , Waller Laura , Fung Jennifer , Fenu Gianni , Bianco Simone
Published: October 2019

Biologists use optical microscopes to study plankton in the lab, but their size, complexity and cost makes widespread deployment of microscopes in lakes and oceans challenging. Monitoring the morphology, behavior and distribution of planktonin situis essential as they are excellent indicators of marine environment health and provide a majority of Earth’s oxygen and carbon sequestration. Direct in-line holographic microscopy (DIHM) eliminates many of these obstacles, but image reconstruction is computationally intensive and produces monochromatic images. By using one laser and one white LED, it is possible to obtain the 3D location plankton by triangulation, limiting holographic reconstruction to only the voxels occupied by the plankton, reducing computation by several orders of magnitude. The color information from the white LED assists in the classification of plankton, as phytoplankton contains green-colored chlorophyll. The reconstructed plankton images are rendered in a 3D interactive environment, viewable from a browser, providing the user the experience of observing plankton from inside a drop of water.
Identifying conservation priorities in a defaunated tropical biodiversity hotspot
Authors: Tilker Andrew , Abrams Jesse F. , Nguyen An , Hörig Lisa , Axtner Jan , Louvrier Julie , Rawson Benjamin M. , Nguyen Quang Hoa Anh , Guegan Francois , Van Nguyen Thanh , Le Minh , Sollmann Rahel , Wilting Andreas
Published: October 2019

Aim

Unsustainable hunting is leading to widespread defaunation across the tropics. To mitigate against this threat with limited conservation resources, stakeholders must make decisions on where to focus anti-poaching activities. Identifying priority areas in a robust way allows decision-makers to target areas of conservation importance, therefore maximizing the impact of conservation interventions.

Location

Annamite mountains, Vietnam and Laos.

Methods

We conducted systematic landscape-scale surveys across five study sites (four protected areas, one unprotected area) using camera-trapping and leech-derived environmental DNA. We analyzed detections within a Bayesian multi-species occupancy framework to evaluate species responses to environmental and anthropogenic influences. Species responses were then used to predict occurrence to unsampled regions. We used predicted species richness maps and occurrence of endemic species to identify areas of conservation importance for targeted conservation interventions.

Results

Analyses showed that habitat-based covariates were uninformative. Our final model therefore incorporated three anthropogenic covariates as well as elevation, which reflects both ecological and anthropogenic factors. Conservation-priority species tended to found in areas that are more remote now or have been less accessible in the past, and at higher elevations. Predicted species richness was low and broadly similar across the sites, but slightly higher in the more remote site. Occupancy of the three endemic species showed a similar trend.

Main conclusion

Identifying spatial patterns of biodiversity in heavily-defaunated landscapes may require novel methodological and analytical approaches. Our results indicate to build robust prediction maps it is beneficial to sample over large spatial scales, use multiple detection methods to increase detections for rare species, include anthropogenic covariates that capture different aspects of hunting pressure, and analyze data within a Bayesian multi-species framework. Our models further suggest that more remote areas should be prioritized for anti-poaching efforts to prevent the loss of rare and endemic species.
Environmental reservoirs ofMycobacterium bovisandMycobacterium tuberculosisin the Ruaha region, Tanzania
Authors: Travis Emma R. , Hung Yujiun , Porter David , Paul Goodluck , James Robert , Roug Annette , Kato-Maeda Midori , Kazwala Rudovick , Smith Woutrina A. , Hopewell Phil , Courtenay Orin , Wellington Elizabeth M.H.
Published: October 2019

This study was designed to investigate the prevalence of members of the Mycobacterium tuberculosis complex (MTBC) in the environment of pastoralists and villagers in the Iringa district, adjacent to the Ruaha National Park in Tanzania. Utilising specific qPCR assays, bothMycobacterium bovisandMycobacterium tuberculosiswere detected in cattle faeces, boma soil, water and household dust.M. boviswas also found in goat faeces and goat boma soil. This is the first report of faecal shedding ofM. bovisin goats and the first molecular survey of faecal shedding in cattle. The prevalence of both bacterial species varied by village, area, season and sample type. Geographical and temporal correlations across sample types were suggestive of cross species transmission. This non-invasive test has previously been rigorously validated for screening other mammals; in this study it has successfully been applied to detectM. bovisandM. tuberculosisin livestock faeces and the environment.
Analysis of diverse eukaryotes suggests the existence of an ancestral mitochondrial apparatus derived from the bacterial type II secretion system
Authors: Horváthová Lenka , Žárský Vojtěch , Pánek Tomáš , Derelle Romain , Pyrih Jan , Motyčková Alžběta , Klápšt’ová Veronika , Vinopalová Martina , Marková Lenka , Voleman Luboš , Klimeš Vladimír , Petrů Markéta , Vaitová Zuzana , Čepička Ivan , Hryzáková Klára , Harant Karel , Gray Michael W. , Chami Mohamed , Guilvout Ingrid , Francetic Olivera , Lang B. Franz , Vlček Čestmír , Tsaousis Anastasios D. , Eliáš Marek , Doležal Pavel
Published: October 2019

The type 2 secretion system (T2SS) is present in some Gram-negative eubacteria and used to secrete proteins across the outer membrane. Here we report that certain representative heteroloboseans, jakobids, malawimonads and hemimastigotes unexpectedly possess homologues of core T2SS components. We show that at least some of them are present in mitochondria, and their behaviour in biochemical assays is consistent with the presence of a mitochondrial T2SS-derived system (miT2SS). We additionally identified 23 protein families co-occurring with miT2SS in eukaryotes. Seven of these proteins could be directly linked to the core miT2SS by functional data and/or sequence features, whereas others may represent different parts of a broader functional pathway, possibly also involving the peroxisome. Its distribution in eukaryotes and phylogenetic evidence together indicate that the miT2SS-centred pathway is an ancestral eukaryotic trait. Our findings thus have direct implications for the functional properties of the early mitochondrion.
Distinct microbial communities in the murine gut are revealed by taxonomy-independent phylogenetic random forests
Authors: Singh Gurdeep , Brass Andrew , Cruickshank Sheena M. , Knight Christopher G.
Published: October 2019

Gut microbiome analysis using 16S rRNA frequently focuses on summary statistics (e.g. diversity) or single taxonomic scales (e.g. Operational Taxonomic units, OTUs). This approach risks misinterpreting the phylogenetic or abundance scales of community differences (e.g. over-emphasising the role of single strains). We therefore constructed a 16S phylogenetic tree from mouse stool and colonic mucus communities. Random forest models, of all 428,234 clades, tested community differences among niches (stool versus mucus), host ages (6 versus 18 weeks), genotypes (wildtype versus colitis prone-mdr1a-/-) and social groups (co-housed siblings). Models discriminated all criteriaexcepthost genotype, where no community differences were found. Host social groups differed in abundant, low-level, taxa whereas intermediate phylogenetic and abundance scales distinguished ages and niches. Thus, treating evolutionary clades of microbes equivalently without reference to OTUs or taxonomy, clearly identifies whether and how gut microbial communities are distinct and provides a novel way to define functionally important bacteria.
FMN-dependent oligomerization of putative lactate oxidase fromPediococcus acidilactici
Authors: Ashok Yashwanth , Maksimainen Mirko M. , Kallio Tuija , Kilpeläinen Pekka , Lehtiö Lari
Published: October 2019

Lactate oxidases belong to a group of FMN-dependent enzymes and they catalyze a conversion of lactate to pyruvate with a release of hydrogen peroxide. Hydrogen peroxide is also utilized as a read out in biosensors to quantitate lactate levels in biological samples.Aerococcus viridanslactate oxidase is the best characterized lactate oxidase and our knowledge of lactate oxidases relies largely to studies conducted with that particular enzyme.Pediococcus acidilacticilactate oxidase is also commercially available for e.g. lactate measurements, but this enzyme has not been characterized before in detail. Here we report structural characterization of the recombinant enzyme and its co-factor dependent oligomerization. The crystal structures revealed two distinct conformations in the loop closing the active site, consistent with previous biochemical studies implicating the role of loop in catalysis. Despite the structural conservation of active site residues when compared toAerococcus viridanslactate oxidase we were not able to detect either oxidase or monooxygenase activity when L-lactate or other potential alpha hydroxyl acids were used as a substrate.Pediococcus acidilacticilactate oxidase is therefore an example of a misannotation of an FMN-dependent enzyme, which catalyzes likely a so far unknown oxidation reaction.
Modeling Dragons: Using linked mechanistic physiological and microclimate models to explore environmental, physiological, and morphological constraints on the early evolution of dinosaurs
Authors: Lovelace David M. , Hartman Scott A. , Mathewson Paul D. , Linzmeier Benjamin J. , Porter Warren P.
Published: October 2019

We employed the widely-tested biophysiological modeling software, Niche Mapper™ to investigate the metabolic function of Late Triassic dinosaursPlateosaurusandCoelophysisduring global greenhouse conditions. We tested them under a variety of assumptions about resting metabolic rate, evaluated within six microclimate models that bound paleoenvironmental conditions at 12° N paleolatitude, as determined by sedimentological and isotopic proxies for climate within the Chinle Formation of the southwestern United States. Sensitivity testing of metabolic variables and simulated “metabolic chamber” analyses support elevated “ratite-like” metabolic rates and intermediate “monotreme-like” core temperature ranges in these species of early saurischian dinosaur. Our results suggest small theropods may have needed partial to full epidermal insulation in temperate environments, while fully grown prosauropods would have likely been heat stressed in open, hot environments and should have been restricted to cooler microclimates such as dense forests (under any vegitative cover) or those seen at higher latitudes and elevations. This is in agreement with the Late Triassic fossil record and may have contributed to the latitudinal gap in the Triassic prosauropod record.
The dynamics and interactions of respiratory pathogen carriage among French pilgrims during the 2018 Hajj
Authors: Hoang Van-Thuan , Dao Thi-Loi , Ly Tran Duc Anh , Belhouchat Khadidja , Chaht Kamel Larbi , Gaudart Jean , Mrenda Bakridine Mmadi , Drali Tassadit , Yezli Saber , Alotaibi Badriah , Fournier Pierre-Edouard , Raoult Didier , Parola Philippe , de Santi Vincent Pommier , Gautret Philippe
Published: October 2019

Respiratory tract infections are frequent among Hajj pilgrims. We conducted this study to describe the dynamics of the acquisition of respiratory pathogens, their potential interactions and risk factors for possible lower respiratory tract infection symptoms (LRTI) among French pilgrims during the 2018 Hajj. Pilgrims from Marseille who were participating in the Hajj were recruited. Each participant underwent four successive systematic nasopharyngeal swabs before and during their stay in Saudi Arabia. Carriage of the main respiratory pathogens was assessed by PCR. 121 pilgrims were included and 93.4% reported respiratory symptoms during the study period. Polymicrobial carriage was observed in 73.8% samples. The acquisition of rhinovirus, coronaviruses and Staphylococcus aureus occurred soon after arrival in Saudi Arabia and rates decreased gradually after days 5 and 6. In contrast, Streptococcus pneumoniae and Klebsiella pneumoniae carriage increased progressively until the end of the stay in Saudi Arabia. Haemophilus influenzae and Moraxella catarrhalis carriage increased starting around days 12 and 13, following an initial clearance. Influenza viruses were rarely isolated. We observed an independent positive mutual association between S. aureus and rhinovirus carriage and between H. influenzae and M. catarrhalis carriage. Dual carriage of H. influenzae and M. catarrhalis was strongly associated with S. pneumoniae carriage (OR = 6.22, 95%CI [2.04-19.01]). Finally, our model showed that M. catarrhalis carriage was negatively associated with K. pneumoniae carriage. Chronic respiratory disease was associated with symptoms of LRTI. K. pneumoniae, M. catarrhalis-S. aureus and H. influenzae-rhinovirus dual carriage was associated with LRTI symptoms. Our data suggest that RTIs at the Hajj are a result of complex interactions between a number of respiratory viruses and bacteria.

Author summary

Despite the recommendation to take individual preventive measures to prevent respiratory tract infections, these infections remain common among Hajj pilgrims. Respiratory pathogens acquired during the Hajj are usually studied individually, although in their natural environment they often compete or coexist with multiple microbial species. A better understanding of polymicrobial interactions in the nasopharynx among Hajj pilgrims is important. Our study describes the dynamics of the acquisition of respiratory pathogens and their potential interactions among pilgrims during the Hajj. We found that polymicrobial carriage was observed in most individuals and that some pathogens associated positively while other did not. Some pathogen associations correlated with symptoms of lower respiratory tract infections.
A wave of embryonic bipotent T/lymphoid tissue inducer progenitors regulates the maturation of medullary thymic epithelial cells
Authors: Elsaid Ramy , Meunier Sylvain , Burlen-Defranoux Odile , Soares-da-Silva Francisca , Perchet Thibaut , Iturri Lorea , Freyer Laina , Vieira Paulo , Pereira Pablo , Golub Rachel , Bandeira Antonio , Perdiguero Elisa Gomez , Cumano Ana
Published: October 2019

Multiple waves of hematopoietic progenitors with distinct lineage potentials are differentially regulated in time and space. We show that the first thymic seeding progenitors comprise a unique population of bipotent cells that generate lymphoid tissue inducer and invariant Vγ5+ T cells. Both populations are of embryonic origin and induce the maturation of medullary thymic epithelial cells. Indeed, temporal depletion of the first wave of thymocytes results in a five-fold reduction of mature medullary thymic epithelial cells, after birth. We further show that these progenitors are of hematopoietic stem cell, and not, of yolk sac origin, despite the temporal overlap between the onset of lymphopoiesis and the transient expression of lymphoid transcripts in yolk sac precursors, that does not impact their strict erythro-myeloid potential. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets required for the establishment of a functionally diverse immune system.
Multiple environmental signaling pathways control the differentiation of RORγt-expressing regulatory T cells
Authors: Hussein Hind , Denanglaire Sébastien , Van Gool Frédéric , Azouz Abdulkader , Ajouaou Yousra , El-Khatib Hana , Oldenhove Guillaume , Leo Oberdan , Andris Fabienne
Published: October 2019

RORγt-expressing Tregs form a specialized subset of intestinal CD4+ Foxp3+ cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of RORγt expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of RORγt+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that RORγt+ Treg development is controlled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3- and TGF-β-derived signals act in favor of RORγt+ Treg development. Ectopic expression of c-Maf did not rescue RORγt expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-γ/STAT1 signaling pathway acts as a negative regulator of RORγt+ Treg differentiation in a c-Maf independent fashion.

These data thus argue for a complex integrative signaling network that finely tunes RORγt expression in Tregs. The finding that type 1 inflammation impedes RORγt+ Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.