bluuebunny/crossref_metadata_2025 huggingface dataset:
Hidden Rice Diversity in the Guianas
Authors: Andel Tinde van , Veltman Margret , Bertin Alice , Maat Harro , Polime Thomas , Ris Lambers Derk Hille , Awie Jerry Tjoe , Boer Hugo de , Manzanilla Vincent
Published: March 2019

Traditional crop varieties are an important source of genetic diversity for crop adaptation and modern breeding. Landraces of Asian (Oryza sativa) and African (Oryza glaberrima) rice have been well studied on the continents where they were domesticated. However, their history of cultivation in northern South America is poorly understood. Here we reveal the rice diversity that is maintained by Maroons, descendants of enslaved Africans who fled to the interior forests of the Guianas ca. 300 years ago. We interviewed subsistence farmers who practice shifting cultivation along the Maroni and Lawa rivers that form the natural border between French Guiana and Suriname, and used ethnobotanical and morphological methods to identify around 50 varieties, of which 15 were previously undocumented. The genetic origin of these varieties was explored using the Angiosperms-353 universal probe set. Despite the large distances between sites and relative inaccessibility of the area, phenotypic and genetic diversity did not display any geographic structure, which is consistent with knowledge of seed exchange among members of the same ethnolinguistic group. Although improved US cultivars were introduced in Maroon villages in the 1940s, these have not displaced the traditional landraces, which are cherished for their taste and nutritious qualities and for their importance in Maroon spiritual life. The unique agricultural and ritual practices of Maroons confirm their role as custodians of rice diversity, a role that is currently under threat from external pressures and encroaching globalization. We expect that the rice diversity uncovered in this study represents only a fraction of the total diversity in the Guianas and may constitute a large untapped resource that holds promise for future rice improvement. Further efforts to inventory and preserve these landraces will help to protect a precious cultural heritage and local food security.
Transient perturbation of the left temporal cortex evokes plasticity-related reconfiguration of the lexical network
Authors: Klaus Jana , Schutter Dennis J.L.G. , Piai Vitória
Published: March 2019

Language impairment is common after left-hemisphere damage. However, the involvement of perilesional and homologous contralateral regions in compensating for left-sided lesions remains poorly understood. The aim of this study was to examine acute organizational changes in brain activity related to conceptual and lexical retrieval in unimpaired language production following transient disruption of the left middle temporal gyrus (MTG). In a randomized singleblind within-subject experiment, we recorded the electroencephalogram from sixteen healthy participants during a context-driven picture-naming task. Prior to the task, the left MTG was perturbed with real neuronavigated continuous theta-burst stimulation (cTBS) or sham stimulation. During the task, participants read lead-in sentences that created a constraining (e.g. “The farmer milks the”) or non-constraining context (e.g. “The farmer buys the”). The last word was shown as a picture that participants had to name (e.g. “cow”). Replicating behavioral studies, participants were overall faster in naming pictures following a constraining relative to a non-constraining context, but this effect did not differ between real and sham cTBS. Real cTBS, however, increased overall error rates compared to sham cTBS. In line with previous studies, we observed a decrease in alpha-beta (8-24 Hz) oscillatory power for constraining relative to non-constraining contexts over left temporal-parietal cortex after participants received sham cTBS. However, following real cTBS, this decrease extended towards left prefrontal regions associated with both domain-general and domain-specific control mechanisms. Our findings provide evidence that immediately after the disruption of the left MTG, the lexical-semantic network is able to quickly reconfigure, also recruiting domain-general regions.
Alanine Metabolism inBacillus subtilis
Authors: Sidiq Karzan R. , Zhao Zhao , Daniel Richard A.
Published: March 2019

Despite a long history of genetic manipulation ofBacillus subtilisusing auxotrophic markers in genetic manipulation, the genes involved in alanine metabolism have not been characterised fully. Here we show thatB. subtilisexpresses an alanine uptake permease, YtnA (DatA), that has a major role in the assimilation of D-alanine from the environment. Since this isomer of the amino acid is not normally abundant it likely source is form the cells own cell wall probably through the action of carboxypeptidases and/or the spontaneous release of D-alanine from the teichoic acids. Also in this work we clarify the synthetic pathways acting in the biosynthesis of alanine. Genetically we show that, unlikeE. coliwhere multiple enzymes have a biochemical activity that can generate alanine, inB. subtilisthe primary synthetic enzyme for alanine is encoded byalaT, although a second gene,dat, is present that can support slow growth of an alanine auxotroph however our data suggests that this enzyme probably synthesises D-alanine. In summary this work has provided an explanation of the observation that growth ofB. subtilisis linked with an efficient recycling system for D-alanine that is released from the cell as the cell envelope is processed to permit cell enlargement. The results also suggest that the relative abundance of D- and L-alanine that might be linked with cytosolic pool of D and L-glutamate, and so enabling tight coupling protein and cell envelope synthesis with the metabolic status of the cell.
Combinations ofSpokgenes create multiple meiotic drivers inPodospora
Authors: Vogan Aaron A. , Ament-Velásquez S. Lorena , Granger-Farbos Alexandra , Svedberg Jesper , Bastiaans Eric , Debets Alfons J. M. , Coustou Virginie , Yvanne Hélène , Clavé Corinne , Saupe Sven J. , Johannesson Hanna
Published: March 2019

Meiotic drive is the preferential transmission of a particular allele at a given locus during sexual reproduction. The phenomenon is observed as spore killing in a variety of fungal lineages, includingPodospora. In natural populations ofPodospora anserina, seven spore killers (Psks) have been identified through classical genetic analyses. Here we show that theSpokgene family underlie thePskspore killers. The combination of the variousSpokgenes at different chromosomal locations defines the spore killers and creates a killing hierarchy within the same population. We identify two novelSpokhomologs that are located within a complex region (theSpokblock) that reside in different chromosomal locations in given natural strains. We confirm that the individual SPOK proteins perform both the killing and resistance functions and show that these activities are dependent on distinct domains, a nuclease and a kinase domain respectively. Genomic data and phylogenetic analysis across ascomycetes suggest that theSpokgenes disperse via cross-species transfer, and evolve by duplication and diversification within several lineages.
Stochastic gene expression influences the selection of antibiotic resistance mutations
Authors: Sun Lei , Ashcroft Peter , Ackermann Martin , Bonhoeffer Sebastian
Published: March 2019

Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme’s catalytic rate alone does not contribute to resistance. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.
Comment on ‘Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size’
Authors: Gapsys Vytautas , de Groot Bert L.
Published: March 2019

A recent molecular dynamics investigation into the stability of hemoglobin concluded that the unliganded protein is only stable in the T state when a solvent box is used in the simulations that is ten times larger than what is usually employed. Here, we express three main concerns about that study. In addition, we show that with an order of magnitude more statistics, the reported box size dependence is not reproducible. Overall, no significant effects on the kinetics or thermodynamics of conformational transitions were observed.
Challenges and opportunities in population monitoring of cheetahs
Authors: Linden Daniel W. , Green David S. , Chelysheva Elena V. , Mandela Salim , Dloniak Stephanie M.
Published: March 2019

Population monitoring is key to wildlife conservation and management but is challenging at the spatial and temporal extents necessary for understanding changes. Non-invasive survey methods and spatial capture-recapture (SCR) models have revolutionized wildlife monitoring by providing the means to more easily acquire data at large scales and the framework to generate spatially-explicit predictions, respectively. Despite the opportunities for improved monitoring, challenges can remain in the study design and model fitting phases of an SCR approach. Here, we used a search-encounter design with multi-session SCR models to collect spatially-indexed photographs and estimate the changes in density of cheetahs between 2005 and 2013–2016 in the Masai Mara National Reserve (MMNR) in southwestern Kenya. Our SCR models of cheetah encounters suggested little change in cheetah density from 2005 to 2013–2016, though there was some evidence that density fluctuated annually in the MMNR. The sampling period length (5 vs. 10 months) and timing (early, late, full year) over which spatial encounters were included in the modeling did not substantially alter inferences about density when sample sizes were adequate (>20 spatially distinct encounters). We estimated an average cheetah density of ~1.2 cheetahs/100 km2, consistent with the impression that the MMNR provides important habitat for cheetahs in Africa. During most years and seasonal periods, the spatial distribution of vegetation greenness (a proxy for ungulate habitat quality) accounted for important variation in encounter rates. The search-encounter design used here could be applied to other regions for the purposes of cheetah monitoring. While snap-shot estimates of population size across time are useful for wildlife monitoring, open population models could identify the mechanisms behind changes and further facilitate better conservation and management decision making.
Transcranial Alternating Current Stimulation (tACS) Entrains Alpha Oscillations by Preferential Phase Synchronization of Fast-Spiking Cortical Neurons to Stimulation Waveform
Authors: Negahbani Ehsan , Stitt Iain M. , Davey Marshall , Doan Thien T. , Dannhauer Moritz , Hoover Anna C. , Peterchev Angel V. , Radtke-Schuller Susanne , Fröhlich Flavio
Published: March 2019

Modeling studies predict that transcranial alternating current stimulation (tACS) entrains brain oscillations, yet direct examination has been lacking or potentially contaminated by stimulation artefact. Here we first demonstrate how the posterior parietal cortex drives primary visual cortex and thalamic LP in the alpha-band in head-fixed awake ferrets. The spike-field synchrony is maximum within alpha frequency, and more prominent for narrow-spiking neurons than broad-spiking ones. Guided by a validated model of electric field distribution, we produced electric fields comparable to those in humans and primates (< 0.5 mV/mm). We found evidence to support the model-driven predictions of how tACS entrains neural oscillations as explained by the triangular Arnold tongue pattern. In agreement with the stronger spike-field coupling of narrow-spiking cells, tACS more strongly entrained this cell population. Our findings provide the firstin vivoevidence of how tACS with electric field amplitudes used in human studies entrains neuronal oscillators.
Comments on the recent crystal structure of TsaBDE complex of bacterial t6A biosynthesis system and its significance for understanding TC-AMP processing
Authors: Stec Boguslaw
Published: March 2019

The N(6)-threonylcarbamoyl adenosine (t6A) modification at position 37 of a tRNA of the anticodon loop is universal and central to the translational fidelity of all known organisms. The ternary complex of TsaBDE is the central and essential workstation for t6A biosynthesis in bacteria. The recently published crystal structure of Thermotoga maritima (T.maritima) TsaBDE complex (Missoury et al., 2018) has ~15% incorrectly-placed, misplaced/mistraced, or missing residues. These structural errors have precipitated incorrect conclusions about the disordering of the active site and inferred action of the TsaE element. In this report, we rectify the published structural model of the T.maritima TsaBDE complex. In stark contrast, a corrected structural model of TsaBDE shows that both active sites of the TsaD element are fully occupied with threonylcarbamoyladenosine (TC-AMP), an unstable intermediate chemical moiety of the t6A biosynthesis pathway. This observation has profound implications for understanding the funneling of intermediates in the t6A pathway and also in helping to elucidate tRNA binding modes. Based on the structural details described in here we propose a unifying principle for binding the tRNA to the TsaD subunit of the complex which is universally required in all known t6A modification pathways.
Combining amoxicillin and relebactam provides new therapeutic potential for Mycobacterium abscessus infection
Authors: Lopeman Rose C. , Harrison James , Desai Maya , Lambert Peter , Cox Jonathan A. G.
Published: March 2019

Infections caused by the opportunistic pathogen Mycobacterium abscessus are increasing in prevalence within the cystic fibrosis population. Our limited understanding of this ubiquitous environmental microorganism matched with its intrinsic resistance to most classes of antibiotic, including β-lactams, has left us with an urgent demand for new, more effective therapeutic interventions. De novo antimicrobial drug discovery is a lengthy process and so we have taken the approach of repurposing known antibiotics in order to provide a rapidly implementable solution to a current problem. Here we report a significant step forward in treatment potential for M. abscessus infection by sensitising the organism to the broad spectrum β-lactam antibiotic, amoxicillin, using the non-competitive β-lactamase inhibitor, relebactam. We demonstrate by disk diffusion and broth microdilution assay that this combination works synergistically to inhibit M. abscessus. We also demonstrate the direct non-competitive inhibition of the M. abscessus β-lactamase, BlaMab using a novel thin-layer chromatography-based assay for β-lactamase inhibition, which is subsequently kinetically validated by spectrophotometric assay using the nitrocefin reporter assay. Finally, we demonstrate the in vitro efficacy of this combination against a collection of M. abscessus clinical isolates, demonstrating the significant therapeutic potential of the amoxicillin and relebactam combination.
Predicting vaccine effectiveness in livestock populations: a theoretical framework applied to PRRS virus infections in pigs
Authors: Bitsouni Vasiliki , Lycett Samantha , Opriessnig Tanja , Doeschl-Wilson Andrea
Published: March 2019

Vaccines remain one of the main tools to control infectious diseases in domestic livestock. Although a plethora of veterinary vaccines are on the market and routinely applied to protect animals against infection with particular pathogens, the disease in question often continues to persist, sometimes at high prevalence. The limited effectiveness of certain vaccines in the field leaves open questions regarding the required properties that an effective vaccine should have, as well as the most efficient vaccination strategy for achieving the intended goal of vaccination programmes. To date a systematic approach for studying the combined effects of different types of vaccines and vaccination strategies is lacking. In this paper, we develop a theoretical framework for modelling the epidemiological consequences of vaccination with imperfect vaccines of various types, administered using different strategies to herds with different replacement rates and heterogeneity in vaccine responsiveness. Applying the model to the Porcine Reproductive and Respiratory Syndrome (PRRS), which despite routine vaccination remains one of the most significant endemic swine diseases worldwide, we then examine the influence of these diverse factors alone and in combination, on within-herd virus transmission. We derive threshold conditions for preventing infection invasion in the case of imperfect vaccines inducing limited sterilizing immunity. The model developed in this study has practical implications for the development of vaccines and vaccination programmes in livestock populations not only for PRRS, but also for other viral infections.
A Multiplex Pharmacogenetics Assay using the MinION Nanopore Sequencing Device
Authors: Liau Yusmiati , Cree Simone L. , Maggo Simran , Miller Allison L. , Pearson John F. , Gladding Patrick A. , Kennedy Martin A.
Published: March 2019

Aim

The MinION nanopore sequencing device opens the opportunity to cost-effective and point-of-care DNA sequencing. We developed a multiplex assay targeting pharmacogenetic variants related to clopidogrel and warfarin, two commonly used drugs that show response variability due to genetic polymorphisms.

Materials & Methods

Six reference and 78 clinical DNA samples were amplified by PCR to generate 15 amplicons targeting key variants. These products were then barcoded to enable sample multiplexing. Three variant calling tools were used to compare genotyping accuracy.

Results and Conclusions

All but three samples were successfully sequenced and genotyped. Nanopolish software achieved accuracy > 90 % for all except one variant. While minor mis-genotyping issues exist, this work demonstrates that drug-specific or broad pharmacogenetic screening assays are possible on the MinION sequencing device.
An Integrated Framework for Genome Analysis Reveals Numerous Previously Unrecognizable Structural Variants in Leukemia Patients’ Samples
Authors: Xu Jie , Song Fan , Schleicher Emily , Pool Christopher , Bann Darrin , Hennessy Max , Sheldon Kathryn , Batchelder Emma , Annageldiyev Charyguly , Sharma Arati , Chang Yuanyuan , Hastie Alex , Miller Barbara , Goldenberg David , Mineishi Shin , Claxton David , Moldovan George-Lucian , Yue Feng , Broach James R.
Published: March 2019

While genomic analysis of tumors has stimulated major advances in cancer diagnosis, prognosis and treatment, current methods fail to identify a large fraction of somatic structural variants in tumors. We have applied a combination of whole genome sequencing and optical genome mapping to a number of adult and pediatric leukemia samples, which revealed in each of these samples a large number of structural variants not recognizable by current tools of genomic analyses. We developed computational methods to determine which of those variants likely arose as somatic mutations. The method identified 97% of the structural variants previously reported by karyotype analysis of these samples and revealed an additional fivefold more such somatic rearrangements. The method identified on average tens of previously unrecognizable inversions and duplications and hundreds of previously unrecognizable insertions and deletions. These structural variants recurrently affected a number of leukemia associated genes as well as cancer driver genes not previously associated with leukemia and genes not previously associated with cancer. A number of variants only affected intergenic regions but caused cis-acting alterations in expression of neighboring genes. Analysis of TCGA data indicates that the status of several of the recurrently mutated genes identified in this study significantly affect survival of AML patients. Our results suggest that current genomic analysis methods fail to identify a majority of structural variants in leukemia samples and this lacunae may hamper diagnostic and prognostic efforts.
Effects of topical PaiTeLing in nude mice implanted with human condyloma acuminatum tissue infected with HPV 6, 31, and 81: comparison with imiquimod and interferon-α-2b
Authors: Xu Rong , Wang Li , Hou Jianmei , Li Jun , Fan Zhiyan , Wu Liangcai , Zhu Congzhong , Ma Miaomiao , Wang Huiping , Hou Shuping
Published: March 2019

BACKGROUND

The standard treatment for condyloma acuminatum is topical imiquimod. In the current study, we used a mouse model to compare the effects of an herbal medication PaiTeLing.

METHODS

Lesion tissue was obtained from a woman with genital condyloma acuminatum. DNA genotyping revealed HPV6, 31, and 81. Tissue prism (0.5 cm3) was implanted to BALB/C nude mice, 22 days after the implantation, mice began to receive topical treatment with imiquimod, interferon-α-2b gel, or PaiTeLing over the site of implantation for 2 consecutive weeks. Mice receiving tissue implantation but no other intervention was included as a control. Skin tissue was collected for H&E staining and anti-CD207 immunohistochemistry. Blood was collected to determine a panel of cytokines.

RESULTS

H&E staining showed lower number of koilocytes and higher number of Langerhans cells in the treatment groups, particularly in mice receiving imiquimod or PaiTeLing. Blood levels of TNFα, IL-2, INF-γ and IL-12p70 were increased in the treatment groups, particularly in mice receiving imiquimod or PaiTeLing.

CONCLUSION

Immune response in nude mice infected with HPV6, 31, and 81 is enhanced by treatment with imiquimod, interferon-α-2b and PaiTeLing. Effects of imiquimod and PaiTeLing seems to be stronger than interferon-α-2b.
Deep learning in bioinformatics: introduction, application, and perspective in big data era
Authors: Li Yu , Huang Chao , Ding Lizhong , Li Zhongxiao , Pan Yijie , Gao Xin
Published: March 2019

Deep learning, which is especially formidable in handling big data, has achieved great success in various fields, including bioinformatics. With the advances of the big data era in biology, it is foreseeable that deep learning will become increasingly important in the field and will be incorporated in vast majorities of analysis pipelines. In this review, we provide both the exoteric introduction of deep learning, and concrete examples and implementations of its representative applications in bioinformatics. We start from the recent achievements of deep learning in the bioinformatics field, pointing out the problems which are suitable to use deep learning. After that, we introduce deep learning in an easy-to-understand fashion, from shallow neural networks to legendary convolutional neural networks, legendary recurrent neural networks, graph neural networks, generative adversarial networks, variational autoencoder, and the most recent state-of-the-art architectures. After that, we provide eight examples, covering five bioinformatics research directions and all the four kinds of data type, with the implementation written in Tensorflow and Keras. Finally, we discuss the common issues, such as overfitting and interpretability, that users will encounter when adopting deep learning methods and provide corresponding suggestions. The implementations are freely available athttps://github.com/lykaust15/Deep_learning_examples.
How important is it to consider lineage diversification heterogeneity in in macroevolutionary studies: lessons from the lizard family Liolaemidae
Authors: Olave Melisa , Avila Luciano J. , Sites Jack W. , Morando Mariana
Published: March 2019

Macroevolutionary studies commonly apply multiple models to test state-dependent diversification. These models track the association between states of interest along a phylogeny, but they do not consider whether independent shifts in character states are associated with shifts in diversification rates. This potentially problematic issue has received little theoretical attention, while macroevolutionary studies implementing such models in increasing larger scale studies continue growing. A recent macroevolutionary study has found that Andean orogeny has acted as a species pump driving diversification of the family Liolaemidae, a highly species-rich lizard family native to temperate southern South America.

This study approaches a distribution-dependent hypothesis using the Geographic State Speciation and Extinction model (GeoSSE). However, more recent analyses have shown that there is a clear heterogeneous diversification pattern in the Liolaemidae, which likely biased the GeoSSE analysis. Specifically, we show here that there are two shifts to accelered speciation rates involving species groups that were classified as “Andean” in their distributions. We demonstrate that this GeoSSE result is meaningless when heterogeneous diversification rates are included. We use the lizard family Liolaemidae to demonstrate potential risks of ignoring clade-specific differences in diversification rates in macroevolutionary studies.
A unicellular relative of animals generates an epithelium-like cell layer by actomyosin-dependent cellularization
Authors: Dudin Omaya , Ondracka Andrej , Grau-Bové Xavier , Haraldsen Arthur A. B. , Toyoda Atsushi , Suga Hiroshi , Bråte Jon , Ruiz-Trillo Iñaki
Published: March 2019

In animals, cellularization of a coenocyte is a specialized form of cytokinesis that results in the formation of a polarized epithelium during early embryonic development. It is characterized by coordinated assembly of an actomyosin network, which drives inward membrane invaginations. However, whether coordinated cellularization driven by membrane invagination exists outside animals is not known. To that end, we investigate cellularization in the ichthyosporean Sphaeroforma arctica, a close unicellular relative of animals. We show that the process of cellularization involves coordinated inward plasma membrane invaginations dependent on an actomyosin network, and reveal the temporal order of its assembly. This leads to the formation of a polarized layer of cells resembling an epithelium. We show that this epithelium-like stage is associated with tightly regulated transcriptional activation of genes involved in cell adhesion. Hereby we demonstrate the presence of a selforganized, clonally-generated, polarized layer of cells in a unicellular relative of animals.
Branched photoswitchable tethered ligands enable ultra-efficient optical control and detection of class C G protein-coupled receptors
Authors: Acosta-Ruiz Amanda , Gutzeit Vanessa A. , Skelly Mary Jane , Meadows Samantha , Lee Joon , Orr Anna G. , Pleil Kristen , Broichhagen Johannes , Levitz Joshua
Published: March 2019

The limitations of classical, soluble drugs in terms of subtype-specificity, spatiotemporal precision, and genetic targeting have spurred the development of advanced pharmacological techniques, including the use of covalently-tethered photoswitchable ligands. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with a comparable efficacy to the native ligand. To overcome the limitations of photoisomerization efficiency and tethered ligand affinity, we have developed a family of branched photoswitchable compounds to target G protein-coupled metabotropic glutamate receptors (mGluRs). These compounds permit photo-agonism of Gi/o-coupled group II mGluRs with near-complete efficiency relative to saturating glutamate when attached to receptors via a range of orthogonal, multiplexable modalities including SNAP-, CLIP-, and Halo-tags, as well as via receptor-targeting nanobodies. Through a chimeric approach, branched ligands also allow efficient optical control of Gq-coupled mGluR5 with precise, dynamic subcellular targeting. Finally, branched ligands enabled the development of dual photoswitch-fluorophore compounds that allow simultaneous imaging and manipulation of receptors via the same attachment point. Together this work provides a new design framework for photoswitchable ligands and demonstrates a toolset suitable for quantitative, mechanistic study of neuromodulatory receptors at the molecular, cellular and circuit levels.
Impact of permagarden intervention on improving fruit and vegetable intake among vulnerable groups. A quasi-experimental study conducted in seven cities of Ethiopia
Authors: Alemu Fikralem , Mecha Medhanit , Medhin Girmaye
Published: March 2019

Background

Increasing nutrient intake through home gardening is a sustainable strategy that can address multiple micronutrient deficiencies in developing countries. This study investigated the impact of permagarden intervention in increasing the frequency and diversity of vegetable and fruit consumption among vulnerable families.

Method

A quasi-experimental study was conducted from August 10 to September 30, 2015. A total of 884 care givers (427 from intervention and 457 control) participated in the study. Data was collected through face to face interview with caregivers of highly vulnerable children. Propensity score matching (PSM) was conducted using STATA software, and the program impact on the frequency and diversity of household’s vegetable consumption between intervention and control groups was assessed using chi square test.

Result

Intervention participants had a 13% greater increase frequency of one-week vegetables and fruits consumption compared with control participants (p<0.01). The diversity (consumption of 2 and more groups of vegetable and fruit) is higher among intervention groups than control groups (percentage difference=9, p-value<0.05). A significant higher percentage of participants in the intervention group reported getting the one-week vegetable and fruits mainly from their own garden (percentage difference 58.3, p<0.05). A significantly larger proportion of participants in the intervention group compared to the control group reported “high likelihood” on intention to grow vegetable in the future (percentage difference = 30%, and P<0.01). Perceived importance to include vegetables in every day meal is higher among intervention groups than control groups (percentage difference = 11.5%, P<0.01).

Conclusions

The observed higher frequency and diversity of household vegetable consumption among intervention group compared to control group suggests that nutrition and health programs need to promote household vegetable gardening as the means for address improve micro nutrient intake for vulnerable societies in least and middle developed countries.
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification
Authors: Thomas Sherine E. , Whitehouse Andrew J. , Brown Karen , Belardinelli Juan M. , Lahiri Ramanuj , Libardo M. Daben J. , Gupta Pooja , Malhotra Sony , Boshoff Helena I. M. , Jackson Mary , Abell Chris , Coyne Anthony G. , Blundell Tom L. , Andres Floto R. , Mendes Vítor
Published: March 2019

Translational frameshift errors are often deleterious to the synthesis of functional proteins as they lead to the production of truncated or inactive proteins. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and has been identified as a therapeutic target for several bacterial infections. Here we validate TrmD as a target inMycobacterium abscessusand describe the application of a structure-guided fragment-based drug discovery approach for the design of a new class of inhibitors against this enzyme. A fragment library screening followed by structure-guided chemical elaboration of hits led to the development of compounds with potentin vitroTrmD inhibitory activity. Several of these compounds exhibit activity against planktonicM. abscessus and Mycobacterium tuberculosis.The compounds were further active in macrophage infection models againstMycobacterium lepraeandM. abscessussuggesting the potential for novel broad-spectrum mycobacterial drugs.
Detection of Mycobacterium tuberculosis in pediatric stool samples using TruTip technology
Authors: Mesman AW , Soto M , Coit J , Calderon R , Aliaga J , Pollock NR , Mendoza M , Mestanza FM , Mendoza CJ , Murray MB , Lecca L , Holmberg R , Franke MF
Published: March 2019

Background

Rapid and accurate diagnosis of childhood tuberculosis (TB) is challenging because children are often unable to produce the sputum sample required for conventional tests. Stool is an alternative sample type that is easy to collect from children, and studies investigating the use of stool for molecular detection of Mycobacterium tuberculosis (Mtb) have led to promising results. However, tests performed thus far are not able to examine multi-drug resistance. The TruTip workstation (Akonni Biosystems) is an automated lysis and extraction platform that can be integrated with a closed amplification system to detect both Mtb and resistance-associated mutations. Our objective here was to evaluate the use of TruTip extraction technology for Mtb detection in stool.

Methods

We tested stool samples of 259 children with TB symptoms, ages 0-14 years old, in Lima, Peru. We used the TruTip workstation for sample processing and extraction, followed by IS6110 real-time PCR to detect the presence of Mtb DNA. We calculated assay sensitivity in two groups: (1) children with culture confirmed TB (N=22); and (2) children with unconfirmed, clinically diagnosed TB (N=84). We calculated specificity among children in whom TB was ruled out (N=153). Among children with TB, we examined factors associated with a positive stool test.

Results

Overall assay sensitivity was 59% (95% confidence interval 39%-80%) and 1.2% (0.0%-6.5%) in children with culture-confirmed and clinically-diagnosed TB, respectively, and specificity was 97% (93%-99%). The assay detected Mtb in stool of 7/7 children with smear-positive TB [100% sensitivity; (59%-100%)], and in 6/15 [40% (16%-68%)] of children with smear-negative, culture-confirmed TB. Older age, smear positivity, culture positivity and cavitary disease were associated with a positive stool result.

Conclusion

For molecular Mtb detection from stool, the TruTip workstation, in combination with IS6110 amplification, led to sensitivity and specificity estimates comparable to other tests such as Xpert. Future optimization is required to also diagnose TB disease in children who now received an unconfirmed diagnosis.
Environmental plasticity and colonisation history in the Atlantic salmon microbiome: a translocation experiment
Authors: Uren Webster Tamsyn M. , Rodriguez-Barreto Deiene , Castaldo Giovanni , Taylor John , Gough Peter , Consuegra Sofia , de Leaniz Carlos Garcia
Published: March 2019

Microbial communities associated with the gut and the skin are strongly influenced by environmental factors, and can rapidly adapt to change. Historical processes may also affect the microbiome. In particular, variation in microbial colonisation in early life has the potential to induce lasting effects on microbial assemblages. However, little is known about the relative extent of microbiome plasticity or the importance of historical colonisation effects following environmental change, especially for non-mammalian species. To investigate this we performed a reciprocal translocation of Atlantic salmon between captive and semi-natural conditions. Wild and hatchery-reared fry were transferred to three common garden experimental environments for six weeks: standard hatchery conditions, hatchery conditions with an enriched diet, and simulated wild conditions. We characterised the faecal and skin microbiome of individual fish before and after the environmental translocation, using a BACI (before-after-control-impact) design. We found evidence of extensive plasticity in both gut and skin microbiota, with the greatest changes in alpha and beta diversity associated with the largest changes in environment and diet. Microbiome richness and diversity were entirely determined by environment, with no detectable historical effects of fish origin. Microbiome structure was also strongly influenced by current environmental conditions but, for the first time in fish, we also found evidence of colonisation history, including a number of OTUs characteristic of captive rearing. These results may have important implications for host adaptation to local selective pressures, and also highlight how conditions during early life can have a long-term influence on the microbiome and, potentially, host health.
In-depth genetic analysis of 6p21.3 reveals insights into associations between HLA types and complex traits and disease
Authors: D’Antonio Matteo , Reyna Joaquin , D’Antonio-Chronowska Agnieszka , Bonder Marc-Jan , Jakubosky David , Matsui Hiroko , Smith Erin N. , Stegle Oliver , Nariai Naoki , Frazer Kelly A.
Published: March 2019

The highly polymorphic major histocompatibility (MHC) region encodes the human leucocyte antigen (HLA) gene complex and is associated with many autoimmune and infectious diseases. Despite the importance of this interval, comprehensive genetic studies interrogating associations between HLA types, expression of non-HLA genes and disease, have not yet been conducted. To address this issue, we collected high-coverage whole genome sequence from 419 individuals and performed HLA typing at the highest resolution. Using RNA-seq from matched iPSC lines, we conducted an in-depth eQTL analysis using “personalized” transcripts, which significantly improved estimated expression levels of HLA genes, and showed HLA types have genetic associations independent from SNPs. We leveraged the eQTL results to examine associations between expression levels of non-HLA genes and disease. As a proof-of-principle, we investigated RNF5, whose protein product is a novel drug target in cystic fibrosis. We observed that decreased expression of RNF5 was associated with the 8.1 ancestral haplotype, which was previously found associated with protection against infection in cystic fibrosis. Overall, our study shows that genetically dissecting the MHC region provides novel insights into mechanisms underlying associations of this interval with disease.
Solid state anaerobic digestion of mixed organic waste: the synergistic effect of food waste addition on the destruction of paper and cardboard
Authors: Guilford Nigel G. H. , Lee HyunWoo Peter , Kanger Kärt , Meyer Torsten , Edwards Elizabeth A.
Published: March 2019

Full-scale anaerobic digestion processes for organic solid waste are common in Europe, but generally unaffordable in Canada and the United States because of inadequate regulations to restrict cheaper forms of disposal, particularly landfill. We investigated the viability of solid-state anaerobic digestion (SS-AD) as an alternative that reduces the costs of waste pretreatment and subsequent wastewater treatment. A laboratory SS-AD digester, comprising six 10L leach beds and an upflow anaerobic sludge blanket reactor treating the leachate, was operated continuously for 88 weeks, with a mass balance of 101±2%. The feed was a mixture of cardboard, boxboard, newsprint, and fine paper, and varying amounts of food waste (from 0% to 29% on a COD basis). No process upset or instability was observed. The addition of food waste showed a synergistic effect, raising CH4 production from the fibre mixture from 52.7 L.kg-1COD fibreadded to 152 L.kg-1COD fibreadded, an increase of 190%. Substrate COD destruction efficiency reached 65% and a methane yield of 225 L.kg-1 CODadded was achieved at 29% food waste on a COD basis, and a solids retention time of 42 days. This performance was similar to that of a completely stirred tank reactor digesting similar wastes, but with much lower energy input.

Abstract Figure
Identification of new MmpL3 inhibitors by untargeted and targeted mutant screens defines MmpL3 domains with differential resistance
Authors: Williams John T. , Haiderer Elizabeth R. , Coulson Garry B. , Conner Kayla N. , Ellsworth Edmund , Chen Chao , Dick Thomas , Abramovitch Robert B.
Published: March 2019

TheMycobacterium tuberculosis(Mtb) mycolic acid flippase MmpL3 has been the proposed target for multiple inhibitors with diverse chemical scaffolds. This diversity in chemical scaffolds has made it difficult to predict compounds that inhibit MmpL3 without whole genome sequencing of isolated resistant mutants. Here we describe the identification of four new inhibitors that select for resistance mutations inmmpL3.Using these resistant mutants, we conducted a targeted whole-cell phenotypic screen of 163 novel Mtb growth inhibitors for differential growth inhibition of wild type Mtb as compared to a pool of twenty-four uniquemmpL3mutants. The screen successfully identified six additional putative MmpL3 inhibitors. The compounds were bactericidal bothin vitroand against intracellular Mtb. Mtb cells treated with these compounds were shown to accumulate trehalose monomycolate and have reduced levels of trehalose dimycolate, supporting MmpL3 as the target. The inhibitors were mycobacteria specific with several also showing activity against the non-tuberculosis mycobacterial speciesM. abscessus.Cluster analysis of cross resistance profiles generated by dose response experiments for each combination of 13 MmpL3 inhibitors against each of the 24mmpL3mutants defined two clades of inhibitors and two clades ofmmpL3mutants. Pairwise combination studies of the inhibitors revealed interactions that were specific to the clades identified in the cross-resistance profiling. Additionally, modeling of resistance substitutions to the MmpL3 crystal structure revealed clade specific localization of the residues to specific domains of MmpL3, with the clades showing differential resistance. Several compounds exhibited high solubility and stability in microsomes and low cytotoxicity in macrophages, supporting their further development. The combined study of multiple mutants and novel compounds provides new insights into structure-function interactions of MmpL3 and small molecule inhibitors.
Higher-order interaction inhibits bacterial invasion of a phototroph-predator microbial community
Authors: Mickalide Harry , Kuehn Seppe
Published: March 2019

In nature, the composition of an ecosystem is thought to be important for determining its resistance to invasion by new species. Studies of invasions in natural ecosystems, from plant to microbial communities, have found that more diverse communities are more resistant to invasion. It is thought that more diverse communities resist invasion by more completely consuming the resources necessary for would-be invaders. Here we show thatEscherichia colican successfully invade cultures of the algaChlamydomonas reinhardtii(phototroph) or the ciliateTetrahymena thermophila(predator), but cannot invade a community where both are present. The invasion resistance of the algae-ciliate community is due to a higher-order (3-way) interaction that is unrelated to resource consumption. We show that the mechanism of this interaction is the algal inhibition of bacterial aggregation which leaves bacteria vulnerable to ciliate predation. This mechanism of invasion resistance requires both the algae and the ciliate to be present and provides an example of invasion resistance through a trait-mediated higher-order interaction.
A continuum of CD4+ T cell “help” defines Memory B cell fate
Authors: Pritchard Gretchen Harms , Krishnamurty Akshay T. , Rodda Lauren , McDougal Courtney , Shehata Laila , Pepper Marion
Published: March 2019

Humoral immunity depends upon long-lived, antibody-secreting plasma cells and memory B cells (MBCs). MBCs exhibit significant phenotypic and functional heterogeneity. Upon homologous rechallenge, memory B cells thought to be of germinal center (GC) origin rapidly form antibody secreting plasmablasts but rarely enter a new GC, while other, less differentiated memory B cells enter secondary GCs, but do not form plasmablasts. These two populations therefore respond to a subsequent infection by generating antibody-secreting cells to epitopes not recognized by pre-existing serum and new populations of GC-derived MBCs that protect against novel variants. Understanding the mechanisms that regulate the differentiation of each unique population of MBCs during infection will help to define how to optimally drive the formation of these heterogeneous MBC cells via vaccination. We demonstrate a hierarchy of T-B interactions that leads to the generation of functionally distinct memory populations.

One Sentence Summary

A hierarchy of T-B interactions leads to the generation of functionally distinct memory B cell populations.
The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs
Authors: Marchant Axelle , Cisneros Angel F. , Dubé Alexandre K , Gagnon-Arsenault Isabelle , Ascencio Diana , Jain Honey A. , Aubé Simon , Eberlein Chris , Evans-Yamamoto Daniel , Yachie Nozomu , Landry Christian R.
Published: March 2019

Many paralogs derive from the duplication of genes encoding homomeric proteins. Such duplication events lead to the formation of homomers and heteromers, thus creating new structures from a single event. We exhaustively characterize this phenomenon using the budding yeast protein-protein interaction network. We observe that paralogs that heteromerize are very frequent and less functionally diverged than those that lost this property, raising the possibility that heteromerization prevents functional divergence. Using in silico evolution, we show that for homomers and heteromers that share binding interfaces, mutations on one complex have pleiotropic effects on the other complex, resulting in highly correlated responses to selection. As a result, heteromerization could be preserved indirectly due to selection for the maintenance of homomers. By integrating data on gene expression and protein localization, we find that regulatory evolution could play a role in overcoming these structural pleiotropic effects and in allowing paralog functional divergence.