bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractMacroevolutionary 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

SummaryIn 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

AbstractThe 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

AbstractBackgroundIncreasing 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.MethodA 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.ResultIntervention 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).ConclusionsThe 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

AbstractTranslational 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

AbstractBackgroundRapid 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.MethodsWe 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.ResultsOverall 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.ConclusionFor 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

AbstractMicrobial 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

AbstractThe 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

ABSTRACTFull-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

AbstractTheMycobacterium 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

AbstractIn 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

AbstractHumoral 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 SummaryA 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

AbstractMany 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.