bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting the window of opportunity for co-transcriptional splicing efficiency and fidelity
Authors: Aslanzadeh Vahid , Beggs Jean D.
Published: December 2018

Recently, we reported that changes in transcription elongation rate affect the efficiency and fidelity of precursor mRNA (pre-mRNA) splicing, especially of ribosomal protein (RP) transcripts. Here, we analyse these results in more detail, finding that the majority of RP transcripts with non-consensus 5’ splice sites have reduced splicing efficiency with faster transcription elongation, and improved efficiency with slower elongation, as might be predicted by the “window of opportunity” model for co-transcriptional splicing. In contrast, both faster and slower elongation reduce splicing fidelity, often for the same splicing events, and both faster and slower transcription increase fidelity with a different set of splicing events. We propose that certain non-consensus 5’ splice sites in ribosomal protein transcripts confer a stronger effect of transcription elongation rate on splicing efficiency, possibly by causing a rate-limiting step that delays activation of spliceosomes. The effects of different rates of transcription elongation on splicing fidelity are more difficult to explain by a simple window of opportunity model. We discuss these new findings in the context of current models of co-transcriptional splicing and splicing fidelity.
Image-based Phenotyping and Disease Screening of Multiple Populations for resistance to Verticillium dahliae in cultivated strawberry Fragaria x ananassa
Authors: Cockerton H.M. , Li B. , Vickerstaff R. J. , Eyre C. A. , Sargent D. J. , Armitage A. D. , Marina-Montes C. , Garcia A. , Passey A. J. , Simpson D. W. , Harrison R. J.
Published: December 2018

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Verticillium dahliae is a highly detrimental pathogen of soil cultivated strawberry (Fragaria x ananassa). Breeding of Verticillium wilt resistance into commercially viable strawberry cultivars can help mitigate the impact of the disease. In this study we describe novel sources of resistance identified in biparental strawberry populations, creating a wealth of data for breeders to exploit. Pathogen-informed experiments have allowed the differentiation of subclade-specific resistance responses, through studying V. dahliae subclade II-1 specific resistance in the cultivar ‘Redgauntlet’ and subclade II-2 specific resistance in ‘Fenella’ and ‘Chandler’.

A large-scale low-cost phenotyping platform was developed utilising automated unmanned vehicles and near infrared imaging cameras to assess field-based disease trials. The images were used to calculate disease susceptibility for infected plants through the normalized difference vegetation index score. The automated disease scores showed a strong correlation with the manual scores.

A co-dominant resistant QTL; FaRVd3D, present in both ‘Redgauntlet’ and ‘Hapil’ cultivars exhibited a major effect of 18.3 % when the two resistance alleles were combined. Another allele, FaRVd5D, identified in the ‘Emily’ cultivar was associated with an increase in Verticillium wilt susceptibility of 17.2%, though whether this allele truly represents a susceptibility factor requires further research, due to the nature of the bi-parental cross.

Markers identified in bi-parental populations were validated across a set of 92 accessions to determine whether they remained closely linked to resistance genes in the wider germplasm. The resistant markers FaRVd2B from ‘Redgauntlet’ and FaRVd6D from ‘Chandler’ were associated with resistance across the wider germplasm. Furthermore, comparison of imaging versus manual phenotyping revealed the automated platform could identify three out of four disease resistance markers. As such, this automated wilt disease phenotyping platform is considered to be a good, time saving, substitute for manual assessment.
Blockade of β-adrenergic receptor signaling improves cancer vaccine efficacy through its effect on naive CD8+T-cell priming
Authors: Daher Clara , Vimeux Lene , Stoeva Ralitsa , Peranzoni Elisa , Bismuth Georges , Donnadieu Emmanuel , Bercovici Nadège , Trautmann Alain , Feuillet Vincent
Published: December 2018

β-adrenergic receptor (β-AR) signaling, by acting directly on tumor cells and angiogenesis, has been showed to exert pro-tumoral effects. Growing evidence also suggests that β-AR expressed by immune cells affect the associated anti-tumor immune response. However, how and where β-AR signaling impinges the anti-tumor immune response is still unclear. Using a mouse model of vaccine-based immunotherapy, we show here that propranolol, a non-selective β-blocker, strongly improved the efficacy of the vaccine by enhancing the frequency of CD8+T lymphocytes infiltrating the tumor (TILs). However, propranolol had no obvious effect on the reactivity of CD8+TILs, a result further strengthened byex-vivoexperiments showing that these cells are insensitive to AR signaling triggered by adrenaline or noradrenaline. In contrast, we show that naive CD8+T cell activation was strongly inhibited by β-AR signaling and that the beneficial effect of propranolol mainly occurred during their initial priming phase. We also demonstrate that the differential sensitivity of CD8+TILs and naive CD8+T cells is related to their activation status sinceinvitro-activated CD8+T cells behaved similarly to CD8+TILs, both exhibiting a down-regulation of the β2-AR expression. These results reveal that the initial priming phase of the anti-tumor response in the tumor-draining lymph node is a decisive part of the suppressive effect of β-AR signaling on the CD8+T-cell response against cancer. These findings provide a rationale for the strategic use of clinically available β-blockers in patients to improve cancer immunotherapies such as anti-cancer vaccination strategies.
Imbalanced Nucleocytoskeletal Connections Create Common Polarity Defects in Progeria and Physiological Aging
Authors: Chang Wakam , Wang Yuexia , Gant Luxton G.W. , Östlund Cecilia , Worman Howard J. , Gundersen Gregg G.
Published: December 2018

Studies of the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called progerin. We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins were reduced in fibroblasts from children with HGPS compared to normal fibroblasts: SUN2, nesprin-2G, and emerin. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 years old and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules, high; actin filaments, low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects.

Significance

The rare, premature aging syndrome HGPS arises from expression of a pathological prelamin A variant, termed progerin. Studies of progerin may identify treatments for HGPS and reveal novel cellular and molecular characteristics of normal aging. Here, we show that progerin selectively affects mobilities of three nuclear membrane proteins, SUN2, nesprin-2G and emerin that position the nucleus and establish cell polarity essential for migration. We find that both processes are defective in fibroblasts from children with HGPS and aged (> 60 years) individuals. The mechanism underlying these defects is excessive interaction of the nucleus with microtubules. Our work identifies nuclear-based defects in cell polarization as intrinsic factors in premature and physiological aging and suggests means for correcting them.
Benchmarker: an unbiased, association-data-driven strategy to evaluate gene prioritization algorithms
Authors: Fine Rebecca S. , Pers Tune H. , Amariuta Tiffany , Raychaudhuri Soumya , Hirschhorn Joel N.
Published: December 2018

Genome-wide association studies (GWAS) are valuable for understanding human biology, but associated loci typically contain multiple associated variants and genes. Thus, algorithms that prioritize likely causal genes and variants for a given phenotype can provide biological interpretations of association data. However, a critical, currently missing capability is to objectively compare performance of such algorithms. Typical comparisons rely on "gold standard" genes harboring causal coding variants, but such gold standards may be biased and incomplete. To address this issue, we developed Benchmarker, an unbiased, data-driven benchmarking method that compares performance of prioritization strategies to each other (and to random chance) by leave-one-chromosome-out cross-validation with stratified linkage disequilibrium (LD) score regression. We first applied Benchmarker to twenty well-powered GWAS and compared gene prioritization based on strategies employing three different data sources, including annotated gene sets and gene expression. No individual strategy clearly outperformed the others, but genes prioritized by multiple strategies had higher per-SNP heritability than those prioritized by one strategy only. We also compared two gene prioritization methods, DEPICT and MAGMA; genes prioritized by both methods strongly outperformed genes prioritized by only one. Our results suggest that combining data sources and algorithms should pinpoint higher quality genes for follow-up. Benchmarker provides an unbiased approach to evaluate any method that provides genome-wide prioritization of gene sets, genes, or variants, and can determine the best such method for any particular GWAS. Our method addresses an important unmet need for rigorous tool assessment and can assist in mapping genetic associations to causal function.
White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study
Authors: Miles Amy , Kaplan Allan , French Leon , Voineskos Aristotle
Published: December 2018

Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n=23), weight-recovered women with a past diagnosis of AN (recAN: n=23), and age-matched healthy control women (HC: n=24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxel-wise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Cluster-wise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for cluster-wise AD and RD. Trait-based increases in diffusivity, consistent with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.
Network modules linking expression and methylation in prefrontal cortex of schizophrenia
Authors: Lin Dongdong , Chen Jiayu , Perrone-Bizzozero Nora , Sui Jing , Calhoun Vince , Liu Jingyu
Published: December 2018

Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SCZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics, as a modulator of environmental factors, in the etiopathogenesis of SCZ still faces many challenges. In this work we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approaches. We identified and replicated two expression and two methylation modules significantly associated with SCZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved aging process with module genes mostly related to oligodendrocyte development and myelination, and specially expressed in oligodendrocytes. Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs. These results support the coherence between methylation and gene expression in a network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation with SCZ and aging process.
The Influence of Magnetic Fields on Selected Physiological Parameters of Blood and Tissues in Mice
Authors: Abdelsalam Hani , Elywa Mohammed
Published: December 2018

This study aimed to highlight the influence of exposure to different applied magnetic fields (MFs) on SOD, MDA and GSH levels in the liver, LDH and CPK activities in the muscle and γ-aminobutyric acid levels in the brain, as well as some haematological parameters. Adult male albino Swiss mice were divided into 5 equal groups (n = 6), the control group (untreated) and four exposure groups that were exposed to MFs of 20, 40, 60 and 80 Gauss for 5 min/day for 5 days.: Exposure to MFs induced significant decreases in total GSH levels and SOD activity but a significant increase in MDA levels in the liver. By contrast, SMF exposure significantly increased total LDH and total CPK activities in the muscle. The results revealed a significant increase in GABA levels in the brain, as well as decreases in haemoglobin, haematocrit, and red blood cell counts, in addition to platelet counts, after exposure to 20, 40, 60 and 80 Gauss MFs. After exposure to a 40 Gauss MF, the mice showed pathological changes in red blood cells, including changes to the outer membrane of the red blood cells (micronucleus and a serrated edge, with a mild incidence of echinocytes). In the group exposed to a 60 Gauss MF, examination of blood smears clearly showed changes in cell size, with the emergence of abnormal forms, including many areas with no red blood cells (rouleaux formation). With increasing intensity of exposure (80 Gauss), the red blood cells appeared completely different from their natural form and took the form of ovalocytes and bi-micronucleated erythrocytes, which appear in patients with anaemia.: MF exposure caused different metabolic and haematological effects, which appeared to be related to the intensity of SMF exposure. The changes in the biochemical parameters of SMF-exposed mice probably reflect hepatic damage and anaemia caused by kidney failure. Further studies are needed to obtain a better understanding of the effects of MF on biological systems.
Functionally distinct high and low theta oscillations in the human hippocampus
Authors: Goyal Abhinav , Miller Jonathan , Qasim Salman E. , Watrous Andrew J. , Stein Joel M. , Inman Cory S. , Gross Robert E. , Willie Jon T. , Lega Bradley , Lin Jui-Jui , Sharan Ashwini , Wu Chengyuan , Sperling Michael R. , Sheth Sameer A. , McKhann Guy M. , Smith Elliot H. , Schevon Catherine , Jacobs Joshua
Published: December 2018

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4–10-Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta’s function. To characterize human hippocampal theta, we examined the properties of theta oscillations throughout the anterior–posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observed hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displayed oscillations at ~8-Hz and the precise frequency of these oscillations correlated with the speed of movement, implicating these signals in spatial navigation. We also observed slower ~3-Hz oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency did not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.
The paradox of Rapid Eye Movement sleep in the light of oscillatory activity and functional synchronization during phasic and tonic microstates
Authors: Simor Peter , van Der Wijk Gwen , Gombos Ferenc , Kovacs Ilona
Published: December 2018

Rapid Eye Movement (REM) sleep is a peculiar neural state showing a combination of muscle atonia and intense cortical activity. REM sleep is usually considered as a unitary state in neuroscientific research; however, it is composed of two different microstates: phasic and tonic REM. These differ in awakening thresholds, sensory processing, and cortical oscillations. Nevertheless, studies examining cortical oscillations during REM microstates are scarce, and used low spatial sampling. Here, we analyzed the data of 18 healthy individuals assessed by high-density sleep EEG recordings. We systematically contrasted phasic and tonic REM periods in terms of topographical distribution, source localization, as well as local, global and long-range synchronization of frequency-specific cortical activity. Tonic periods showed relatively increased high alpha and beta power over frontocentral derivations. In addition, higher frequency components of beta power exhibited increased global synchronization during tonic compared to phasic states. In contrast, in phasic periods we found increased power and synchronization of low frequency oscillations coexisting with increased and synchronized gamma activity. Source localization revealed several multimodal, higher-order associative, as well as sensorimotor areas as potential sources of increased high alpha/beta power during tonic compared to phasic REM. Increased gamma power in phasic REM was attributed to medial prefrontal and right lateralized temporal areas associated with emotional processing. Our findings emphasize the heterogeneous nature of REM sleep, expressed in two microstates with remarkably different neural activity. Considering the microarchitecture of REM sleep may provide new insights into the mechanisms of REM sleep in health and disease.
The molecular architecture of engulfment during Bacillussubtilis sporulation
Authors: Khanna Kanika , Lopez-Garrido Javier , Zhao Ziyi , Watanabe Reika , Yuan Yuan , Pogliano Kit , Villa Elizabeth
Published: December 2018

The study of cell biology is limited by the difficulty in visualizing cellular structures at high spatial resolution within their native milieu. Here, we have visualized sporulation inBacillus subtilisusing cryo-electron tomography coupled with cryo-focused ion beam milling, a technique that allows the 3D reconstruction of cellular structures in near-native state at molecular resolution. During sporulation, an asymmetrically-positioned septum divides the cell into a larger mother cell and a smaller forespore. Subsequently, the mother cell phagocytoses the forespore in a process called engulfment, which entails a dramatic rearrangement of the peptidoglycan (PG) cell wall around the forespore. By imaging wild-type sporangia, engulfment mutants, and sporangia treated with PG synthesis inhibitors, we show that the initiation of engulfment does not entail the complete dissolution of the septal PG by the mother cell SpoIIDMP complex, as was previously thought. Instead, DMP is required to maintain a flexible septum that is uniformly and only slightly thinned at the onset of engulfment. Then, the mother cell membrane migrates around the forespore by forming tiny finger-like projections, the formation of which requires both SpoIIDMP and new PG synthesized ahead of the leading edge of the engulfing membrane. We propose a molecular model for engulfment membrane migration in which a limited number of SpoIIDMP complexes tether the membrane to and degrade the new PG ahead of the leading edge, thereby generating an irregular engulfing membrane front. Our data also reveal other structures that will provide a valuable resource for future mechanistic studies of endospore formation.
Nucleus accumbens neurochemistry in human anxiety: A 7 T1H-MRS study
Authors: Strasser Alina , Xin Lijing , Gruetter Rolf , Sandi Carmen
Published: December 2018

Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20-30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), depression (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy (1H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc with. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. These findings were specific, as no correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, depression, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.
Dicer-like 5deficiency confers temperature-sensitive male sterility in maize
Authors: Teng Chong , Zhang Han , Hammond Reza , Huang Kun , Meyers Blake C. , Walbot Virginia
Published: December 2018

Small RNAs play important roles during plant development by regulating transcript levels of target mRNAs, maintaining genome integrity, and reinforcing DNA methylation.Dicer-like 5(Dcl5) is proposed to be responsible for precise slicing in many monocots to generate diverse 24-nt phased, secondary small interfering RNAs (phasiRNAs), which are exceptionally abundant in meiotic anthers of diverse flowering plants. The importance and functions of these phasiRNAs remain unclear. Here, we characterized several mutants ofdcl5, including alleles generated by the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)Cas9system and a transposon-disrupted allele. We report thatdcl5mutants have few or no 24-nt phasiRNAs, develop short anthers with defective tapetal cells, and exhibit temperature-sensitive male fertility. We propose that DCL5 and 24-nt phasiRNAs are critical for fertility under growth regimes for optimal yield.
Multiple modes of convergent adaptation in the spread of glyphosate-resistant Amaranthus tuberculatus
Authors: Kreiner Julia M. , Giacomini Darci Ann , Bemm Felix , Waithaka Bridgit , Regalado Julian , Lanz Christa , Hildebrandt Julia , Sikkema Peter H. , Tranel Patrick J. , Weigel Detlef , Stinchcombe John R. , Wright Stephen I.
Published: December 2018

The selection pressure exerted by herbicides has led to the repeated evolution of herbicide resistance in weeds. The evolution of herbicide resistance on contemporary timescales in turn provides an outstanding opportunity to investigate key questions about the genetics of adaptation, in particular, the relative importance of adaptation from new mutations, standing genetic variation, or geographic spread of adaptive alleles through gene flow. Glyphosate-resistant Amaranthus tuberculatus poses one of the most significant threats to crop yields in the midwestern United States (1), with both agricultural populations and herbicide resistance only recently emerging in Canada (2, 3). To understand the evolutionary mechanisms driving the spread of resistance, we sequenced and assembled the A. tuberculatus genome and investigated the origins and population genomics of 163 resequenced glyphosate-resistant and susceptible individuals from Canada and the USA. In Canada, we discovered multiple modes of convergent evolution: in one locality, resistance appears to have evolved through introductions of preadapted US genotypes, while in another, there is evidence for the independent evolution of resistance on genomic backgrounds that are historically non-agricultural. Moreover, resistance on these local, non-agricultural backgrounds appears to have occurred predominantly through the partial sweep of a single haplotype. In contrast, resistant haplotypes arising from the midwestern US show multiple amplification haplotypes segregating both between and within populations. Therefore, while the remarkable species-wide diversity of A. tuberculatus has facilitated geographic parallel adaptation of glyphosate resistance, more recently established agricultural populations are limited to adaptation in a more mutation-limited framework.

Significance

While evolution is often thought of as playing out over millions of years, adaptation to new enviroments can occur in real time, presenting key opportunities to understand evolutionary processes. An important example comes from agriculture, where many weeds have evolved herbicide resistance. We have studied glyphosate resistant Amaranthus tuberculatus, a significant threat to crop yields in the midwestern US and Canada. Genome analyses showed that rapid evolution can either occur by “borrowing” resistance alleles from other locations, or by de novo evolution of herbicide resistance in a genetic background that was not previously associated with agriculture. Differences in recent evolutionary histories have thus favored either adaptation from pre-existing variation or new mutation in different parts of the A. tuberculatus range.
Microbial Biosynthesis of Lactate Esters
Authors: Lee Jong-Won , Trinh Cong T.
Published: December 2018

Background

Green organic solvents such as lactate esters have broad industrial applications and favorable environmental profiles. Thus, manufacturing and use of these biodegradable solvents from renewable feedstocks help benefit the environment. However, to date, the direct microbial biosynthesis of lactate esters from fermentable sugars has not yet been demonstrated.

Results

In this study, we present a microbial conversion platform for direct biosynthesis of lactate esters from fermentable sugars. First, we designed a pyruvate-to-lactate ester module, consisting of a lactate dehydrogenase (ldhA) to convert pyruvate to lactate, a propionate CoA-transferase (pct) to convert lactate to lactyl-CoA, and an alcohol acyltransferase (AAT) to condense lactyl-CoA and alcohol(s) to make lactate ester(s). By generating a library of five pyruvate-to-lactate ester modules with divergent AATs, we screened for the best module(s) capable of producing a wide range of linear, branched, and aromatic lactate esters with an external alcohol supply. By co-introducing a pyruvate-to-lactate ester module and an alcohol (i.e., ethanol, isobutanol) module into a modularEscherichia coli(chassis) cell, we demonstrated for the first time the microbial biosynthesis of ethyl and isobutyl lactate esters directly from glucose. In an attempt to enhance ethyl lactate production as a proof-of-study, we re-modularized the pathway into 1) the upstream module to generate the ethanol and lactate precursors and 2) the downstream module to generate lactyl-CoA and condense it with ethanol to produce the target ethyl lactate. By manipulating the metabolic fluxes of the upstream and downstream modules through plasmid copy numbers, promoters, ribosome binding sites, and environmental perturbation, we were able to probe and alleviate the metabolic bottlenecks by improving ethyl lactate production by 4.96-fold. We found that AAT is the most rate limiting step in biosynthesis of lactate esters likely due to its low activity and specificity towards the non-natural substrate lactyl-CoA and alcohols.

Conclusions

We have successfully established the biosynthesis pathway of lactate esters from fermentable sugars and demonstrated for the first time the direct fermentative production of lactate esters from glucose using anE. colimodular cell. This study defines a cornerstone for the microbial production of lactate esters as green solvents from renewable resources with novel industrial applications.
Genome-wide Population Structure Analyses of Three Minor Millets: Kodo Millet, Little Millet, and Proso Millet
Authors: Johnson Matthew , Deshpande Santosh , Vetriventhan Mani , Upadhyaya Hari D , Wallace Jason G.
Published: December 2018

Millets are a diverse group of small-seeded grains that are rich in nutrients but have received relatively little advanced plant breeding research. Millets are important to smallholder farmers in Africa and Asia because of their short growing season, good stress tolerance, and high nutritional content. To advance the study and use of these species, we present a genome-wide marker datasets and population structure analyses for three minor millets: kodo millet (Paspalum scrobiculatum), little millet (Panicum sumatrense), and proso millet (Panicum miliaceum). We generated genome-wide marker data sets for 190 accessions of each species with genotyping-by-sequencing (GBS). After filtering, we retained between 161 and 165 accessions of each species, with 3461, 2245, and 1882 single-nucleotide polymorphisms (SNPs) for kodo, proso, and little millet, respectively. Population genetic analysis revealed 7 putative subpopulations of kodo millet and 8 each of proso millet and little millet. To confirm the accuracy of this genetic data, we used public phenotype data on a subset of these accessions to estimate the heritability of various agronomically relevant phenotypes. Heritability values largely agree with the prior expectation for each phenotype, indicating that these SNPs provide an accurate genome-wide sample of genetic variation. These data represent one of first genome-wide population genetics analyses, and the most extensive, in these species and the first genomic analyses of any sort for little millet and kodo millet. These data will be a valuable resource for researchers and breeders trying to improve these crops for smallholder farmers.
Comparison of antibody titres between intradermal and intramuscular rabies vaccination using inactivated vaccine in cattle in Bhutan.
Authors: Wangmo Karma , Laven Richard , Cliquet Florence , Wasniewski Marine , Yang Aaron
Published: December 2018

In developing countries, the cost of vaccination limits the use of prophylactic rabies vaccination, especially in cattle. Intradermal vaccination delivers antigen directly to an area with higher number of antigen-presenting cells. Therefore, it could produce equivalent or higher antibody titres than conventional intramuscular vaccination even when a lower dose is given.
This study aimed to compare the antibody response in cattle vaccinated intramuscularly with 1mL of inactivated rabies vaccine (Raksharab, Indian Immunologicals) against intradermally vaccinated cattle with 0.2mL of the same vaccine. The study was conducted in Haa province of Bhutan where rabies is not endemic. One hundred cattle from 27 farms were selected for the study. Virus neutralising antibody (VNA) response was measured using the fluorescent antibody virus neutralisation test on the day of vaccination (day 0) and 14, 30, 60 and 90 days later.
Overall, 71% of intradermally vaccinated cattle and 89% of the intramuscularly vaccinated cattle produced a protective response (≥0.5IU/mL). This difference was significant (P<0.02) on days 14 and 30 post vaccination with 36 and 58% in the intradermal group having titres ≥0.5 IU/mL respectively compared to the equivalent figures of 78 and 77% in the intramuscular group. The mean VNA titres were lower for intradermal group than intramuscular group (p<0.001) with the mean difference being greater than 0.6 IU/mL. Although low dose intradermal vaccination did produce a detectable antibody response, it was inferior to intramuscular vaccination. Thus, although intradermal vaccination has the potential to reduce the cost of vaccination by reducing the dose required, this study showed that a single dose of 0.2mL intradermally was inferior to an intramuscular dose of 1mL. Further research evaluating dose and dose regimen is needed before intradermal vaccination using the Raksharab rabies vaccine can be recommended in cattle.
Tolerance and dependence to Δ9-tetrahydrocannabinol in rhesus monkeys: activity assessments
Authors: Schulze David R. , McMahon Lance
Published: December 2018

Cannabis withdrawal upon discontinuation of long-term, heavy Cannabis use is reported in humans; however, methods to establish the nature and intensity of cannabinoid withdrawal, especially directly observable signs, have not been widely established. This study quantified activity in the home cage of rhesus monkeys, and examined the extent to which activity can be used to quantify tolerance to and dependence on Δ9-tetrahydrocannabinol (Δ9-THC). Home-cage activity was measured in one group that received Δ9-THC (1 mg/kg s.c.) every 12 h (i.e., chronic Δ9-THC), and a second group that received Δ9-THC (0.1 mg/kg i.v.) once every 3 days (i.e., intermittent Δ9-THC). Treatment was temporarily discontinued in the chronic Δ9-THC group and the effects of rimonabant and Δ9-THC were examined in both groups. Activity counts were highest during the day (lights on 0600-2000 h) and were lower at night. Rimonabant (0.1-3.2 mg/kg i.v.) dose-dependently increased activity (maximum 20-fold) in the chronic Δ9-THC group, but did not significantly alter activity in the intermittent Δ9-THC group. Δ9-THC (0.32-3.2 mg/kg i.v.) dose-dependently decreased activity counts (maximum 4-fold) in both groups, but was somewhat more potent in the intermittent as compared with the Δ9-THC group. Discontinuation of Δ9-THC treatment resulted in an immediate (i.e., within 24 h) and time-related increase in activity. Resumption of Δ9-THC treatment (1 mg/kg/12 h) produced hypoactivity that was no longer evident within 9 days of treatment. The time-related increase in home-cage activity upon abrupt discontinuation of chronic Δ9-THC treatment, as well as the effects of rimonabant to increase activity in monkeys receiving chronic, but not intermittent, Δ9-THC treatment, are consistent with signs of physical dependence on Δ9-THC in primates.
Cold Response of the Mediterranean fruit fly (Ceratitis capitata) in the Lab Diet
Authors: Al-behadili Farhan jasim
Published: December 2018

Cold treatment at 0.0 °C with different exposure durations (0-12 days) was applied to the Mediterranean fruit fly Ceratitis capitata (Wiedemann) fed on lab diet. The examined developmental stages were early eggs (<6 hr) (E.E), late eggs (>42 hr)(L.E),first instar (1st ), second instar(2nd ) and third instar larvae (3rd ). Pupation, adult emergence and sex ratios of survived flies were investigated to study the C. capitata responses to this low temperature treatment. Our results showed that based on pupation ratios, the 3rd instar is the most cold tolerant stage with LT99=7.36 days. The second most cold tolerant stage is the 1st instar with LT99=7.33 days. Cold tolerance at both two stages are very close, so they should be paid attention during the cold treatment. There were no significant differences on C. capitata sex ratios among different stages after treatment. This study improves our understanding of C. capitata responses to cold treatment, which may assist in the improvement of the current treatment strategies to control this destructive horticulture pest species
Inactivation of ventral hippocampus projections promotes sensitivity to changes in contingency
Authors: Barker Jacqueline M. , Bryant Kathleen G. , Chandler L. Judson
Published: December 2018

The loss of behavioral flexibility is common across a number of neuropsychiatric illnesses. This may be in part due to the loss of the ability to detect or use changes in action–outcome contingencies to guide behavior. There is growing evidence that the ventral hippocampus plays a critical role in the regulation of flexible behavior and reward-related decision making. Here, we investigated the role of glutamatergic projections from the ventral hippocampus in the expression of contingency-mediated reward seeking. We demonstrate that selectively silencing ventral hippocampus projections can restore the use of action–outcome contingencies to guide behavior, while sparing cue-guided behavior and extinction learning. Our findings further indicated that the ability of the ventral hippocampus to promote habitual response strategies may be in part mediated by selective projections from the ventral hippocampus to the nucleus accumbens shell. Together these results implicate glutamatergic projections from the ventral hippocampus in the regulation of behavioral flexibility and suggest that alterations in ventral hippocampus function may contribute to overreliance on habitual response strategy observed in neuropsychiatric illnesses including addiction and obsessive–compulsive disorder.
Methods for operando coherent X-ray diffraction of battery materials at the Advanced Photon Source
Authors: Li Luxi , Xie Yingying , Maxey Evan , Harder Ross
Published: December 2018

Bragg coherent X-ray diffraction imaging has become valuable for visualization of the structural, morphological and strain evolution of crystals in operando electrode materials. As the electrode material particles (either in a single-crystal form or an aggregation form of single crystals) are evenly dispersed and randomly oriented in the electrode laminate, the submicrometer-sized coherentX-ray beam can be used to probe the local properties of electrode material crystals using two approaches. Coherent multi-crystal diffraction provides collective structural information of phase transitions in tens of crystals simultaneously as well as the individual behavior from single crystals, which are oriented at the Bragg condition in the X-ray illumination volume. Bragg coherent diffractive imaging enables one to monitor the evolution of the morphology and strain in individual crystals. This work explores and highlights the Bragg coherent X-ray diffraction measurements of battery electrode materials in operando conditions at the 34-ID-C beamline at the Advanced Photon Source. The experiment is demonstrated with NaNi1/3Fe1/3Mn1/3O2, a sodium-ion cathode material loaded in a half cell. The paper will discuss, in detail, the beamline setup, sample mounting and handling, alignment strategies and the data acquisition protocols.
A qualitative evaluation of an ACT-based substance misuse treatment programme for service users within a secure mental health setting
Authors: Johnson Lacey M. , Elsegood Kelly J. , Lennox Charlotte
Published: December 2018

Purpose

The purpose of this paper is to understand service users’ experience of a new acceptance and commitment therapy (ACT)-based substance misuse programme. The programme is designed for people in secure mental health services, presenting with complex mental health difficulties and co-occurring substance misuse problems.

Design/methodology/approach

A qualitative approach informed an exploratory pilot of this novel intervention. Service users completing a 16-week ACT programme were invited to participate in the current study. Out of the nine individuals enroled on the programme, six opted to take part in the exploratory pilot and completed semi-structured interviews following part 1 of the programme (eight weeks). Four of these participants proceeded into part 2 of the programme (eight weeks) and completed a further semi-structured interview.

Findings

The thematic analysis identified five main themes: “Increased awareness of personal values and the impact of substance use on values”, “Taking committed action towards values”, “Coping skills and the application of skills to manage difficult thoughts and feelings”, “Personal development” and “Use of metaphors/analogies”.

Research limitations/implications

A quantitative evaluation of clinical outcomes is recommended to gauge further programme effectiveness.

Practical implications

The findings provide preliminary support for the use of an ACT-based substance misuse programme in a secure mental health setting.

Originality/value

This study evaluates the use of a novel ACT-based substance misuse intervention with people in secure mental health care with co-occurring mental health and substance misuse difficulties. This paper provides an in-depth understanding of service users’ experience of participating in this new treatment programme.
The implications of the construction industry to national wealth
Authors: Fulford Richard Glenn
Published: December 2018

Purpose

The purpose of this paper is to explore how construction projects should be conceived and how the productivity of the construction industry impacts upon a nation’s wealth.

Design/methodology/approach

The approach has been to marshal the extant literature about the construction industry, construction industry productivity and the economic value of the built environment. Whilst there are many lenses that are used to understand the industry, different ways to measure productivity performance and differing practices between nations, it has been determined that construction industry productivity improvement significantly lags behind other industries.

Findings

There is a strong argument that construction productivity improvement correlates to advances in a nation’s economy. Nonetheless, it is the decisions about the nature of infrastructure, the standardisation of infrastructure and the effect upon labour productivity that will have the greatest implications for a nation’s economic future. These economic improvements will be inhibited by legacy infrastructure, particularly in densely populated areas. If substantial innovation occurs, the nations currently holding the highest stock of infrastructure might be economically constrained.

Research limitations/implications

The construction industry is highly fragmented and has the uncertainties of a cyclic industry. It is, therefore, necessary for governments to identify standards and facilitate innovation. The implications for short- and long-term economic performance require that the industry is a fundamental at the highest level of government.

Originality/value

Scholars can use the propositions to further analyse construction productivity improvement and the provision of different types of infrastructure with regard to a nation’s economic performance. Hypotheses are offered to support future research.
Determinants of willingness to practice medicine in underdeveloped areas
Authors: Rezaei Satar , Hajizadeh Mohammad , Kazemi Karyani Ali , Soltani Shahin , Asadi Heshmatollah , Bazyar Mohammad , Mohammadi Zahra , Kazemzadeh Neshat , Nouri Bijan
Published: December 2018

Purpose

Appropriate access to formally-trained health workers for people living in rural and underdeveloped areas is a continuing challenge worldwide. The purpose of this paper is to investigate the willingness of formally-trained health workers to practice in underdeveloped areas and its main determinants among medical students in the western provinces of Iran.

Design/methodology/approach

A total of 753 medical students from four provinces in western Iran (Kermanshah, Ilam, Lorestan and Kurdistan) were surveyed cross-sectionally in 2017. A self-administrated questionnaire was used to collect data on sociodemographic characteristics, willingness to practice in underdeveloped areas, intrinsic (e.g. desire to help others and self-interest in medicine) and extrinsic (e.g. the high income of physicians and social prestige) motivations of the study population. Multivariable logistic regression was used to identify the main determinants of willingness to practice in underdeveloped areas among medical students after their graduation.

Findings

The results indicated that 58.3 percent of students were willing to practice in underdeveloped areas. While 59 percent of the study population had a strong extrinsic motivation to study medicine, the remaining 41 percent of the study population had a strong intrinsic motivation to study medicine. The logistic regression results indicated that low parental professional and educational status, an experience of living in rural areas and having strong intrinsic motivation were associated with greater willingness to practice in underdeveloped areas.

Originality/value

This is the first study to investigate the willingness to practice in underdeveloped areas and its main determinants among medical students in the west of Iran.