bluuebunny/crossref_metadata_2025 huggingface dataset:
Insights into the salivaryN-glycome ofLutzomyia longipalpis, vector of visceral leishmaniasis
Authors: Mondragon-Shem Karina , Wongtrakul-Kish Katherine , Kozak Radoslaw P. , Yan Shi , Wilson Iain , Paschinger Katharina , Rogers Matthew E. , Spencer Daniel I. R. , Acosta-Serrano Alvaro
Published: June 2020

DuringLeishmaniatransmission sand flies inoculate parasites and saliva into the skin of vertebrates. Saliva has anti-haemostatic and anti-inflammatory activities that evolved to facilitate bloodfeeding, but also modulate the host’s immune responses. Sand fly salivary proteins have been extensively studied, but the nature and biological roles of protein-linked glycans remain overlooked. Here, we characterised the profile ofN-glycans from the salivary glycoproteins ofLutzomyia longipalpis, vector of visceral leishmaniasis in the Americas.In silicopredictions suggest half ofLu. longipalpissalivary proteins may beN-glycosylated. SDS-PAGE coupled to LC-MS analysis of sand fly saliva, before and after enzymatic deglycosylation, revealed several candidate glycoproteins. To determine the diversity ofN-glycan structures in sand fly saliva, enzymatically released sugars were fluorescently tagged and analysed by HPLC, combined with highly sensitive LC-MS/MS, MALDI-TOF-MS, and exoglycosidase treatments. We found that theN-glycan composition ofLu. longipalpissaliva mostly consists of oligomannose sugars, with Man5GlcNAc2being the most abundant, and a few hybrid-type species. Interestingly, some glycans appear modified with a group of 144 Da, whose identity has yet to be confirmed. Our work presents the first detailed structural analysis of sand fly salivary glycans.
Maize Biochemical Defences against a Rootworm Were Mediated by Domestication, Spread, and Breeding
Authors: Fontes-Puebla Ana A. , Borrego Eli J. , Kolomiets Michael V. , Bernal Julio S.
Published: June 2020

Plant physiological processes generally are regulated by phytohormones, including plant biochemical responses to herbivory. Here, we addressed whether a suite of maize (Zea mays mays) phytohormones, including some precursor and derivative metabolites, relevant to herbivory defence were mediated by the crop’s domestication, northward spread, and modern breeding. For this, we compared phytohormone and metabolite levels among four plant types representing the evolutionary and agronomic transitions from maize’s wild ancestor, Balsas teosinte (Zea mays parviglumis), to Mexican and US maize landraces, and to highly-bred US maize cultivars, as affected by root herbivory by Western corn rootworm (Diabrotica virgifera virgifera). Following ecological-evolutionary hypotheses, we expected to find changes in: (i) maize defence strategy, from reliance on induced to constitutive defences; (ii) levels of phytohormones relevant to herbivore resistance consistent with gradual weakening of defences, and; (iii) levels of a phytohormone relevant to herbivory tolerance because it positively affects plant growth. We found that with its domestication, maize seemed to have transitioned from reliance on induced defences in Balsas teosinte to reliance on constitutive defences in maize. Also, we found that while one subset of phytohormones relevant to herbivory was suppressed (13-oxylipins), another was enhanced (9-oxylipins) with domestication, and both subsets were variably affected by spread and breeding. Finally, an auxin phytohormone directly linked to growth (indole-3-acetic acid), increased significantly with domestication, and seemingly with spread and breeding. We concluded that rootworm defences in maize were mediated by domestication and ensuing processes, such as spread and breeding, and argued that agricultural intensification mediated maize defence evolution in parallel with modern breeding.
Transcriptome analysis of threeAgavefiber-producing cultivars suitable for biochemicals and biofuels production in semiarid regions
Authors: Raya Fabio Trigo , Marone Marina Pupke , Carvalho Lucas Miguel , Rabelo Sarita Candida , de Paula Maiki Soares , Campanari Maria Fernanda Zaneli , Freschi Luciano , Mayer Juliana Lischka Sampaio , Silva Odilon Reny Ribeiro Ferreira , Mieczkowski Piotr , Carazzolle Marcelo Falsarella , Pereira Gonçalo Amarante Guimarães
Published: June 2020

Agaves, which have been grown commercially for fiber or alcoholic beverages, are emerging as a candidate crop for biochemicals and biofuels production in semiarid regions because of their high productivity in low rainfall areas, drought tolerance, and low lignin content.

In this work, we present the transcriptomic atlas ofAgave sisalana,Agave fourcroydes, and agave hybrid 11648 (A. amaniensisxA. angustifolia) under prolonged drought in field conditions. Leaf, stem, and root tissues were sequenced, and gene expression profiles were correlated with biomass composition, enzymatic hydrolysis of cell wall carbohydrates, histochemical analysis, and non-structural carbohydrates content.

Differences in biomass accessibility were attributed to either lignin content or lignin composition, possibly through modification of s/g ratio promoted by changes in Caffeic Acid 3-O-Methyltransferase (COMT) transcript abundance. Unlike most plants, the most highly expressed transcripts do not encode photosynthetic proteins, but rather involved in stress response. Although the three cultivars presented quantitative differences in global gene expression, they activated a highly overlapping set of genes. The main molecular strategies employed by agave to cope with high-temperature and drought seem to consist in overexpressing HSP and LEA, as well as promoting raffinose accumulation as an osmolyte.

In conclusion, our data provide vital new genetic information for the study of Agave species and provide new insights into cell wall architecture, recalcitrance, and resistance to abiotic stresses for these species.
Identification of ADAMTS19 as a novel retinal factor involved in ocular growth regulation
Authors: Koli Swanand , Labelle-Dumais Cassandre , Zhao Yin , Paylakhi Seyyedhassan , Nair K Saidas
Published: June 2020

Refractive errors are the most common ocular disorders and are a leading cause of visual impairment worldwide. Although ocular axial length is well established to be a major determinant of refractive errors, the molecular and cellular processes regulating ocular axial growth are poorly understood. Mutations in genes encoding the PRSS56 and MFRP are a major cause of nanophthalmos. Accordingly, mouse models with mutations in the genes encoding the retinal factor PRSS56 or MFRP, a gene predominantly localized in the retinal pigment epithelial (RPE) exhibit ocular axial length reduction and extreme hyperopia. However, the precise mechanisms underlying PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show thatAdamts19expression is significantly upregulated in retina of mice lacking eitherPrss56orMfrp. Using a combination of genetic approaches and mouse models, we show that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in bothPrss56orMfrpmutant mice. These results suggest that the upregulation of retinalAdamts19expression is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach. We further demonstrate that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of developmental myopia caused by a null mutation inIrpb, demonstrating that ocular axial elongation inIrbp-/-mice is fully dependent on PRSS56 and MFRP functions. Collectively, our findings provide insight into the molecular network involved in ocular axial growth regulation and refractive development and support the notion that relay of the signal between the retina and RPE could be critical for promoting ocular axial elongation.
Protein structure-based gene expression signatures
Authors: Rahman R. , Xiong Y. , van Hasselt J. G. C. , Hansen J. , Sobie E. A. , Birtwistle M. R. , Azeloglu E. , Iyengar R. , Schlessinger A.
Published: June 2020

Gene expression signatures (GES) connect phenotypes to mRNA expression patterns, providing a powerful approach to define cellular identity, function, and the effects of perturbations. However, the use of GES has suffered from vague assessment criteria and limited reproducibility. The structure of proteins defines the functional capability of genes, and hence, we hypothesized that enrichment of structural features could be a generalizable representation of gene sets. We derive structural gene expression signatures (sGES) using features from various levels of protein structure (e.g. domain, fold) encoded by the transcribed genes in GES, to describe cellular phenotypes. Comprehensive analyses of data from the Genotype-Tissue Expression Project (GTEx), ARCHS4, and mRNA expression of drug effects on cardiomyocytes show that structural GES (sGES) are useful for identifying robust signatures of biological phenomena. sGES also enables the characterization of signatures across experimental platforms, facilitates the interoperability of expression datasets, and can describe drug action on cells.
Neonatal hypothermia and adherence to World Health Organisation thermal care guidelines among newborns at Moi Teaching and Referral Hospital, Kenya
Authors: Nyandiko Winstone Mokaya , Kiptoon Paul , Lubuya Florence Ajaya
Published: June 2020

Background

Neonatal hypothermia is a great concern with near epidemic levels globally. The prevalence in Kenya is as high as 87%. Local data on the associated factors including adherence to warm chain guidelines as recommended by the World Health Organisation (WHO) is limited.

Objective

To determine the prevalence of hypothermia and level of adherence to the WHO thermal care guidelines among newborns admitted at Moi Teaching and Referral Hospital (MTRH).

Methods

This descriptive cross-sectional study was carried out among neonates admitted at the MTRH newborn unit. Systematic sampling was used to recruit 372 eligible participants. Axillary thermometry, interview of respective mothers and observation of thermal care practices was done. Means and medians described continuous variables while frequencies with corresponding percentages summarized categorical variables. Associations between various variables and neonatal hypothermia were computed using the Pearson chi-square test. Relative Risks and Odds Ratios were assessed between predictor and outcome variables. Independence among significant variables was determined through the logistic regression model at 5% prediction level.

Results

Among the 372 participants, 64.5% (n=240) were born at MTRH, 47.6% (177) were preterm while 53.2% (198) had birth weights below 2500 grams. Admission hypothermia was noted among 73.7% (n= 274) while 13% (49) died on day one of admission. Only 7.8 % (29) newborns accessed optimal thermal care. Prematurity (RR=1.62, 95% CI: 1.43-1.84), day one mortality (RR=17.7, 95% CI: 2.40, 122.71) and adherence to the warm chain (p<0.001) was significantly associated with admission hypothermia. Inappropriate thermal resuscitation appliance (RR=1.50, 95% CI: 1.34-1.67) inappropriate clothing (RR = 1.78, 95% CI: 1.54 - 2.05) and late breastfeeding (RR = 2.01, 95% CI: 1.39-2.89) significantly increased the risk of hypothermia. Non hypothermic newborns had twenty-fold increased odds of survival (AOR=20.91, 95% CI: 2.15-153.62).

Conclusion

Three out four neonates at the MTRH newborn unit had hypothermia at admission. Hypothermia was significantly associated with prematurity, adherence to warm chain and day one mortality. There was notably low adherence to the warm chain.

Recommendation

Strategies to optimize adherence to the warm chain at MTRH with emphasis on 1thermal care of the preterm neonate should be instituted.
Attentional compensation in neurodegenerative diseases: the model of premanifest Huntington’s disease mutation carriers
Authors: Le Stanc Lorna , Lunven Marine , Giavazzi Maria , Sliwinski Agnès , Brugières Pierre , Youssov Katia , Bachoud-Lévi Anne-Catherine , Jacquemot Charlotte
Published: June 2020

The ability of the brain to actively cope with neuropathological insults is known as neural compensation. It explains the delayed appearance of cognitive symptoms in neurodegenerative diseases. In contrast to the neural signature of compensation, its cognitive counterpart is largely unknown due to the difficulty of identifying cognitive dysfunctions concealed by compensation mechanisms. We combined computational modelling and neuroanatomical analysis to explore cognitive compensation. We used Huntington’s disease (HD) as a genetic model of neurodegenerative disease allowing to study compensation in premanifest mutation carriers (preHDs) free from overt cognitive deficits despite incipient brain atrophy.

Twenty preHDs, 28 HD patients and 45 controls performed a discrimination task. We investigated the processes underlying cognitive compensation using drift diffusion models. They assume that the discrimination process relies on the accumulation of evidence at a certain rate and terminates when a response threshold is reached.

HD patients’ performances were lower than controls’ and explained by a higher response threshold and a lower accumulation rate compared to controls. PreHDs performed similarly to controls but had a response threshold between those of controls and HD patients. This nascent increase in response threshold predicted the accumulation rate, which was faster than controls. This suggests that the higher accumulation rate conceals the nascent deficit in response threshold corroborating the capacity of the brain to resist neuropathological insults in preHDs. The higher accumulation rate was associated with parietal hypertrophy in mutation carriers, and with higher hippocampal volumes in preHDs suggesting that cognitive compensation may rely on attentional capacities.

Significance statement

Enhancing mechanisms compensating brain degeneration in neurodegenerative diseases might allow to delay their onset and progression. Yet, the cognitive mechanisms of compensation remain to be identified. In order to explore this issue, we used Huntington’s disease as a genetic model of neurodegenerative diseases and combined computational modelling (drift diffusion models) and neuroanatomical data analysis. In the early stage of the disease, before the appearance of overt cognitive symptoms, we showed the involvement of the left superior parietal cortex and hippocampus in maintaining normal behavioural performances. This suggests that attention is used to compensate for brain atrophy early in the disease. This work describes promising means of measuring and understanding compensation mechanisms in neurodegenerative diseases and might help developing new therapies.
Identification of spatial variations in COVID-19 epidemiological data using K-Means clustering algorithm: a global perspective
Authors: Chandu Viswa Chaitanya
Published: June 2020

Background

Discerning spatial variations of COVID-19 through quantitative analysis operating on the geographically designated datasets relating to socio-demographics and epidemiological data facilitate strategy planning in curtailing the transmission of the disease and focus on articulation of necessary interventions in an informed manner.

Methods

K-means clustering was employed on the available country-specific COVID-19 epidemiological data and the influential background characteristics. Country-specific case fatality rates and the average number of people tested positive for COVID-19 per every 10,000 population in each country were derived from the WHO COVID-19 situation report 107, and were used for clustering along with the background characteristics of proportion of country’s population aged >65 years and percentage GDP spent as public health expenditure.

Results

The algorithm grouped the 89 countries into cluster ‘1’ and Cluster ‘2’ of sizes 54 and 35, respectively. It is apparent that Americas, European countries, and Australia formed a major part of cluster ‘2’ with high COVID-19 case fatality rate, higher proportion of country’s population tested COVID-19 positive, higher percentage of GDP spent as public health expenditure, and greater percentage of population being more than 65 years of age.

Conclusion

In spite of the positive correlation between high public health expenditure (%GDP) and COVID-19 incidence, case fatality rate, the immediate task ahead of most of the low and middle income countries is to strengthen their public health systems realizing that the correlation found in this study could be spurious in light of the underreported number of cases and poor death registration.
Brain network connectivity in major depression: extending findings from a large public data set by meta-analysis across sites
Authors: Tozzi Leonardo , Williams Leanne M.
Published: June 2020

Abstract

In this short communication, we test whether patients with major depression and healthy individuals have different functional connectivity within established brain networks. To this end, we leverage a very large multi-site data set of resting state fMRI data (1,300 depressed patients and 1,128 controls) collected by 25 groups. A previous study conducted on this data set compared functional connectivity of the default mode network between the two groups. In our investigation, we performed a meta-analysis across sites quantifying the effects of depression and symptom severity on connectivity of several brain-wide networks beyond the default mode. Running a meta-analysis instead of a mega-analysis also allowed us to calculate effect sizes, heterogeneity and prediction intervals that will be valuable to inform future studies wishing to investigate network functional connectivity in depression. Our results indicate that network connectivity differences between depressed and healthy subjects are consistently small, with confidence intervals almost always encompassing zero, in line with the mixed findings from previous research. Default mode network connectivity differences between depressed patients and controls were exceptionally heterogeneous across sites, suggesting the existence of depression sub-types with normo- and hypo-connected default mode network or a strong impact of clinical confounds on default mode network connectivity. The only networks for which connectivity in depressed individuals was consistently lower than in controls were the somatomotor and visual networks, which could be promising understudied targets for future investigation. Overall, we highlight the need of minimizing heterogeneity in future multi-site studies on functional connectivity in depression and the need for more research on novel taxonomies of mental illness that are robustly anchored in brain function.
CT-derived measurements of pulmonary blood volume in small vessels and need for oxygen in COVID-19 patients
Authors: De Backer Wilfried , Lins Muriel , Dierckx Wendel , Vandevenne Jan , De Backer Jan , Lavon Ben R. , Lanclus Maarten , Rijckaert Karen , Kendall Irvin , Thillai Muhunthan
Published: June 2020

In contrast to early reports of conventional acute respiratory distress syndrome (ARDS) as the underlying pathophysiology of hypoxemic respiratory failure observed in patients with severe COVID-19, more recent findings implicate direct involvement of the pulmonary vasculature in giving rise to these symptoms. In earlier research, we demonstrated that patients with COVID-19 showed markedly reduced pulmonary blood volumes in pulmonary vessels <5 mm2 in cross-sectional area visible on imaging (termed “BV5”), with attendant dilation of larger, more proximal vessels. Here, we present preliminary results in which reduced BV5 is shown to correlate significantly with increased need for supplemental oxygen and abnormal arterial blood gas measurements in hospitalized COVID-19 patients. We suggest a potential mechanistic link between observed clinical, pathological, and imaging findings, and outline how these may be helpful in clinical assessment as well as the development of novel therapies.
A modified SEIR meta-population transmission based Modeling and Forecasting of the COVID-19 pandemic in Pakistan
Authors: Hassan Sohaib , Mughal Bilal Javed , Siwiak Marian , Yasin Zafar
Published: June 2020

The coronavirus disease 2019 (COVID-19) started from China at the end of 2019, has now spread across the globe. Modeling and simulation of the COVID-19 outspread is significant for timely and effective measures to be taken. Scientists around the world are using various epidemiological models to help policymakers to plan and determine what interventions and resources will be needed in case of a surge and to estimate the potential future burden on health care system. Pakistan is also among the affected countries with 18th highest number of total detected number of cases, as of 3rd of June, 2020. A modified time-dependent Susceptible-Exposed-Infected-Recovered (SEIR) metapopulation transmission model is used in the Global Epidemic and Mobility Model (GLEaM) for this simulation. The simulation assumes the index case in Wuhan, China and models the global spread of SARS-COV-2 with reasonable results for several countries within the 95% confidence interval. This model was then tuned with parameters for Pakistan to predict the outspread of COVID-19 in Pakistan. The impact of Non-Drug Interventions on “flattening the curve” are also incorporated in the simulation and the results are further extended to find the peak of the pandemic and future predictions. It has been observed that in the current scenario, the epidemic trend of COVID-19 spread in Pakistan would attain a peak in the second decade of month of June with approximately (3600-4200) daily cases. The current wave of SARS-COV-2 in Pakistan with is estimated to cause some (210,000 – 226,000) cumulative cases and (4400-4750) cumulative lost lives by the end of August when the epidemic is reduced by 99%. However, the disease is controllable in the likely future if inclusive and strict control measures are taken.
Molecular, spatial and projection diversity of neurons in primary motor cortex revealed by in situ single-cell transcriptomics
Authors: Zhang Meng , Eichhorn Stephen W. , Zingg Brian , Yao Zizhen , Zeng Hongkui , Dong Hongwei , Zhuang Xiaowei
Published: June 2020

A mammalian brain is comprised of numerous cell types organized in an intricate manner to form functional neural circuits. Single-cell RNA sequencing provides a powerful approach to identify cell types based on their gene expression profiles and has revealed many distinct cell populations in the brain1-3. Single-cell epigenomic profiling4,5 further provides information on gene-regulatory signatures of different cell types. Understanding how different cell types contribute to brain function, however, requires knowledge of their spatial organization and connectivity, which is not preserved in sequencing-based methods that involve cell dissociation3,6. Here, we used an in situ single-cell transcriptome-imaging method, multiplexed error-robust fluorescence in situ hybridization (MERFISH)7, to generate a molecularly defined and spatially resolved cell atlas of the mouse primary motor cortex (MOp). We profiled ∼300,000 cells in the MOp, identified 95 neuronal and non-neuronal cell clusters, and revealed a complex spatial map in which not only excitatory neuronal clusters but also most inhibitory neuronal clusters adopted layered organizations. Notably, intratelencephalic (IT) cells, the largest branch of neurons in the MOp, formed a continuous spectrum of cells with gradual changes in both gene expression profiles and cortical depth positions in a highly correlated manner. Furthermore, we integrated MERFISH with retrograde tracing to probe the projection targets for different MOp neuronal cell types and found that projections of MOp neurons to other cortical regions formed a many-to-many network with each target region receiving input preferentially from a different composition of IT clusters. Overall, our results provide a high-resolution spatial and projection map of molecularly defined cell types in the MOp. We anticipate that the imaging platform described here can be broadly applied to create high-resolution cell atlases of a wide range of systems.
A systematic screen of breast cancer patients’ exomes for retrotransposon insertions reveals disease associated genes
Authors: De Brakeleer Sylvia , De Grève Jacques , Teugels Erik
Published: June 2020

Background

Retrotransposons are genetic elements that jump within the genome via an RNA intermediate. Although they had a strong impact on human genome evolution, only a very tiny fraction of them can be reactivated nowadays, most often with neutral or detrimental consequences. The pathological outcomes associated with such genetic alterations are poorly investigated in the clinic, merely due to their difficult detection.

Results

We developed a strategy to detect rare retrotransposon mediated insertions in Whole Exome Sequencing data from 65 familial breast cancer patients. When restricting our search to high confidence retrotransposition events occurring in less than 10% of the samples, we identified only ten different Alu elements, two L1 elements, one SVA and two processed pseudogenes. Only two of these insertions occurred within protein coding sequences and interestingly, several of the targeted genes have been previously linked to cancer, in three cases even to increased breast cancer risk (GHR, DMBT1andNEK10). When investigating the molecular consequences of four Alu insertions at the mRNA level, we found that the element present in the 3’UTR ofGHRrepressed expression of the corresponding allele. oMreover, the analysis of a near exonic Alu insertion inPTPN14(a mediator ofP53tumor suppressor activity) revealed that this gene was imprinted and that the presence of an intronic Alu element can lead to loss of imprinting.

Conclusions

Our data underline the relevance of incorporating the search for uncommon retrotransposition events in Next Generation Sequencing pipelines when analyzing patients with a suspected genetic disease.
Improving emotional-action control by targeting long-range phase-amplitude neuronal coupling
Authors: Bramson Bob , den Ouden Hanneke , Toni Ivan , Roelofs Karin
Published: June 2020

Control over emotional action tendencies is essential for every-day interactions. This cognitive function can fail during socially challenging situations, and is chronically attenuated in social psychopathologies such as social anxiety and aggression. Previous studies have shown that control over social-emotional action tendencies depends on phase-amplitude coupling between prefrontal theta-band (6 Hz) rhythmic activity and broadband gamma-band activity in sensorimotor areas. Here, we delivered dual-site phase-coupled brain stimulation to facilitate theta-gamma phase-amplitude coupling between frontal regions known to implement that form of control, while participants were challenged to control their automatic action tendencies in a social-emotional approach/avoidance-task. Participants had increased control over their emotional action tendencies, depending on the relative phase and dose of the intervention. Concurrently measured fMRI effects of task and stimulation, and estimated changes in effective connectivity, indicated that the intervention improved control by increasing the efficacy of anterior prefrontal inhibition over sensorimotor cortex. This enhancement of emotional action control provides causal evidence for a phase-amplitude coupling mechanism guiding action selection during emotional-action control. More generally, the finding illustrates the potential of physiologically-grounded interventions aimed at reducing neural noise in cerebral circuits where communication relies on phase-amplitude coupling.
Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence
Authors: Scott Jennifer , Sueiro-Olivares Monica , Thornton Benjamin P. , Owens Rebecca A. , Muhamadali Howbeer , Fortune-Grant Rachael , Thomson Darren , Thomas Riba , Hollywood Katherine , Doyle Sean , Goodacre Royston , Tabernero Lydia , Bignell Elaine , Amich Jorge
Published: June 2020

There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. In this work, we have performed a comprehensive characterisation and validation of the promising target methionine synthase (MetH). We uncover that inAspergillus fumigatusthe absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which evidences thatmetHis a conditionally essential gene. As this implies that for a correct validation MetH should be targeted in established infections, we have validated the use of the tetOFF genetic model for fungal research and optimised its performance to mimic treatment of established infections. We show that repression ofmetHin growing hyphae halts growthin vitro, which translates into a beneficial effect when targeting established infections using this modelin vivo. Finally, a structural-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals.

IMPORTANCE

Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs often is to identify molecular targets which inhibition during infection can prevent pathogen growth. However, the current models are not suitable to validate targets in established infections. Here we have characterised the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogenAspergillus fumigatusas a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimised the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we propose that antifungal targets should be validated in a model of established infection.
High Resolution Biomolecular Condensate Phase Diagrams with a Combinatorial Microdroplet Platform
Authors: Arter William E. , Qi Runzhang , Erkamp Nadia A. , Krainer Georg , Didi Kieran , Welsh Timothy J. , Acker Julia , Nixon-Abell Jonathan , Qamar Seema , Guillén-Boixet Jordina , Franzmann Titus M. , Kuster David , Hyman Anthony A. , Borodavka Alexander , St George-Hyslop Peter , Alberti Simon , Knowles Tuomas P.J.
Published: June 2020

The assembly of intracellular proteins into biomolecular condensates is a fundamental process underlying the organisation of intracellular space and the regulation of many cellular processes. Mapping and characterising phase behaviour of biomolecules is essential to understand the mechanisms of condensate assembly, and to develop therapeutic strategies targeting biomolecular condensate systems. A central concept for characterising phase-separating systems is the phase diagram. Phase diagrams are typically built from numerous individual measurements sampling different parts of the parameter space. However, even when performed in microwell plate format, this process is slow, low throughput and requires significant sample consumption. To address this challenge, we present here a combinatorial droplet microfluidic platform, termed PhaseScan, for rapid and high-resolution acquisition of multidimensional biomolecular phase diagrams. Using this platform, we characterise the phase behaviour of a wide range of systems under a variety of conditions and demonstrate that this approach allows the quantitative characterisation of the effect of small molecules on biomolecular phase transitions.
Production the industrial levels of bioethanol from glycerol by engineered yeast “Bioethanol-4thgeneration”
Authors: Khattab Sadat Mohamed Rezk , Watanabe Takashi
Published: June 2020

Besides the pledges for expanding uses of biofuels to sustain the humanosphere, abruptly massive needs emerged for sanitizers with turns COVID-19 to a pandemic. Therefore, ethanol is topping the social-demanding, although the three generations of production, from molasses/starch, lignocelluloses, and algae. Owing to the limited-availability of fermentable sugars from these resources, we addressed glycerol as a fourth bio-based carbon resource from biodiesel, soap, and fatty acid industries, which considers as a non-applicable source for bioethanol production. Here, we show the full strategy to generate efficient glycerol fermenting yeast by innovative rewriting the oxidation of cytosolic nicotinamide-adenine-dinucleotide (NADH) by O2-dependent dynamic shuttle while abolishing glycerol biosynthesis route. Besides, imposing a vigorous glycerol-oxidative pathway, the engineered strain demonstrated a breakthrough in conversion efficiency (up to 98%). Its capacity extending to produce up to 90g /l ethanol and > 2 g 1-1h-1, which promoting the industrial view. Visionary metabolic engineering here provides horizons for further tremendous economic and health benefits with assuring for its enhancing for the other scenarios of biorefineries.

Efficiently fermenting glycerol in yeast was developed by comprehensive engineering the glycerol pathways and rewriting NADH pathways.
Fibroblasts as an Alternative to Mesenchymal Stem Cells with Successful Treatment and Immune Modulation in EAE Model of Multiple Sclerosis
Authors: Ichim Thomas E , O’Heeron Pete , Perez Jesus , Liu Peter , Min Wei-Ping , Kesari Santosh
Published: June 2020

The immune modulatory potential of mesenchymal stem cells (MSCs) is well known and is the basis for multiple clinical trials in treatment of autoimmune conditions. Unfortunately, MSCs are relatively rare, difficult to expand in culture, and methods of obtaining MSCs are complicated and expensive. In contrast, fibroblasts are found in copious amounts in various tissues, are a robust cellular population, and can be cultured without need for costs associated with culture media. Previous studies by our group and others have demonstrated fibroblasts possess regenerative activities. In the current study we demonstrated: a) fibroblasts inhibit mixed lymphocyte reaction; b) suppress T cell activation; c) inhibit DC maturation; and d) stimulate T regulatory (Treg) cell formation. Importantly, administration of fibroblasts in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis resulted in disease inhibition, which was abrogated upon depletion of Treg cells. This data, combined with existing clinical safety data on fibroblast administration, supports the clinical translation of fibroblast-based therapies for multiple sclerosis.
Skipping and sliding to optimize target search on protein-bound DNA and RNA
Authors: Klein Misha , Cui Tao Ju , MacRae Ian , Joo Chirlmin , Depken Martin
Published: June 2020

Rapidly finding a specific nucleic-acid sequences in a large pool of competing off-targets is a fundamental challenge overcome by all living systems. To optimize the search and beat the diffusion limit, it is known that searchers should spend time sliding along the nucleic-acid substrate. Still, such sliding generally has to contend with high levels of molecular crowding on the substrate, and it remains unclear what effect this has on optimal search strategies. Using mechanistic modelling informed by single-molecule data, we show how sliding combined with correlated short-ranged skips allow searchers to maintain search speed on densely crowded substrates. We determine the conditions of optimal search, which show that an optimized searchers always spend more than half its time skipping and sliding along the substrate. Applying our theory to single-molecule data, we determine that both human and bacterial Argonaute proteins alternate between sliding 10 nt and skipping 30 nt along the substrate. We show that this combination of skipping and sliding lengths allows the searcher to maintain search speeds largely unaffected by molecular roadblocks covering up to 70% of the substrate. Our novel combination of experimental and theoretical approach could also help elucidate how other systems ensure rapid search in crowded environments.
An economic dilemma between weapon systems may explain an arachno-atypical venom in wasp spiders (Argiope bruennichi)
Authors: Lüddecke Tim , von Reumont Björn M. , Förster Frank , Billion André , Timm Thomas , Lochnit Günter , Vilcinskas Andreas , Lemke Sarah
Published: June 2020

Spiders use venom to subdue their prey, but little is known about the diversity of venoms in different spider families. Given the limited data available for orb-weaver spiders (Araneidae) we selected the wasp spiderArgiope bruennichifor detailed analysis. Our strategy combined a transcriptomics pipeline based on multiple assemblies with a dual proteomics workflow involving parallel mass spectrometry techniques and electrophoretic profiling. We found that the remarkably simple venom ofA. bruennichihas an atypical composition compared to other spider venoms, prominently featuring members of the CAP superfamily and other, mostly high-molecular-weight proteins. We also detected a subset of potentially novel toxins similar to neuropeptides. We discuss the potential function of these proteins in the context of the unique hunting behavior of wasp spiders, which rely mostly on silk to trap their prey. We propose that the simplicity of the venom evolved to solve an economic dilemma between two competing yet metabolically expensive weapon systems. This study emphasizes the importance of cutting-edge methods to encompass smaller lineages of venomous species that have yet to be characterized in detail, allowing us to understand the biology of their venom systems and to mine this prolific resource for translational research.
The impact of transposable elements on tomato diversity
Authors: Domínguez Marisol , Dugas Elise , Benchouaia Médine , Leduque Basile , Jimenez-Gomez José , Colot Vincent , Quadrana Leandro
Published: June 2020

Tomatoes come in a multitude of shapes and flavors despite a narrow genetic pool. Here, we leveraged whole-genome resequencing data available for 602 cultivated and wild accessions to determine the contribution of transposable elements (TEs) to tomato diversity. We identified 6,906 TE insertions polymorphisms (TIPs), which result from the mobilization of 337 distinct TE families. Most TIPs are low frequency variants and disproportionately located within or adjacent to genes involved in environmental response. In addition, we show that genic TE insertions tend to have strong transcriptional effects and can notably lead to the generation of multiple transcript isoforms. We also uncovered through genome-wide association studies (GWAS) ~180 TIPs associated with extreme variations in major agronomic traits or secondary metabolites. Importantly, these TIPs tend to affect loci that are distinct from those tagged by SNPs. Collectively, our findings suggest a unique and important role for TE mobilization in tomato diversification, with important implications for future breeding.
Sensitivity of radio-photoluminescence glass dosimeters to accumulated doses
Authors: Kim Dong Wook , Sung Jiwon , Son Jaeman , Shin Han-Back , Kim Min-Joo , Noh Yu-Yun , Kim Hojae , Han Min Cheol , Kim Jihun , Han Su Chul , Chang Kyung Hwan , Kim Hojin , Park Kwangwoo , Yoon Myonggeun , Kim Jinsung , Shin Dongoh
Published: June 2020

Background

This study investigated the effect of accumulated doses on radio-photoluminescence glass dosimeters (RPLGDs) from measurements involving mega-voltage photons.

Methods

Forty-five commercially available RPLGDs were irradiated to estimate their dose responses. Photon beams of 6, 10, and 15 MV were irradiated onto the RPLGDs inside a phantom, which were divided into five groups with different doses and energies. Groups 1 and 2 were irradiated at 1, 5, 10, 50, and 100 Gy in a sequential manner; Group 3 was irradiated 10 times with a dose of 10 Gy; and Groups 4 and 5 followed the same method as that of Group 3, but with doses of 50 Gy and 100 Gy, respectively.

Results

For the annealed Group 1, RPLGD exhibited a linearity response with variance within 5%. For the non-annealed Group 2, readings demonstrated hyperlinearity at 6 MV and 10 MV, and linearity at 15 MV. Following the 100 Gy irradiation, the readings for Group 2 were 118.7 ± 1.9%, 112.2 ± 2.7%, and 101.5 ± 2.3% at 6, 10, and 15 MV, respectively. For Groups 3, 4, and 5, the responsiveness of the RPLGDs gradually decreased as the number of repeated irradiations increased. The percentage readings for the 10th beam irradiation with respect to the readings for the primary beam irradiation were 84.6 ± 1.9%, 87.5 ± 2.4%, and 93.0 ± 3.0% at 6 MV, 10 MV, and 15 MV, respectively.

Conclusions

The non-annealed RPLGD response to dose was hyperlinear for the 6 MV and 10 MV photon beams but not for the 15 MV photon beam. Additionally, the annealed RPLGD exhibited a fading phenomenon when the measurement was repeated several times and demonstrated a relatively large fading effect at low energies than at high energies.
The role of gene dosage in budding yeast centrosome scaling and spontaneous diploidization
Authors: Chen Jingjing , Xiong Zhiyong , Miller Danny E. , Yu Zulin , McCroskey Scott , Bradford William D. , Cavanaugh Ann M. , Jaspersen Sue L.
Published: June 2020

Ploidy is the number of whole sets of chromosomes in a species. Ploidy is typically a stable cellular feature that is critical for survival. Polyploidization is a route recognized to increase gene dosage, improve fitness under stressful conditions and promote evolutionary diversity. However, the mechanism of regulation and maintenance of ploidy is not well characterized. Here, we examine the spontaneous diploidization associated with mutations in components of theSaccharomyces cerevisiaecentrosome, known as the spindle pole body (SPB). Although SPB mutants are associated with defects in spindle formation, we show that two copies of the mutant in a haploid yeast favors diploidization in some cases, leading us to speculate that the increased gene dosage in diploids ‘rescues’ SPB duplication defects, allowing cells to successfully propagate with a stable diploid karyotype. This copy number-based rescue is linked to SPB scaling: certain SPB subcomplexes do not scale or only minimally scale with ploidy. We hypothesize that acquisition of lesions in structures with incompatible allometries such as the centrosome may drive changes such as whole genome duplication, which have shaped the evolutionary landscape of many eukaryotes.

Author Summary

Ploidy is the number of whole sets of chromosomes in a species. Most eukaryotes alternate between a diploid (two copy) and haploid (one copy) state during their life and sexual cycle. However, as part of normal human development, specific tissues increase their DNA content. This gain of entire sets of chromosomes is known as polyploidization, and it is observed in invertebrates, plants and fungi, as well. Polyploidy is thought to improve fitness under stressful conditions and promote evolutionary diversity, but how ploidy is determined is poorly understood. Here, we use budding yeast to investigate mechanisms underlying the ploidy of wild-type cells and specific mutants that affect the centrosome, a conserved structure involved in chromosome segregation during cell division. Our work suggests that different scaling relationships (allometry) between the genome and cellular structures underlies alterations in ploidy. Furthermore, mutations in cellular structures with incompatible allometric relationships with the genome may drive genomic changes such duplications, which are underly the evolution of many species including both yeasts and humans.
Spatial distribution and factors associated with low birth weight in Ethiopia using data from Ethiopian demographic and health survey 2016: spatial and multilevel analysis
Authors: Liyew Alemneh Mekuriaw , Sisay Malede Mequanent , Muche Achenef Asmamaw
Published: June 2020

Background

Low birth weight (LBW) was a leading cause of neonatal mortality. It showed an increasing trend in Sub-Saharan Africa for the last one and half decade. Moreover, it was a public health problem in Ethiopia. Even though different studies were conducted to identify its predictors, contextual factors were insufficiently addressed in Ethiopia. There was also limited evidence on the spatial distribution of low birth weight. Therefore, this study aimed to explore spatial distribution and factors associated with low birth weight in Ethiopia.

Method

Secondary data analysis was conducted using the 2016 EDHS data. A total of 1502 (weighted sample) mothers whose neonates were weighed at birth five years preceding the survey were included. GIS 10.1, SaTscan, stata, and Excel were used for data cleaning and analysis. A multi-level mixed-effects logistic regression model was fitted to identify factors associated with low birth weight. Finally, hotspot areas from GIS results, log-likelihood ratio (LLR) and relative risk with p-value of spatial scan statistics, AOR with 95% CI and random effects for mixed-effects logistic regression model were reported.

Results

Low birth weight was spatially clustered in Ethiopia. Primary(LLR=11.57; P=0.002) clusters were detected in the Amhara region. Whereas secondary (LLR=11.4; P=0.003;LLR=10.14,P=0.0075)clusters were identified at Southwest Oromia, north Oromia, south Afar, and Southeast Amhara regions. Being severely anemic (AOR=1.47;95%CI1.04,2.01), having no education (AOR=1.82;95%CI1.12,2.96), Prematurity (AOR=5.91;95%CI3.21,10.10) female neonate (AOR=1.38;95%CI1.04,1.84)were significantly associated with LBW

Conclusion

LBW was spatially clustered in Ethiopia with high-risk areas in Amhara,Oromia, and Afar regions and it was affected by socio demographic factors. Therefore, focusing the policy intervention in those geogrsphically low birth weight risk areas and improving maternal education and nutrtion could be vital to reduce the low birth weight disparity in Ethiopia.
Fine tuning of calcium constitutive entry by optogenetically-controlled membrane polarization: impact on cell migration
Authors: Chapotte-Baldacci C-A. , Lizot G. , Jajkiewicz C. , Lévêque M. , Penna A. , Magaud C. , Thoreau V. , Bois P. , Sebille S. , Chatelier A.
Published: June 2020

Anomalies in constitutive calcium entry (CCE) have been commonly attributed to cell dysfunction in pathological conditions such as cancer. Calcium influxes of this type rely on channels, such as TRP, to be constitutively opened and strongly depend on membrane potential and calcium driving force. We developed an optogenetic approach based on expression of the halorhodopsin chloride pump to study CCE in non-excitable cells. Using C2C12 cells, we found that halorhodopsin can be used to achieve a finely-tuned control of membrane polarization. Escalating the membrane polarization by incremental changes in light led to a concomitant increase in CCE through TRPV2 channels. Moreover, light-induced calcium entry through TRPV2 channels promoted cell migration. Our study shows for the first time that by modulating CCE and related physiological responses such as cell motility, halorhodopsin serves as a potentially powerful tool that could open new avenues for the study of CCE and associated cellular behaviors.