bluuebunny/crossref_metadata_2025 huggingface dataset:
Complex Autoantibody Responses Occur Following Moderate to Severe Traumatic Brain Injury
Authors: Needham Edward J , Stoevesandt Oda , Thelin Eric P , Zetterberg Henrik , Zanier Elisa R , Nimer Faiez Al , Ashton Nicholas J , Outtrim Joanne G , Newcombe Virginia FJ , Mousa Hani S , Simren Joel , Blennow Kaj , Yang Z Zhihui , Hutchinson Peter J , Piehl Fredrik , Helmy Adel E , Taussig Mike J , Wang Kevin KW , Jones Joanne L , Menon David K , Coles Alasdair J
Published: July 2020

The majority of variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognised prognostic factors, suggesting a contribution from unaccounted variables. One key candidate variable is neuroinflammation, including the generation of autoantibodies against brain specific antigens which have been described in some individuals following TBI. Here we hypothesised that autoantibody responses following TBI would differ between individuals, and would explain a proportion of outcome variance.

We developed a custom protein microarray to characterise the generation of autoantibodies to both central nervous system and systemic antigens in the acute-phase of TBI (within ten days of injury), and to determine their late (6-12 months) and long-term (6-13 years) persistence.

We identified two distinct patterns of response. The first was a broad response to the majority of antigens tested, predominantly IgM-mediated in the acute-phase, then IgG-dominant at late and long-term time-points. The second was of dominant responses to certain antigens, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved.

Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with serum neurofilament light concentrations, suggesting an association with ongoing neurodegeneration over the first year post-injury.

Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and may affect patient outcome. The complexity of responses mean that conventional approaches based on measuring responses to single antigenic targets may be misleading.
Covid-19 automated diagnosis and risk assessment through Metabolomics and Machine-Learning
Authors: Delafiori Jeany , Navarro Luiz Claudio , Siciliano Rinaldo Focaccia , de Melo Gisely Cardoso , Busanello Estela Natacha Brandt , Nicolau José Carlos , Sales Geovana Manzan , de Oliveira Arthur Noin , Almeida Val Fernando Fonseca , de Oliveira Diogo Noin , Eguti Adriana , dos Santos Luiz Augusto , Falcão Dalçóquio Talia , Bertolin Adriadne Justi , Cardoso Alonso João Carlos , Abreu-Netto Rebeca Linhares , Salsoso Rocio , Baía-da-Silva Djane , Sampaio Vanderson Souza , Judice Carla Cristina , Maranhão Costa Fabio Trindade , Durán Nelson , Perroud Mauricio Wesley , Sabino Ester Cerdeira , Guimarães Lacerda Marcus Vinicius , Reis Leonardo Oliveira , José Fávaro Wagner , Monteiro Wuelton Marcelo , Rocha Anderson Rezende , Catharino Rodrigo Ramos
Published: July 2020

COVID-19 is still placing a heavy health and financial burden worldwide. Impairments in patient screening and risk management play a fundamental role on how governments and authorities are directing resources, planning reopening, as well as sanitary countermeasures, especially in regions where poverty is a major component in the equation. An efficient diagnostic method must be highly accurate, while having a cost-effective profile.

We combined a machine learning-based algorithm with instrumental analysis using mass spectrometry to create an expeditious platform that discriminate COVID-19 in plasma samples within minutes, while also providing tools for risk assessment, to assist healthcare professionals in patient management and decision-making. A cross-sectional study with 728 patients (369 confirmed COVID-19 and 359 controls) was enrolled from three Brazilian epicentres (São Paulo capital, São Paulo countryside and Manaus) in the months of April, May, June and July 2020.

We were able to elect and identify 21 molecules that are related to the disease’s pathophysiology and 26 features to patient’s health-related outcomes. With specificity >97% and sensitivity >83% from blinded data, this screening approach is understood as a tool with great potential for real-world application.
SMAP – A Modular Superresolution Microscopy Analysis Platform for SMLM Data
Authors: Ries Jonas
Published: July 2020

Reconstruction of superresolved images from the raw data of blinking fluorophores in single-molecule localization microscopy (SMLM) requires extensive data analysis. Current software solutions often lack functionality, continuous development and cannot easily be extended with own algorithms. Here we release as open source a comprehensive Superresolution Microscopy Analysis Platform (SMAP) for SMLM. Its modular architecture makes it easy for anyone with basic programming experience to add own plugins, limiting development effort to implementing algorithms. It has a freely configurable graphical user interface (GUI) and currently contains more than 200 plugins spanning all steps of data analysis from single molecule fitting to post-processing, rendering and advanced quantitative analyses. SMAP is a powerful, ready-to-use software package for all steps of SMLM data analysis, that enables anyone to use state-of-the art algorithms and complex analysis workflows and that provides a versatile platform for developers to share and publish new SMLM algorithms.
Validating layer-specific VASO across species
Authors: Huber Laurentius Renzo , Poser Benedikt A , Kaas Amanda L , Fear Elizabeth J , Desbach Sebastian , Berwick Jason , Goebel Rainer , Turner Robert , Kennerley Aneurin J
Published: July 2020

Cerebral blood volume (CBV) has been shown to be a robust and important physiological parameter for quantitative interpretation of functional (f)MRI, capable of delivering highly localized mapping of neural activity. Indeed, with recent advances in ultra-high-field (>=7T) MRI hardware and associated sequence libraries, it has become possible to capture non-invasive CBV weighted fMRI signals across cortical layers. One of the most widely used approaches to achieve this (in humans) is through vascular-space-occupancy (VASO) fMRI. Unfortunately, the exact contrast mechanisms of layer-dependent VASO fMRI have not been validated and thus interpretation of such data is confounded. Here we cross-validate layer-dependent VASO fMRI contrast in a preclinical rat model using well established (but invasive) imaging methods in response to neuronal activation (somatosensory cortex) and respiratory challenge (hypercapnia). In particular VASO derived CBV measures are directly compared to concurrent measures of total haemoglobin changes from high resolution intrinsic optical imaging spectroscopy (OIS). Through direct comparison of response magnitude, across time, negligible changes in hematocrit ratio during activation (neuronal or vascular) are inferred. Quantified cortical layer profiling is demonstrated and in agreement between both VASO and contrast enhanced fMRI (using monocrystalline iron oxide nanoparticles, MION). Responses show high spatial localisation to layers of cortical excitatory and inhibitory processing independent of confounding large draining veins which hamper BOLD fMRI studies. While we find increased VASO based CBV reactivity (3.1 ± 1.2 fold increase) in humans compared to rats it is demonstrated that this reflects differences in stimulus design rather than confounds of the VASO signal source. Together, our findings confirm that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes. This validation study increases the neuronal interpretability of human layer-dependent fMRI results and should supersede BOLD fMRI as the method of choice in neuroscience application studies.

Highlights

Our goal is to validate layer-specific VASO fMRI with gold standard methods

Layer-specific VASO sequences are implemented for 7T imaging in humans and rats

Comparisons of VASO, optical imaging, and MION confirm the expected contrast origin

Somatosensory stimulation in humans and rats reveal the same layer-fMRI signatures

We confirm that VASO is a valid measure to estimate layer-specific neural activity

Graphical abstract
Opportunities and challenges in using remote sensing for identifying grassland restoration sites and invasive tree species management in a global biodiversity hotspot
Authors: Arasumani M. , Bunyan Milind , Robin V. V.
Published: July 2020

Tropical montane grasslands (TMG) support biodiverse and endemic taxa and provide vital ecosystems services to downstream communities. Yet invasive alien tree species across the world have threatened tropical grasslands and grassland endemic species. In India, TMG in the Shola Sky Islands of the Western Ghats have been reduced due to exotic tree invasions (acacias, pines, and eucalyptus species). The loss of grassland habitat has, in turn, reduced the range sizes of species endemic to grasslands (plants, birds, amphibians, and mammals), driving some populations to local extinction. Grassland conversion to exotic trees has also reduced the annual runoff in the Western Ghats. Conserving existing grassland and restoring invaded habitat is critical to reverse these losses. This research focused on identifying grassland restoration sites using satellite images with a high spatial resolution (RapidEye). We used an object-oriented Random Forest classification to map the area for grassland restoration. We have identified an area of 254 sq. km. as suitable for grassland restoration and an area of 362 sq. km. for grassland conservation and prevention from invasion by exotic tree species. For restoration, we recommend a cautious removal of young and isolated exotic trees at the invasion front and restoring grasslands, instead of removing dense stands of mature exotic trees. We find that areas with low fire frequency areas tend to be invaded, but areas invaded by exotic trees tend to burn hotter which may be harmful to grassland species and ecosystems. We assume that removing exotic tree species in the identified restoration sites and restoring the grassland will be helpful in recovering lost habitat and ensuring the viability of populations of indigenous and endemic species and increasing streamflow.
Combined Vapor Exposure to THC and Alcohol in Pregnant Rats: Maternal Outcomes and Pharmacokinetic Effects
Authors: Breit Kristen R. , Rodriguez Cristina , Lei Annie , Thomas Jennifer D.
Published: July 2020

Cannabis is the most frequently used illicit drug among pregnant women, yet the potential consequences of prenatal cannabis exposure on development are not well understood. Electronic cigarettes have become an increasingly popular route of administration among pregnant women, in part to user’s perception that e-cigarettes are a safer route for consuming cannabis products. Importantly, half of pregnant women who consume cannabis also report consuming alcohol, but research investigating co-consumption of these drugs is limited, particularly with current routes of administration. The purpose of this study was to establish a co-exposure vapor inhalation model of alcohol and THC in pregnant rats, to ultimately determine the effects on fetal development. Pregnant Sprague-Dawley rats were exposed to moderate doses of THC via e-cigarettes, alcohol, the combination, or vehicle daily from gestational days 5-20. Importantly, pharmacokinetic interactions of alcohol and THC were observed during pregnancy. Combined exposure consistently increased blood alcohol concentrations, indicating that THC alters alcohol metabolism. In addition, THC levels also increased over the course of pregnancy and THC metabolism was altered by alcohol. Alcohol, but not THC, exposure during pregnancy reduced maternal weight gain, despite no group differences in food intake. Neither prenatal alcohol nor THC exposure altered gestational length, litter size, sex ratio or birth weight. However, prenatal alcohol exposure delayed eye opening, and prenatal THC exposure decreased body weights during adolescence among offspring. These individual and synergistic effects suggest that this novel co-exposure vapor inhalation paradigm can effectively be used to expose pregnant dams, exerting some effects on fetal development, while avoiding nutritional confounds, birth complications, or changes in litter size. With this model, we have demonstrated that combining THC and alcohol alters drug metabolism, which could have important consequences on prenatal development.
Degenerate circuits use distinct mechanisms to respond similarly to the same perturbation
Authors: Powell D.J. , Marder E. , Nusbaum M.P.
Published: July 2020

There is considerable flexibility embedded within neural circuits. For example, separate modulatory inputs can differently configure the same underlying circuit but these different configurations generate comparable, or degenerate, activity patterns. However, little is known about whether these mechanistically different circuits in turn exhibit degenerate responses to the same inputs. We examined this issue using the crab (Cancer borealis) stomatogastric nervous system, in which stimulating the modulatory projection neuron MCN1 and bath applying the neuropeptide CabPK II elicit similar gastric mill (chewing) rhythms in the stomatogastric ganglion, despite differentially configuring the same neural circuit. We showed previously that bath applying the peptide hormone CCAP or stimulating the muscle stretch-sensitive sensory neuron GPR during the MCN1-elicited gastric mill rhythm selectively prolongs the protraction or retraction phase, respectively. Here, we found that these two influences on the CabPK-rhythm elicited some unique and unexpected consequences compared to their actions on the MCN1-rhythm. For example, in contrast to its effect on the MCN1-rhythm, CCAP selectively decreased the CabPK-rhythm retraction phase and thus increased the rhythm speed, whereas the CabPK-rhythm response to stimulating GPR during the retraction phase was similar its effect on the MCN1-rhythm (i.e. prolonging retraction). Interestingly, despite the comparable GPR actions on these degenerate rhythms, the underlying synaptic mechanism was distinct. Thus, degenerate circuits do not necessarily exhibit degenerate responses to the same influence, but when they do, it can occur via different underlying mechanisms.

Significance Statement

Circuits generating seemingly identical behaviors are often thought to arise from identical circuit states, as that is the most parsimonious explanation. Here we take advantage of an alternate scenario wherein a well-defined circuit with known connectivity generates similar activity patterns using distinct circuit states, via known mechanisms. The same peptide hormone modulation of these distinct circuit states produced divergent activity patterns, whereas the same sensory feedback altered these circuit outputs similarly but via different synaptic pathways. The latter observation limits the insights available from comparable studies in systems lacking detailed access to the underlying circuit.
Impact of COronaVirus Disease-2019 (COVID-19) pandemic on Haemodialysis care delivery pattern in Karnataka, India - a cross-sectional, questionnaire based survey
Authors: Anupama Y J , Conjeevaram Arvind , Ravindra Prabhu A , Doshetty Manjunath , Srinivasa Sanjay , Moger Venkatesh
Published: July 2020

The COVID-19 pandemic has disrupted health care delivery globally. Patients on in-centre haemodialysis(HD) are particularly affected due to their multiple hospital visits and the need for uninterrupted care for their well-being and survival. We studied the impact of the pandemic and the national policy for pandemic control on the HD care delivery in Karnataka state in India in April 2020, when the first and second national lockdown were in place. An online, questionnaire based survey of dialysis facilities was conducted and the responses analysed. The questions were pertaining to the key areas such as changes in number of dialysis treatments, frequency, duration, expenses, transportation to and from dialysis units, impact on availability of consumables, effect on dialysis personnel and on machine maintenance. 62 centres participated. Median of dialysis treatments for the months of March and April 2020 were 695.5 and 650 respectively. Reduction in dialysis treatments was noted in 29(46.8%) facilities, decreased frequency reported by 60 centres. In at least 35(56.5%) centres, dialysis patients had to bear increased expenses. Cost and availability of dialysis consumables were affected in 40(64.5%) and 55(88.7%) centres respectively. Problems with transportation and movement restriction were the two key factors affecting both patients and dialysis facilities.This survey documents the collateral impact of COVID-19 on the vulnerable group of patients on HD, even when not affected by COVID. It identifies the key areas of challenges faced by the patients and the facilities and implores the care-providers for finding newer avenues for mitigation of the problems.
Adapting for the COVID-19 pandemic in Ecuador, a characterization of hospital strategies and patients
Authors: Garzon-Chavez Daniel , Romero-Alvarez Daniel , Bonifaz Marco , Gaviria Juan , Mero Daniel , Gunsha Narcisa , Perez Asiris , Garcia María , Espejo Hugo , Espinosa Franklin , Ligña Edison , Espinel Mauricio , Quentin Emmanuelle , Teran Enrique , Mora Francisco , Reyes Jorge.
Published: July 2020

The World Health Organization (WHO) declared coronavirus disease-2019 (COVID-19) a global pandemic on March 11th. In Ecuador, the first case of COVID-19 was recorded on February 29th. Despite efforts to control its spread, SARS-CoV-2 overrun the Ecuadorian public health system which became one of the most affected in Latin America with 22,719 cases reported up to April, 24th. Public health control measures, including social distancing and lockdowns, were implemented at different times in the biggest cities of the country: Guayaquil and Quito. The Hospital General del Sur de Quito (HGSQ) had to transition from a general to a specific COVID-19 health center in a short period of time to fulfill the health demand from patients with respiratory afflictions. Here, we summarized the implementations applied in the HGSQ to become a COVID-19 exclusive hospital, including the rearrangement of hospital rooms and a triage strategy based on a severity score calculated through an artificial intelligence (AI)-assisted chest computed tomography (CT). Moreover, we present clinical, epidemiological, and laboratory data from 75 laboratory tested COVID-19 patients, which represent the first outbreak of Quito city.
Mathematical modelling based study and prediction of COVID-19 epidemic dissemination under the impact of lockdown in India
Authors: Tiwari Vipin , Deyal Namrata , Bisht Nandan S.
Published: July 2020

COVID-19 (SARS-CoV-2) is rapidly spreading in South Asian countries especially in India. India is the fourth most COVID-19 affected country at present (as on July 10, 2020). With limited medical facilities and high transmission rate, study of COVID-19 progression and its subsequence trajectory need to be analyzed in India. Epidemiologic mathematical models have the potential to predict the epidemic peak of COVID-19 under different scenario. Lockdown is one of the most effective mitigation policy adapted worldwide to control the transmission rate of COVID-19 cases. In this study, we use an improvised five compartment mathematical model i.e. Susceptible (S) - exposed (E)- infected (I)- recovered (R)- death (D) (SEIRD) to investigate the progression of COVID-19 and predict the epidemic peak under the impact of lockdown in India. The aim of this study to provide the most accurate prediction of epidemic peak and to evaluate the impact of lockdown on epidemic peak shift in India. For this purpose, we examine most recent data (up to July 10, 2020) to enhance the accuracy of outcomes from the proposed model. The obtained results indicate that COVID-19 epidemic peak would appear on around mid-August 2020 in India and corresponding estimated cases would be 2.5×106under current scenario. In addition, our study indicates that existence of under-reported cases (∼105) during post-lockdown period in India. It is expected that nationwide lockdown would lead to epidemic peak suppression in India. The obtained results would be beneficial for determining further COVID-19 mitigation policies not only in India but globally.
Power Law in COVID-19 Cases in China
Authors: Ahundjanov Behzod B. , Akhundjanov Sherzod B. , Okhunjanov Botir B.
Published: July 2020

The novel coronavirus (COVID-19) was first identified in China in December 2019. Within a short period of time, the infectious disease has spread far and wide. This study focuses on the distribution of COVID-19 confirmed cases in China—the original epicenter of the outbreak. We show that the upper tail of COVID-19 cases in Chinese cities is well described by a power law distribution, with exponent around one in the early phases of the outbreak (when the number of cases was growing rapidly) and less than one thereafter. This finding is significant because it implies that (i) COVID-19 cases in China is heavy-tailed and disperse; (ii) a few cities account for a disproportionate share of COVID-19 cases; and (iii) the distribution generally has no finite mean or variance. We find that a proportionate random growth model predicated by Gibrat’s law offers a plausible explanation for the emergence of a power law in the distribution of COVID-19 cases in Chinese cities in the early phases of the outbreak.
Global dynamics of microbial communities emerge from local interaction rules
Authors: van Vliet Simon , Hauert Christoph , Ackermann Martin , Dal Co Alma
Published: July 2020

Interactions between cells drive biological processes across all of life, from microbes in the environment to cells in multicellular organisms. Interactions often arise in spatially structured settings, where cells mostly interact with their neighbors. A central question is how local interactions shape the properties of biological systems. This question is very relevant in the context of microbial communities, such as biofilms, where cells live close by in space and are connected via a dense network of biochemical interactions. To understand and control the functioning of these communities, it is essential to uncover how community-level properties, such as the community composition, spatial arrangement, and growth rate, arise from these interactions. Here, we develop a mathematical framework that can predict community-level properties from the molecular mechanisms underlying the cell-cell interactions for systems consisting of two cell types. Our predictions can qualitatively reproduce measurements from an experimental cross-feeding community. For these cross-feeding communities, the community growth rate is reduced when cells interact only with few neighbors; as a result, some communities can co-exist in a well-mixed system, where cells can interact with all other cells, but not in systems where cells can interact only with close by neighbors. In general, our framework shows that key molecular parameters underlying the cell-cell interactions (e.g. the uptake and leakage rates of molecules) determine community-level properties. Our framework can be extended to a variety of systems of two interacting cell types, within and beyond the microbial world, and contributes to our understanding of how community-level dynamics and biological functions emerge from microscopic interactions between single cells.
Evaluation of near infrared spectroscopy for sporozoite detection in mosquitoes infected with wild-strain parasites from asymptomatic gametocyte carriers in Kilifi Kenya
Authors: Maia Marta F. , Wagah Martin G. , Karisa Jonathan , Mwakesi Robert , Mure Festus , Muturi Martha , Wambua Juliana , Hamaluba Mainga , Dowell Floyd E. , Bejon Philip , Kapulu Melissa C.
Published: July 2020

Background

Screening forPlasmodiumspp. sporozoite infection in mosquitoes is routinely done using ELISA (enzyme-linked immunosorbent assay). Near infrared spectroscopy (NIRS), a fast and non-destructive method, has recently been shown to distinguish, with 95% accuracy, between uninfected and sporozoite-infected mosquitoes using laboratory strains ofPlasmodium falciparum(PfN54). The aim of this present study was to further investigate the reproducibility of NIRS to identify sporozoite infection in mosquitoes infected using field isolates ofP. falciparumgametocytes from asymptomatic carriers.

Methods

Healthy individuals (aged 5 years and above) were screened for gametocytaemia by thick-smear microscopy in an area of moderate transmission along the Coast of Kenya between May and September 2018. Asymptomatic gametocyte carriers were recruited for mosquito feeding assays, direct membrane feeding (DMFA) and direct skin feeding (DFA), using insectary-rearedAnopheles gambiaes.s (Kilifi strain). Mosquitoes were kept for 14-days post feeding after which they were scanned using NIRS and subsequently analysed for sporozoite infection using circumsporozoite-ELISA. Predictive models were explored using partial least square regressions (PLS).

Results

Two hundred and ninety-nine (299) individuals were screened for malaria parasites, 74 (24.8%) were found with circulating asexual parasites, and 16 (5.4%) withP. falciparumgametocyte stages. Fourteen (14) asymptomatic gametocyte carriers were recruited to the study for mosquito feeding assays. A total of 134 (7%, 134/1881) sporozoite-infected mosquitoes were obtained from 9 successful experiments. Three different training datasets composed of infected and uninfected mosquitoes were analysed. The PLS models were unable to distinguish between sporozoite-infected and uninfected mosquitoes. A predictive model could not be generated.

Conclusions

The results of this study were not consistent with previous published research on NIRS for detection of sporozoite infection in the same mosquito species and may reflect differences between laboratory and field conditions. The current findings indicate that methods for sporozoite detection should be tested on field isolates at an early stage in their development and are informative for future research seeking novel high-throughput methods for parasite detection in mosquitoes.
Expression ofWnt5adefines the major progenitors of fetal and adult Leydig cells
Authors: Ademi Herta , Stévant Isabelle , Rands Chris M , Conne Béatrice , Nef Serge
Published: July 2020

Leydig cells (LCs) are the major androgen-producing cells in the testes. They arise from steroidogenic progenitors, whose origins, maintenance and differentiation dynamics remain largely unknown. Here, we identifiedWnt5aas a specific marker of steroidogenic progenitors, whose expression begins at around E11.5-E12.5 in interstitial cells of the fetal mouse testis.In vivolineage tracing indicates thatWnt5a-expressing progenitors are initially present in large numbers in the fetal testis and then progressively decrease as development progresses. We provide evidence thatWnt5a-expressing cells arebona fideprogenitors of peritubular myoid cells as well as fetal and adult LCs, contributing to most of the LCs present in the fetal and adult testis. Additionally, we show in the adult testis thatWnt5aexpression is restricted to a subset of LCs exhibiting a slow but noticeable clonal expansion, revealing hitherto unappreciated proliferation of fully differentiated LCs as a contribution to the adult LC pool.
A>G substitutions on a heavy chain of mitochondrial genome marks an increased level of aerobic metabolism in warm versus cold vertebrates
Authors: Mikhailova Alina G. , Iliushchenko Dmitrii , Shamansky Victor , Mikhailova Alina A. , Ushakova Kristina , Tretyakov Evgenii , Oreshkov Sergey , Knorre Dmitry , Polishchuk Leonard , Lawless Dylan , Kuzmin Aleksandr , Denisov Stepan , Kozenkov Ivan , Mazunin Ilya , Kunz Wolfram , Tanaka Masashi , Makeev Vsevolod , Castilho Rita , Yurov Valerian , Kuptsov Alexander , Fellay Jacques , Khrapko Konstantin , Gunbin Konstantin , Popadin Konstantin
Published: July 2020

The variation in the mutational spectrum of the mitochondrial genome (mtDNA) among species is not well understood. Recently, we demonstrated an increase in A>G substitutions on a heavy chain (hereafter AH>GH) of mtDNA in aged mammals, interpreting it as a hallmark of age-related oxidative damage. In this study, we hypothesized that the occurrence of AH>GHsubstitutions may depend on the level of aerobic metabolism, which can be inferred from an organism’s body temperature. To test this hypothesis, we used body temperature in endotherms and environmental temperature in ectotherms as proxies for metabolic rate and reconstructed mtDNA mutational spectra for 1350 vertebrate species. Our results showed that temperature was associated with increased rates of AH>GHand asymmetry of AH>GHin different species of ray-finned fishes and within geographically distinct clades of European anchovy. Analysis of nucleotide composition in the most neutral synonymous sites of fishes revealed that warm-water species were expectedly more A-poor and G-rich compared to cold-water species. Finally, we extended our analyses to all vertebrates and observed higher AH>GHand increased asymmetry of AH>GHin warm-blooded (mammals and birds) compared to cold-blooded (Actinopterygii, amphibia, reptilia) vertebrate classes. Overall, our findings suggest that temperature, through its influence on metabolism and oxidative damage, shapes the mutational properties and nucleotide content of the mtDNA in all vertebrates.
Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model
Authors: Safa Alireza , Lau Allison R. , Aten Sydney , Schilling Karl , Bales Karen L. , Miller Victoria A. , Fitzgerald Julie , Chen Min , Hill Kasey , Dzwigalski Kyle , Obrietan Karl , Phelps Mitch A. , Sadee Wolfgang , Oberdick John
Published: July 2020

Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective neutral opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ∼0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence as compared to its low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.
Characterization of Induced Susceptibility Effects of Soybean Aphid on Soybean
Authors: Neupane Surendra , Varenhorst Adam J. , Nepal Madhav P.
Published: July 2020

Soybean aphid (SBA) is one of the major pests of soybean (Glycine max) in the United States of America. The main objective of this research was to characterize interactions between two different biotypes of soybean aphids in susceptible and resistant soybean cultivars. Demographic and transcriptomic responses of susceptible and resistant (Rag1) soybean cultivars to aphid feeding were investigated in soybean plants colonized by aphids (biotype 1) in the presence or absence of inducer population (biotype 2) at day 1 and day 11. Leaves tissues collected at day 1 and day 11 post infestation were used for RNA sequencing, and ten RNA datasets with 266,535,654 sequence reads were analyzed. In the presence of inducer population, we found 746 and 243 differentially expressed genes (DEGs) in susceptible and resistant cultivars, respectively at day 1, whereas 981 and 377 DEGs were found in susceptible and resistant cultivars, respectively at day 11. Enrichment analysis showed a response to chitin, lignin catabolic and metabolic process, asparagine metabolic process, response to chemical unique to treatment with no inducer population, whereas, response to reactive oxygen species, photosynthesis, regulation of endopeptidase activity unique to treatment with inducer population. Furthermore, 14 DEGs were observed inRagQTLs regions, particularly six DEGs inRag1containing QTL. The identified DEGs in the experiment in both resistant and susceptible cultivars during the interaction of soybean and SBA are potential candidates for furthering investigation into induced susceptibility.
Integration of phenomics and transcriptomics data to reveal drivers of inflammatory processes in the skin
Authors: Batra Richa , Garzorz-Stark Natalie , Lauffer Felix , Jargosch Manja , Pilz Caroline , Roenneberg Sophie , Schäbitz Alexander , Böhner Alexander , Seiringer Peter , Thomas Jenny , Fereydouni Bentolhoda , Kutkaite Ginte , Menden Michael , Tsoi Lam C , Gudjonsson Johann E , Theis F Fabian , Biedermann Tilo , Schmidt-Weber Carsten B , Müller Nikola , Eyerich Stefanie , Eyerich Kilian
Published: July 2020

Chronic inflammatory diseases are characterized by complex interactions between genetic predisposition and tissue-specific immune responses. This heterogeneity complicates diagnoses and the ability to exploit omics approaches to improve disease management, develop more effective therapeutics, and apply precision medicine. Using skin inflammation as a model, we developed a method that integrates deep clinical phenotyping information (phenomics) with transcriptome data of lesional and non-lesional skin (564 samples) to identify clinically-relevant gene signatures. It led us to discover so-far unexplored factors, including CCAAT Enhancer-Binding Protein Beta (CEBPB) in neutrophil invasion, and Pituitary Tumor-Transforming 2 (PTTG2) in the pathogenic epithelial response to inflammation. These factors were validated using genetically-modified human skin equivalents, migration assays, andin situimaging. Thus, by meaningful integration of deep clinical phenotyping and omics data we reveal hidden drivers of clinically-relevant biological processes.
Laminin N-terminus α31 expression during development is lethal and causes widespread tissue-specific defects in a transgenic mouse model
Authors: Sugden Conor J. , Iorio Valentina , Troughton Lee D. , Liu Ke , Bou-Gharios George , Hamill Kevin J.
Published: July 2020

Laminins are essential components of all basement membranes where they regulate an extensive array of tissue functions. Alternative splicing from the laminin α3 gene produces a non-laminin but netrin-like protein, Laminin N terminus α31 (LaNt α31). LaNt α31 is widely expressed in intact tissue and is upregulated in epithelial cancers and during wound healing. In vitro functional studies have shown that LaNt α31 can influence numerous aspects of epithelial cell behaviourviamodifying matrix organisation, suggesting a new model of laminin auto-regulation. However, the function of this protein has not been established beyond the epithelium and it has never been studied in vivo. Here, a mouse transgenic line was generated using the ubiquitin C promoter to drive inducible expression of LaNt α31. When expression was induced at embryonic day 15.5, LaNt α31 transgenic animals were not viable at birth, exhibiting localised regions of erythema. Numerous striking defects were apparent histologically, including extra-vascular erythrocytes in multiple tissues, kidney epithelial detachment, tubular dilation, interstitial bleeding, and thickening of tubule basement membranes, disruption of the epidermal basal cell layer and of the hair follicle outer root sheath, and ~50% reduction of cell numbers in the liver associated with depletion of hematopoietic erythrocytic foci. These findings demonstrate that LaNt α31 can influence tissue morphogenesis during development. More broadly, these data provide the first in vivo evidence to support an emerging model of laminin self-regulation and provide a valuable model for onward investigation into this important area.

Summary Statement

Expression during development of Laminin N-terminus α31, a netrin-like laminin splice isoform, caused defects indicating basement membrane disruption in multiple tissues; providing the first in vivo evidence for laminin self-regulation.
Sex-specific responses to cold in a very cold-tolerant, northernDrosophila species
Authors: Parker Darren J. , Envall Tapio , Ritchie Michael G. , Kankare Maaria
Published: July 2020

Organisms can plastically alter resource allocation in response to changing environmental factors. For example, in harsh conditions organisms are expected to shift investment from reproduction towards survival, however, the factors and mechanisms that govern the magnitude of such shifts are relatively poorly studied. Here we compared the impact of cold on males and females of the highly cold-tolerant speciesDrosophila montanaat the phenotypic and transcriptomic levels. Although both sexes showed similar changes in cold tolerance and gene expression in response to cold treatment, indicating that the majority of changes are concordant between the sexes, we identified a clear reduction in sexually dimorphic gene expression, suggesting that preparing for colder season also involves reducing investment in sex-specific traits. This reduction was larger in males than females, as expected if male sexual traits are more condition-dependent than female traits, as predicted by theory. Gene expression changes were primarily associated with shifts in metabolic profile which likely play a role in increasing cold tolerance. Finally, we found that the expression of immune genes was reduced following cold treatment, suggesting that reduced investment in immunity may be important in helping flies survive colder periods.
Differences in developmental potential predict the contrasting patterns of dental diversification in characiform and cypriniform fishes
Authors: Jandzik David , Stock David W
Published: July 2020

Morphological diversification during adaptive radiation may depend on factors external or internal to the lineage. We provide evidence for the latter in characiform fishes (tetras and piranhas), which exhibit extensive dental diversity. Phylogenetic character mapping supported regain of lost teeth as contributing to this diversity. To test for latent potential for dentition that would facilitate its evolutionary expansion, we overexpressed a tooth initiation signal, the tumor necrosis factor pathway ligand ectodysplasin, in a model characiform, the Mexican Tetra (Astyanax mexicanus). This manipulation resulted in extensive ectopic dentition, in contrast to its previously-reported limited effect in the Zebrafish (Danio rerio). Tooth location in the Order Cypriniformes, to which the Zebrafish belongs, is much more restricted than in characiforms, a pattern that may be explained by differences in the retention of ancestral developmental potential. Our results suggest that differences in evolvability between lineages may lead to contrasting patterns of diversification.
Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response
Authors: McMahon Kerrie-Ann , Stroud David A. , Gambin Yann , Tillu Vikas A. , Bastiani Michele , Sierecki Emma , Polinkovsky Mark , Hall Thomas E. , Gomez Guillermo A. , Wu Yeping , Parat Marie-Odile , Martel Nick , Lo Harriet P. , Khanna Kum Kum , Alexandrov Kirill , Daly Roger , Yap Alpha S. , Ryan Michael T. , Parton Robert G.
Published: July 2020

Caveolae-associated protein 3 (cavin3), a putative tumor suppressor protein, is inactivated in most cancers. We characterized how cavin3 affects the cellular proteome using genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair with BRCA1 and BRCA1 A-complex components being downregulated on cavin3 deletion. Cellular and cell-free expression assays, we show a direct interaction between BRCA1 and cavin3. Association of BRCA1 and cavin3 occurs when cavin3 is released from caveolae that are disassembled in response to UV and mechanical stress. Supporting a role in DNA repair, cavin3-deficient cells were sensitized to the effects of PARP inhibition, which compromises DNA repair, and showed reduced recruitment of the BRCA1 A-complex to UV DNA damage foci. Overexpression and RNAi-depletion revealed that cavin3 sensitized various cancer cells to UV-induced apoptosis. We conclude that cavin3 functions together with BRCA1 in multiple pathways that contribute to tumorigenesis.
Dynamic control over feedback regulatory mechanisms improves NADPH fluxes and xylitol biosynthesis in engineeredE. coli
Authors: Li Shuai , Moreb Eirik A. , Ye Zhixia , Hennigan Jennifer N. , Castellanos Daniel Baez , Yang Tian , Lynch Michael D.
Published: July 2020

We report improved NADPH flux and xylitol biosynthesis in engineeredE. coli. Xylitol is produced from xylose via an NADPH dependent reductase. We utilize two-stage dynamic metabolic control to compare two approaches to optimize xylitol biosynthesis, a stoichiometric approach, wherein competitive fluxes are decreased, and a regulatory approach wherein the levels of key regulatory metabolites are reduced. The stoichiometric and regulatory approaches lead to a 16 fold and 100 fold improvement in xylitol production, respectively. Strains with reduced levels of enoyl-ACP reductase and glucose-6-phosphate dehydrogenase, led to altered metabolite pools resulting in the activation of the membrane bound transhydrogenase and a new NADPH generation pathway, namely pyruvate ferredoxin oxidoreductase coupled with NADPH dependent ferredoxin reductase, leading to increased NADPH fluxes, despite a reduction in NADPH pools. These strains produced titers of 200 g/L of xylitol from xylose at 86% of theoretical yield in instrumented bioreactors. We expect dynamic control over enoyl-ACP reductase and glucose-6-phosphate dehydrogenase to broadly enable improved NADPH dependent bioconversions.

Highlights

Decreases in NADPH pools lead to increased NADPH fluxes

Pyruvate ferredoxin oxidoreductase coupled with NADPH-ferredoxin reductase improves NADPH productionin vivo.

Dynamic reduction in acyl-ACP/CoA pools alleviate inhibition of membrane bound transhydrogenase and improve NADPH flux

Xylitol titers > 200g/L in fed batch fermentations with xylose as a sole feedstock.
Functional annotation of human long noncoding RNAs via molecular phenotyping
Authors: Ramilowski Jordan A. , Yip Chi Wai , Agrawal Saumya , Chang Jen-Chien , Ciani Yari , Kulakovskiy Ivan V. , Mendez Mickaël , Ooi Jasmine Li Ching , Ouyang John F. , Parkinson Nick , Petri Andreas , Roos Leonie , Severin Jessica , Yasuzawa Kayoko , Abugessaisa Imad , Akalin Altuna , Antonov Ivan V. , Arner Erik , Bonetti Alessandro , Bono Hidemasa , Borsari Beatrice , Brombacher Frank , Cameron Christopher J.F. , Cannistraci Carlo Vittorio , Cardenas Ryan , Cardon Melissa , Chang Howard , Dostie Josée , Ducoli Luca , Favorov Alexander , Fort Alexandre , Garrido Diego , Gil Noa , Gimenez Juliette , Guler Reto , Handoko Lusy , Harshbarger Jayson , Hasegawa Akira , Hasegawa Yuki , Hashimoto Kosuke , Hayatsu Norihito , Heutink Peter , Hirose Tetsuro , Imada Eddie L. , Itoh Masayoshi , Kaczkowski Bogumil , Kanhere Aditi , Kawabata Emily , Kawaji Hideya , Kawashima Tsugumi , Kelly S. Thomas , Kojima Miki , Kondo Naoto , Koseki Haruhiko , Kouno Tsukasa , Kratz Anton , Kurowska-Stolarska Mariola , Kwon Andrew Tae Jun , Leek Jeffrey , Lennartsson Andreas , Lizio Marina , López-Redondo Fernando , Luginbühl Joachim , Maeda Shiori , Makeev Vsevolod J. , Marchionni Luigi , Medvedeva Yulia A. , Minoda Aki , Müller Ferenc , Muñoz-Aguirre Manuel , Murata Mitsuyoshi , Nishiyori Hiromi , Nitta Kazuhiro R. , Noguchi Shuhei , Noro Yukihiko , Nurtdinov Ramil , Okazaki Yasushi , Orlando Valerio , Paquette Denis , Parr Callum J.C. , Rackham Owen J.L. , Rizzu Patrizia , Sánchez Martinez Diego Fernando , Sandelin Albin , Sanjana Pillay , Semple Colin A.M. , Shibayama Youtaro , Sivaraman Divya M. , Suzuki Takahiro , Szumowski Suzannah C. , Tagami Michihira , Taylor Martin S. , Terao Chikashi , Thodberg Malte , Thongjuea Supat , Tripathi Vidisha , Ulitsky Igor , Verardo Roberto , Vorontsov Ilya E. , Yamamoto Chinatsu , Young Robert S. , Baillie J. Kenneth , Forrest Alistair R.R. , Guigó Roderic , Hoffman Michael M. , Hon Chung Chau , Kasukawa Takeya , Kauppinen Sakari , Kere Juha , Lenhard Boris , Schneider Claudio , Suzuki Harukazu , Yagi Ken , de Hoon Michiel J.L. , Shin Jay W. , Carninci Piero
Published: July 2020

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.