bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative genomics of the genus Roseburia reveals divergent biosynthetic pathways that may influence colonic competition among species
Authors: Hillman Ethan T. , Kozik Ariangela J. , Hooker Casey A. , Burnett John L. , Heo Yoojung , Kiesel Violet A. , Nevins Clayton J. , Oshiro Jordan M.K.I. , Robins Melissa M. , Thakkar Riya D. , Wu Sophie Tongyu , Lindemann Stephen R.
Published: July 2020

Roseburia

species are important denizens of the human gut microbiome that ferment complex polysaccharides to butyrate as a terminal fermentation product, which influences human physiology and serves as an energy source for colonocytes. Previous comparative genomics analyses of the genus

Roseburia

have examined polysaccharide degradation genes. Here, we characterize the core and pangenomes of the genus

Roseburia

with respect to central carbon and energy metabolism, as well as biosynthesis of amino acids and B vitamins using orthology-based methods, uncovering significant differences among species in their biosynthetic capacities. Variation in gene content among

Roseburia

species and strains was most significant for cofactor biosynthesis. Unlike all other species of

Roseburia

that we analysed,

Roseburia inulinivorans

strains lacked biosynthetic genes for riboflavin or pantothenate but possessed folate biosynthesis genes. Differences in gene content for B vitamin synthesis were matched with differences in putative salvage and synthesis strategies among species. For example, we observed extended biotin salvage capabilities in

R. intestinalis

strains, which further suggest that B vitamin acquisition strategies may impact fitness in the gut ecosystem. As differences in the functional potential to synthesize components of biomass (e.g. amino acids, vitamins) can drive interspecies interactions, variation in auxotrophies of the

Roseburia

spp. genomes may influence in vivo gut ecology. This study serves to advance our understanding of the potential metabolic interactions that influence the ecology of

Roseburia

spp. and, ultimately, may provide a basis for rational strategies to manipulate the abundances of these species.
Metabolic pathway analysis in the presence of biological constraints
Authors: Dague Philippe
Published: July 2020

Metabolic pathway analysis is a key method to study a metabolism in its steady state and the concept of elementary fluxes (EFs) plays a major role in the analysis of a network in terms of non-decomposable pathways. The supports of theEFscontain in particular those of the elementary flux modes (EFMs), which are the support-minimal pathways, andEFscoincide withEFMswhen the only flux constraints are given by the irreversibility of certain reactions. Practical use of bothEFMsandEFshas been hampered by the combinatorial explosion of their number in large, genomescale, systems. TheEFsgive the possible pathways in a steady state but the real pathways are limited by biological constraints, such as thermodynamic or, more generally, kinetic constraints and regulatory constraints from the genetic network. We provide results on the mathematical structure and geometrical characterization of the solution space in the presence of such biological constraints and revisit the concept ofEFMsandEFsin this framework. We show that most of the results depend only on very general properties of compatibility of constraints with the sign function: either signinvariance for regulatory constraints or sign-monotonicity (a stronger property) for thermodynamic and kinetic constraints. We show in particular thatEFsfor sign-monotone constraints are just those of the originalEFsthat satisfy the constraint and we show how to integrate their computation efficiently in the double description method, the most widely used method in the tools dedicated to EFMs computation.
Sample pooling on triplets to speed up SARS-CoV-2 diagnosis using CDC FDA EUA RT-qPCR kit
Authors: Freire-Paspuel Byron , Vega-Mariño Patricio , Velez Alberto , Cruz Marilyn , Garcia-Bereguiain Miguel Angel
Published: July 2020

The CDC designed “FDA Emergeny Use Autorization” 2019-nCoV CDC RT-qPCR kit uses 3 different FAM probes for SARS-CoV-2 diagnosis so 3 reactions per sample are needed. We herein describe a sample pooling protocol: 3 RNA extractions are combined into a single PCR reaction. The sensitivity for this protocol is 100% as no shift on Ct values for N1 or N2 probes were observed. For a typical 96-well plate, triplet assay allows 96 samples processing, speeding up diagnosis.
Predicting Adverse Drug Reactions of Two-drug Combinations using Structural and Transcriptomic Drug Representations to Train a Artificial Neural Network
Authors: Shankar Susmitha , Bhandari Ishita , Okou David T. , Srinivasa Gowri , Athri Prashanth
Published: July 2020

Adverse drug reactions (ADRs) are pharmacological events triggered by drug interactions with various sources of origin including drug-drug interactions. While there are many computational studies that explore models to predict ADRs originating from single drugs, only a few of them explore models that predict ADRs from drug combinations. Further, as far as we know, none of them have developed models using transcriptomic data, specifically the LINCS L1000 drug induced gene expression data to predict ADRs for drug combinations. In this study we use the TWOSIDES database as a source of ADRs originating from two-drug combinations. 34,549 common drug pairs between these two databases were used to train an artificial neural network (ANN), to predict 243 ADRs that were induced by at least 10% of the drug pairs. Our model predicts the occurrence of these ADRs with an average accuracy of 82% across a multi fold cross validation.

Source Code and input dataset used in this study can be found at:https://bitbucket.org/ishita98/prediction-of-adr/src/master/
Hyperosmotic stress induces downstream-of-gene transcription and alters the RNA Polymerase II interactome despite widespread transcriptional repression
Authors: Rosa-Mercado Nicolle A. , Zimmer Joshua T. , Apostolidi Maria , Rinehart Jesse , Simon Matthew D. , Steitz Joan A.
Published: July 2020

Stress-induced readthrough transcription results in the synthesis of thousands of downstream-of-gene (DoG) containing transcripts. The mechanisms underlying DoG formation during cellular stress remain unknown. Nascent transcription profiles during DoG induction in human cell lines using TT-TimeLapse-seq revealed that hyperosmotic stress induces widespread transcriptional repression. Yet, DoGs are produced regardless of the transcriptional level of their upstream genes. ChIP-seq confirmed that the stress-induced redistribution of RNA Polymerase (Pol) II correlates with the transcriptional output of genes. Stress-induced alterations in the Pol II interactome are observed by mass spectrometry. While subunits of the cleavage and polyadenylation machinery remained Pol II-associated, Integrator complex subunits dissociated from Pol II under stress conditions. Depleting the catalytic subunit of the Integrator complex, Int11, using siRNAs induces hundreds of readthrough transcripts, whose parental genes partially overlap those of stress-induced DoGs. Our results provide insights into the mechanisms underlying DoG production and how Integrator activity influences DoG transcription.

In brief

Rosa-Mercado et al. report that hyperosmotic stress causes widespread transcriptional repression in human cells, yet DoGs arise regardless of the transcriptional response of their upstream genes. They find that the interaction between Pol II and Integrator is disrupted by hypertonicity and that knocking down the Integrator nuclease leads to DoG production.

Highlights

Hyperosmotic stress triggers transcriptional repression of many genes.

DoG RNAs arise independent of the transcriptional level of their upstream gene.

The interaction between Pol II and Integrator subunits decreases after salt stress.

Depletion of the Int11 nuclease subunit induces the production of hundreds of DoGs.
Important effect of the X chromosome in genomic evaluations of reproductive traits in beef cattle
Authors: Solar Diaz Iara Del Pilar , de Camargo Gregório Miguel Ferreira , da Cruz Valdecy Aparecida Rocha , Costa Hermisdorff Isis da , Damasceno Carvalho Caio Victor , de Albuquerque Lucia Galvão , Costa Raphael Bermal
Published: July 2020

The aim of this study was to evaluate the efficiency of inclusion and the prediction ability of the X chromosome for reproductive (occurrence of early pregnancy – P16 and age at first calving - AFC) and andrological traits (scrotal circumference -SC) in a herd of Nellore beef cattle herd. 3,263 genotypes of females and males were used. Genomic prediction for SC, AFC and P16 was carried out considering two scenarios: 1) only autosomal markers or 2) autosomal + X chromosome markers. To evaluate the effect of inclusion of the X chromosome on selection, the responses to the selection performed were compared including or not the X chromosome in the evaluation of the traits. Higher heritability estimates were obtained for SC (0.40 and 0.31), AFC (0.11 and 0.09) and P16 (0.43 and 0.38) for the analyses including the X chromosome compared to those without. The percent reduction on mean genomic breeding values when selection was based on the results of analysis that did not include the X chromosome to 1, 5 and 10% of the top males, was for SC slightly more than 7% of the mean genomic breeding value of the selected animals. For P16, the loss can reach more than 4%, while this loss does not seem to be as important for AFC. Average predictive correlation of 0.79, 0.98 and 0.84 for SC, AFC and P16 was obtained, respectively. These estimates demonstrate that inclusion of the X chromosome in the analysis can improve the prediction of genomic breeding values, especially for SC.
DIRT/3D: 3D root phenotyping for field grown maize (Zea mays)
Authors: Liu Suxing , Barrow Carlos Sherard , Hanlon Meredith , Lynch Jonathan P. , Bucksch Alexander
Published: July 2020

The development of crops with deeper roots holds substantial promise to mitigate the consequences of climate change. Deeper roots are an essential factor to improve water uptake as a way to enhance crop resilience to drought, to increase nitrogen capture, to reduce fertilizer inputs and, to increase carbon sequestration from the atmosphere to improve soil organic fertility. A major bottleneck to achieving these improvements is high-throughput phenotyping to quantify root phenotypes of field-grown roots. We address this bottleneck with DIRT/3D, a newly developed image-based 3D root phenotyping platform, which measures 18 architecture traits from mature field-grown maize root crowns excavated with the Shovelomics technique. DIRT/3D reliably computed all 18 traits, including distance between whorls and the number, angles, and diameters of nodal roots, on a test panel of 12 contrasting maize genotypes. The computed results were validated through comparison with manual measurements. Overall, we observed a coefficient of determination ofr2>0.84 and a high broad-sense heritability offor all but one trait. The average values of the 18 traits and a newly developed descriptor to characterize a complete root architecture distinguished all genotypes. DIRT/3D is a step towards automated quantification of highly occluded maize root crowns. Therefore, DIRT/3D supports breeders and root biologists in improving carbon sequestration and food security in the face of the adverse effects of climate change.
Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM)viaaltering TWIST1 nonsense-mediated decay through lncRNA-TANAR
Authors: You Bosen , Sun Yin , Liu Qing , Wang Keliang , Fang Ruizhe , Liu Bingmei , Chou Fuju , Luo Jie , Wang Ronghao , Meng Jialin , Huang Chi-Ping , Yeh Shuyuan , Xu Wanhai , Chang Chawnshang
Published: July 2020

While the androgen receptor (AR) may influence the progression of clear cell renal cell carcinoma (ccRCC), its role to impact vasculogenic mimicry (VM) to alter the ccRCC progression and metastasis remains obscure. Here we demonstrated that elevated AR expression was positively correlated with tumor-originated vasculogenesis in ccRCC patients. Consistently,in vitroresearch revealed AR promoted VM formation in ccRCC cell linesviamodulating lncRNA-TANAR/TWIST1 signals. Mechanism dissection showed that AR could increase lncRNA-TANAR (TANAR) expression through binding to the androgen response elements (AREs) located on its promoter region. Moreover, we found that TANAR could impede nonsense-mediated mRNA decay (NMD) of TWIST1 mRNA by direct interaction with TWIST1 5’UTR. A preclinical study usingin vivomouse model with orthotopic xenografts of ccRCC cells further confirmed thein vitrodata. Together, these results illustrated that AR-mediated lnc-TANAR signals might play a crucial role in ccRCC VM formation and metastasis, and targeting this newly identified AR/lncRNA-TANAR/TWIST1 signaling may help in the development of a novel anti-angiogenesis therapy to better suppress the ccRCC progression.
Mimicry drives convergence in structural and light transmission features of transparent wings in Lepidoptera
Authors: Pinna Charline , Vilbert Maëlle , Borensztajn Stephan , de Marcillac Willy Daney , Piron-Prunier Florence , Pomerantz Aaron F. , Patel Nipam , Berthier Serge , Andraud Christine , Gomez Doris , Elias Marianne
Published: July 2020

Müllerian mimicry is a positive interspecific interaction, whereby co-occurring defended prey species share a common aposematic signal. In Lepidoptera, aposematic species typically harbour conspicuous opaque wing colour patterns with convergent optical properties among co-mimetic species. Surprisingly, some aposematic mimetic species have partially transparent wings, raising the questions of whether optical properties of transparent patches are also convergent, and of how transparency is achieved. Here we conducted a comparative study of wing optics, micro and nanostructures in neotropical mimetic clearwing Lepidoptera, using spectrophotometry and microscopy imaging. We show that transparency, as perceived by predators, is convergent among co-mimics. Underlying micro- and nanostructures are also convergent despite a large structural diversity. We reveal that while transparency is primarily produced by microstructure modifications, nanostructures largely influence light transmission, maybe enabling additional fine-tuning in transmission properties. This study shows that transparency might not only enable camouflage but can also be part of aposematic signals.
Chronic Pb2+exposure causes theta-band hypersynchrony disrupting sensory motor gating and exacerbating absence seizures
Authors: Schultheiss Nathan W. , McGlothan Jennifer L. , Guilarte Tomás R. , Allen Timothy A.
Published: July 2020

Chronic lead (Pb2+) exposure from childhood contributes to an array of cognitive and behavioral dysfunctions including impaired attention and intellectual ability, learning and memory deficits, and delinquency. It is also an environmental risk factor for adult psychopathologies, most notably schizophrenia and epilepsy. Pb2+is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist and exposure during early life elicits a cascade of cellular neurotoxic effects that alter the developmental trajectory leading to a loss of parvalbumin-expressing interneurons in hippocampus and altered synaptic transmission. Little is known, however, about the impact of chronic Pb2+exposure on hippocampal network dynamics which serve as a link between cellular-molecular effects and cognitive-behavioral consequences of Pb2+neurotoxicity. Here, we tested the effects of chronic Pb2+exposure on the hippocampal local field potential (LFP) of freely-behaving rats. Pb2+exposure caused striking theta rhythmic hypersynchrony and heightened behavioral modulation of theta during locomotor behavior. Pb2+exposure also markedly exacerbated absence seizures appearing in the LFP as spike-wave discharges with a theta-band fundamental frequency and strong theta-harmonic synchronization. Mechanisms of theta rhythmogenesis have been implicated in impairments of prepulse inhibition of the acoustic startle reflex (PPI), so we tested the effect of Pb2+exposure on PPI in male and female rats at different developmental timepoints. We found that adult males (PN50 and 120), but neither females nor juvenile males showed reduced PPI independent of changes in the startle reflex. This pattern recapitulates sex- and age-dependencies of PPI disruption in schizophrenic patients. Overall, these results are consistent with the hypothesis that Pb2+is an environmental risk factor for psychopathology in adulthood, especially those symptoms related to cognitive and sensory-motor gating processes that depend on rhythmic coordination of network activity in the hippocampus.
Prevalence and experience of fatigue in survivors of critical illness: A mixed-methods systematic review
Authors: Bench Suzanne , Stayt Louise , Shah Akshay , Dhiman Paula , Czuber-Dochan Wladyslawa
Published: July 2020

Objective

To investigate the prevalence, experience and management of fatigue in adult survivors of critical illness.

Data sources

An electronic search was performed on seven databases: CINAHL, Medline, EMBASE, PsycINFO, Emcare, British Nursing Index, and Web of Science.

Study selection and data extraction

Seventy-six peer-reviewed, English language studies that investigated fatigue or vitality in adult patients admitted to an Intensive Care Unit (ICU) and followed up for any period were included. Extracted data were split into three datasets for analysis: data from vitality domain of SF-36 (dataset A); other quantitative data (dataset B); and qualitative data (dataset C). Methodological quality was assessed using the critical appraisal skills programme (CASP) tools.

Data synthesis

We adopted a segregated approach to mixed-methods synthesis. We merged all datasets, attributing all results to one of four qualitative themes: prevalence and severity; contributing factors; impacts on quality of life; assessment and management.

Results

The prevalence of fatigue ranged from 13.8 to 80.9%; fatigue severity reached its nadir at approximately one-month post-ICU discharge, improved over time but seldom reached reference population scores. Various biological, disease-related and psychological factors associated with fatigue were identified including age, poor pre-morbid status and sleep disturbance. No critical illness specific tool to assess fatigue in ICU survivors was identified. A paucity of evidence-based interventions for management of fatigue in ICU survivors were identified despite fatigue negatively impacting on survivors’ quality of life.

Conclusions

This mixed method review shows that fatigue is highly prevalent in ICU survivors, negatively impacting their recovery. To date, no ICU specific fatigue assessment tool or targeted intervention has been designed to manage this symptom. Our review has identified factors, which may increase or mitigate against fatigue, along with potential management strategies, which should be used to inform future research and practice.
Orthogonal Functions for Evaluating Social Distancing Impact on CoVID-19 Spread
Authors: Eng Genghmun
Published: July 2020

Early CoVID-19 growth often obeys: , with Ko = [(ln 2)/(tdbl)], where tdbl is the pandemic doubling time, prior to society-wide Social Distancing. Previously, we modeled Social Distancing with tdbl as a linear function of time, where N [t] 1 ≈ exp[+KAt/ (1+,γot)] is used here. Additional parameters besides {Ko, γo} are needed to better model different ρ[t] = dN [t]/dt shapes. Thus, a new Orthogonal Function Model [OFM] is developed here using these orthogonal function series:

where N (Z) and Z[t] form an implicit N [t] N (Z[t]) function, giving:

with Lm(Z) being the Laguerre Polynomials. At large MF values, nearly arbitrary functions for N [t] and ρ [t] = dN [t]/dt can be accommodated. How to determine {KA, γo} and the {gm; m = (0, +MF)} constants from any given N (Z) dataset is derived, with ρ [t] set by:

The bing com USA CoVID-19 data was analyzed using MF = (0, 1, 2) in the OFM. All results agreed to within about 10 percent, showing model robustness. Averaging over all these predictions gives the following overall estimates for the number of USA CoVID-19 cases at the pandemic end:

which compares the pre- and post-early May bing com revisions. The CoVID-19 pandemic in Italy was examined next. The MF = 2 limit was inadequate to model the Italy ρ [t] pandemic tail. Thus, regions with a quick CoVID-19 pandemic shutoff may have additional Social Distancing factors operating, beyond what can be easily modeled by just progressively lengthening pandemic doubling times (with 13 Figures).
ASSOCIATIONS OF AGE, BODY MASS INDEX, AND BIOCHEMICAL PARAMETERS WITH BRAIN MORPHOLOGY IN PATIENTS WITH ANOREXIA NERVOSA
Authors: Bang Lasse , Tamnes Christian K. , Norbom Linn B. , Thomassen Rut A. , Holm Jill S. , Skotte Laila H. , Juliusson Petur B. , Mejlænder-Evjensvold Magnus , Rø Øyvind
Published: July 2020

INTRODUCTION

Accumulating evidence shows that patients with anorexia nervosa (AN) have globally reduced brain mass, including lower cortical volume and thickness, which largely normalizes following weight restoration. The dynamic underlying mechanisms for these processes are unknown, and how age and severity of emaciation are associated with brain morphology in AN is poorly understood. We investigated associations of age, body mass index (BMI) and biochemical parameters with brain morphology in a large sample of patients in treatment. METHODS: We included 85 patients (94% female) aged 12-48 (mean = 23) years with clinical and quality controlled magnetic resonance imaging (MRI) data. T1-weighted MRI images, clinical characteristics, and biochemical parameters were retrospectively collected from hospital records. Brain morphology was measured using FreeSurfer, and associations were investigated using regression models and correlations. RESULTS: Controlling for BMI, age showed significant associations with brain morphology generally concordant with known typical brain developmental patterns. Controlling for age, BMI showed significant positive associations with cortical volume and thickness. There were no significant interaction effects between age and BMI. None of the biochemical parameters correlated significantly with brain morphology.

DISCUSSION

Our findings suggest the presence of normal neurodevelopmental patterns in AN and highlight the value of considering age-related effects on brain morphology. Importantly, we showed that severity of emaciation is related to brain morphology reductions, underscoring the importance of weight restoration. More studies are needed to shed light on potential biochemical mechanisms associated with brain alterations in AN.
Stealth fluorescence labeling for live microscopy imaging of mRNA delivery
Authors: Baladi Tom , Nilsson Jesper R. , Gallud Audrey , Celauro Emanuele , Gasse Cécile , Levi-Acobas Fabienne , Sarac Ivo , Hollenstein Marcel , Dahlén Anders , Esbjörner Elin K. , Wilhelmsson L. Marcus
Published: July 2020

Methods for tracking of RNA molecules inside living cells are critical to probe their dynamics and biological functions, but also to monitor delivery of therapeutic RNA. We here describe a method for fluorescence labeling of RNAs of any length, via the enzymatic incorporation of the minimally perturbing and intrinsically fluorescent tricyclic cytosine analogue tCO. Using this approach, we demonstrate incorporation of tCOin up to 100% of all natural cytosine positions of a 1.2 kb mRNA encoding for the histone H2B fused to GFP (H2B:GFP). The resulting transcript is fully compatible with both in vitro transcription and subsequent in cell translation. Spectroscopic characterization of the in vitro transcribed mRNA, shows that the incorporation rate of tCOis on par with cytosine, facilitating efficient labeling and controlled tuning of labeling ratios for different applications. Using live cell confocal microscopy and flow cytometry, we show that the tCO-labeled mRNA is efficiently and correctly translated into H2B:GFP upon electroporation as well as lipid-mediated transfection of human Huh-7 cells; correct translation was further confirmed in cell-free systems. Importantly, the spectral properties of the tCO-modified transcripts and their translation product, in this case H2B:GFP, allow for their straightforward and simultaneous visualization in live cells.
A controlled thermoalgesic stimulation device to identify novel pain perception biomarkers
Authors: Ibero Maider Núñez , Camino-Pontes Borja , Diez Ibai , Erramuzpe Asier , Gutiérrez Endika Martínez , Stramaglia Sebastiano , Álvarez-Cienfuegos Javier Ortiz , Cortes Jesus M.
Published: July 2020

Objective

To develop a new device that will help identify physiological markers of pain perception by reading the brain’s electrical activity and the bodies hemodynamic interactions while applying thermoalgesic stimulation. Methods: We designed a compact prototype that generates well-controlled thermal stimuli using a computer driven Peltier cell while simultaneously capturing electroencephalography (EEG) and photoplethysmography (PPG) signals as the stimuli are varied. The study was performed on 35 healthy subjects (mean age 30.46 years, SD 4.93 years; 20 males, 15 females) and to account for the inter-subject variability in the tolerance to thermal pain, we first determined the heat pain threshold (HPT) for each subject, defined as the maximum temperature that the subject can withstand when the Peltier cell gradually increases the temperature. Subsequently, we defined the pain parameters associated with a stimulation temperature equivalent to 90% of the HPT, comparing this to the no-pain state (control) in the absence of thermoalgesic stimulation. Results: Both the one-dimensional and the two-dimensional spectral entropy (SE) obtained from both the EEG and PPG signals could differentiate the condition of pain. In particular, the PPG SE was significantly reduced in association with pain, while the SE for EEG increased slightly. Moreover, significant discrimination occurred within a specific range of frequencies, 26-30 Hz for EEG and about 5-10 Hz for PPG. Conclusion: Hemodynamics, brain dynamics and their interactions can discriminate thermal pain perception. Significance: The possibility of monitoring on-line variations in thermal pain perception using a similar device and algorithms may be of interest to study different pathologies that affect the peripheral nervous system, such as small fiber neuropathies, fibromyalgia or painful diabetic neuropathy.
Sleep deprivation triggers somatostatin neurons in prefrontal cortex to initiate nesting and sleep via the preoptic and lateral hypothalamus
Authors: Tossell Kyoko , Yu Xiao , Soto Berta Anuncibay , Vicente Mikal , Miracca Giulia , Giannos Panagiotis , Miao Andawei , Hsieh Bryan , Ma Ying , Yustos Raquel , Vyssotski Alexei L. , Constandinou Tim , Franks Nicholas P. , Wisden William
Published: July 2020

Animals undertake specific behaviors before sleep. Little is known about whether these innate behaviors, such as nest building, are actually an intrinsic part of the sleep-inducing circuitry. We found, using activity-tagging genetics, that mouse prefrontal cortex (PFC) somatostatin/GABAergic (SOM/GABA) neurons, which become activated during sleep deprivation, induce nest building when opto-activated. These tagged neurons induce sustained global NREM sleep if their activation is prolonged metabotropically. Sleep-deprivation-tagged PFC SOM/GABA neurons have long-range projections to the lateral preoptic (LPO) and lateral hypothalamus (LH). Local activation of tagged PFC SOM/GABA terminals in LPO and the LH induced nesting and NREM sleep respectively. Our findings provide a circuit link for how the PFC responds to sleep deprivation by coordinating sleep preparatory behavior and subsequent sleep.
Phylogeny of the species-richPileaLindl. (Urticaceae) supports its revised delimitation and infrageneric classification, including the resurrection ofAchudemiaBlume
Authors: Fu Long-Fei , Wen Fang , Maurin Olivier , Rodda Michele , Wei Yi-Gang , Monro Alexandre K.
Published: July 2020

PileaLindl., with 933 published names is the largest genus within the Urticaceae.Pileawas last monographed in 1869 and whilst the monophyly of the genus has been proposed by previous authors, this has been based on incomplete taxon sampling and the failure to resolve the position of key taxa. We aimed to generate a robust phylogeny forPileaand allied genera that could provide a framework for testing the monophyly ofPilea, revising its delimitation and for answering broader scientific questions about this species-rich genus. To do so, we sought to sample taxa representative of previous infrageneric classifications and with anomalous inflorescences or flower configurations and to use the resulting phylogeny to evaluate the delimitation ofPileaand to establish an infrageneric classification. In addition, we included a representative of the Polynesian genusHaroldiellawhich, morphologically, is very similar toPilea. Using Sanger sequence data from two plastid and one nuclear regions we constructed a phylogeny using Bayesian Inference, Maximum Likelihood and Maximum Parsiomony approaches. We used our phylogeny to evaluate the informativness of 19 morphological traits and applied both to delimit a monophyletic genus and infrageneric sections. Our results recoveredPileaas paraphyletic with respect toLecanthus, a consequence of the recovery of a monophyletic clade comprising sectionsAchudemiaandSmithiella, neither of which had been adequately sampled in previous studies. We also recoveredPileaas polyphyletic with respect toHaroldiella. We identified isomery between male and female flowers, flower part number and male sepal arrangement as being phylogenetically informative traits that can be used to delimit two genera,Achudemia, including sectionSmithiella, recovered as sister toLecanthus, andPilea, includingHaroldiella, recovered as sister to both. On the basis of our evaluation of both morphological traits and phylogenetic relationships we propose a new infrageneric classification for the genus comprising seven sections, five of which we describe for the first time, §TrimerisY.G.Wei & A.K.Monro, §LecanthoidesC.J.Chen, §AngulataL.F.Fu & Y.G.Wei, §TetramerisC.J.Chen, §VerrucosaL.F.Fu & Y.G.Wei, §PlatanifloraL.F.Fu & Y.G.Wei and §LeiocarpaL.F.Fu & Y.G.Wei. We also identify a trend of decreasing merism and fruit size, and increasing species-richness asPileadiverges. In addition, we recover strong geographical structure within our phylogeny, sufficient to propose thatPileaoriginated in the IndoMalaya biogeographic domain.
Human bone mesoscale 3D structure revisited by plasma focused ion beam serial sectioning
Authors: Binkley Dakota Marie , Deering Joseph , Yuan Hui , Gourrier Aurélien , Grandfield Kathryn
Published: July 2020

Visualizing bone mineralization and collagen microfibril organization at intermediate scales between the nanometer and the 100s of microns range, the mesoscale, is still an important challenge. Similarly, visualizing cellular components which locally affect the tissue structure requires a precision of a few tens of nanometers at maximum while spanning several tens of micrometers. To address this issue, we employed a plasma focused ion beam (PFIB) equipped with a scanning electron microscope (SEM) to sequentially section nanometer-scale layers of demineralized and mineralized human femoral lamellar bone over volumes of approximately 46 × 40 × 9 μm3, and 29 × 26 × 9 μm3, respectively. This large scale view retained high enough resolution to visualize the collagen microfibrils while partly visualizing the lacuno-canalicular network (LCN) in three-dimensions (3D). We showed that serial sectioning can be performed on mineralized sections, and does not require demineralization. Moreover, this method revealed ellipsoidal mineral clusters, noted by others in high resolution studies, as a ubiquitous motif in lamellar bone over tens of microns, suggesting a heterogeneous and yet regular pattern of mineral deposition past the single collagen fibril level. These findings are strong evidence for the need to revisit bone mineralization over multi-length scales.

Graphical Abstract
Brain-wide electrical dynamics encode an appetitive socioemotional state
Authors: Mague Stephen D. , Talbot Austin , Blount Cameron , Duffney Lara J. , Walder-Christensen Kathryn K. , Adamson Elise , Bey Alexandra L. , Ndubuizu Nkemdilim , Thomas Gwenaёlle , Hughes Dalton N. , Sinha Saurabh , Fink Alexandra M. , Gallagher Neil M. , Fisher Rachel L. , Jiang Yong-hui , Carlson David E. , Dzirasa Kafui
Published: July 2020

Many cortical and subcortical regions contribute to complex social behavior; nevertheless, the network level architecture whereby the brain integrates this information to encode appetitive socioemotional behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover an explainable brain network that encodes the extent to which mice chose to engage another mouse. This socioemotional network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on ventral tegmental area, and network activity is synchronized with brain-wide cellular firing. The network generalizes, on a mouse-by-mouse basis, to encode socioemotional behaviors in healthy animals, but fails to encode an appetitive socioemotional state in a ‘high confidence’ genetic mouse model of autism. Thus, our findings reveal the architecture whereby the brain integrates spatially distributed activity across timescales to encode an appetitive socioemotional brain state in health and disease.
Docosahexaenoic acid (DHA), a nutritional supplement, modulates steroid insensitivity in asthma
Authors: Panda Lipsa , Gheware Atish P , Jaiswal Ashish , Saha Dhurjhoti , Desiraju Bapu Koundinya , Rehman Rakhshinda , Ray Archita , Dutta Joytri , Singh Sabita , Yadav Manish Kumar , Sowpati Divya Tej , Chattopadhyay Samit , SubbaRao Madhunapantula V. , Mahesh Padukudru Anand , Prakash Y. S. , Chowdhury Shantanu , Agrawal Anurag , Ghosh Balaram , Mabalirajan Ulaganathan
Published: July 2020

Asthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that a ω-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRγ) and Docosahexaenoic acid (DHA), a ω3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRγ was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRγ knockdown in naïve mice led to spontaneous asthma like features whereas RXRγ knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRγ binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRα expression in human bronchial epithelial cells and reverses the steroid insensitive features in mice with allergic airway inflammation. Docosahexaenoic acid (DHA), a ligand of RXR, was reduced in the sera of steroid-insensitive asthmatics. We conclude that DHA may prove to be a promising steroid sensitizing agent for the treatment of steroid insensitive asthmatics.

The molecular regulation of glucocorticoid receptor by retinoid-x-receptor gamma (RXRgama) has an implication in steroid insensitive asthma as we found that Docosahexaenoic acid (DHA), a nutritional supplement and natural ligand of RXRgamma, improves steroid sensitivity in steroid insensitive mice model of asthma and DHA levels are found to be low in steroid insensitive asthmatic patients.
Comparative analysis of clonal evolution among patients with right-sided colon cancer, left-sided colon cancer and rectal cancer
Authors: Banerjee Santasree , Zhang Xianxiang , Kuang Shan , Wang Jigang , Li Lei , Fan Guangyi , Luo Yonglun , Sun Shuai , Han Peng , Wu Qingyao , Yang Shujian , Ji Xiaobin , Li Yong , Deng Li , Tian Xiaofen , Wang Zhiwei , Zhang Yue , Wu Kui , Zhu Shida , Bolund Lars , Yang Huanming , Xu Xun , Liu Junnian , Lu Yun , Liu Xin
Published: July 2020

Background

Tumor multi-region sequencing reveals intratumor heterogeneity (ITH) and clonal evolution which play a key role in progression and metastases of the tumor. However, large-scale high depths multiregional sequencing of colorectal cancer (CRC) has not been well studied. In addition, the comparative analysis among right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer (RC) patients as well as the study of lymph node metastasis (LN) with extranodal tumor deposits (ENTD) from evolutionary perspective remain unknown.

Results

In this prospective study, we recruited different stages of 68 CRC patients with RCC (18), LCC (20) and RC (30). We performed high-depth whole exome sequencing (WES) of 206 tumor regions including 176 primary tumors, 19 LN and 11 ENTD samples. Our results showed ITH with a Darwinian pattern of evolution. We identified that the evolution pattern of LCC and RC was more complex and divergent than RCC, suggesting the evolutionary diversity in the initiation and progression of LCC and RC. Genetic and evolutionary evidences found that both LN and ENTD were of polyclonal in origin. Moreover, ENTD was a distinct entity from LN and evolved later.

Conclusions

In conclusion, our study showed the Darwinian pattern of evolution with differences in clonal evolution between RCC with LCC and RC.
Plasma membrane localization of paralogous leucine permeases Bap2 and Bap3 is regulated by Bul1
Authors: Maheswaran S , Bhat Paike Jayadeva
Published: July 2020

Timeliness in expression and degradation of the nutrient permeases is crucial for any organism. InSaccharomyces cerevisiae, post translational regulation of nutrient permeases such as trafficking and turnover are poorly understood. We found that loss of a leucine permeaseBAP2, but not other permeases lead to severe growth retardation when the carbon source is glucose or galactose but not glycerol and lactate. Leucine prototrophy suppressed the retardation, showingBAP2andLEU2are synthetically lethal. We discovered that loss ofBUL1, an arrestin involved in trafficking of diverse permeases suppressed this lethality. The suppression required another leucine permease,BAP3. Our results suggest thatBUL1downregulate permeasesBAP2andBAP3present in plasma membrane through Rsp5 dependent endocytosis. We speculate that by regulating leucine importBUL1regulates the activity of TORC1.
Transcription-dependent domain-scale 3D genome organization in dinoflagellates
Authors: Marinov Georgi K. , Trevino Alexandro E. , Xiang Tingting , Kundaje Anshul , Grossman Arthur R. , Greenleaf William J.
Published: July 2020

Dinoflagellate chromosomes represent a unique evolutionary experiment, as they exist in a permanently condensed, liquid crystalline state, are not packaged by histones, and contain genes organized into polycistronic arrays, with minimal transcriptional regulation. We analyze the 3D genome ofBreviolum minutum, and find large topological domains without chromatin loops, demarcated by convergent gene array boundaries (“dinoTADs). Transcriptional inhibition degrades dinoTADs, implicating transcription-induced supercoiling as the primary topological force in dinoflagellates.
mTOR inhibitors as radiosensitizers in neuroendocrine neoplasms
Authors: Exner Samantha , Arrey Gerard , Prasad Vikas , Grötzinger Carsten
Published: July 2020

Peptide receptor radioligand therapy (PRRT) has evolved as an important second-line treatment option in the management of inoperable and metastatic neuroendocrine neoplasms (NEN). Though high radiation doses can be delivered to the tumors, complete remission is still rare. Radiosensitization prior to PRRT is therefore considered to be a promising strategy to improve the treatment effect. In this study, effect and mechanism of mTOR inhibitors were investigated in a comprehensive panel of five NEN cell lines (BON, QGP-1, LCC-18, H727, UMC-11), employing assays for cellular proliferation, clonogenic survival, cell cycle modification and signaling. mTOR inhibition lead to growth arrest with a biphasic concentration-response pattern: a partial response at approximately 1 nM and full response at micromolar concentrations (8-48 μM). All cell lines demonstrated elevated p70S6K phosphorylation yet also increased phosphorylation of counterregulatory Akt. The pulmonary NEN cell line UMC-11 showed the lowest induction of phospho-Akt and strongest growth arrest by mTOR inhibitors. Radiation sensitivity of the cells (50% reduction versus control) was found to range between 4 and 8 Gy. Further, mTOR inhibition was employed together with irradiation to evaluate radiosensitizing effects of this combination treatment. mTOR inhibition was found to radiosensitize all five NEN cells in an additive manner with a moderate overall effect. The radiation-induced G2/M arrest was diminished under combination treatment, leading to an increased G1 arrest. Further investigation involving a suitable animal model as well as radioligand application such as177Lu-DOTATATE or177Lu-DOTATOC will have to demonstrate the full potential of this strategy for radiosensitization in NEN.
Trial-by-trial variability in cortical responses exhibits scaling in spatial correlations predicted from critical dynamics
Authors: Ribeiro Tiago L. , Yu Shan , Martin Daniel A. , Winkowski Daniel , Kanold Patrick , Chialvo Dante R. , Plenz Dietmar
Published: July 2020

Simple sensory stimuli or motor outputs engage large populations of neurons in the mammalian cortex. When stimuli or outputs repeat, the robust population response contrasts with fluctuating responses of individual neurons, known as trial-by-trial variability. To understand this apparent discrepancy, a detailed identification of the underlying spatiotemporal correlations is required. Here, we analyze spatial correlations in the instantaneous fluctuations between neurons relative to the neuronal population. Using 2-photon imaging of visual and auditory responses in primary cortices of awake mice, we show that these correlations grow linearly with the size of the observed cortical area. We extend these observations to the cortical mesoscale by analyzing local field potentials in behaving nonhuman primates. In network simulations, we demonstrate this linear growth in spatial correlation to emerge at criticality. Our findings suggest that trial-by-trial variability is a signature of critical dynamics in cortex maintaining robust, long-range spatial correlations among neurons.
Association between SARS-CoV-2 neutralizing antibodies and commercial serological assays
Authors: Tang Mei San , Case James Brett , Franks Caroline E. , Chen Rita E. , Anderson Neil W. , Henderson Jeffrey P. , Diamond Michael S. , Gronowski Ann M. , Farnsworth Christopher W.
Published: July 2020

Introduction

Commercially available SARS-CoV-2 serological assays based on different viral antigens have been approved for the qualitative determination of anti-SARS-CoV-2 antibodies. However, there is limited published data associating the results from commercial assays with neutralizing antibodies.

Methods

67 specimens from 48 patients with PCR-confirmed COVID-19 and a positive result by the Roche Elecsys SARS-CoV-2, Abbott SARS-CoV-2 IgG, or EUROIMMUN SARS-CoV-2 IgG assays and 5 control specimens were analyzed for the presence of neutralizing antibodies to SARS-CoV-2. Correlation, concordance, positive percent agreement (PPA), and negative percent agreement (NPA) were calculated at several cutoffs. Results were compared in patients categorized by clinical outcomes.

Results

The correlation between SARS-CoV-2 neutralizing titer (EC50) and the Roche, Abbott, and EUROIMMUN assays was 0.29, 0.47, and 0.46 respectively. At an EC50of 1:32, the concordance kappa with Roche was 0.49 (95% CI; 0.23-0.75), with Abbott was 0.52 (0.28-0.77), and with EUROIMMUN was 0.61 (0.4-0.82). At the same neutralizing titer, the PPA and NPA for the Roche was 100% (94-100) & 56% (30-80); Abbott was 96% (88-99) & 69% (44-86); and EUROIMMUN was 91% (80-96) & 81% (57-93) for distinguishing neutralizing antibodies. Patients who died, were intubated, or had a cardiac injury from COVID-19 infection had significantly higher neutralizing titers relative to those with mild symptoms.

Conclusion

COVID-19 patients generate an antibody response to multiple viral proteins such that the calibrator ratios on the Roche, Abbott, and EUROIMMUN assays are all associated with SARS-CoV-2 neutralization. Nevertheless, commercial serological assays have poor NPA for SARS-CoV-2 neutralization, making them imperfect proxies for neutralization.
Ontogeny of the VIP+ interneuron sensory-motor circuit prior to active whisking
Authors: Vagnoni Cristiana , Baruchin Liad J. , Ghezzi Filippo , Ratti Sara , Molnár Zoltán , Butt Simon J. B.
Published: July 2020

Development of the cortical circuits for sensory-motor processing require the coordinated integration of both columnar and long-range synaptic connections. To understand how this occurs at the level of individual neurons we have explored the timeline over which vasoactive intestinal peptide (VIP)-expressing interneurons integrate into mouse somatosensory cortex. We find a distinction in emergent long-range anterior-motor and columnar glutamatergic inputs onto layer (L)2 and L3 VIP+ interneurons respectively. In parallel, VIP+ interneurons form efferent connections onto both pyramidal cells and interneurons in the immediate column in an inside-out manner. Cell-autonomous deletion of the fate-determinant transcription factor,Prox1, spares long-range anterior-motor inputs onto VIP+ interneurons, but leads to deficits in local connectivity. This imbalance in the somatosensory circuit results in altered spontaneous and sensory-evoked cortical activityin vivo. This identifies a critical role for VIP+ interneurons, and more broadly interneuron heterogeneity, in formative circuits of neocortex.
The evolution of trait variance creates a tension between species diversity and functional diversity
Authors: Barabás György , Parent Christine , Kraemer Andrew , Van de Perre Frederik , De Laender Frederik
Published: July 2020

It seems intuitive that species diversity promotes functional diversity. For example, more plant species imply more diverse leaf chemistry and thus more kinds of food for herbivores. Here we argue that the evolution of functional trait variance challenges this view. We show that trait-based eco-evolutionary processes force species to evolve narrower trait breadths in tightly packed communities, in their effort to avoid competition with neighboring species. This effect is so strong as to reduce overall trait space coverage, overhauling the expected positive relationship between species- and functional diversity. Empirical data from Galápagos land snail communities proved consistent with this claim. As a consequence, trait data from species-poor communities may misjudge functional diversity in species-rich ones, and vice versa.