bluuebunny/crossref_metadata_2025 huggingface dataset:
The social construction of the space race: then and now
Authors: Cross Mai'a K. Davis
Published: October 2019

The proposed creation of a US Space Force has led to a ratcheting up of a sense of competition and threat among spacefaring powers. Many top government officials and experts around the world believe that space will inevitably become the next battlefield, either among countries, or private companies, or both. India successfully blew up a satellite, China landed a probe on the dark side of the moon and many other countries have rapidly developed launch capabilities. The term ‘Space Race 2.0’ is increasingly invoked. But are we in the midst of a new space race, or on the verge of a new space age? This article argues that despite many governmental efforts to militarize space over the past 70 years, on the whole, non-state actors have ensured that space has been a highly cooperative realm of human interaction, even during the height of the Cold War. While on the surface there has been a narrative of threat-based competition, the author argues that this has largely been socially constructed. Drawing upon fresh archival research and participant observation, the author provides the historical context for understanding the increasingly diverse field of space actors today.
Matchability of heterogeneous networks pairs
Authors: Lyzinski Vince , Sussman Daniel L
Published: October 2019

We consider the problem of graph matchability in non-identically distributed networks. In a general class of edge-independent networks, we demonstrate that graph matchability can be lost with high probability when matching the networks directly. We further demonstrate that under mild model assumptions, matchability is almost perfectly recovered by centering the networks using universal singular value thresholding before matching. These theoretical results are then demonstrated in both real and synthetic simulation settings. We also recover analogous core-matchability results in a very general core-junk network model, wherein some vertices do not correspond between the graph pair.
A Novel Antiparasitic Compound Kills Ring-Stage Plasmodium falciparum and Retains Activity Against Artemisinin-Resistant Parasites
Authors: Clements Rebecca L , Streva Vincent , Dumoulin Peter , Huang Weigang , Owens Edward , Raj Dipak K , Burleigh Barbara , Llinás Manuel , Winzeler Elizabeth A , Zhang Qisheng , Dvorin Jeffrey D
Published: October 2019

Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1–2 µM), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.
A rule-based approach to identify patient eligibility criteria for clinical trials from narrative longitudinal records
Authors: Karystianis George , Florez-Vargas Oscar , Butler Tony , Nenadic Goran
Published: October 2019

Objective

Achieving unbiased recognition of eligible patients for clinical trials from their narrative longitudinal clinical records can be time consuming. We describe and evaluate a knowledge-driven method that identifies whether a patient meets a selected set of 13 eligibility clinical trial criteria from their longitudinal clinical records, which was one of the tasks of the 2018 National NLP Clinical Challenges.

Materials and Methods

The approach developed uses rules combined with manually crafted dictionaries that characterize the domain. The rules are based on common syntactical patterns observed in text indicating or describing explicitly a criterion. Certain criteria were classified as “met” only when they occurred within a designated time period prior to the most recent narrative of a patient record and were dealt through their position in text.

Results

The system was applied to an evaluation set of 86 unseen clinical records and achieved a microaverage F1-score of 89.1% (with a micro F1-score of 87.0% and 91.2% for the patients that met and did not meet the criteria, respectively). Most criteria returned reliable results (drug abuse, 92.5%; Hba1c, 91.3%) while few (eg, advanced coronary artery disease, 72.0%; myocardial infarction within 6 months of the most recent narrative, 47.5%) proved challenging enough.

Conclusion

Overall, the results are encouraging and indicate that automated text mining methods can be used to process clinical records to recognize whether a patient meets a set of clinical trial criteria and could be leveraged to reduce the workload of humans screening patients for trials.
Mannan oligosaccharide supplementation in diets of sow and (or) their offspring improved immunity and regulated intestinal bacteria in piglet1
Authors: Duan Xudong , Tian Gang , Chen Daiwen , Huang Linhui , Zhang Dan , Zheng Ping , Mao Xiangbing , Yu Jie , He Jun , Huang Zhiqing , Yu Bing
Published: October 2019

The objectives of the current study were to explore the effects of mannan oligosaccharide (MOS) supplementation in the diets of sow and (or) their offspring on intestinal bacteria, intestinal and systemic inflammation in the piglet. A total of 60 multiparous sows (4 ± 1 parity; Landrace × Yorkshire) were fed either control diet (sCON, n = 30) or a diet containing 400 mg kg−1 MOS (sMOS, n = 30) from day 86 of gestation until weaning (day 20 of postpartum). On day 7 of age, offspring (Duroc × Landrace Yorkshire) were assigned within sow treatments and fed control diet (pCON) or diet containing 800 mg kg−1 MOS (pMOS) for 28 d (end at 35 d of age), resulting in four piglet diet groups (n = 15 litters per diet group): sCON-pCON, sCON-pMOS, sMOS-pCON, and sMOS-pMOS. Results found that piglet diet MOS increased or tend to increase Lactobacillus amount in the ileum digesta (P < 0.01) and jejunum digesta (P = 0.07), respectively; while tend to decrease Escherichia coli amount in jejunum digesta (P =0.06) and cecum digesta (P = 0.08). Both sow and piglet diets add MOS (sMOS-pMOS) increased Lactobacillus amount but decreased E. coli amount in jejunum digesta (P < 0.05) compared with the sCON-pCON diet group. In addition, sow diet MOS (rather than piglet diet MOS) increased sIgA content in piglet jejunum mucosa compared with control (P = 0.04). Sow diet MOS decreased toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), and interleukin 8 (IL-8) mRNA levels (P < 0.05) and tended to decrease nuclear factor-κB p65 (NF-κB p65) mRNA level (P = 0.07) in piglet intestinal lymphatic. The interaction effects between sow and piglet diets were found on the mRNA levels of NF- κB p65 (P = 0.03) and IL-8 (P = 0.02) in piglet jejunum. Finally, the sow diet MOS decreased proinflammatory cytokines IL-2 (P < 0.01) and IL-4 (P < 0.01) concentrations in piglet serum. Piglets diet MOS decreased the contents of IL-2 (P = 0.03), IL-4 (P = 0.01) and interferon (IFN)-γ (P < 0.01) while increased anti-inflammatory cytokine IL-10 (P < 0.01) content in serum. The interaction effects between sows and piglet diets on IL-4 (P = 0.02), IL-10 (P < 0.01), and IFN-γ (P = 0.08) were observed. In conclusion, sow and/or piglet diet MOS could improve intestinal microbiota, enhance intestinal mucosal immune competence, and suppress intestinal and systemic inflammation in the piglet.
A combined endoscopic and open surgical approach for chronic retracted proximal hamstring avulsion
Authors: Atzmon Ran , Amar Eyal , Maor Dror , Rath Ehud
Published: October 2019

Proximal hamstring avulsion is an uncommon injury which usually requires surgical intervention. When possible, primary surgical fixation is recommended. In chronic hamstring avulsion with significant retraction of the tendon, hamstring reconstructions using an autograft or allograft are required in order to bridge the gap. This is mainly performed using an open surgical technique. We describe a combined endoscopic and open surgical approach to hamstring reconstruction surgery.
Effectiveness of Building-Wide Integrated Pest Management Programs for German Cockroach and Bed Bug in a High-Rise Apartment Building
Authors: Wang Changlu , Eiden Amanda , Cooper Richard , Zha Chen , Wang Desen
Published: October 2019

Bed bug, Cimex lectularius (L.) (Hemiptera: Cimicidae), and German cockroach, Blattella germanica (L.) (Blattodea: Ectobiidae), infestations are commonly found in low-income housing communities and result in negative health effects and economic burden. Integrated Pest Management (IPM) has been shown to be an effective approach for managing these pests, yet practice of IPM in housing communities is very limited. We evaluated the effectiveness of a contractor-led bed bug IPM program and researcher-led cockroach IPM program in a high-rise apartment building for 1 yr. A second apartment building that received conventional monthly pest control service was used as control. The bed bug infestation rate decreased from 9% at 0 mo to 3% at 12 mo (63% reduction), even though the contractor only partially followed the IPM protocol; the German cockroach infestation rate decreased from 49% at 0 mo to 12% at 12 mo (75% reduction). In the control building, no monitors were installed in the infested apartments and the apartments received cursory treatment services from an existing pest control contractor. The bed bug infestation rate increased from 6% at 0 mo to 12% at 12 mo (117% increase); the German cockroach infestation rate decreased from 47% at 0 mo to 29% at 12 mo (39% reduction). IPM is a much more effective approach for building-wide control of cockroaches and bed bugs than conventional pest control service. This study confirms the benefit of building-wide IPM on pest reduction and challenges existed for carrying out IPM programs in low-income communities.
Dural Extranodal Marginal Zone Lymphoma in an XRCC2 Mutation Carrier
Authors: Gvozdjan Kristina , Zacharia Brad E , Bayerl Michael G , Tomi-Olugbodi Adeola , Boyer Cinda , Specht Charles S
Published: October 2019

Dural extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a rare entity without an associated recurrent genetic abnormality. Only one case has been described in a woman with history of breast carcinoma without a known genetic predisposition. Here, we report a case of a 56-year-old woman heterozygous for XRCC2 mutation with a history of Graves’ disease and bilateral breast carcinomas, who was found to have a diffusely infiltrative extra-axial mass in the high parietal convexity with infiltration into the adjacent superior sagittal sinus. The morphologic, immunophenotypic, and molecular findings were diagnostic of MALT lymphoma. Staging bone marrow demonstrated involvement by the neoplasm. Although the study was limited to only the clinically significant laboratory evaluation, it may serve as an important addition to the current knowledge of the pathogenic potential of a loss of function mutation in this rarely reported cancer predisposition gene.
Geometric morphometrics and machine learning challenge currently accepted species limits of the land snail Placostylus (Pulmonata: Bothriembryontidae) on the Isle of Pines, New Caledonia
Authors: Quenu Mathieu , Trewick Steven A , Brescia Fabrice , Morgan-Richards Mary
Published: October 2019

Size and shape variations of shells can be used to identify natural phenotypic clusters and thus delimit snail species. Here, we apply both supervised and unsupervised machine learning algorithms to a geometric morphometric dataset to investigate size and shape variations of the shells of the endemic land snail Placostylus from New Caledonia. We sampled eight populations of Placostylus from the Isle of Pines, where two species of this genus reportedly coexist. We used neural network analysis as a supervised learning algorithm and Gaussian mixture models as an unsupervised learning algorithm. Using a training dataset of individuals assigned to species using nuclear markers, we found that supervised learning algorithms could not unambiguously classify all individuals of our expanded dataset using shell size and shape. Unsupervised learning showed that the optimal division of our data consisted of three phenotypic clusters. Two of these clusters correspond to the established species Placostylus fibratus and P. porphyrostomus, while the third cluster was intermediate in both shape and size. Most of the individuals that were not clearly classified using supervised learning were classified to this intermediate phenotype by unsupervised learning, and most of these individuals came from previously unsampled populations. These results may indicate the presence of persistent putative-hybrid populations of Placostylus in the Isle of Pines.
Ensembl 2020
Authors: Yates Andrew D , Achuthan Premanand , Akanni Wasiu , Allen James , Allen Jamie , Alvarez-Jarreta Jorge , Amode M Ridwan , Armean Irina M , Azov Andrey G , Bennett Ruth , Bhai Jyothish , Billis Konstantinos , Boddu Sanjay , Marugán José Carlos , Cummins Carla , Davidson Claire , Dodiya Kamalkumar , Fatima Reham , Gall Astrid , Giron Carlos Garcia , Gil Laurent , Grego Tiago , Haggerty Leanne , Haskell Erin , Hourlier Thibaut , Izuogu Osagie G , Janacek Sophie H , Juettemann Thomas , Kay Mike , Lavidas Ilias , Le Tuan , Lemos Diana , Martinez Jose Gonzalez , Maurel Thomas , McDowall Mark , McMahon Aoife , Mohanan Shamika , Moore Benjamin , Nuhn Michael , Oheh Denye N , Parker Anne , Parton Andrew , Patricio Mateus , Sakthivel Manoj Pandian , Abdul Salam Ahamed Imran , Schmitt Bianca M , Schuilenburg Helen , Sheppard Dan , Sycheva Mira , Szuba Marek , Taylor Kieron , Thormann Anja , Threadgold Glen , Vullo Alessandro , Walts Brandon , Winterbottom Andrea , Zadissa Amonida , Chakiachvili Marc , Flint Bethany , Frankish Adam , Hunt Sarah E , IIsley Garth , Kostadima Myrto , Langridge Nick , Loveland Jane E , Martin Fergal J , Morales Joannella , Mudge Jonathan M , Muffato Matthieu , Perry Emily , Ruffier Magali , Trevanion Stephen J , Cunningham Fiona , Howe Kevin L , Zerbino Daniel R , Flicek Paul
Published: October 2019

The Ensembl (https://www.ensembl.org) is a system for generating and distributing genome annotation such as genes, variation, regulation and comparative genomics across the vertebrate subphylum and key model organisms. The Ensembl annotation pipeline is capable of integrating experimental and reference data from multiple providers into a single integrated resource. Here, we present 94 newly annotated and re-annotated genomes, bringing the total number of genomes offered by Ensembl to 227. This represents the single largest expansion of the resource since its inception. We also detail our continued efforts to improve human annotation, developments in our epigenome analysis and display, a new tool for imputing causal genes from genome-wide association studies and visualisation of variation within a 3D protein model. Finally, we present information on our new website. Both software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license) and data updates made available four times a year.
TFBSshape: an expanded motif database for DNA shape features of transcription factor binding sites
Authors: Chiu Tsu-Pei , Xin Beibei , Markarian Nicholas , Wang Yingfei , Rohs Remo
Published: October 2019

TFBSshape (https://tfbsshape.usc.edu) is a motif database for analyzing structural profiles of transcription factor binding sites (TFBSs). The main rationale for this database is to be able to derive mechanistic insights in protein–DNA readout modes from sequencing data without available structures. We extended the quantity and dimensionality of TFBSshape, from mostly in vitro to in vivo binding and from unmethylated to methylated DNA. This new release of TFBSshape improves its functionality and launches a responsive and user-friendly web interface for easy access to the data. The current expansion includes new entries from the most recent collections of transcription factors (TFs) from the JASPAR and UniPROBE databases, methylated TFBSs derived from in vitro high-throughput EpiSELEX-seq binding assays and in vivo methylated TFBSs from the MeDReaders database. TFBSshape content has increased to 2428 structural profiles for 1900 TFs from 39 different species. The structural profiles for each TFBS entry now include 13 shape features and minor groove electrostatic potential for standard DNA and four shape features for methylated DNA. We improved the flexibility and accuracy for the shape-based alignment of TFBSs and designed new tools to compare methylated and unmethylated structural profiles of TFs and methods to derive DNA shape-preserving nucleotide mutations in TFBSs.
The economics of dams
Authors: Jeuland Marc
Published: October 2019

Dams provide a host of benefits to societies, helping to balance variability in water availability with demand for multiple uses, allowing power generation, providing and enhancing recreation opportunities, and offering protection against damaging floods. Yet dams are often controversial due to their high investment requirements, unequal distributional effects, and concerns over the irreparable harm they may cause to free-flowing rivers and ecosystems. This paper considers the economic case for such projects, organized around a review of what we know about their value and impacts. Though heterogeneity across contexts is a common feature of interventions in many sectors, we argue that it is particularly acute in the case of dams, and that this creates difficulties for drawing general conclusions about their social value. Still, evidence suggests that investment in additional surface water storage may not always be the best solution for addressing water scarcity. Furthermore, a number of biases and blind spots exist in economic frameworks used to evaluate dams, and these often challenge analysts’ ability to correctly identify which projects will be most attractive. Perhaps due to some of these perceived deficiencies, policy-makers do not appear to make much use of economic analyses for decision-making about dams. If progress is to be made in avoiding costly mistakes related to construction and removal of such infrastructures in the future, economists need to improve the realism and methods underlying their analyses of the value of dams, and offer more useful interpretations of the results that these approaches produce.
Surgical Reconstruction of Complex Distal Foot Defects With Vascularized Fascia Lata
Authors: Liu Mengdong , Yang Yunshu , Zhang Yong , Yang Xuekang , Hu Dahai
Published: October 2019

Background

Reconstruction of distal foot defect remains a challenge in plastic surgery. The purpose of this report is to present a new procedure that repairs these defects in severe burn patients. Results of application and follow-up in 7 patients were presented.

Methods

From January 2016 to March 2018, a total of 7 patients (age ranging from 21 to 57 years) with distal foot defects were treated in our department. All the wounds were caused by severe burns and repaired by the free vascularized fascia lata combined with thin split-skin graft. After the operation, the status of the fascia flaps and grafted skin was observed, and follow-up information and complications were documented.

Results

Among the 7 patients, the flaps and grafted skins completely survived in 5 patients. One patient was found to have grafted skin necrosis in the perioperative period, and 1 patient was found to have partial flap necrosis in the follow-up period. After conventional dressing treatment and skin grafting, the wounds healed in both patients. The mean follow-up was 6 months.

Conclusions

The method of combining the free vascularized fascia lata with thin split-skin graft represents a satisfactory approach for the repairing of distal foot defects.
Psychotropic Medication Effects on Seizure Threshold and Seizure Duration During Electroconvulsive Therapy Stimulus Titration
Authors: Chiao Stephanie , Isenberg Keith , North Carol S.
Published: October 2019

Objectives

Decisions about psychotropic medication administration before electroconvulsive therapy (ECT) are central to management of a very psychiatrically ill patient population. Given that many psychotropic medications are thought to either promote or prevent seizures, there is ongoing concern about concurrent psychotropic medication and ECT administration. This study examined the effect of psychotropic medications on seizure threshold and duration during ECT stimulus titration.

Methods

The study sample consisted of 550 patients receiving ECT stimulus titration at a single site during a 27-month period. Systematic chart review provided clinical data, including patients' demographics, psychiatric diagnoses, medications administered in the 48 hours before ECT, and information on the ECT procedure. Referring psychiatrists were advised to discontinue lithium before ECT but otherwise managed psychotropic medications as clinically indicated. A fixed charge titration schedule was used to estimate seizure threshold. Electroconvulsive therapy motor seizure duration was estimated by the cuff method, and electroencephalogram seizure duration was estimated by review of a 2-lead strip.

Results

Administration of psychotropic medications, including benzodiazepines, antiepileptics, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, bupropion, and stimulants, was not associated with seizure threshold as estimated by electrical charge eliciting a generalized seizure or duration during the initial ECT titration. Tricyclic and tetracyclic antidepressant dosage was associated with seizure threshold.

Conclusions

Psychotropic medications may have little effect on seizure threshold and duration during titration of electrical dose at ECT initiation. Integrating this work with other literature supports making recommendations for medication discontinuation before ECT on an individual basis.
Cardiac structure and function in schizophrenia: a cardiac MR imaging study
Authors: Osimo Emanuele F. , Brugger Stefan P. , de Marvao Antonio , Pillinger Toby , Whitehurst Thomas , Statton Ben , Quinlan Marina , Berry Alaine , Cook Stuart A. , O’Regan Declan P. , Howes Oliver D.
Published: October 2019

Background

Heart disease is the leading cause of death in schizophrenia.

Aims

We investigated cardiac structure and function in patients with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.

Methods

80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity, and glycated haemoglobin levels. Patients and controls were matched for age, sex, ethnicity, and body surface area.

Results

Patients with schizophrenia had significantly smaller indexed left ventricular (LV) end-diastolic volume, end-systolic volume, stroke volume, right ventricular (RV) end-diastolic volume, end-systolic volume, and stroke volume but unaltered ejection fractions relative to controls. LV concentricity and septal thickness were significantly larger in schizophrenia. The findings were largely unchanged after adjusting for smoking or exercise levels and were independent of medication dose and duration.

Conclusions

Patients with schizophrenia show evidence of prognostically-adverse cardiac remodelling compared to matched controls, independent of conventional risk factors.
FUS-dependent liquid-liquid phase separation is an early event in double-strand break repair
Authors: Levone Brunno R. , Lenzken Silvia C. , Antonaci Marco , Maiser Andreas , Rapp Alexander , Conte Francesca , Reber Stefan , Ronchi Antonella E. , Mühlemann Oliver , Leonhardt Heinrich , Cardoso M. Cristina , Ruepp Marc-David , Barabino Silvia M.L.
Published: October 2019

RNA-binding proteins (RBPs) are emerging as important effectors of the cellular DNA damage response (DDR). The RBP FUS is implicated in RNA metabolism and DNA repair, and it undergoes reversible liquid-liquid phase separation (LLPS)in vitro. Here, we demonstrate that FUS-dependent LLPS is necessary for the initiation of the DDR. Using laser microirradiation in FUS-knockout cells, we show that FUS is required for the recruitment to DNA damage sites of the DDR factors KU80, NBS1, 53BP1, and of SFPQ, another RBP implicated in the DDR. The relocation of KU80, NBS1, and SFPQ is similarly impaired by LLPS inhibitors, or LLPS-deficient FUS variants. We also show that LLPS is necessary for efficient γH2AX foci formation. Finally, using super-resolution structured illumination microscopy, we demonstrate that the absence of FUS impairs the proper arrangement of γH2AX nano-foci into higher-order clusters. These findings demonstrate the early requirement for FUS-dependent LLPS in the activation of the DDR and the proper assembly of DSBs repair complexes.
DAMEfinder: A method to detect differential allele-specific methylation
Authors: Orjuela Stephany , Machlab Dania , Menigatti Mirco , Marra Giancarlo , Robinson Mark D.
Published: October 2019

DNA methylation is a highly studied epigenetic signature that is associated with regulation of gene expression, whereby genes with high levels of promoter methylation are generally repressed. Genomic imprinting occurs when one of the parental alleles is methylated, i.e, when there is inherited allele-specific methylation (ASM). A special case of imprinting occurs during X chromosome inactivation in females, where one of the two X chromosomes is silenced, in order to achieve dosage compensation between the sexes. Another more widespread form of ASM is sequence dependent (SD-ASM), where ASM is linked to a nearby heterozygous single nucleotide polymorphism (SNP).

We developed a method to screen for genomic regions that exhibit loss or gain of ASM in samples from two conditions (treatments, diseases, etc.). The method relies on the availability of bisulfite sequencing data from multiple samples of the two conditions. We leverage other established computational methods to screen for these regions within a new R package called DAMEfinder. It calculates an ASM score for all CpG sites or pairs in the genome of each sample, and then quantifies the change in ASM between conditions. It then clusters nearby CpG sites with consistent change into regions.

In the absence of SNP information, our method relies only on reads to quantify ASM. This novel ASM score compares favourably to current methods that also screen for ASM. Not only does it easily discern between imprinted and non-imprinted regions, but also females from males based on X chromosome inactivation. We also applied DAMEfinder to a colorectal cancer dataset and observed that colorectal cancer subtypes are distinguishable according to their ASM signature. We also re-discover known cases of loss of imprinting.

We have designed DAMEfinder to detect regions of differential ASM (DAMEs), which is a more refined definition of differential methylation, and can therefore help in breaking down the complexity of DNA methylation and its influence in development and disease.
Genomic profiling of plasma circulating tumor DNA reveals genetics and residual disease in extranodal NK/T-cell lymphoma
Authors: Li Qiong , Zhang Wei , Li Jiali , Xiong Jingkang , Liu Jia , Chen Ting , Wen Qin , Zeng Yunjing , Gao Li , Gao Lei , Zhang Cheng , Kong Peiyan , Liu Yao , Zhang Xi , Rao Jun
Published: October 2019

Background

Extranodal NK/T-cell lymphoma, nasal type (ENTKL), is an aggressive hematological malignancy with poor prognosis. Early detection of tumors at initial diagnosis or during routine surveillance is important for improving survival outcomes. Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool for monitoring disease status. Here, we investigated the feasible of ctDNA detection in ENTKL.

Methods

Plasma ctDNA was assessment were based on blood specimens that were collected from 65 patients recently diagnosed with ENKTL at the hematology medical center of Xinqiao Hospital, longitudinal samples collected under chemotherapy also included. Gene mutation spectrum of ENKTL was analyzed via cancer personalized profiling sequencing (CAPP-Seq). This study is registered with ClinicalTrials.gov (ChiCTR1800014813)

Results

From February 2017 to September 2019, 65 patients were enrolled, we found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%), NOTCH1 (7.7%). The mutation frequencies of KMT2D was significantly higher in stage III-IV, and mutations in KMT2D, ASXL3 and JAK3 were significantly correlated with the metabolic tumor burden of the patients. Compared with tumor tissue DNA, ctDNA profiling showed good concordance. Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequency of genes. Compared with PET/CT, ctDNA has more advantages for tracking residual disease in patients. In addition, we also found that mutated KMT2D predicted poor prognosis in patients.

Conclusion

Collectively, our results provide evidence that ctDNA may serve as a novel precision medicine biomarker in ENKTL.
Control of Social Withdrawal of Mice Deficient for the Autism Gene Magel2 by Restoration of Vasopressin-Oxytocin Dialogue in Septum
Authors: Borie Amélie M. , Dromard Yann , Dufner Djodi , Pollozi Emi , Huzard Damien , Tömböli Csaba , Olma Aleksandra , Manning Maurice , Colson Pascal , Guillon Gilles , Muscatelli Françoise , Desarménien Michel G. , Jeanneteau Freddy
Published: October 2019

Intellectual and social disabilities are common comorbidities in adolescents and adults with Magel2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are unexplored. Here we used Magel2 knockout mice combined with optogenetic/pharmacological tools to characterize disease modifications in the social brain network. We find that the degree of social novelty moderates a dialogue between vasopressin and oxytocin in the lateral septum, a region organizing sequential content of sensory experiences. Social withdrawal of mice lacking Magel2 is alleviated by restoration of dialogue-lead by vasopressin. This preclinical study identifies the collective actions of vasopressin and oxytocin in the lateral septum as a key factor in the pathophysiology.
Genomes of Symbiodiniaceae reveal extensive sequence divergence but conserved functions at family and genus levels
Authors: González-Pech Raúl A. , Chen Yibi , Stephens Timothy G. , Shah Sarah , Mohamed Amin R. , Lagorce Rémi , Bhattacharya Debashish , Ragan Mark A. , Chan Cheong Xin
Published: October 2019

Dinoflagellates of the family Symbiodiniaceae (Order Suessiales) are predominantly symbiotic, and many are known for their association with corals. The genetic and functional diversity among Symbiodiniaceae is well acknowledged, but the genome-wide sequence divergence among these lineages remains little known. Here, we present de novo genome assemblies of five isolates from the basal genus Symbiodinium, encompassing distinct ecological niches. Incorporating existing data from Symbiodiniaceae and other Suessiales (15 genome datasets in total), we investigated genome features that are common or unique to these Symbiodiniaceae, to genus Symbiodinium, and to the individual species S. microadriaticum and S. tridacnidorum. Our whole-genome comparisons reveal extensive sequence divergence, with no sequence regions common to all 15. Based on similarity of k-mers from whole-genome sequences, the distances among Symbiodinium isolates are similar to those between isolates of distinct genera. We observed extensive structural rearrangements among symbiodiniacean genomes; those from two distinct Symbiodinium species share the most (853) syntenic gene blocks. Functions enriched in genes core to Symbiodiniaceae are also enriched in those core to Symbiodinium. Gene functions related to symbiosis and stress response exhibit similar relative abundance in all analysed genomes. Our results suggest that structural rearrangements contribute to genome sequence divergence in Symbiodiniaceae even within a same species, but the gene functions have remained largely conserved in Suessiales. This is the first comprehensive comparison of Symbiodiniaceae based on whole-genome sequence data, including comparisons at the intra-genus and intra-species levels.
Conditional knockout of RAD51-related genes inLeishmania majorreveals a critical role for homologous recombination during genome replication
Authors: Damasceno Jeziel D. , Reis-Cunha João , Crouch Kathryn , Lapsley Craig , Tosi Luiz R. O. , Bartholomeu Daniella , McCulloch Richard
Published: October 2019

Homologous recombination (HR) has an intimate relationship with genome replication, both during repair of DNA lesions that might prevent DNA synthesis and in tackling stalls to the replication fork. Recent studies led us to ask if HR might have a more central role in replicating the genome ofLeishmania, a eukaryotic parasite. Conflicting evidence has emerged regarding whether or not HR genes are essential, and genome-wide mapping has provided evidence for an unorthodox organisation of DNA replication initiation sites, termed origins. To answer this question, we have employed a combined CRISPR/Cas9 and DiCre approach to rapidly generate and assess the effect of conditional ablation of RAD51 and three RAD51-related proteins inLeishmania major. Using this approach, we demonstrate that loss of any of these HR factors is not immediately lethal, but in each case growth slows with time and leads to DNA damage, accumulation of cells with aberrant DNA content, and genome-wide mutation. Despite these similarities, we show that only loss of RAD51 and RAD51-3 impairs DNA synthesis, and that the factors act in distinct ways. Finally, we reveal that loss of RAD51 has a profound effect on DNA replication, causing loss of initiation at the major origins and increased DNA synthesis at subtelomeres. Our work clarifies questions regarding the importance of HR to survival ofLeishmaniaand reveals an unanticipated, central role for RAD51 in the programme of genome replication in a microbial eukaryote.
Properties of rhizosphere soil associated with herbaceous plant roots analyzed using small-scale protocols
Authors: Yamazaki Shinichi , Ochiai Kumiko , Motokawa Junko , Hamamoto Shoichiro , Sugiyama Akifumi , Kobayashi Masaru
Published: October 2019

The rhizosphere, which is the region of soil adjacent to plant roots, is affected by the activities of both plant roots and associated microorganisms which cause changes in soil properties including nutrient mineral composition. Accordingly, the actual availability of plant nutrients may not be the same as that estimated on the basis of bulk soil analysis. However, the extent and manner in which the availability of plant nutrients in bulk and rhizosphere soils differ remain unclear. Therefore, the present study defined the rhizosphere as the soil adhered to plant roots, established a set of small-scale protocols for analyzing the nutrient minerals of small soil samples, and then characterized the rhizosphere soil of sorghum, Sorghum bicolor (L.) Moench. The mineral contents of the bulk and rhizosphere soil differed significantly, with nutrient contents generally greater in the rhizosphere, and particularly remarkable accumulation was observed in regards to ammonium ion and exchangeable potassium concentrations. Such accumulation might be due, in part, to the greater per weight surface areas of rhizosphere soil particles, but other mechanisms, including the accumulation of organic matter, could also be involved.
Multi-timescale hybrid components of the functional brain connectome: A bimodal EEG-fMRI decomposition
Authors: Wirsich Jonathan , Amico Enrico , Giraud Anne-Lise , Goñi Joaquín , Sadaghiani Sepideh
Published: October 2019

Concurrent electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) bridge brain connectivity across timescales. During concurrent EEG-fMRI resting-state recordings, whole-brain functional connectivity (FC) strength is spatially correlated across modalities. However, cross-modal investigations have commonly remained correlational, and joint analysis of EEG-fMRI connectivity is largely unexplored.

Here we investigated if there exist (spatially) independent FC networks linked between modalities. We applied the recently proposed hybrid connectivity independent component analysis (connICA) framework to two concurrent EEG-fMRI resting state datasets (total 40 subjects). Two robust components were found across both datasets. The first component has a uniformly distributed EEG-frequency fingerprint linked mainly to intrinsic connectivity networks (ICNs) in both modalities. Conversely, the second component is sensitive to different EEG-frequencies and is primarily linked to intra-ICN connectivity in fMRI but to inter-ICN connectivity in EEG.

The first hybrid component suggests that connectivity dynamics within well-known ICNs span timescales, from millisecond-range in all canonical frequencies of FCEEGto second-range of FCfMRI. Conversely, the second component additionally exposes linked but spatially divergent neuronal processing at the two timescales. This work reveals the existence of joint spatially independent components, suggesting that parts of resting-state connectivity are co-expressed in a linked manner across EEG and fMRI over individuals.
Chromatiblock: scalable whole-genome visualization of structural differences in prokaryotes
Authors: Sullivan Mitchell John , van Bakel Harm
Published: October 2019

Chromatiblock is a Python application for visualizing the presence, absence and arrangement of syntenic blocks across large numbers of complete bacterial genomes.

Availability

Chromatiblock is freely available under a GPL license, for macOS, GNU/Linux and and Microsoft Windows from https://github.com/mjsull/chromatiblock/

Contact

harm.vanbakel@mssm.edu
Heterogeneity in VEGF Receptor-2 mobility and organization on the endothelial cell surface leads to diverse activation models by VEGF
Authors: da Rocha-Azevedo Bruno , Lee Sungsoo , Dasgupta Aparajita , Vega Anthony R. , de Oliveira Luciana R. , Kim Tae , Kittisopikul Mark , Jaqaman Khuloud
Published: October 2019

The nanoscale organization of cell surface receptors plays an important role in signaling. We determined this organization and its relation to receptor activation for VEGF Receptor-2 (VEGFR-2), a critical receptor tyrosine kinase in endothelial cells (ECs), by combining live-cell single-molecule imaging of endogenous VEGFR-2 with rigorous computational analysis. We found that surface VEGFR-2 can be mobile or immobile/confined, and monomeric or non-monomeric, with a complex interplay between the two. The mobility and interaction heterogeneity of VEGFR-2 in the basal state led to heterogeneity in the sequence of steps leading to VEGFR-2 activation by VEGF. Specifically, we found that VEGF can bind to both monomeric and non-monomeric VEGFR-2, and, when binding to monomeric VEGFR-2, promotes dimer formation but only for immobile/confined receptors. Overall, our study highlights the dynamic and heterogeneous nature of cell surface receptor organization and its complex relationships with receptor activation and signaling.
Tailor-made sRNAs: a toolbox to control metabolic targets
Authors: Apura Patrícia , Peregrina Alexandra , Saramago Margarida , Viegas Sandra C. , Carvalho Sandra M. , Saraiva Lígia M. , Domingues Susana , Arraiano Cecília M.
Published: October 2019

Pseudomonas putida is a highly attractive production system for industrial needs. Modulation of gene expression is an urgent need to redesign P. putida metabolism for its improvement as biocatalyst at industrial level. We report the construction of a small RNA-based system with potential to be used for different purposes in synthetic biology. Due to their modular composition, design facilities and ability in tuning gene expression, sRNAs constitute a powerful tool in genetic and metabolic engineering. In the toolbox presented here, the synthetic sRNA is specifically directed to any region of a chosen target. The expression of the synthetic sRNAs is shown to differentially modulate the level of endogenous and reporter genes. The antisense interaction of the sRNA with the mRNA results in different outcomes. Depending on the particularity of each sRNA-target mRNA pair, we managed to demonstrate the duality of this system, able either to repress or overexpress a given gene. This system combines a high specificity with a wide applicability due to its ability to modulate the expression of virtually any given gene. By plugging-in and -out genetic circuits, this tailor-made regulatory system can be used to redesign P. putida metabolism, fulfilling an important industrial gap in synthetic biology.
FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism
Authors: Shah Sneha , Molinaro Gemma , Liu Botao , Wang Ruijia , Huber Kimberly M. , Richter Joel D.
Published: October 2019

Silencing of FMR1 and loss of its gene product FMRP results in Fragile X Syndrome. FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wildtype tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes; and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. ChIP-Seq demonstrates that loss of FMRP alters the deployment of this epigenetic mark on chromatin. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders.

Highlights

- Loss of FMRP results in decline of ribosome stalling on specific mRNAs (eg., SETD2)

- Increased SETD2 protein levels alter H3K36me3 marks in FMRP deficient hippocampus

- Genome-wide changes in mRNA alternative splicing occur in FMRP deficient hippocampus

- H3K36me3 marks and alternative splicing changes occur on transcripts linked to autism
Transient Reprogramming of Neonatal Cardiomyocytes to a Proliferative Dedifferentiated State
Authors: Kisby Thomas , de Lázaro Irene , Stylianou Maria , Cossu Giulio , Kostarelos Kostas
Published: October 2019

Zebrafish and urodele amphibians are capable of extraordinary myocardial regeneration thanks to the ability of their cardiomyocytes to undergo transient dedifferentiation and proliferation. Somatic cells can be temporarily reprogrammed to a proliferative, dedifferentiated state through transient expression ofOct3/4, Sox2, Klf4andc-Myc(OSKM) transcription factors. Here, we utilized an OSKM-encoding non-integrating vector to induce transient reprogramming of mammalian cardiomyocytesin vitro. Reprogramming factor expression in neonatal rat cardiomyocytes triggered rapid cell dedifferentiation characterized by downregulation of cardiomyocyte specific gene and protein expression, sarcomere dis-assembly and loss of autorhythmic contractile activity. Concomitantly, a significant increase in cell cycle related gene expression and Ki67 positive cells was observed, indicating that dedifferentiated cardiomyocytes possess an enhanced proliferative capacity. A small proportion of cardiomyocytes progressed through mesenchymal to epithelial transition, further indicating the initiation of cell reprogramming. However, complete reprogramming to a pluripotent-like state was not achieved for the duration of the study (20 days), both in standard and embryonic stem cell culture media conditions. The transient nature of this partial reprogramming response was confirmed as cardiomyocyte-specific cell morphology, gene expression and contractile activity were recovered by day 15 after viral transduction. Further investigations into the complete downstream biological effects of ectopic OSKM expression in cardiomyocytes and the fate of these reprogrammed cells are warranted. Our results to date suggest that transient reprogramming could be a feasible strategy to recapitulate regenerative mechanisms of lower vertebrates and inform direct gene therapy approaches to cardiac regenerative medicine.
S-conLSH: Alignment-free gapped mapping of noisy long reads
Authors: Chakraborty Angana , Morgenstern Burkhard , Bandyopadhyay Sanghamitra
Published: October 2019

Motivation

The advancement of SMRT technology has unfolded new opportunities of genome analysis with its longer read length and low GC bias. Alignment of the reads to their appropriate positions in the respective reference genome is the first but costliest step of any analysis pipeline based on SMRT sequencing. However, the state-of-the-art aligners often fail to identify distant homologies due to lack of conserved regions, caused by frequent genetic duplication and recombination. Therefore, we developed a novel alignment-free method of sequence mapping that is fast and accurate.

Results

We present a new mapper called S-conLSH that usesSpacedcontext basedLocalitySensitiveHashing. With multiple spaced patterns, S-conLSH facilitates a gapped mapping of noisy long reads to the corresponding target locations of a reference genome. We have examined the performance of the proposed method on 5 different real and simulated datasets. S-conLSH is at least 2 times faster than the state-of-the-art alignment-based methods. It achieves a sensitivity of 99%, without using any traditional base-to-base alignment, on human simulated sequence data. By default, S-conLSH provides an alignment-free mapping in PAF format. However, it has an option of generating aligned output as SAM-file, if it is required for any downstream processing.

Availability

The source code of our software is freely available athttps://github.com/anganachakraborty/S-conLSH