bluuebunny/crossref_metadata_2025 huggingface dataset:
uORFlight: a vehicle toward uORF-mediated translational regulation mechanisms in eukaryotes
Authors: Niu Ruixia , Zhou Yulu , Zhang Yu , Mou Rui , Tang Zhijuan , Wang Zhao , Zhou Guilong , Guo Sibin , Yuan Meng , Xu Guoyong
Published: January 2020

Upstream open reading frames (uORFs) are prevalent in eukaryotic mRNAs. They act as a translational control element for precisely tuning the expression of the downstream major open reading frame (mORF). uORF variation has been clearly associated with several human diseases. In contrast, natural uORF variants in plants have not ever been identified or linked with any phenotypic changes. The paucity of such evidence encouraged us to generate this database-uORFlight (http://uorflight.whu.edu.cn). It facilitates the exploration of uORF variation among different splicing models of Arabidopsis and rice genes. Most importantly, users can evaluate uORF frequency among different accessions at the population scale and find out the causal single nucleotide polymorphism (SNP) or insertion/deletion (INDEL), which can be associated with phenotypic variation through database mining or simple experiments. Such information will help to make hypothesis of uORF function in plant development or adaption to changing environments on the basis of the cognate mORF function. This database also curates plant uORF relevant literature into distinct groups. To be broadly interesting, our database expands uORF annotation into more species of fungus (Botrytis cinerea and Saccharomyces cerevisiae), plant (Brassica napus, Glycine max, Gossypium raimondii, Medicago truncatula, Solanum lycopersicum, Solanum tuberosum, Triticum aestivum and Zea mays), metazoan (Caenorhabditis elegans and Drosophila melanogaster) and vertebrate (Homo sapiens, Mus musculus and Danio rerio). Therefore, uORFlight will light up the runway toward how uORF genetic variation determines phenotypic diversity and advance our understanding of translational control mechanisms in eukaryotes.
Intraoperative localization of cardiac conduction tissue regions using real-time fibre-optic confocal microscopy: first in human trial
Authors: Kaza Aditya K , Mondal Abhijit , Piekarski Breanna , Sachse Frank B , Hitchcock Robert
Published: January 2020

OBJECTIVES

The aim of this study was to evaluate the feasibility and safety of fibre-optic confocal microscopy (FCM) using fluorescein sodium dye for the intraoperative location of conduction tissue regions during paediatric heart surgery.

METHODS

The pilot study included 6 patients undergoing elective surgery for the closure of isolated secundum atrial septal defect aged 30 days to 21 years. FCM imaging was integrated within the normal intraoperative protocol for atrial septal defect repair. Fluorescein sodium dye was applied on the arrested heart. FCM images were acquired at the atrioventricular node region, sinus node region and right ventricle (RV). Total imaging time was limited to 3 min. Any adverse events related to the study were recorded and analysed. Subjects received standard postoperative care. Trained reviewers (n = 9) classified, de-identified and randomized FCM images (n = 60) recorded from the patients as presenting striated, reticulated or indistinguishable microstructures. The reliability of reviewer agreement was assessed using Fleiss’ kappa.

RESULTS

The FCM imaging instruments were integrated effectively into the cardiac surgery operating room. All adverse events found in the study were deemed expected and not related to FCM imaging. Reticulated myocardial microstructures were found during FCM imaging at atrioventricular node and sinus node regions, while striated microstructures were observed in RV. Reliability of agreement of reviewers classifying the FCM images was high (Fleiss’ kappa: 0.822).

CONCLUSIONS

FCM using fluorescein sodium dye was found to be safe for use during paediatric heart surgery. The study demonstrates the potential for FCM to be effective in identifying conduction tissue regions during congenital heart surgery.

Clinical trial registration number

NCT03189134.
The distribution and relative ecological roles of autotrophic and heterotrophic diazotrophs in the McMurdo Dry Valleys, Antarctica
Authors: Coyne Kathryn J , Parker Alexander E , Lee Charles K , Sohm Jill A , Kalmbach Andrew , Gunderson Troy , León-Zayas Rosa , Capone Douglas G , Carpenter Edward J , Cary S Craig
Published: January 2020

The McMurdo Dry Valleys (MDV) in Antarctica harbor a diverse assemblage of mat-forming diazotrophic cyanobacteria that play a key role in nitrogen cycling. Prior research showed that heterotrophic diazotrophs also make a substantial contribution to nitrogen fixation in MDV. The goals of this study were to survey autotrophic and heterotrophic diazotrophs across the MDV to investigate factors that regulate the distribution and relative ecological roles of each group. Results indicated that diazotrophs were present only in samples with mats, suggesting a metabolic coupling between autotrophic and heterotrophic diazotrophs. Analysis of 16S rRNA and nifH gene sequences also showed that diazotrophs were significantly correlated to the broader bacterial community, while co-occurrence network analysis revealed potential interspecific interactions. Consistent with previous studies, heterotrophic diazotrophs in MDV were diverse, but largely limited to lakes and their outlet streams, or other environments protected from desiccation. Despite the limited distribution, heterotrophic diazotrophs may make a substantial contribution to the nitrogen budget of MDV due to larger surface area and longer residence times of lakes. This work contributes to our understanding of key drivers of bacterial community structure in polar deserts and informs future efforts to investigate the contribution of nitrogen fixation to MDV ecosystems.
16S rRNA gene-based primer pair showed high specificity and quantification accuracy in detecting freshwater Brocadiales anammox bacteria
Authors: Ding Chang , Adrian Lorenz , Peng Yongzhen , He Jianzhong
Published: January 2020

Anaerobic ammonium oxidizing (anammox) bacteria are widely distributed and contribute significantly to the global nitrogen cycle. Traditionally, identification and quantification based on the 16S rRNA gene were considered not reliable because of low 16S rRNA gene sequence identity within Brocadiales. Here we hypothesize that by using appropriate primers and methodology, 16S-based detection and quantification of anammox bacteria can be accurate. We modified an existing 16S rRNA gene-based primer pair (Amx694F–Amx960R) by changing one nucleotide (Amx694F position 18, G→C) (Amx694PF–Amx960R) so that they match the sequences of most Brocadiales anammox bacteria, and evaluated the modified primer pair with 29 freshwater samples from microcosms, anammox reactors and wastewater treatment plants of various geographical origins. The primer pair showed high specificity in detection and quantification of anammox populations in samples that contained >0.1% anammox bacteria. Quantification of anammox abundance by quantitative real-time PCR and delineation of anammox species by denaturing gradient gel electrophoresis agreed well with amplicon sequencing results. A clear shift of anammox population towards ‘Candidatus Kuenenia’ was observed under laboratory cultivation conditions. With the help of amplicon sequencing, we demonstrated that 16S rRNA gene-based anammox-specific primers are able to achieve qualitative and quantitative monitoring of anammox communities in wastewater treatment plants and natural freshwater environments.2007;73:5261–7.
Bacterial Taxa and Functions Are Predictive of Sustained Remission Following Exclusive Enteral Nutrition in Pediatric Crohn’s Disease
Authors: Jones Casey M A , Connors Jessica , Dunn Katherine A , Bielawski Joseph P , Comeau André M , Langille Morgan G I , Van Limbergen Johan
Published: January 2020

Background

The gut microbiome is extensively involved in induction of remission in pediatric Crohn’s disease (CD) patients by exclusive enteral nutrition (EEN). In this follow-up study of pediatric CD patients undergoing treatment with EEN, we employ machine learning models trained on baseline gut microbiome data to distinguish patients who achieved and sustained remission (SR) from those who did not achieve remission nor relapse (non-SR) by 24 weeks.

Methods

A total of 139 fecal samples were obtained from 22 patients (8–15 years of age) for up to 96 weeks. Gut microbiome taxonomy was assessed by 16S rRNA gene sequencing, and functional capacity was assessed by metagenomic sequencing. We used standard metrics of diversity and taxonomy to quantify differences between SR and non-SR patients and to associate gut microbial shifts with fecal calprotectin (FCP), and disease severity as defined by weighted Pediatric Crohn’s Disease Activity Index. We used microbial data sets in addition to clinical metadata in random forests (RFs) models to classify treatment response and predict FCP levels.

Results

Microbial diversity did not change after EEN, but species richness was lower in low-FCP samples (<250 µg/g). An RF model using microbial abundances, species richness, and Paris disease classification was the best at classifying treatment response (area under the curve [AUC] = 0.9). KEGG Pathways also significantly classified treatment response with the addition of the same clinical data (AUC = 0.8). Top features of the RF model are consistent with previously identified IBD taxa, such as Ruminococcaceae and Ruminococcus gnavus.

Conclusions

Our machine learning approach is able to distinguish SR and non-SR samples using baseline microbiome and clinical data.
Using parent-reported experience measures as quality improvement tools in paediatric cardiothoracic services: making it happen
Authors: Wray Jo , Oldham Geralyn
Published: January 2020

Objective

Patient experience is a core component of quality and service improvement. In the case of child health, it is parents who often report on their experiences of the child’s healthcare. However, these parent experiences are rarely used to drive change. Our aim was to develop and implement the systematic collection of parent experience data across a range of cardiothoracic services, using quality improvement methodology to implement change.

Design

Plan-Do-Study-Act methodology was used to develop parent-reported experience measures. Setting: Specialist children’s hospital.

Participants

Parents of children under the care of one of a number of cardiothoracic services at the hospital.

Intervention(s)

Completion of questionnaires about hospital experience comprising quantitative and qualitative questions.

Main Outcome Measure(s)

Response rates and completion of a specific-measurable-achievable-realistic-timely (SMART) action plan by the individual clinical teams.

Results

During the first cycle 17 surveys were developed for different clinical services and questionnaires sent/given to 1876 parents. The overall response rate was 30% (15–100%). Clinical teams developed SMART plans following eight (47%) surveys; three teams have reviewed and reported back on their progress against their plan and started on the second cycle of questionnaires. Challenges included lack of resources (time, finances and electronic data collection tools) and problems with actioning SMART plans. However, teams engaged positively, recognizing the importance of parent experience and actively seeking solutions to problems.

Conclusions

Parent-reported experience measures are practical and acceptable quality improvement tools in healthcare but challenges need to be addressed, primarily related to resources, training and sustainability.
Constitutive activation of the EGFR–STAT1 axis increases proliferation of meningioma tumor cells
Authors: Ferluga Sara , Baiz Daniele , Hilton David A , Adams Claire L , Ercolano Emanuela , Dunn Jemma , Bassiri Kayleigh , Kurian Kathreena M , Hanemann Clemens O
Published: January 2020

Background

Meningiomas are the most frequent primary brain tumors of the central nervous system. The standard of treatment is surgery and radiotherapy, but effective pharmacological options are not available yet. The well-characterized genetic background stratifies these tumors in several subgroups, thus increasing diversification. We identified epidermal growth factor receptor–signal transducer and activator of transcription 1 (EGFR–STAT1) overexpression and activation as a common identifier of these tumors.

Methods

We analyzed STAT1 overexpression and phosphorylation in 131 meningiomas of different grades and locations by utilizing several techniques, including Western blots, qPCR, and immunocytochemistry. We also silenced and overexpressed wild-type and mutant forms of the gene to assess its biological function and its network. Results were further validated by drug testing.

Results

STAT1 was found widely overexpressed in meningioma but not in the corresponding healthy controls. The protein showed constitutive phosphorylation not dependent on the JAK–STAT pathway. STAT1 knockdown resulted in a significant reduction of cellular proliferation and deactivation of AKT and ERK1/2. STAT1 is known to be activated by EGFR, so we investigated the tyrosine kinase and found that EGFR was also constitutively phosphorylated in meningioma and was responsible for the aberrant phosphorylation of STAT1. The pharmaceutical inhibition of EGFR caused a significant reduction in cellular proliferation and of overall levels of cyclin D1, pAKT, and pERK1/2.

Conclusions

STAT1–EGFR-dependent constitutive phosphorylation is responsible for a positive feedback loop that causes its own overexpression and consequently an increased proliferation of the tumor cells. These findings provide the rationale for further studies aiming to identify effective therapeutic options in meningioma.
Clinical Features and Outcomes of Bloodstream Infections Caused by New Delhi Metallo-β-Lactamase–Producing Enterobacterales During a Regional Outbreak
Authors: Falcone Marco , Tiseo Giusy , Antonelli Alberto , Giordano Cesira , Di Pilato Vincenzo , Bertolucci Pietro , Parisio Eva Maria , Leonildi Alessandro , Aiezza Noemi , Baccani Ilaria , Tagliaferri Enrico , Righi Lorenzo , Forni Silvia , Sani Spartaco , Mechi Maria Teresa , Pieralli Filippo , Barnini Simona , Rossolini Gian Maria , Menichetti Francesco
Published: January 2020

Limited data about New Delhi metallo-β-lactamase (NDM) bacteremia are available. Blood isolates from 40 patients with NDM bacteremia were studied for antibiotic susceptibility and whole-genomic sequencing. NDM bacteremia has high 30-day mortality. In most cases, aztreonam-avibactam is active in vitro. Ceftazidime-avibactam plus aztreonam may represent a feasible therapeutic option.
Comparative Evaluation of 3-Dimensional High Definition and 2-Dimensional 4-K Ultra-High Definition Endoscopy Systems in Endonasal Skull Base Surgery
Authors: Uozumi Yoichi , Taniguchi Masaaki , Nakai Tomoaki , Kimura Hidehito , Umehara Toru , Kohmura Eiji
Published: January 2020

BACKGROUND

The differences between 3-dimensional (3D) high definition (HD) and 2-dimensional (2D) 4-K ultra-HD (4K) endoscopy and their respective advantages remain unclear.

OBJECTIVE

To evaluate the utility of these endoscopy systems in endonasal skull base surgery.

METHODS

Consecutive series of endoscopic endonasal surgeries performed after introduction of 3D/HD and 2D/4K systems (July 2017) were retrospectively evaluated. Sporadic cases treated with either system, or a conventional 2D standard definition (SD) system, during the rental period from March 2016 were also included. Objective comparisons between the systems were made for newly diagnosed Knosp grade 0 to 3 pituitary adenomas. Surgical procedures were divided into nasal, sphenoidal, and intradural phases, and the surgical procedural time was compared for each phase. The time required for and accuracy of suturing the sellar floor dura was also evaluated.

RESULTS

A total of 74 cases were treated with 3D/HD and/or 2D/4K, and 12 cases with 2D/SD. 3D/HD was advantageous in the nasal phase because of its intuitive depth perception. 2D/4K was advantageous in the intradural phase because of its superior image quality. Surgical time of the nasal phase with 3D/HD, and that of the intradural phase with 2D/4K, were significantly shorter than that with 2D/SD. The time required for and accuracy of sellar floor dural suturing showed a trend toward improving in the order of 2D/SD, 2D/4K, and 3D/HD.

CONCLUSION

3D/HD and 2D/4K endoscopy systems have different advantages, which are useful in distinct surgical phases. Understanding the characteristics of endoscopy systems is important for selecting the most appropriate system for distinct surgical situations.
Pain Agreements and Time-to-Event Analysis of Substance Misuse in a Primary Care Chronic Pain Program
Authors: Ghodke Ameer , Ives Timothy J , Austin Anna E , Bennett William C , Patel Naishal Y , Eshet Sharon A , Chelminski Paul R
Published: January 2020

Background

Types and correlates of pain medication agreement (PMA) violations in the primary care setting have not been analyzed.

Methods

A retrospective analysis was completed to examine patient characteristics and correlates of PMA violations, a proxy for substance misuse, over a 15-year period in an outpatient General Medicine Pain Service within the Division of General Medicine and Clinical Epidemiology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill. Patients who signed the PMA were managed for chronic pain from 2002 through 2017 (N = 1,210). The incidence of PMA violations was measured over a 15-year span. Substance misuse was defined a priori in the study as urine toxicology screen positive for illicit or nonprescribed controlled substances, patient engagement in prescription alteration, doctor-shopping, or diversion.

Results

Most patients received a prescription for a controlled substance (77.4%). During enrollment, 488 (40.3%) patients had one or more violations of their PMA. One-third (33.4%) of pain service patients had a violation within 365 days of signing the agreement. Active tobacco smokers had double the incidence of agreement violation within the first 30 days of enrollment. Almost one-half (49.8%) of violations were due to inconsistent use of controlled substances. Patients with any prior DWI/DUI or drug-related offense had a significantly increased rate of substance misuse (P < 0.0001).

Conclusions

PMA violations were common among a population of patients managed for chronic nonmalignant pain. Universal opioid prescribing precautions, including PMAs, require further investigation to assess their roles in mitigating the potential patient and societal harms associated with opioid prescribing.
Relationship between Stunting, Wasting, Underweight and Geophagy and Cognitive Function of Children
Authors: Mireku Michael O , Cot Michel , Massougbodji Achille , Bodeau-Livinec Florence
Published: January 2020

Objectives

The aim of this study was to investigate the relationship between anthropometric characteristics and both geophagy and cognitive function of children.

Study design

The study prospectively followed singleton children whose mothers participated in the MiPPAD clinical trial in Allada, Benin, from birth to age 12 months. Anthropometric measurements were taken at birth and 9 and 12 months. Wasting, stunting and underweight were defined as weight-for-length, length-for-age and weight-for-age Z-scores less than −2, respectively. Cognitive and motor functions were assessed using the Mullen Scales of Early Learning. Parent-reported geophageous habits of children were collected when the children were 12 months. Multiple linear and logistic regressions were used to analyse the data.

Results

A total of 632 children (49.7% girls) were involved in the study. Stunting, wasting and underweight were observed in 14.1%, 13.6% and 17.7%, respectively, at 9 months and 17.3%, 12.7% and 17.2%, respectively, at 12 months. The prevalence of geophagy among the children was 48.2%. Impaired growth at 9 and 12 months was consistently associated with low cognitive and gross motor (GM) score. Children stunted at 9 months had lower GM scores at 12 months compared with their non-stunted peers (β = −3.48, 95% confidence interval −6.62 to −0.35).

Conclusions

Stunting, wasting and underweight are associated with cognitive and GM deficits in infants. In this setting, impaired growth was not associated with geophagy. Further research evaluating geophagy and growth prospectively and concurrently from birth to 36 months is needed.
Bayesian spatio-temporal models for mapping TB mortality risk and its relationship with social inequities in a region from Brazilian Legal Amazon
Authors: Alves Josilene D , Chiaravalloti-Neto Francisco , Arroyo Luiz H , Arcoverde Marcos A M , Santos Danielle T , Berra Thaís Z , Alves Luana S , Ramos Antônio C V , Campoy Laura T , Belchior Aylana S , Assis Ivaneliza S , Nunes Carla , Forati Regina C , Serrano-Gallardo Pilar , Arcêncio Ricardo A
Published: January 2020

Background

Reducing TB mortality is a great challenge in Brazil due to its territorial extension, cultural variations and economic and political crises, which impact the health system. This study aimed to estimate in space and time the risk of TB mortality and test its relationship with social inequities.

Methods

This was an ecological study that included deaths from TB between 2006 and 2016 in Cuiabá, Brazilian Legal Amazon. Bayesian models based on the integrated nested Laplace approximation approach were used to estimate spatio-temporal RRs. RRs for TB mortality were obtained according to the covariables representative of social inequities.

Results

The risk of TB mortality was stable between 2006 and 2016 and high-risk areas were identified throughout the municipality studied. Regarding social inequities, income was an important factor associated with TB mortality risk, as an increase of 1 SD in income resulted in a 35.4% (RR 0.646; CI 95% 0.476 to 0.837) decrease in risk.

Conclusions

The results provided evidence of areas with higher TB mortality risks that have persisted over time and are related to social inequities. Advancing social policies and protections in these areas will contribute to achieving the WHO's End TB strategy.
Research presented at the 14th International Symposium on Tardigrada: progress in studies on water bears
Authors: Møbjerg Nadja , Michalczyk Łukasz , Mcinnes Sandra J , Christenhusz Maarten J M
Published: January 2020

The 14th International Symposium on Tardigrada took place in Copenhagen, Denmark from 30 July to 3 August 2018. Approximately 140 participants, representing 28 countries from five continents attended the meeting, and there were 58 talks and 74 posters of which 20 were selected for the Symposium Proceedings published in this special issue. The studies span phylogenomics, systematics, anatomy, morphology, reproductive biology, cryobiology, ecology, diet, microbial interactions and biogeography, taking the next step forward in broadening and deepening our understanding of tardigrade biology.
Validation of Emotional Stimuli Flashcards for Conducting ‘Response to Reward’ fMRI study among Malaysian students
Authors: Nasser Nisha Syed , Sharifat Hamed , Rashid Aida Abdul , Hamid Suzana Ab , Rahim Ezamin Abdul , Mohamad Mazlyfarina , Tyagi Rohit , Ismail Siti Irma Fadhilah , Mooi Ching Siew , Suppiah Subapriya
Published: January 2020

Problematic Instagram Use (PIGU) is a specific-Internet-addiction disorder observed among the youth of today. fMRI, is able to objectively assess regional brain activation in response to addiction-specific rewards, e.g. viewing picture flashcards. Pictures uploaded onto Instagram by PIGUs have often been associated with risky behaviours in their efforts to gain more ‘Likes’, thus it is hypothesized that PIGUs are more drawn to ‘Negative-Emotional’ cues. To date, there is no local database with addiction-specific cues.

Objective

To conduct an out-of-scanner validation study to create a database of pictures using ‘Negative-Emotional’ cues that evoke responses of arousal among PIGUs.

Method

Forty-four Malaysian undergraduate students (20 PIGUs, 24 controls) were randomly recruited based on the evaluation using the Smartphone-Addiction-Scale-Malay version (SAS-M) and modified Instagram Addiction Test (IGAT); and fulfilled Lin et al. (2016) definition of addiction. They were administered 200 content-specific pictures that were multidimensional i.e. arousal (excitation/relaxation effects), approach-avoidance (motivational direction) and emotional valence (positive/negative feelings) to describe the PIGUs perception of the psychological properties of the pictures using a 9-point Likert scale.

Results

PIGUs viewing ‘Negative-Emotional’ cues demonstrated significant positive correlations between arousal & valence (z = 4.834, p < .001, effect size = 0.69) and arousal & avoidance-approach (z = 4.625, p < .001, effect size= 0.66) as compared to controls and were more frequently aroused by ‘Negative-Emotional’ type of stimuli.

Conclusion

A database of validated, addiction-specific pictures can be developed to potentiate any future cue-induced response to reward fMRI studies to assess PIGU.
Venous Thromboembolism and Intracranial Hemorrhage in Patients with High-grade Glioma
Authors: Borges Clara , Lemos Carlota , Soares Pedro , Silva Roberto , Fernandes Catarina , Costa Andreia , Caeiro Cláudia , Sarmento Cristina
Published: January 2020

Background

Patients with high-grade glioma (HGG) are at increased risk of venous thromboembolism (VTE), throughout the course of disease. Prophylactic anticoagulation is not established among patients with HGG, outside of perioperative context, due to potential for intracranial hemorrhage (ICH) and the limited data available for predictive VTE scores in primary brain tumors. The aim of this study was to characterize VTE prevalence in adult patients with HGG and assess ICH risk during therapeutic anticoagulation.

Methods

Retrospective analysis of patients diagnosed with HGG at our institution, between 2009 and 2018. All adult patients proposed to systemic treatment were included into this study. Exclusion criteria was anticoagulation previous to diagnosis. VTE was defined as any radiographic-confirmed thrombus in the venous system. Risk factors of interest for VTE and bleeding risk scores were analyzed by chi-squared test and multivariate logistic regression. Survival analysis was performed using Kaplan-Meier method.

Results

A total of 410 patients were included of whom 31 (7,8%) developed a VTE, including 22 deep vein, 6 pulmonary and 3 central venous thrombosis. Twenty-nine patients with VTE had a WHO grade 4 glioma and 2 patients had grade 3 (anaplastic astrocytoma and oligodendroglioma).

In 22 cases, the VTE occurred during systemic treatment, more frequently during Temozolomide (n=15), followed by Irinotecan+Bevacizumab (n=6), Lomustine+Bevacizumab (n=1) and PCV (n=1). The median time between diagnosis and VTE was 10,11 months (95CI 6,46-14,79). Khorana score, age, ECOG performance status, smoking and obesity did not significantly differ in the VTE population. All VTE were initially treated with low molecular weight heparin (LMWH), of which 64.5% maintained LMWH, and the remainder switched to warfarin (19.4%) or to direct oral anticoagulant (16.1%). Six patients (19,4%) had spontaneous ICH under anticoagulation. Patients with grade 3 glioma (p=0,032) had significantly higher rates of ICH than grade 4. Patients with higher ECOG had significantly higher risk of ICH (OR 3,23 (95CI 1,18-8,81), p=0,022). HAS-BLED and ACCP bleeding scores were not associated with ICH. There was no significant difference in overall survival for TVE or ICH.

Conclusion

According to our data, ICH occurred in nearly 20% anticoagulated patients with HGG, as described in literature, and did not correlate with poorer prognosis. High ECOG performance status was an independent risk factor for ICH. Further effort towards better prediction models for VTE and ICH in HGG is warranted.
Achieving stable dynamics in neural circuits
Authors: Kozachkov Leo , Lundqvist Mikael , Slotine Jean-Jacques , Miller Earl K.
Published: January 2020

1

The brain consists of many interconnected networks with time-varying, partially autonomous activity. There are multiple sources of noise and variation yet activity has to eventually converge to a stable, reproducible state (or sequence of states) for its computations to make sense. We approached this problem from a control-theory perspective by applying contraction analysis to recurrent neural networks. This allowed us to find mechanisms for achieving stability in multiple connected networks with biologically realistic dynamics, including synaptic plasticity and time-varying inputs. These mechanisms included inhibitory Hebbian plasticity, excitatory anti-Hebbian plasticity, synaptic sparsity and excitatory-inhibitory balance. Our findings shed light on how stable computations might be achieved despite biological complexity.
Complete connectomic reconstruction of olfactory projection neurons in the fly brain
Authors: Bates A.S. , Schlegel P. , Roberts R.J.V. , Drummond N. , Tamimi I.F.M. , Turnbull R. , Zhao X. , Marin E.C. , Popovici P.D. , Dhawan S. , Jamasb A. , Javier A. , Li F. , Rubin G.M. , Waddell S. , Bock D.D. , Costa M. , Jefferis G.S.X.E.
Published: January 2020

Nervous systems contain sensory neurons, local neurons, projection neurons and motor neurons. To understand how these building blocks form whole circuits, we must distil these broad classes into neuronal cell types and describe their network connectivity. Using an electron micrograph dataset for an entireDrosophila melanogasterbrain, we reconstruct the first complete inventory of olfactory projections connecting the antennal lobe, the insect analogue of the mammalian olfactory bulb, to higher-order brain regions in an adult animal brain. We then connect this inventory to extant data in the literature, providing synaptic-resolution ‘holotypes’ both for heavily investigated and previously unknown cell types. Projection neurons are approximately twice as numerous as reported by light level studies; cell types are stereotyped, but not identical, in cell and synapse numbers between brain hemispheres. The lateral horn, the insect analogue of the mammalian cortical amygdala, is the main target for this olfactory information and has been shown to guide innate behaviour. Here, we find new connectivity motifs, including: axo-axonic connectivity between projection neurons; feedback and lateral inhibition of these axons by local neurons; and the convergence of different inputs, including non-olfactory inputs and memory-related feedback onto lateral horn neurons. This differs from the configuration of the second most prominent target for olfactory projection neurons: the mushroom body calyx, the insect analogue of the mammalian piriform cortex and a centre for associative memory. Our work provides a complete neuroanatomical platform for future studies of the adultDrosophilaolfactory system.

Highlights

First complete parts list for second-order neurons of an adult olfactory system

Quantification of left-right stereotypy in cell and synapse number

Axo-axonic connections form hierarchical communities in the lateral horn

Local neurons and memory-related feedback target projection neuron axons
Creeping yeast: a simple, cheap, and robust protocol for the identification of mating type inSaccharomyces cerevisiae
Authors: Arras Samantha D. M. , Hibbard Taylor R. , Mitsugi-McHattie Lucy , Woods Matthew A. , Johnson Charlotte E. , Munkacsi Andrew , Denmat Sylvie Hermann-Le , Ganley Austen R. D.
Published: January 2020

Saccharomyces cerevisiaeis an exceptional genetic system, with genetic crosses facilitated by its ability to be maintained in haploid and diploid forms. Such crosses are straightforward if the mating type/ploidy of the strains are known. Several techniques can be used to determine mating type (or ploidy), but all have limitations. Here we validate a simple, cheap and robust method to rapidly identifyS. cerevisiaemating types. When cells of opposite mating type are mixed in liquid media, they “creep” up the culture vessel sides, a phenotype that can be easily detected visually. In contrast, mixtures of the same mating type or with a diploid simply settle out. The phenotype is robust to different media, cell densities, temperatures and strains, and is observable for several days. Microscopy suggests that cell aggregation during mating is responsible for the phenotype. Yeast knockout collection analysis identified 107 genes required for the creeping phenotype, with these being enriched for mating-specific genes. Surprisingly, the RIM101 signalling pathway was strongly represented. We propose that RIM101 signalling regulates aggregation as part of a wider, previously-unrecognized role in mating. The simplicity and robustness of this method makes it ideal for routine verification ofS. cerevisiaemating type, with future studies required to verify its molecular basis.
Single-nucleus RNA-Seq reveals a new type of brown adipocyte regulating thermogenesis
Authors: Sun Wenfei , Dong Hua , Balaz Miroslav , Slyper Michal , Drokhlyansky Eugene , Colleluori Georgia , Giordano Antonio , Kovanicova Zuzana , Stefanicka Patrik , Ding Lianggong , Rudofsky Gottfried , Ukropec Jozef , Cinti Saverio , Regev Aviv , Wolfrum Christian
Published: January 2020

Adipose tissue usually is classified as either white, brown or beige/brite, based on whether it functions as an energy storage or thermogenic organ(Cannon and Nedergaard, 2004; Rosen and Spiegelman, 2014). It serves as an important regulator of systemic metabolism, exemplified by the fact that dysfunctional adipose tissue in obesity leads to a host of secondary metabolic complications such as diabetes, cardiovascular diseases and cancer(Hajer et al., 2008; Lauby-Secretan et al., 2016). In addition, adipose tissue is an important endocrine organ, which regulates the function of other metabolic tissues through paracrine and endocrine signals(Scheele and Wolfrum, 2019; Scherer, 2006). Work in recent years has demonstrated that tissue heterogeneity is an important factor regulating the functionality of various organs(Cao et al., 2017; Ginhoux et al., 2016; Park et al., 2018). Here we used single nucleus analysis in mice and men to deconvolute adipocyte heterogeneity. We are able to identify a novel subpopulation of adipocytes whose abundance is low in mice (2-8%) and which is increased under higher ambient temperatures. Interestingly, this population is abundant in humans who live close to thermoneutrality. We demonstrate that this novel adipocyte subtype functions as a paracrine cell regulating the activity of brown adipocytes through acetate-mediated regulation of thermogenesis. These findings could explain, why human brown adipose tissue is substantially less active than mouse tissue and targeting this pathway in humans might be utilized to restore thermogenic activity of this tissue.
Genome-wide discovery of SLE genetic risk variant allelic enhancer activity
Authors: Lu Xiaoming , Chen Xiaoting , Forney Carmy , Donmez Omer , Miller Daniel , Parameswaran Sreeja , Hong Ted , Huang Yongbo , Pujato Mario , Cazares Tareian , Miraldi Emily R. , Ray John P. , de Boer Carl G. , Harley John B. , Weirauch Matthew T. , Kottyan Leah C.
Published: January 2020

Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into the Epstein-Barr virus-transformed B cell line GM12878 revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Comparison of MPRA results in GM12878 and Jurkat T cell lines highlights shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around allelic variants identifies one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that bind allelically without direct alteration of their motif by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.
Middle-level IM-MS and CIU experiments for improved therapeutic immunoglobulin isotype fingerprinting
Authors: Botzanowski Thomas , Hernandez-Alba Oscar , Malissard Martine , Wagner-Rousset Elsa , Deslignière Evolène , Colas Olivier , Haeuw Jean-François , Beck Alain , Cianférani Sarah
Published: January 2020

Currently approved therapeutic monoclonal antibodies (mAbs) are based on immunoglobulin G (IgG) 1, 2 or 4 isotypes, which differ in their specific inter-chains disulfide bridge connectivities. Different analytical techniques have been reported for mAb isotyping, among which native ion mobility mass spectrometry (IM-MS) and collision induced unfolding (CIU) experiments. However, mAb isotyping by these approaches is based on detection of subtle differences and thus remains challenging at the intactlevel. We report here on middle-level (after IdeS digestion) IM-MS and CIU approaches to afford better differentiation of mAb isotypes. Our method provides simultaneously CIU patterns of F(ab’)2and Fc domains within a single run. Middle-level CIU patterns of F(ab’)2 domains enable more reliable classification of mAb isotypes compared to intact level CIU, while CIU fingerprints of Fc domains are overall less informative for mAb isotyping. F(ab’)2regions can thus be considered as diagnostic domains providing specific CIU signatures for mAb isotyping. Benefits of middle-level IM-MS and CIU approaches are further illustrated on the hybrid IgG2/IgG4 eculizumab. While classical analytical techniques led to controversial results, middle-level CIU uniquely allowed to face the challenge of eculizumab « hybridicity », highlighting that its F(ab’)2and Fc CIU patterns corresponds to an IgG2 and an IgG4, respectively. Altogether, the middle-level CIU approach is more clear-cut, accurate and straightforward for canonical but also more complex, engineered next generation mAb formats isotyping. Middle-level CIU thus constitutes a real breakthrough for therapeutic protein analysis, paving the way for its implementation in R&D laboratories.
The effect of statistical normalisation on network propagation scores
Authors: Picart-Armada Sergio , Thompson Wesley K. , Buil Alfonso , Perera-Lluna Alexandre
Published: January 2020

Motivation

Network diffusion and label propagation are fundamental tools in computational biology, with applications like gene-disease association, protein function prediction and module discovery. More recently, several publications have introduced a permutation analysis after the propagation process, due to concerns that network topology can bias diffusion scores. This opens the question of the statistical properties and the presence of bias of such diffusion processes in each of its applications. In this work, we characterised some common null models behind the permutation analysis and the statistical properties of the diffusion scores. We benchmarked seven diffusion scores on three case studies: synthetic signals on a yeast interactome, simulated differential gene expression on a protein-protein interaction network and prospective gene set prediction on another interaction network. For clarity, all the datasets were based on binary labels, but we also present theoretical results for quantitative labels.

Results

Diffusion scores starting from binary labels were affected by the label codification, and exhibited a problem-dependent topological bias that could be removed by the statistical normalisation. Parametric and non-parametric normalisation addressed both points by being codification-independent and by equalising the bias. We identified and quantified two sources of bias -mean value and variance- that yielded performance differences when normalising the scores. We provided closed formulae for both and showed how the null covariance is related to the spectral properties of the graph. Despite none of the proposed scores systematically outperformed the others, normalisation was preferred when the sought positive labels were not aligned with the bias. We conclude that the decision on bias removal should be problem and data-driven, i.e. based on a quantitative analysis of the bias and its relation to the positive entities.

Availability

The code is publicly available athttps://github.com/b2slab/diffuBench

Contact

sergi.picart@upc.edu
Characterising open chromatin identifies novel cis-regulatory elements important for paraxial mesoderm formation and axis extension
Authors: Mok Gi Fay , Folkes Leighton , Weldon Shannon , Maniou Eirini , Martinez-Heredia Victor , Godden Alice , Williams Ruth , Wheeler Grant N. , Moxon Simon , Münsterberg Andrea E.
Published: January 2020

The development of multicellular organisms is exquisitely regulated through differential gene activity, which governs cell differentiation programs. However, many details of spatiotemporal control of gene regulation are still poorly understood. We used the accessibility of chick embryos to examine genome-wide signatures characterizing the progressive differentiation of paraxial mesoderm along the head-to-tail axis. Paraxial mesoderm becomes organized into repetitive units, termed somites, the hallmark of the segmented vertebrate body plan. New somite pairs form periodically as the axis extends at the posterior end. This process generates a developmental gradient within a single embryo, with anterior somites more advanced in their differentiation compared to posterior somites. Following somite formation, cell rearrangements generate compartments, comprising lineages of the musculoskeletal system, including cartilage of the vertebral column and ribs, and skeletal muscle cells of the trunk and limbs. To examine how paraxial mesoderm becomes regionalized and patterned to eventually generate these discrete lineages, we investigated dynamic changes of the transcriptome and of chromatin accessibility using RNA-seq and ATAC-seq across a spatiotemporal series along the embryonic axis. Footprint analysis uncovers differential coverage of binding sites for a number of key transcription factors known to be involved in axial patterning and differentiation, including HOX genes. Furthermore, associating accessible chromatin with nearby expressed genes identifies candidatecis-regulatoryelements (CRE). As exemplars we use TCF15 and MEOX1, which are crucial for somite formation and differentiation, to experimentally validate CREsin vivousing fluorescent reporters. Time-lapse microscopy reveals CRE spatiotemporal activity and mutation analysis uncovers necessary upstream regulators. The CRE for MEOX1 is conserved and recognized in Xenopus. In addition, a human element is active in chicken.In vivoepigenome editing of TCF15 and MEOX1 CREs disrupts gene expression regulation and recapitulates phenotypic abnormalities of anterior-posterior axis extension.
Barley shoot biomass responds strongly to N:P stoichiometry and intraspecific competition, whereas roots only alter their foraging
Authors: Kumar Amit , van Duijnen Richard , Delory Benjamin M. , Reichel Rüdiger , Brüggemann Nicolas , Temperton Vicky M.
Published: January 2020

Background and Aims

Plants respond to various environmental stimuli, and root systems are highly responsive to the availability and distribution of nutrients in the soil. Root system responses to the limitation of either nitrogen (N) or phosphorus (P) are well documented, but how the early root system responds to (co-) limitation of one (N or P) or both (N and P) in a stoichiometric framework is not well known despite its relevance in agriculture. In addition, how plant-plant competition (here intra-specific) alters plant responses to N:P stoichiometry is understudied. Therefore, we aimed to investigate the effects of N:P stoichiometry and competition on root system responses and overall plant performance.

Methods

Plants (Hordeum vulgareL.) were grown in rhizoboxes for 24 days in the presence or absence of competition (three vs. one plant per rhizobox), and fertilized with different combinations of N:P (low N+low P, low N+high P, high N+low P, and high N+high P).

Key Results

Shoot biomass was highest when both N and P were provided in high amounts. In competition, shoot biomass decreased on average by 22%. Interestingly, N:P stoichiometry and competition had no clear effect on root biomass. However, we found distinct root responses in relation to biomass allocation across depths. Specific root length depended on the identity of limiting nutrient (N or P) and presence/absence of competition. Plants rooted deeper when N was the most limiting compared to shallower rooting when P was the most limiting nutrient.

Conclusions

Overall, our study sheds light on the early plant responses to plant-plant competition and stoichiometric availability of two macronutrients most limiting plant performance. With low N and P availability during early growth, higher investments in root system development can significantly trade off with aboveground productivity, and strong intra-specific competition can further strengthen such effects.
Use of Transabdominal Ultrasound for the Detection of Intra-Peritoneal Tumor Engraftment and Growth in Mouse Xenografts of Epithelial Ovarian Cancer
Authors: Chambers Laura M. , Esakov Emily , Braley Chad , AlHilli Mariam , Michener Chad , Reizes Ofer
Published: January 2020

Objective

To evaluate intraperitoneal (IP) tumor engraftment, metastasis and growth in a pre-clinical murine epithelial ovarian cancer (EOC) model using both transabdominal ultrasound (TAUS) and bioluminescencein vivoimaging system (IVIS).

Methods

Ten female C57Bl/6J mice at six weeks of age were included in this study. Five mice underwent IP injection of 5×106ID8-luc cells (+ D-luciferin) and the remaining five mice underwent IP injection of ID8-VEGF cells. Monitoring of tumor growth and ascites was performed weekly starting at seven days post-injection until study endpoint. ID8-luc mice were monitored using both TAUS and IVIS, and ID8-VEGF mice underwent TAUS monitoring only. Individual tumor implant dimension and total tumor volume were calculated. Average luminescent intensity was calculated and reported per mouse abdomen. Tumor detection was confirmed by gross evaluation and histopathology. All data are presented as mean +/- standard deviation.

Results

Overall, tumors were successfully detected in all ten mice using TAUS and IVIS, and tumor detection correlated with terminal endpoint histology/ H&E staining. For TAUS, the smallest confirmed tumor measurements were at seven days post-injection with mean long axis of 2.23mm and mean tumor volume of 4.17mm3. However, IVIS imaging was able to detect tumor growth at 14 days post-injection.

Conclusions

TAUS is highly discriminatory for monitoring EOC in pre-clinical murine model, allowing for detection of tumor dimension as small as 2 mm and as early as seven days post-injection compared to IVUS. In addition, TAUS provides relevant information for ascites development and detection of multiple small metastatic tumor implants. TAUS provides an accurate and reliable method to detect and monitor IP EOC growth in mouse xenografts.