bluuebunny/crossref_metadata_2025 huggingface dataset:
COT-12 The role of clinical research professional in the registration study of pediatric solid tumor in Japan Children’s Cancer Group
Authors: Furukawa Keiko , Makino Yasuhide , Mineharu Yohei , Umeda Katsutsugu , Takita Junko , Arakawa Yoshiki
Published: November 2020

A larger scale prospective registration study for pediatric solid tumor has been conducted nationwide in Japan since 2011 in Japan Children’s Cancer Group (JCCG). In the study, the clinical data and surgical specimen are collected into the National Center for Child Health. Kyoto University Hospital has participated in the study since IRB approval in 2011. We reviewed our patients registered to the study and assessed the role of clinical research professional in the registration study. Fifty-one patients with pediatric brain tumors participated in this study from 2011 to 2020. There were 17 intracranial germ cell tumors, 9 medulloblastomas, 14 gliomas and ependymomas in 5 diffuse midline gliomas, 9 pilocytic astrocytoma, and 2 other types of tumor. Forty surgical specimens were collected for central review. The status of clinical data entry was complete in 33 patients. The registrations and sending of clinical data and specimens have remarkably increased without exceptions since a clinical research professional supported the study in 2018. The study collecting and analyzing pathological diagnosis, molecular diagnosis, treatment, and clinical information in patients with pediatric brain tumor are important to realize the current status. The clinical research professional plays an important role to register patients and to send the specimens and clinical data into the study.
Sources of Dynamism in Modern Administrative Law
Authors: Bell Joanna
Published: November 2020

The list of recognised grounds of judicial review has remained constant in England and Wales for several decades. Modern administrative law may therefore appear to be characterised by high levels of stability or perhaps stagnancy. The essays in The Frontiers of Public Law are, however, an important reminder of three important sources of dynamism across modern administrative law. First, legislation can change regularly in this field, generating novel legal questions. Secondly, internal administrative practices are not static but evolving, creating questions about the adequacy of existing doctrinal structures. Thirdly, principles can emerge within sub-branches of judicial review, giving rise to questions about whether and how those same principles apply elsewhere. These sources of dynamism make modern administrative law ripe territory for novel and important legal issues.
The Early Impact of COVID-19 on Chronic Pain: A Cross-Sectional Investigation of a Large Online Sample of Individuals with Chronic Pain in the United States, April to May, 2020
Authors: Mun Chung Jung , Campbell Claudia M , McGill Lakeya S , Aaron Rachel V
Published: November 2020

Objective

Individuals with chronic pain are uniquely challenged by the COVID-19 pandemic, as increased stress may exacerbate chronic pain, and there are new barriers to receiving chronic pain treatment. In light of this, using a large online sample in the United States, we examined 1) the early impact of COVID-19 on pain severity, pain interference, and chronic pain management; and 2) variables associated with perceived changes in pain severity and pain interference.

Design

A cross-sectional study.

Methods

Online survey data for 1,453 adults with chronic pain were collected via Amazon’s Mechanical Turk platform.

Results

Although a large proportion of participants reported no perceived changes in their pain severity and pain interference since the outbreak, approximately 25–30% of individuals reported exacerbation in these domains. Individuals identifying as Black and of non-Hispanic origin, who experienced greater disruptions in their mood and sleep quality, were more likely to report worsened pain interference. The majority of participants reported engaging in self-management strategies as usual. However, most appointments for chronic pain treatment were either postponed or canceled, with no future session scheduled. Furthermore, a notable proportion of participants had concerns about or difficulty accessing prescription opioids due to COVID-19.

Conclusions

We may expect to see a long-term exacerbation of chronic pain and related interference in functioning and chronic pain management among individuals most impacted by the pandemic. These individuals may benefit from remotely delivered intervention to effectively mitigate COVID-19–related exacerbations in chronic pain and interruptions in face-to-face treatment.
The Use of the Seattle Angina Questionnaire in Patients Who Underwent Spinal Cord Stimulation for Refractory Angina Pectoris
Authors: Langford Brendan , Hunt Christine , Lerman Amir , Mauck William D
Published: November 2020

Background

The Seattle Angina Questionnaire (SAQ) is a self-administered questionnaire used in cardiac patients to quantify angina based on five scales: physical limitation scale, anginal stability scale, anginal frequency scale, treatment satisfaction scale, and the disease perception scale. Here we report the use of the SAQ to assess angina symptoms in 18 patients who underwent spinal cord stimulation (SCS) for refractory angina pectoris (RAP) at the Mayo Clinic.

Methods

Electronic health records were searched to find patients who underwent SCS for the treatment of RAP at a single institution from 2003 to 2018. Eligible patients were asked to participate in a phone survey that included the SAQ.

Results

Out of 13 patients who still had their implant, six (46%) had minimal physical limitations. Ten patients (76.9%) had favorable anginal frequency scores, defined as minimal or mild. Out of the five patients who had their device removed, one (20%) had minimal physical limitations and three (60%) had favorable anginal frequency scores. There was a high treatment satisfaction score for both those with their implant in place and those with the device removed.

Conclusion

The SAQ is useful as a comprehensive measure specific to patients with RAP assessing function, pain, and satisfaction. The utilization of this tool pre- and post-operatively may provide additional information to analyze the effectiveness of SCS for RAP.
Regeneration of critical-sized defects, in a goat model, using a dextrin-based hydrogel associated with granular synthetic bone substitute
Authors: Pereira Isabel , Pereira José Eduardo , Maltez Luís , Rodrigues Alexandra , Rodrigues Catarina , Oliveira Manuela , Silva Dina M , Caseiro Ana Rita , Prada Justina , Maurício Ana Colette , Santos José Domingos , Gama Miguel
Published: November 2020

The development of injectable bone substitutes (IBS) have obtained great importance in the bone regeneration field, as a strategy to reach hardly accessible defects using minimally invasive techniques and able to fit to irregular topographies. In this scenario, the association of injectable hydrogels and bone graft granules is emerging as a well-established trend. Particularly, in situ forming hydrogels have arisen as a new IBS generation. An in situ forming and injectable dextrin-based hydrogel (HG) was developed, aiming to act as a carrier of granular bone substitutes and bioactive agents. In this work, the HG was associated to a granular bone substitute (Bonelike®) and implanted in goat critical-sized calvarial defects (14 mm) for 3, 6 and 12 weeks. The results showed that HG improved the handling properties of the Bonelike® granules and did not affect its osteoconductive features, neither impairing the bone regeneration process. Human multipotent mesenchymal stromal cells from the umbilical cord, extracellular matrix hydrolysates and the pro-angiogenic peptide LLKKK18 were also combined with the IBS. These bioactive agents did not enhance the new bone formation significantly under the conditions tested, according to micro-computed tomography and histological analysis.
Strontium ranelate incorporated 3D porous sulfonated PEEK simulating MC3T3-E1 cell differentiation
Authors: Sun Yingxiao , Liu Xingdan , Tan Ji , Lv Dan , Song Wengang , Su Rui , Li Ling , Liu Xuanyong , Ouyang Liping , Liao Yun
Published: November 2020

Polyetheretherketone (PEEK) has been used as an implant material because it has similar mechanical properties to natural bone. However, inferior osseointegration and bioinertness hamper the clinical application of PEEK. In this study, the surfaces of sulfonated three-dimensional (3D) PEEK porous structures were loaded with different concentrations of strontium ranelate, a compound commonly used in the treatment or prevention of osteoporosis by promoting bone formation and inhibiting bone resorption. Field-emission scanning electron microscopy was used to characterize the topography of the structures, elemental carbon, oxygen and strontium contents were measured by X-ray photoelectron spectroscopy, and surface zeta potentials and water-contact angle were also measured. The results indicated that strontium ranelate was successfully loaded onto the 3D porous structures. In vitro cellular results showed that strontium ranelate-treated sulfonated PEEK (SP-SR) strengthened the adhesion of MC3T3-E1 cells. The activity of alkaline phosphatase, collagen secretion and extracellular matrix mineralization deposition of MC3T3-E1 cells were also improved on the surface of SP-SR. These results indicate that SP-SR could serve a new implant candidate for surgical treatment.
A Multimodal Sepsis Quality-Improvement Initiative Including 24/7 Screening and a Dedicated Sepsis Response Team-Reduced Readmissions and Mortality
Authors: Alnababteh Muhtadi H. , Huang Sean Shenghsiu , Ryan Andrea , McGowan Kevin M. , Yohannes Seife
Published: November 2020

Objectives:

To evaluate if a hospitalwide sepsis performance improvement initiative improves compliance with the Centers for Medicare and Medicaid Services-mandated sepsis bundle interventions and patient outcomes.

Study Design:

Retrospective analysis comparing 6 months before and 14 months after intervention.

Setting:

Tertiary teaching hospital in Washington, DC.

Subjects:

Patients admitted with a diagnosis of sepsis to a tertiary hospital.

Interventions:

Implementation of a multimodal quality-improvement initiative.

Measurements and Main Results:

A total of 4,102 patients were diagnosed with sepsis, severe sepsis, or septic shock during the study period, 861 patients (21%) were diagnosed during a 6-month preintervention period, and 3,241 (79%) were diagnosed in a 13-month postintervention period. Adjusted for patient case-mix, the prevalence of simple sepsis increased by 12%, but it decreased for severe sepsis and septic shock by 5.3% and 6.9%, respectively. Compliance with all sepsis bundle interventions increased by 31.1 percentage points (p < 0.01). All-cause hospital readmission and readmission due to infection were both reduced by 1.6% and 1.7 percentage points (p < 0.05). Death from any sepsis diagnosis was reduced 4.5% (p < 0.01). Death from severe sepsis and septic shock both was reduced by 5% (p < 0.01) and 6.5% (p < 0.01), respectively.

Conclusions:

After the implementation of multimodal sepsis performance initiatives, we observed a higher prevalence of sepsis secondary to screening but a lower prevalence of severe sepsis and septic shock, an improvement in compliance with the sepsis bundle interventions bundle, as well as reduction in hospital readmission and all- cause mortality rate.
The Unyvero Hospital-Acquired pneumonia panel for diagnosis of secondary bacterial pneumonia in COVID-19 patients
Authors: Tellapragada Chaitanya , Giske Christian G.
Published: November 2020

The study was undertaken to evaluate the performance of Unyvero Hospitalized Pneumonia Panel (HPN) Application, a multiplex PCR based method for the detection of bacterial pathogens from lower respiratory tract (LRT) samples, obtained from COVID-19 patients with suspected secondary hospital-acquired pneumonia. Residual LRT samples obtained from critically ill COVID-19 patients with predetermined microbiological culture results were tested using the Unyvero HPN Application. Performance evaluation of the HPN Application was carried out using the standard-of-care (SoC) microbiological culture findings as the reference method. Eighty-three LRT samples were used in the evaluation. The HPN Application had a full concordance with SoC findings in 59/83 (71%) samples. The new method detected additional bacterial species in 21 (25%) and failed at detecting a bacterial species present in lower respiratory culture in 3 (3.6%) samples. Overall the sensitivity, specificity, positive and negative predictive values of the HPN Application were 95.1% (95%CI: 96.5-98.3%); 98.3% (95% CI: 97.5-98.9%); 71.6% (95% CI: 61.0-80.3%) and 99.8% (95% CI: 99.3-99.9%) respectively. In conclusion, the HPN Application demonstrated higher diagnostic yield in comparison with the culture and generated results within 5 hours.
Clonal hematopoiesis is associated with risk of severe Covid-19
Authors: Bolton Kelly L. , Koh Youngil , Foote Michael B. , Im Hogune , Jee Justin , Sun Choong Hyun , Safonov Anton , Ptashkin Ryan , Moon Joon Ho , Lee Ji Yeon , Jung Jongtak , Kang Chang Kyung , Song Kyoung-Ho , Choe Pyeong Gyun , Park Wan Beom , Kim Hong Bin , Oh Myoung-don , Song Han , Kim Sugyeong , Patel Minal , Derkach Andriy , Gedvilaite Erika , Tkachuk Kaitlyn A. , Braunstein Lior Z. , Gao Teng , Papaemmanuil Elli , Babady N. Esther , Pessin Melissa S. , Kamboj Mini , Diaz Luis A. , Ladanyi Marc , Rauh Michael J. , Natarajan Pradeep , Machiela Mitchell J. , Awadalla Philip , Joseph Vijai , Offit Kenneth , Norton Larry , Berger Michael F , Levine Ross L , Kim Eu Suk , Kim Nam Joong , Zehir Ahmet
Published: November 2020

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival.1–4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH.2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19.7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10−3) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
Can machine learning aid in identifying disease genes? The case of autism spectrum disorder
Authors: Gunning Margot , Pavlidis Paul
Published: November 2020

Discovering genes involved in complex human genetic disorders is a major challenge. Many have suggested that machine learning (ML) algorithms using gene networks can be used to supplement traditional genetic association-based approaches to predict or prioritize disease genes. However, questions have been raised about the utility of ML methods for this type of task due to biases within the data, and poor real-world performance. Using autism spectrum disorder (ASD) as a test case, we sought to investigate the question: Can machine learning aid in the discovery of disease genes? We collected thirteen published ASD gene prioritization studies and evaluated their performance using known and novel high-confidence ASD genes. We also investigated their biases towards generic gene annotations, like number of association publications. We found that ML methods which do not incorporate genetics information have limited utility for prioritization of ASD risk genes. These studies perform at a comparable level to generic measures of likelihood for the involvement of genes in any condition, and do not out-perform genetic association studies. Future efforts to discover disease genes should be focused on developing and validating statistical models for genetic association, specifically for association between rare variants and disease, rather than developing complex machine learning methods using complex heterogeneous biological data with unknown reliability.
Infection-Induced Extracellular Vesicles Evoke Neuronal Transcriptional and Epigenetic Changes
Authors: Tedford Ellen , Badya Norhidayah Binti , Laing Conor , Asaoka Nozomi , Kaneko Shuji , Filippi Beatrice Maria , McConkey Glenn Alan
Published: November 2020

Infection with the protozoanToxoplasma gondiiinduces changes in neurotransmission, neuroinflammation, and behavior, yet it remains elusive how these changes come about. In this study we investigated how norepinephrine levels are altered by infection. TINEV (Toxoplasma-induced neuronal extracellular vesicles) isolated from infected noradrenergic cells down-regulated dopamine β-hydroxylase (DBH) gene expression in human and rodent cells. Here we report that intracerebral injection of TINEVs into the brain is sufficient to induceDBHdown-regulation and distrupt catecholaminergic signalling. Further, TINEV treatment induced hypermethylation upstream of the DBH gene. An antisense lncRNA toDBHwas found in purified TINEV preparations. Paracrine signalling to induce transcriptional gene silencing and DNA methylation may be a common mode to regulate neurologic function.
Spatial heterogeneity of glioblastoma cells reveals sensitivity to NAD+ depletion at tumor edge
Authors: Yamashita Daisuke , Botta Davide , Cho Hee Jin , Guo Xiaoxian , Ozaki Saya , Flanary Victoria L , Sirota Inna , Gao Mu , Yamaguchi Shinobu , Nakano Mayu A , Zhou Fen , Zhou Hongyi , Kondo Toru , Kunieda Takeharu , Crossman David K , Kornblum Harley I , Gorospe Myriam , Nam Do-Hyun , Zamboni Nicola , Skolnick Jeffrey , Gu Zhenglong , Lund Frances E , Nakano Ichiro
Published: November 2020

Even after total resection of glioblastoma core lesions by surgery and aggressive post-surgical treatments, life-threatening tumors inevitably recur. A characteristic obstacle in effective treatment is high intratumoral heterogeneity, both longitudinally and spatially. Recurrence occurs predominantly at the brain parenchyma-tumor core interface, a region termed tumor edge. Given the difficulty of accessing it surgically, the composition of the tumor edge, harboring both cancerous and non-cancerous cells, remains largely unknown. Here, to identify phenotypic diversity among heterogeneous glioblastoma core and edge lesions, we uncovered the existence of three phenotypically-distinct clonal subpopulations within individual tumors from glioblastoma patients. Clones from the tumor core shared the same phenotype, exclusively generating tumor-core cells. In contrast, two distinct clonal subtypes were identified at the tumor edge: one generated only edge-lesion cells and the other expanded more broadly to establish both edge- and core-lesions. Using multiple xenograft experimental models in mouse brains, tumor edge development was found to require that both somatic and tumor cells express the NADase CD38, combinedly elevating glioblastoma malignancy. In vitro data suggested that intracellular NADase activity at the edge was provoked through intercellular communication between edge clones and normal astrocytes. Systemic treatment of tumor-bearing mice with 78c, a small-molecule CD38 inhibitor, attenuated the formation of glioblastoma edge lesions, suggesting its clinical potential to pharmacologically eliminate tumor-edge lesions. Collectively, these findings provide novel phenotypic and mechanistic insights into clonal heterogeneity within glioblastoma, particularly in the surgically unresectable, currently understudied tumor edge.
Integrated Ligand and Structure based approaches towards developing novel Janus Kinase 2 inhibitors for the treatment of myeloproliferative neoplasms
Authors: Ambili Unni.P , Pillai Girinath G. , Sajitha Lulu.S
Published: November 2020

Myeloproliferative neoplasms (MPNs) are a group of diseases affecting hematopoiesis in humans. Types of MPNs include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and myelofibrosis. JAK2 gene mutation at 617thposition act as a major causative factor for the onset and progression of MPNs. So, JAK2 inhibitors are widely used for the treatment of MPNs. But, increased incidence of adverse drug reactions associated with JAK2 inhibitors acts as a paramount challenge in the treatment of MPNs. Hence, there exists an urgent need for the identification of novel lead molecules with enhanced potency and bioavailability. We employed ligand and structure-based approaches to identify novel lead molecules which could act as JAK2 inhibitors. The dataset for QSAR modeling (ligand-based approach) comprised of 49 compounds. We have developed a QSAR model, which has got statistical as well as biological significance. Further, all the compounds in the dataset were subjected to molecular docking and bioavailability assessment studies. Derivative compounds with higher potency and bioavailability were identified for the best lead molecule present in the dataset by employing chemical space exploration. Dataset and models are available athttps://github.com/giribio/agingdata

Abstract Figure

Graphical abstract
Patient-derived models of brain metastases recapitulate the histopathology and biology of human metastatic cancers
Authors: Faria Claudia C. , Custódia Carlos , Cascão Rita , Paisana Eunice , Carvalho Tânia , Pereira Pedro , Roque Rafael , Pimentel José , Miguéns José , Barata João T.
Published: November 2020

Purpose

Dissemination of cancer cells from primary tumors to the brain is observed in the great majority of cancer patients, contributing to increased morbidity and being the main cause of death. Most mechanistic and preclinical studies have relied on aggressive cancer cell lines, which fail to represent tumor heterogeneity and are unsuitable to validate therapies due to fast cancer progressionin vivo.

Experimental design

We established a unique library of subcutaneous and intracardiac patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumor origins. Cancer progression in mice was compared to the matched patient clinical outcome, metastatic dissemination pattern and histopathological features. Preclinical studies with FDA approved drugs were performed.

Results

In vivotumor formation of flank-implanted BMs correlated with patients’ poor survival and serial passaging increased tumor aggressiveness. Subcutaneous xenografts originated spontaneous metastases in 61% of the cases, including in the leptomeningeal space (21%). The intracardiac model increased the tropism to the brain and leptomeninges (46%). Strikingly, 62% of intracardiac PDXs shared metastatic sites with the donor patients, including the primary cancer organ and the central nervous system (CNS). Of therapeutic relevance, PDX-derived cultures and corresponding mouse xenografts can be effectively treated with targeted anticancer drugs.

Conclusions

Patient-derived models of BMs recapitulate the biology of human metastatic disease and can be a valuable translational platform for precision medicine.

TRANSLATIONAL RELEVANCE

Subcutaneous and intracardiac mouse xenografts of human brain metastases exhibit a spontaneous dissemination pattern that resembles patients’ metastatic disease. The preclinical testing of targeted anticancer drugs using patient-derived cultures and patient-derived xenografts of brain metastasis showed an effective therapeutic response. These translational models represent an outstanding tool to advance the understanding of the biology of brain metastases and to foster the rapid discovery of novel therapeutics.
RangeShifter 2.0: An extended and enhanced platform for modelling spatial eco-evolutionary dynamics and species’ responses to environmental changes
Authors: Bocedi Greta , Palmer Stephen C. F. , Malchow Anne-Kathleen , Zurell Damaris , Watts Kevin , Travis Justin M. J.
Published: November 2020

Process-based models are becoming increasingly used tools for understanding how species are likely to respond to environmental changes and to potential management options. RangeShifter is one such modelling platform, which has been used to address a range of questions including identifying effective reintroduction strategies, understanding patterns of range expansion and assessing population viability of species across complex landscapes.

Here we introduce a new version, RangeShifter 2.0, which incorporates important new functionality. It is now possible to simulate dynamics over user-specified, temporally changing landscapes. Additionally, the genetic and evolutionary capabilities have been strengthened, notably by introducing an explicit genetic modelling architecture, which allows for simulation of neutral and adaptive genetic processes. Furthermore, emigration, transfer and settlement rules can now all evolve, allowing for sophisticated simulation of the evolution of dispersal. We illustrate the potential application of RangeShifter 2.0’s new functionality by two examples. The first illustrates the range expansion of a virtual species across a dynamically changing UK landscape. The second demonstrates how the software can be used to explore the concept of evolving connectivity in response to land-use modification, by examining how movement rules come under selection over landscapes of different structure and composition.

RangeShifter 2.0 is built using object-oriented C++ providing computationally efficient simulation of complex individual-based, eco-evolutionary models. The code has been redeveloped to enable use across operating systems, including on high performance computing clusters, and the Windows GUI has been enhanced. Furthermore, the recoding of the package has supported the development of a new version running under the R platform, RangeShiftR.

RangeShifter 2.0 will facilitate the development of in-silico assessments of how species will respond to environmental changes and to potential management options for conserving or controlling them. By making the code available open source, we hope to inspire further collaborations and extensions by the ecological community.
Predicting the impact of sequence motifs on gene regulation using single-cell data
Authors: Hepkema Jacob , Lee Nicholas Keone , Stewart Benjamin J. , Ruangroengkulrith Siwat , Charoensawan Varodom , Clatworthy Menna R. , Hemberg Martin
Published: November 2020

Background

Binding of transcription factors (TFs) at proximal promoters and distal enhancers is central to gene regulation. Yet, identification of TF binding sites, also known as regulatory motifs, and quantification of their impact on gene expression remains challenging.

Results

Here we infer putative regulatory motifs along with their cell type-specific importance using a convolutional neural network trained on single-cell data. Comparison of the importance score to expression levels across cells allows us to identify the TFs most likely to be binding at a given motif. Using multiple mouse tissues we obtain a model with cell type resolution which explains 29% of the variance in gene expression. Finally, by applying scover to distal enhancers identified using scATAC-seq from the mouse cerebral cortex we characterize changes in distal regulatory motifs during development.

Conclusions

It is possible to identify regulatory motifs as well as their importance from single-cell data using a neural network model where all of the parameters and outputs are easily interpretable to the user.
Naturalistic affective behaviors decoded from spectro-spatial features of multi-day human intracranial recordings
Authors: Bijanzadeh Maryam , Khambhati Ankit N. , Desai Maansi , Wallace Deanna L. , Shafi Alia , Dawes Heather E. , Sturm Virginia E. , Chang Edward F.
Published: November 2020

Task-based studies have uncovered distributed neural networks that support emotions, but little is known about how these networks produce affective behaviors in non-laboratory, ecological settings. We obtained continuous intracranial electroencephalography (iEEG) recordings from the emotion network in 11 patients with epilepsy during multi-day hospitalizations. We coded naturalistic affective behaviors (spontaneous expressions of positive or negative affect) from 116 hours of time-locked video recordings obtained over multiple days from subjects’ hospital rooms and utilized data driven classifiers to determine whether we could decode naturalistic affective behaviors from the neural data. Results indicated that binary within-subject random forest models could decode positive and negative affective behaviors from affectless behaviors (behaviors lacking valence) with up to 93% accuracy. Across the emotion network, positive and negative affective behaviors were associated with increased high frequency activity and decreased lower frequency activity. The anterior insula, amygdala, hippocampus, and anterior cingulate cortex (ACC) made strong contributions to affective behaviors in general. In a subset of subjects, three-state decoders distinguished among the positive, negative, and affectless behaviors using the spectro-spatial features from the emotion network. This study demonstrates that multi-day, highly resolved iEEG recordings in cortical and deep brain structures can reveal the circuit-level physiology of affective behaviors. By measuring behavior in an ecologically valid setting, our findings provide novel insights into the spatially distributed dynamics of local neural populations underlying naturalistic affective behaviors.

Significance

Previous neuroimaging and neurophysiological studies have identified a distributed network that supports emotions, but much remains unknown about how this network produces affective behaviors in ecological settings. We used intracranial electroencephalography recordings from the emotion network to decode naturalistic affective behaviors—spontaneous expressions of positive and negative affect that occurred during multi-day hospital stays—from neural data in patients with epilepsy. Our results complement prior neuroscientific studies of emotion and offer novel insights into the spectral and spatial dynamics of the emotion network that characterize naturalistic affective behaviors. The present study suggests intracranial electroencephalography can uncover new details about emotion network physiology and help to expand current neuroanatomical frameworks of human emotions.
Revisiting the Neural Architecture of Adolescent Decision-Making: Univariate and Multivariate Evidence for System-Based Models
Authors: Moreira João F. Guassi , Méndez Leal Adriana S. , Waizman Yael H. , Saragosa-Harris Natalie , Ninova Emilia , Silvers Jennifer A.
Published: November 2020

Understanding adolescent decision-making is significant for informing basic models of neurodevelopment as well as for the domains of public health and criminal justice. System-based theories posit that adolescent decision-making is guided by activity amongst reward and control processes. While successful at explaining behavior, system-based theories have received inconsistent support at the neural level, perhaps because of methodological limitations. Here, we used two complementary approaches to overcome said limitations and rigorously evaluate system-based models. Using decision-level modeling of fMRI data from a risk-taking task in a sample of 2000+ decisions across 51 human adolescents (25 females, mean age = 15.00 years), we find support for system-based theories of decision-making. Neural activity in lateral prefrontal cortex and a multivariate pattern of cognitive control both predicted a reduced likelihood of risk-taking, whereas increased activity in the nucleus accumbens predicted a greater likelihood of risk-taking. Interactions between decision-level brain activity and age were not observed. These results garner support for system-based accounts of adolescent decision-making behavior.

Significance Statement

Adolescent decision-making behavior is of great import for basic science, and carries equally consequential implications for public health and criminal justice. While dominant psychological theories seeking to explain adolescent decision-making have found empirical support, their neuroscientific implementations have received inconsistent support. This may be partly due to statistical approaches employed by prior neuroimaging studies of system-based theories. We used brain modeling—an approach that predicts behavior from brain activity—of univariate and multivariate neural activity metrics to better understand how neural components of psychological systems guide decision behavior in adolescents. We found broad support for system-based theories such that neural systems involved in cognitive control predicted a reduced likelihood to make risky decisions, whereas value-based systems predicted greater risk-taking propensity.
FrustratometeR: an R-package to compute local frustration in protein structures, point mutants and MD simulations
Authors: Rausch Atilio O. , Freiberger Maria I. , Leonetti Cesar O. , Luna Diego M. , Radusky Leandro G. , Wolynes Peter G. , Ferreiro Diego U. , Parra R. Gonzalo
Published: November 2020

Once folded, natural protein molecules have few energetic conflicts within their polypeptide chains. Many protein structures do however contain regions where energetic conflicts remain after folding, i. e. they have highly frustrated regions. These regions, kept in place over evolutionary and physiological timescales, are related to several functional aspects of natural proteins such as protein-protein interactions, small ligand recognition, catalytic sites and allostery. Here we present FrustratometeR, an R package that easily computes local energetic frustration on a personal computer or a cluster. This package facilitates large scale analysis of local frustration, point mutants and molecular dynamics (MD) trajectories, allowing straightforward integration of local frustration analysis into pipelines for protein structural analysis.

Contact

gonzalo.parra@embl.de

Availability and implementation

https://github.com/proteinphysiologylab/frustratometeR
Study of Real-Valued Distance Prediction For Protein Structure Prediction with Deep Learning
Authors: Li Jin , Xu Jinbo
Published: November 2020

Inter-residue distance prediction by deep ResNet (convolutional residual neural network) has greatly advanced protein structure prediction. Currently the most successful structure prediction methods predict distance by discretizing it into dozens of bins. Here we study how well real-valued distance can be predicted and how useful it is for 3D structure modeling by comparing it with discrete-valued prediction based upon the same deep ResNet. Different from the recent methods that predict only a single real value for the distance of an atom pair, we predict both the mean and standard deviation of a distance and then employ a novel method to fold a protein by the predicted mean and deviation. Our findings include: 1) tested on the CASP13 FM (free-modeling) targets, our real-valued distance prediction obtains 81% precision on top L/5 long-range contact prediction, much better than the best CASP13 results (70%); 2) our real-valued prediction can predict correct folds for the same number of CASP13 FM targets as the best CASP13 group, despite generating only 20 decoys for each target; 3) our method greatly outperforms a very new real-valued prediction method DeepDist in both contact prediction and 3D structure modeling; and 4) when the same deep ResNet is used, our real-valued distance prediction has 1-6% higher contact and distance accuracy than our own discrete-valued prediction, but less accurate 3D structure models.
New Structural Insights into the Function of the Catalytically Active Human Taspase1
Authors: Nagaratnam Nirupa , Delker Silvia L. , Jernigan Rebecca , Edwards Thomas E. , Snider Janey , Thifault Darren , Williams Dewight , Nannenga Brent L. , Stofega Mary , Sambucetti Lidia , Hsieh James J. , Flint Andrew J. , Fromme Petra , Martin-Garcia Jose M.
Published: November 2020

Proteases can play essential roles in severe human pathology, ranging from degenerative and inflammatory illnesses to infectious diseases, with some, such as Taspase1, involved in growth and progression of tumors at primary and metastatic sites. Taspase1 is a N-terminal nucleophile (Ntn)-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cellsin vitroand in mouse xenograft models of glioblastoma, thus this protein has the potential to become a novel anticancer drug target. It belongs to the family of Ntn-hydrolases, a unique family of proteins synthesized as enzymatically inactive proenzymes that become activated upon cleavage of the peptide bond on the N-terminal side of a threonine residue, which then becomes the catalytic site nucleophile. The activation process simultaneously changes the conformation of a long domain at the C-terminus of the alpha-subunit for which no full-length structural information exists and its function is poorly understood. Here we present a novel cloning strategy to generate a fully active, circularly permuted form of Taspase1 to determine the crystallographic structure of catalytically active human Taspase1 to 3.04Å. We discovered that this region forms a long helical domain and is indispensable for the catalytic activity of Taspase1. Together, our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases and suggests that this long domain could be a novel target for the design of inhibitors with the potential to be developed into anticancer therapeutics.
DANGO: Predicting higher-order genetic interactions
Authors: Zhang Ruochi , Bafna Mihir , Ma Jianzhu , Ma Jian
Published: November 2020

Higher-order genetic interactions, which have profound implications for understanding the molecular mechanisms of phenotypic variation, remain poorly characterized. Most studies to date have focused on pairwise interactions, as designing high-throughput experimental screenings for the vast combinatorial search space of higher-order molecular interactions is dauntingly challenging. Here, we develop Dango, a computational method based on a self-attention hypergraph neural network, designed to effectively predict higher-order genetic interaction among groups of genes. As a proof-of-concept, we provide comprehensive predictions for over 400 million trigenic interactions in the yeastS. cerevisiae, significantly expanding the quantitative characterization of such interactions. Our results demonstrate that Dangoaccurately predicts trigenic interactions, uncovering both known and novel biological functions related to cell growth. We further incorporate protein embeddings and model uncertainty scoring to enhance the biological relevance and interpretability of the predicted interactions. Moreover, the predicted interactions can serve as powerful genetic markers for growth response under diverse conditions. Together, Dangoenables a more complete map of complex genetic interactions that impinge upon phenotypic diversity.
Linear integration of sensory evidence over space and time underlies face categorization
Authors: Okazawa Gouki , Sha Long , Kiani Roozbeh
Published: November 2020

Visual object recognition relies on elaborate sensory processes that transform retinal inputs to object representations, but it also requires decision-making processes that read out object representations and function over prolonged time scales. The computational properties of these decision-making processes remain underexplored for object recognition. Here, we study these computations by developing a stochastic multi-feature face categorization task. Using quantitative models and tight control of spatiotemporal visual information, we demonstrate that humans categorize faces through an integration process that first linearly adds the evidence conferred by task-relevant features over space to create aggregated momentary evidence, and then linearly integrates it over time with minimum information loss. Discrimination of stimuli along different category boundaries (e.g., identity or expression of a face) is implemented by adjusting feature weights of spatial integration. This linear but flexible integration process overspaceandtimebridges past studies on simple perceptual decisions to complex object recognition behavior.
Hemoglobin drives inflammation and initiates antigen spread and nephritis in lupus
Authors: Sharma Hritika , Bose Anjali , Kumar Uma , Pal Rahul
Published: November 2020

Hemoglobin (Hb) has well-documented inflammatory effects and is normally efficiently scavenged; clearance mechanisms can be overwhelmed during conditions of erythrocyte lysis, a condition that may occur in systemic lupus erythematosus. Whether Hb is preferentially inflammatory in lupus and additionally induces autoreactivity against prominent autoantigens was assessed. Peripheral blood mononuclear cells derived from SLE patients secreted higher levels of lupus-associated inflammatory cytokines when incubated with Hb, effects negated by haptoglobin. Hb (more particularly, ferric Hb) triggered the preferential release of lupus-associated cytokines from splenocytes, B cells, CD4 T cells, CD8 T cells and plasmacytoid dendritic cells isolated from aging NZM2410 mice, and also had mitogenic effects on B cells. Ferric Hb activated multiple signaling pathways which were differentially responsible for the generation of specific cytokines; inflammatory signaling also appeared to be cell-context dependent. Pull-downs, followed by mass spectrometry, revealed interactions of Hb with several lupus-associated autoantigens; co-incubation of ferric Hb with apoptotic blebs (structures which contain packaged autoantigens, believed to trigger lupus autoreactivity) revealed synergies (in terms of cytokine release and autoantibody productionin vitro) that were also restricted to the lupus genotype. Infusion of ferric Hb into NZM2410 mice led to enhanced release of lupus-associated cytokines, the generation of a spectrum of autoantibodies, and enhanced-onset glomerulosclerosis. Given that the biased recognition of ferric Hb in a lupus milieu, in concert with lupus-associated autoantigens, elicits the generation of inflammatory cytokines from multiple immune cell types and stimulates the generation of potentially pathogenic autoantibodies, neutralization of Hb could have beneficial effects.
Investigations into modifications of neuromuscular physiology by axonal transport disruptions inDrosophilaSOD1 mutants
Authors: O’Harrow Tristan C. D. G. , Ueda Atsushi , Xing Xiaomin , Wu Chun-Fang
Published: November 2020

The reactive oxygen species (ROS)-scavenging enzyme Cu/Zn superoxide dismutase (SOD1) is an evolutionarily conserved mechanism for the maintenance of oxidative homeostasis, and missense mutations in the human SOD1 gene are associated with the motor neuron degenerative disease amyotrophic lateral sclerosis (ALS). Mutations in theDrosophila melanogasterSOD1 gene (Sod) shorten fly lifespan, attenuate motor function, and induce developmental mortality. We have previously found morphological and physiological defects at the neuromuscular junctions (NMJs) of hypomorphicSodn108and ALS modelSodG85Rmutant larvae. Here, we report genetic interactions causing striking modifications ofSodmutant phenotypes by mutations in the genePrickle(Pk), which are linked to planar cell polarity, epilepsy, and axonal transport disruptions.Pkis expressed as two isoformsprickle-spiny-legs(sple) andprickle-prickle(pk), which are each suppressed by specific hypomorphic mutations (sple1andpk1). Interestingly,Sodphenotypes are distinctly modified depending on both thePkisoform suppressed, and whether said suppression is heterozygous or homozygous. Heterozygoussple1andpk1improved the developmental survival ofSodmutants, whereas homozygoussple1andpk1drastically increased mortality. Further, only heterozygoussple1andpk1clearly ameliorated morphological defects at the neuromuscular junctions ofSodmutant larvae. Pharmacological treatment ofSodmutants reveals allele-specific motor neuron terminal hyperexcitability, characterized by synaptic transmissions of extended duration and abnormal presynaptic Ca2+transients. Heterozygoussple1mutation suppresses thisSodmutant terminal hyperexcitability, butpk1does not. We reversed this suppressive effect ofsple1by pharmacological blockade of Ca2+-activated K+channelslowpoke. Altogether, this study builds on our prior knowledge ofSodmutant development and physiology to show that axonal transport-linked gene mutations strikingly modifySodmutant phenotypes, providing strong evidence for a role of intracellular transport in alterations of neuromuscular morphology and physiology by SOD1 mutations.
Unheeded SARS-CoV-2 proteins? A deep look into negative-sense RNA
Authors: Bartas Martin , Volná Adriana , Beaudoin Christopher A. , Poulsen Ebbe Toftgaard , Červeň Jiří , Brázda Václav , Špunda Vladimír , Blundell Tom L. , Pečinka Petr
Published: November 2020

SARS-CoV-2 is a novel positive-sense single-stranded RNA virus from the Coronaviridae family (genus Betacoronavirus), which has been established as causing the COVID-19 pandemic. The genome of SARS-CoV-2 is one of the largest among known RNA viruses, comprising of at least 26 known protein-coding loci. Studies thus far have outlined the coding capacity of the positive-sense strand of the SARS-CoV-2 genome, which can be used directly for protein translation. However, it has been recently shown that transcribed negative-sense viral RNA intermediates that arise during viral genome replication from positive-sense viruses can also code for proteins. No studies have yet explored the potential for negative-sense SARS-CoV-2 RNA intermediates to contain protein coding-loci. Thus, using sequence and structure-based bioinformatics methodologies, we have investigated the presence and validity of putative negative-sense ORFs (nsORFs) in the SARS-CoV-2 genome. Nine nsORFs were discovered to contain strong eukaryotic translation initiation signals and high codon adaptability scores, and several of the nsORFs were predicted to interact with RNA-binding proteins. Evolutionary conservation analyses indicated that some of the nsORFs are deeply conserved among related coronaviruses. Three-dimensional protein modelling revealed the presence of higher order folding among all putative SARS-CoV-2 nsORFs, and subsequent structural mimicry analyses suggest similarity of the nsORFs to DNA/RNA-binding proteins and proteins involved in immune signaling pathways. Altogether, these results suggest the potential existence of still undescribed SARS-CoV-2 proteins, which may play an important role in the viral lifecycle and COVID-19 pathogenesis.

Contact

petr.pecinka@osu.cz; tlb20@cam.ac.uk