bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining the size of the helium core of KIC 9970396 using asteroseismology: a red giant approaching the red giant bump
Authors: Zhang Xinyi , Li Yan , Wu Tao , Su Jie
Published: March 2020

Mixed modes are less affected by the surface effect and carry internal information of a star. Asteroseismic modelling of mixed modes can constrain the size of the helium core of a star. Previous work has shown that the evolution stage of KIC 9970396 may be near the red giant bump phase, which is one of the most interesting regions in the red giant evolution stage. It is known that there is a clear relation between the core and mass luminosity, following homological principles on the low-luminosity giant branch. Our aim in this paper is to determine the size of the helium core and constrain the internal structure of the star. Our approach is first to identify the most p-dominated frequencies in the observational mixed modes. The calculated frequencies are then fitted to the observational frequencies, which we choose not to correct for surface effect offsets. We have computed a grid of theoretical models to fit the l = 1 modes of KIC 9970396. The size of the helium core of KIC 9970396 is determined to be MHe  = 0.229 ± 0.001 M⊙ and RHe  = 0.03055 ± 0.00015 R⊙. The best-fitting model shows that KIC 9970396 is undergoing a stage that is between the first dredge-up event and the red giant bump. Compared with the results of our model, the previous core–mass luminosity relation overestimates the helium core mass by 0.009 M⊙ when the stellar luminosity of a red giant star is known.
Long-term variation of trochid populations in an Irish sea lough
Authors: Little Colin , Trowbridge Cynthia D , Pilling Graham M , Williams Gray A , Morritt David , Stirling Penny
Published: March 2020

Snapshot assessments of species, which live for a number of years, are often misleading if they are conducted at an inappropriately short temporal scale. Densities of the trochid gastropods Steromphala umbilicalis (da Costa, 1778) and S. cineraria (Linnaeus, 1758) fluctuated widely between 1996 and 2014 at ten rocky-shore sites within Lough Hyne, southwest Ireland. Between 2014 and 2019, the abundance of S. cineraria decreased to levels not seen in the previous two decades. This significant reduction was possibly in response to extreme dissolved oxygen fluctuations related to eutrophication of the semi-enclosed lough. Steromphala umbilicalis showed low density in 2018 and 2019, but this was within the limits of interannual fluctuations. The Lusitanian trochid Phorcus lineatus (da Costa, 1778) was first recorded by us in the lough in the early 2000s, just as it was establishing a flourishing population with densities of c. 6 snails/0.25 m2. Although this native trochid survived the cold winters of 2009–2012, the population suffered high adult mortality and little recruitment. Between 2013 and 2019, the population increased and the population density stabilized. The increase in P. lineatus reflects its position high on the shore, where air temperatures have risen over the last two decades. It may, therefore, be a sentinel species to detect the effects of climate change. By contrast, the decrease in S. cineraria was related to its shallow subtidal habitat where hypoxia and superoxia have recently become marked in the lough. This trochid, therefore, offers potential as an indicator of eutrophication-associated stress. These temporal variations in trochid species emphasize the need for longer term assessments when estimating the importance of any one species to the ecosystem.
Structural basis of UCUU RNA motif recognition by splicing factor RBM20
Authors: Upadhyay Santosh Kumar , Mackereth Cameron D
Published: March 2020

The vertebrate splicing factor RBM20 (RNA binding motif protein 20) regulates protein isoforms important for heart development and function, with mutations in the gene linked to cardiomyopathy. Previous studies have identified the four nucleotide RNA motif UCUU as a common element in pre-mRNA targeted by RBM20. Here, we have determined the structure of the RNA Recognition Motif (RRM) domain from mouse RBM20 bound to RNA containing a UCUU sequence. The atomic details show that the RRM domain spans a larger region than initially proposed in order to interact with the complete UCUU motif, with a well-folded C-terminal helix encoded by exon 8 critical for high affinity binding. This helix only forms upon binding RNA with the final uracil, and removing the helix reduces affinity as well as specificity. We therefore find that RBM20 uses a coupled folding-binding mechanism by the C-terminal helix to specifically recognize the UCUU RNA motif.
Phase I trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) for brainstem recurrent glioma
Authors: Saito Ryuta , Kanamori Masayuki , Sonoda Yukihiko , Yamashita Yoji , Nagamatsu Kenichi , Murata Takaki , Mugikura Shunji , Kumabe Toshihiro , Wembacher-Schröder Eva , Thomson Rowena , Tominaga Teiji
Published: March 2020

Background

Treatment options for patients suffering brainstem gliomas are quite limited as surgery is not an option against intrinsic tumors at brainstem and chemotherapy generally failed to demonstrate its efficacy. Intracerebral convection-enhanced delivery (CED) is a novel approach for administering chemotherapy to patients with brain tumors. We present the results of phase I trial of CED of nimustine hydrochloride (ACNU), designed to determine the maximum tolerable concentration of ACNU, for patients with recurrent brainstem gliomas.

Methods

Sixteen patients, aged 3–81 years old, suffering from recurrent brainstem gliomas, including diffuse intrinsic pontine glioma patients as well as patients with recurrent gliomas that originated from non-brainstem sites, were enrolled in this trial between February 2011 and April 2016. The dose/concentration escalation trial included 3 dose/concentration groups (0.25, 0.5, and 0.75 mg/mL, all at 7 mL) to determine the safety and tolerability of CED of ACNU. Real-time monitoring of drug distribution was performed by mixing gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) in the infusion solution. CED of ACNU was given in combination with oral or intravenous temozolomide chemotherapy.

Results

CED of ACNU demonstrated antitumor activity, as assessed by radiographic changes and prolonged overall survival. The recommended dosage was 0.75 mg/mL. Drug-associated toxicity was minimal.

Conclusions

Intracerebral CED of ACNU under real-time monitoring of drug distribution, in combination with systemic temozolomide, was well tolerated among patients with recurrent brainstem gliomas. The safety and efficacy observed suggest the clinical benefits of this strategy against this devastating disease. Based on this phase I study, further clinical development of ACNU is warranted.
Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury
Authors: Liu Yingxia , Zhang Cong , Huang Fengming , Yang Yang , Wang Fuxiang , Yuan Jing , Zhang Zheng , Qin Yuhao , Li Xiaoyun , Zhao Dandan , Li Shunwang , Tan Shuguang , Wang Zhaoqin , Li Jinxiu , Shen Chenguang , Li Jianming , Peng Ling , Wu Weibo , Cao Mengli , Xing Li , Xu Zhixiang , Chen Li , Zhou Congzhao , Liu William J , Liu Lei , Jiang Chengyu
Published: March 2020

A recent outbreak of pneumonia in Wuhan, China was found to be caused by a 2019 novel coronavirus (2019-nCoV or SARS-CoV-2 or HCoV-19). We previously reported the clinical features of 12 patients with 2019-nCoV infections in Shenzhen, China. To further understand the pathogenesis of COVID-19 and find better ways to monitor and treat the disease caused by 2019-nCoV, we measured the levels of 48 cytokines in the blood plasma of those 12 COVID-19 patients. Thirty-eight out of the 48 measured cytokines in the plasma of 2019-nCoV-infected patients were significantly elevated compared to healthy individuals. Seventeen cytokines were linked to 2019-nCoV loads. Fifteen cytokines, namely M-CSF, IL-10, IFN-α2, IL-17, IL-4, IP-10, IL-7, IL-1ra, G-CSF, IL-12, IFN-γ, IL-1α, IL-2, HGF and PDGF-BB, were strongly associated with the lung-injury Murray score and could be used to predict the disease severity of 2019-nCoV infections by calculating the area under the curve of the receiver-operating characteristics. Our results suggest that 2019-nCoV infections trigger extensive changes in a wide array of cytokines, some of which could be potential biomarkers of disease severity of 2019-nCoV infections. These findings will likely improve our understanding of the immunopathologic mechanisms of this emerging disease. Our results also suggest that modulators of cytokine responses may play a therapeutic role in combating the disease once the functions of these elevated cytokines have been characterized.
Effect of Virtual Reality on Balance in Individuals With Parkinson Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Chen Yi , Gao Qiang , He Cheng-Qi , Bian Rong
Published: March 2020

Background

Virtual reality (VR) is a frequently used intervention for the rehabilitation of individuals with neurological disorders.

Purpose

The aims of this review were to identify the short-term effect of VR on balance and to compare it with the effect of active interventions in individuals with Parkinson disease (PD).

Data Sources

Searches for relevant articles available in English were conducted using the MEDLINE (via PubMed), EMBASE, CENTRAL, CINAHL, PsycINFO, and Physiotherapy Evidence Database databases from inception until March 2019.

Study Selection

All randomized controlled trials comparing the effect of training with VR and the effect of training without VR on balance in individuals with PD were included.

Data Extraction

Two authors independently extracted data, assessed the methodological quality, and evaluated the evidence quality of the studies.

Data Synthesis

Fourteen randomized controlled trials including 574 individuals were eligible for qualitative analyses, and 12 of the studies involving 481 individuals were identified as being eligible for meta-analyses. Compared with active interventions, the use of VR improved the Berg Balance Scale score (mean difference = 1.23; 95% CI = 0.15 to 2.31; I2 = 56%). The Dynamic Gait Index and Functional Gait Assessment results were also significant after the sensitivity analyses (mean difference = 0.69; 95% CI = 0.12 to 1.26; I2 = 0%). Both provided moderate statistical evidence. However, the Timed “Up & Go” Test and the Activities-Specific Balance Confidence Scale did not differ significantly.

Limitations

Publication bias and diversity in the interventions were the main limitations.

Conclusions

Existing moderate evidence of the effectiveness of VR with the Berg Balance Scale, Dynamic Gait Index, and Functional Gait Assessment for individuals with PD was promising. Although the differences did not reach the clinically important change threshold, VR was comparable to active interventions and could be considered an adjuvant therapy for balance rehabilitation in individuals with PD.
A Carol by James Ryman in the Holkham Archives
Authors: Beadle Richard , Smith Anthony
Published: March 2020

A late fifteenth-century manorial notebook in the archives of the Earl of Leicester at Holkham Hall, Norfolk, has been found to contain a hitherto unnoticed and apparently unique late medieval English carol, based on the Latin hymn Te deum. Comparison with other examples of the genre suggests that its author is more likely than not to have been James Ryman, a Franciscan friar of Canterbury, and a prolific writer of carols. His oeuvre includes a number of compositions deriving from the Te deum, to some of which the Holkham text bears significant similarities. The owner of the notebook is identified as William Wayte Jr of Tittleshall, Norfolk, who is known to have served as an estate administrator and agent for the well-known Norfolk lawyer Sir Roger Townshend of Raynham (c.1430–1493). Certain provisions in Wayte’s will suggest that his interest in the carol may have been connected to a devotion on his part to the Trinity, which in late medieval art was often expressed through imagery drawn from the Te deum.
Organizational determinants and idiosyncrasies of firms’ absorptive capacity in a developing country
Authors: Teixeira André Luiz da Silva , Rapini Márcia Siqueira , Caliari Thiago
Published: March 2020

This article analyses the idiosyncrasies and organizational determinants of the absorptive capacity (AC) of firms located in a developing country. Theoretically, this article characterizes a ‘vicious circle of limited AC’ in Latin American firms. Empirically, the Brazilian Innovation Survey (2011 and 2014) is employed to analyze the role of organizational innovation and different innovative efforts to build two types of AC: (1) academic AC (to absorb knowledge from universities or research institutes); (2) market AC (to absorb knowledge from suppliers, clients, or competitors). The main results indicate that firms develop both types of AC through training and acquisition of external Research and Development (R&D), instead of expenditure on internal R&D; academic AC is also built by external relationships and the firms’ researchers’ skills, while market AC is primarily affected by better internal knowledge diffusion. These results qualify the generic argument of limited AC for firms in a Latin American context.
Orchestrating collaborative projects: Inside ICT networks in Horizon 2020
Authors: Enger Simen G , Gulbrandsen Magnus
Published: March 2020

This article investigates decisions taken at the project level in establishing and managing collaborative ICT projects under the European Framework Programme Horizon 2020. Based on interviews with project coordinators from European research organizations, we offer a detailed examination of how projects are built and managed, and how decisions influence the formation of collaborative networks. Projects are typically set up in three stages. In the first, a smaller group that has worked together before decides on the main idea. This leads in the second stage to a gradual invitation of partners to satisfy professional and formal demands, which also defines the structure of the project. If funded, more detailed decisions on ownership and interaction are taken in the third stage. Coordinators are under pressure from the regulatory control of the EU Commission, which can explain the strong preference for well-known partners, but the formal monitoring also provides tools for project managers.
An international Delphi consensus study to define motivational communication in the context of developing a training program for physicians
Authors: Dragomir Anda I , Boucher Vincent Gosselin , Bacon Simon L , Gemme Claudia , Szczepanik Geneviève , Corace Kimberly , Campbell Tavis S , Vallis Michael T , Garber Gary , Rouleau Codie , Rabi Doreen , Diodati Jean G , Ghali William , Lavoie Kim L
Published: March 2020

Poor health behaviors (e.g., smoking, poor diet, and physical inactivity) are major risk factors for noncommunicable chronic diseases (NCDs). Evidence supporting traditional advice-giving approaches to promote behavior change is weak or short lived. Training physicians to improve their behavior change counseling/communication skills is important, yet the evidence for the efficacy and acceptability of existing training programs is lacking and there is little consensus on the core competencies that physicians should master in the context of NCD management. The purpose of this study is to generate an acceptable, evidence-based, stakeholder-informed list of the core communication competencies that physicians should master in the context of NCD management. Using a modified Delphi process for consensus achievement, international behavior change experts, physicians, and allied health care professionals completed four phases of research, including eight rounds of online surveys and in-person meetings over 2 years (n = 13–17 participated in Phases I, III, and IV and n = 39–46 in Phase II). Eleven core communication competencies were identified: reflective listening, expressing empathy, demonstrating acceptance, tolerance, and respect, responding to resistance, (not) negatively judging or blaming, (not) expressing hostility or impatience, eliciting “change-talk”/evocation, (not) being argumentative or confrontational, setting goals, being collaborative, and providing information neutrally. These competencies were used to define a unified approach for conducting behavior change counseling in medical settings: Motivational Communication. The results may be used to inform and standardize physician training in behavior change counseling and communication skills to reduce morbidity and mortality related to poor health behaviors in the context of NCD prevention and management.
A trust model for spreading gossip in social networks: a multi-type bootstrap percolation model
Authors: Bhansali Rinni , Schaposnik Laura P.
Published: March 2020

We introduce here a multi-type bootstrap percolation model, which we call

T

-Bootstrap Percolation

(

T

-BP), and apply it to study information propagation in social networks. In this model, a social network is represented by a graph
G
whose vertices have different labels corresponding to the type of role the person plays in the network (e.g. a student, an educator etc.). Once an initial set of vertices of
G
is randomly selected to be carrying a gossip (e.g. to be infected), the gossip propagates to a new vertex provided it is transmitted by a minimum threshold of vertices with different labels. By considering random graphs, which have been shown to closely represent social networks, we study different properties of the

T

-BP model through numerical simulations, and describe its implications when applied to rumour spread, fake news and marketing strategies.
Reclassification of Francisella noatunensis subsp. orientalis Ottem et al. 2009 as Francisella orientalis sp. nov., Francisella noatunensis subsp. chilensis subsp. nov. and emended description of Francisella noatunensis
Authors: Ramirez-Paredes Jose Gustavo , Larsson Pär , Thompson Kim D. , Penman David J. , Busse Hans-Jürgen , Öhrman Caroline , Sjödin Andreas , Soto Esteban , Richards Randolph H. , Adams Alexandra , Colquhoun Duncan J.
Published: March 2020

Francisella noatunensisis a fastidious facultative intracellular bacterial pathogen that causes ‘piscine francisellosis’, a serious disease affecting both marine and fresh water farmed and wild fish worldwide. Currently twoF. noatunensissubspecies are recognized, i.e.F. noatunensissubsp.noatunensisandF. noatunensissubsp.orientalis. In the present study, the taxonomy ofF. noatunensiswas revisited using a polyphasic approach, including whole genome derived parameters such as digital DNA–DNA hybridization, whole genome average nucleotide identity (wg-ANIm), whole genome phylogenetic analysis, whole genome G+C content, metabolic fingerprinting and chemotaxonomic analyses. The results indicated that isolates belonging toF. noatunensissubsp.orientalisrepresent a phenotypically and genetically homogenous taxon, clearly distinguishable fromF. noatunensissubsp.noatunensisthat fulfils requirements for separate species status. We propose, therefore, elevation ofF. noatunensissubsp.orientalisto the species rank asFrancisella orientalissp. nov. with the type strain remaining as Ehime-1T(DSM 21254T=LMG 24544T). Furthermore, we identified sufficient phenotypic and genetic differences betweenF. noatunensissubsp.noatunensisrecovered from diseased farmed Atlantic salmon in Chile and those isolated from wild and farmed Atlantic cod in Northern Europe to warrant proposal of the Chilean as a novelF. noatunensissubspecies, i.e.Francisella noatunensissubsp.chilensissubsp. nov. with strain PQ1106T(CECT 9798T=NCTC14375T) as the type strain. Finally, we emend the description ofF. noatunensisby including further metabolic information and the description of atypical strains.
Epidemiologic Characteristics of COVID-19 in Guizhou, China
Authors: Ping Kaike , Lei Mingyu , Gou Yun , Tao Ying , Huang Yan
Published: March 2020

At the end of 2019, a coronavirus disease 2019 (COVID-19) outbroke in Wuhan, China, and spread to Guizhou province on January of 2020. To acquire the epidemiologic characteristics of COVID-19 in Guizhou, China, we collected data on 162 laboratory-confirmed cases related to COVID-19. We described the demographic characteristics of the cases and estimated the incubation period, serial interval and basic reproduction number. With an estimation of 8 days incubation period and 6 days serial interval, our results indicate that there may exist infectiousness during the incubation period for 2019-nCoV. This increases the difficulty of screening or identifying cases related to COVID-19.
The Seattle Flu Study: a multi-arm community-based prospective study protocol for assessing influenza prevalence, transmission, and genomic epidemiology
Authors:   Seattle Flu Study Investigators, Chu Helen Y. , Boeckh Michael , Englund Janet A. , Famulare Michael , Lutz Barry R. , Nickerson Deborah A. , Rieder Mark J. , Starita Lea M. , Shendure Jay , Bedford Trevor ,   Co-Investigators, Adler Amanda , Brandstetter Elisabeth , Frazar Chris D. , Han Peter D. , Gulati Reena K. , Hadfield James , Jackson Michael L. , Kiavand Anahita , Kimball Louise E. , Lacombe Kirsten , Logue Jennifer , Lyon Victoria , Newman Kira L. , Sibley Thomas R. , Suchsland Monica L. Zigman , Wolf Caitlin
Published: March 2020

Introduction

Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterize, and potentially contain new and emerging influenza strains at a population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population.

Methods and Analysis

Starting in the 2018-19 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses, and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modeling platforms are in development to characterize the regional spread of influenza and other respiratory pathogens.

Ethics and Dissemination

The study was approved by the University of Washington’s Institutional Review Board. Results will be disseminated through talks at conferences, peer-reviewed publications, and on the study website (www.seattleflu.org).

Article Summary

Strengths and limitations of this study

-

Large-scale multiple-arm study of respiratory illness characterization with collection of samples from individuals in the community as well as in ambulatory care and hospital settings

-

Integration of sociodemographic, clinical, and geospatial data on a regional level

-

Multiplex molecular testing for multiple viral and bacterial pathogens and whole genome sequencing of influenza for detailed molecular epidemiologic characterization and transmission mapping

-

Geographically and socioeconomically diverse sampling of community-based acute respiratory illnesses
Rapid Motor Fluctuations Reveal Short-Timescale Neurophysiological Biomarkers of Parkinson’s Disease
Authors: Ahn Minkyu , Lee Shane , Lauro Peter M. , Schaeffer Erin L. , Akbar Umer , Asaad Wael F.
Published: March 2020

Identifying neural activity biomarkers of brain disease is essential to provide objective estimates of disease burden, obtain reliable feedback regarding therapeutic efficacy, and potentially to serve as a source of control for closed-loop neuromodulation. In Parkinson’s Disease (PD), microelectrode recordings (MER) are routinely performed in the basal ganglia to guide electrode implantation for deep brain stimulation (DBS). While pathologically-excessive oscillatory activity has been observed and linked to PD motor dysfunction broadly, the extent to which these signals provide quantitative information about disease expression and fluctuations, particularly at short timescales, is unknown. Furthermore, the degree to which informative signal features are similar or different across patients has not been rigorously investigated. Here, we recorded neural activity from the subthalamic nucleus (STN) of patients with PD undergoing awake DBS surgery while they performed an objective, continuous behavioral assessment. This approach leveraged natural motor performance variations as a basis to identify corresponding neurophysiological biomarkers. Using machine learning techniques, we show it was possible to use neural signals from the STN to decode the level of motor impairment at short timescales (as short as one second). Spectral power across a wide range of frequencies, beyond the classic “β” oscillations, contributed to this decoding. While signals providing significant information about the quality of motor performance were found throughout the STN, the most informative signals tended to arise from locations in or near the dorsolateral, sensorimotor portion. Importantly, the informative patterns of neural oscillations were not fully generalizable across subjects, suggesting a patient-specific approach will be critical for optimal disease tracking and closed-loop neuromodulation.
Seattle Flu Study - Swab and Send: Study Protocol for At-Home Surveillance Methods to Estimate the Burden of Respiratory Pathogens on a City-Wide Scale
Authors: Kim Ashley E. , Brandstetter Elisabeth , Graham Chelsey , Heimonen Jessica , Osterbind Audrey , McCulloch Denise J. , Han Peter D. , Starita Lea M. , Nickerson Deborah A. , Van de Loo Margaret M. , Mooney Jennifer , Rieder Mark J. , Ilcisin Misja , Fay Kairsten A. , Lee Jover , Sibley Thomas R. , Bedford Trevor , Englund Janet A. , Boeckh Michael , Chu Helen Y.
Published: March 2020

Introduction

While seasonal influenza and other respiratory pathogens cause significant morbidity and mortality each year, the community-based burden of these infections remains incompletely understood. Understanding the prevalence, epidemiology, and transmission dynamics of respiratory pathogen infections among community-dwelling individuals is essential during pandemic and epidemic settings and for developing pandemic-preparedness infrastructure.

Methods and Analysis

We present the protocol for a novel, city-wide home-based cross-sectional study in the Seattle Metropolitan area, utilizing rapid delivery systems for self-collection of a nasal swab and return to the laboratory for respiratory pathogen testing. All participation takes place electronically, including recruitment, consent, and data collection. Within 48 hours of participants self-reporting respiratory symptoms, a nasal swab kit is delivered to the household via a courier service. Demographic and illness characteristics are collected at the time of sample collection and recovery and behavioral information collected one week later. Specimens are tested in the laboratory for multiple respiratory pathogens, and results are available on a public website for participants.

Ethics and Dissemination

The study was approved by the University of Washington Institutional Review Board (Protocol #00006181). Results will be disseminated through peer-reviewed publications, talks at conferences, and on the Study Website (www.seattleflu.org).

Article Summary

The findings of this study will inform whether a home-based approach to city-wide respiratory surveillance is possible in epidemic settings

A key strength of this study is that it is conducted across diverse neighborhoods spanning a major metropolitan area

Clinical findings may not be generalizable, as they are reliant on self-report (vaccination status, symptoms, healthcare utilization, etc.)
Midbrain dopamine neurons encode internal effort signal
Authors: Wang Dong V
Published: March 2020

Midbrain dopamine neurons of the ventral tegmental area (VTA) play a central role in both positive and negative motivation. As motivation and effort are intrinsically connected, we asked how the VTA dopamine neurons may also process internally driven effort signal. We designed two novel jumping tasks, the reward- and escape-motivated jumps, and revealed that the VTA dopamine neurons exhibit an effort-correlated activation during both jumping behaviors.
High-contrast in-vivo imaging of tau pathologies in Alzheimer’s and non-Alzheimer’s disease tauopathies
Authors: Tagai Kenji , Ono Maiko , Kubota Manabu , Kitamura Soichiro , Takahata Keisuke , Seki Chie , Takado Yuhei , Shinotoh Hitoshi , Sano Yasunori , Matsuoka Kiwamu , Takuwa Hiroyuki , Shimojo Masafumi , Takahashi Manami , Kawamura Kazunori , Kikuchi Tatsuya , Okada Maki , Akiyama Haruhiko , Suzuki Hisaomi , Onaya Mitsumoto , Takeda Takahiro , Arai Kimihito , Arai Nobutaka , Araki Nobuyuki , Saito Yuko , Kimura Yasuyuki , Ichise Masanori , Tomita Yutaka , Zhang Ming-Rong , Suhara Tetsuya , Shigeta Masahiro , Sahara Naruhiko , Higuchi Makoto , Shimada Hitoshi
Published: March 2020

SUMMRAY

A panel of radiochemicals has enabled in-vivo positron emission tomography (PET) of tau pathologies in Alzheimer’s disease (AD), while sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In-vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant PSP tau topologies. Notably, the in-vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of autopsied and biopsied brains derived from Pick’s disease, PSP and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on the neuropathological basis.
Integrating Genomic and Transcriptomic Data to Reveal Genetic Mechanisms Underlying Piao Chicken Rumpless Trait
Authors: Wang Yun-Mei , Khederzadeh Saber , Li Shi-Rong , Otecko Newton Otieno , Irwin David M , Thakur Mukesh , Ren Xiao-Die , Wang Ming-Shan , Wu Dong-Dong , Zhang Ya-Ping
Published: March 2020

Piao chicken, a rare Chinese native poultry breed, lacks primary tail structures, such as pygostyle, caudal vertebra, uropygial gland and tail feathers. So far, the molecular mechanisms underlying tail absence in this breed have remained unclear. We employed comprehensive comparative transcriptomic and genomic analyses to unravel potential genetic underpinnings of rumplessness in the Piao chicken. Our results reveal many biological factors involved in tail development and several genomic regions under strong positive selection in this breed. These regions contain candidate genes associated with rumplessness, includingIRX4, IL-18, HSPB2, andCRYAB. Retrieval of quantitative trait loci (QTL) and gene functions implied that rumplessness might be consciously or unconsciously selected along with the high-yield traits in Piao chicken. We hypothesize that strong selection pressures on regulatory elements might lead to gene activity changes in mesenchymal stem cells of the tail bud and eventually result in tail truncation by impeding differentiation and proliferation of the stem cells. Our study provides fundamental insights into early initiation and genetic bases of the rumpless phenotype in Piao chicken.
Tead1 reciprocally regulates adult β-cell proliferation and function to maintain glucose homeostasis
Authors: Lee Jeongkyung , Liu Ruya , Kim Byung S. , Zhang Yiqun , Li Feng , Jagannathan Rajaganapti , Yang Ping , Negi Vinny , Danvers Joseph , Perez-Garcia Eliana Melissa , Saha Pradip K. , Sabek Omaima , Creighton Chad J. , Coarfa Cristian , Huising Mark O. , Shih Hung-Ping , Bottino Rita , Ma Ke , Moulik Mousumi , Yechoor Vijay K.
Published: March 2020

Proliferative quiescence in β-cells is required to maintain functional competence. While this presents a significant hurdle in regenerative therapy for diabetes, the molecular underpinnings of this reciprocal relationship remain unclear. Here, we demonstrate that TEAD1, the transcription effector of the mammalian-Hippo pathway, drives developmental stage-specific β-cell proliferative capacity in conjunction with its functional maturation. TEAD1 promotes adult β-cell mature identity by direct transcriptional control of a network of critical β-cell transcription factors, including,Pdx1, Nkx6.1, and MafA,while its regulation ofCdkn2amaintains proliferative quiescence. Consequently, mice with either constitutive or inducible genetic deletion ofTEAD1in β-cells developed overt diabetes due to a severe loss of secretory function despite induction of proliferation. Furthermore, we show that TEAD1 has a similar regulatory role in human β-cells. Consistent with this function in β-cells, variants inTEAD1have been associated with c-HOMA-B in American Indians. We propose that TEAD1 is an essential intrinsic molecular switch coordinating adult β-cell proliferative quiescence with mature identity and its differential modulation may be necessary to overcome the challenge of inducing proliferation with functional competence in human beta cells.
Molecular Graph Enhanced Transformer for Retrosynthesis Prediction
Authors: Mao Kelong , Zhao Peilin , Xu Tingyang , Rong Yu , Xiao Xi , Huang Junzhou
Published: March 2020

With massive possible synthetic routes in chemistry, retrosynthesis prediction is still a challenge for researchers. Recently, retrosynthesis prediction is formulated as a Machine Translation (MT) task. Namely, since each molecule can be represented as a Simplified Molecular-Input Line-Entry System (SMILES) string, the process of retrosynthesis is analogized to a process of language translation from the product to reactants. However, the MT models that applied on SMILES data usually ignore the information of natural atomic connections and the topology of molecules. To make more chemically plausible constrains on the atom representation learning for better performance, in this paper, we propose a Graph Enhanced Transformer (GET) framework, which adopts both the sequential and graphical information of molecules. Four different GET designs are proposed, which fuse the SMILES representations with atom embeddings learned from our improved Graph Neural Network (GNN). Empirical results show that our model significantly outperforms the vanilla Transformer model in test accuracy.
Algorithm for theoretical mapping of bio-strings for co-expression: bridging genotype to phenotype
Authors: Prakash Om
Published: March 2020

Identification of possibility of co-expression or co-performance directly from set of bio-strings as protein sequences represents an important problem of bridging between genotype to phenotype. This algorithm presents above bridging. Algorithm was implemented with proteins known from human hormone signaling system. Co-expression of proteins was cross-validated through human gene COXPRESdb v7 database. Possibility of protein-protein interaction (PPI) was also cross checked through STRING database. Results were found to be effectively fascinating. Considering the indications from results, this algorithm can be adopted for theoretical identification of co-expression or co-performance of bio-strings.
Differential Regulation of Single Microtubules and Bundles by a Three-Protein Module
Authors: Mani Nandini , Jiang Shuo , Neary Alex E. , Wijeratne Sithara S. , Subramanian Radhika
Published: March 2020

A remarkable feature of the microtubule cytoskeleton is co-existence of sub-populations having different dynamic properties. A prominent example is the anaphase spindle, where stable antiparallel bundles exist alongside dynamic microtubules and provide spatial cues for cytokinesis. How are dynamics of spatially proximal arrays differentially regulated? We reconstitute a minimal system of three midzone proteins: microtubule-crosslinker PRC1, and its interactors CLASP1 and Kif4A, proteins that promote and suppress microtubule elongation, respectively. We find their collective activity promotes elongation of single microtubules, while simultaneously stalling polymerization of crosslinked bundles. This differentiation arises from (i) Strong rescue activity of CLASP1, which overcomes weaker effects of Kif4A on single microtubules, (ii) Lower microtubule and PRC1-binding affinity of CLASP1, which permit dominance of Kif4A at overlaps. In addition to canonical mechanisms where antagonistic regulators set microtubule lengths, our findings illuminate design principles by which collective regulator activity creates microenvironments of arrays with distinct dynamic properties.
Mycobacterium tuberculosisRv0991c is a redox-regulated molecular chaperone
Authors: Becker Samuel H. , Ulrich Kathrin , Dhabaria Avantika , Ueberheide Beatrix , Beavers William , Skaar Eric P. , Iyer Lakshminarayan M. , Aravind L. , Jakob Ursula , Darwin K. Heran
Published: March 2020

The bacterial pathogenMycobacterium (M.) tuberculosisis the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterizedM. tuberculosisprotein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologues in most bacterial lineages and appears to function analogously to the well-characterizedEscherichia coliredox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally co-regulated withhsp60andhsp70chaperone genes inM. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded proteinin vitro, and promotes its refolding by theM. tuberculosisHsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and associates with many otherM. tuberculosisproteins. Importantly, we found Rv0991c is required for the full virulence ofM. tuberculosisin mice. We therefore propose that Rv0991c, which we named “Ruc” (redox-regulated protein withunstructuredC-terminus), represents a founding member of a new chaperone family that protectsM. tuberculosisand other species from proteotoxicity during oxidative stress.

IMPORTANCE

M. tuberculosisinfections are responsible for more than one million human deaths per year. Developing effective strategies to combat this disease requires a greater understanding ofM. tuberculosisbiology. As in all cells, protein quality control is essential for the viability ofM. tuberculosis, which likely faces proteome stress within a host. Here, we identify anM. tuberculosisprotein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial super-kingdom. In addition to elucidating the activity of this chaperone, we found that Ruc was required for fullM. tuberculosisvirulence in mice. This work contributes to a growing appreciation that oxidative stress may provide a particular strain on protein stability in cells, and may likewise play a role inM. tuberculosispathogenesis.
Building Blocks for Integrating Image Analysis Algorithms into a Clinical Workflow
Authors: Juluru Krishna , Shih Hao-Hsin , Elnajjar Pierre , El-Rowmeim Amin , Fox Josef , Siegel Eliot , Keshava Murthy Krishna Nand
Published: March 2020

Purpose

Starting from a broad-based needs assessment and utilizing an image analysis algorithm (IAA) developed at our institution, the purpose of this study was to define generalizable building blocks necessary for the integration of any IAA into a clinical practice.

Methods

An IAA was developed in our institution to process lymphoscintigraphy exams. A team of radiologists defined a set of building blocks for integration of this IAA into clinical workflow. The building blocks served the following roles: (1) Timely delivery of images to the IAA, (2) quality control, (3) IAA results processing, (4) results presentation & delivery, (5) IAA error correction, (6) system performance monitoring, and (7) active learning. Utilizing these modules, the lymphoscintigraphy IAA was integrated into the clinical workflow at our institution. System performance was tested over a 1 month period, including assessment of number of exams processed and delivered, and error rates and corrections.

Results

From June 26-July 27, 2019, the building blocks were used to integrate IAA results from 132 lymphoscintigraphy exams into the clinical workflow, representing 100% of the exams performed during the time period. The system enabled radiologists to correct 21 of the IAA results. All results and corrections were successfully stored in a database. A dashboard allowed the development team to monitor system performance in real-time.

Conclusions

We describe seven building blocks that optimize the integration of IAAs into clinical workflow. The implementation of these building blocks in this study can be used to inform development of more robust, standards-based solutions.
Computer-assisted beat-pattern analysis and the flagellar waveforms of bovine spermatozoa
Authors: Walker Benjamin J. , Phuyal Shiva , Ishimoto Kenta , Tung Chih-Kuan , Gaffney Eamonn A.
Published: March 2020

Plagued by hurdles in information extraction, handling, and processing, computer-assisted sperm analysis (CASA) systems have typically neglected the complex flagellar waveforms of spermatozoa, despite their defining role in cell motility. Recent developments in imaging techniques and data processing have produced significantly-improved methods of waveform digitisation. Here, we utilise these improvements to demonstrate that near-complete flagellar capture is realisable on the scale of hundreds of cells, and, further, that meaningful statistical comparisons of flagellar waveforms may be readily performed with widely-available tools. Representing the advent of high-fidelity computer-assisted beat-pattern analysis (CABA), we show how such a statistical approach can distinguish between samples using complex flagellar beating patterns rather than crude summary statistics. Dimensionality-reduction techniques applied to entire samples also reveal qualitatively-distinct components of the beat, and a novel data-driven methodology for the generation of representative synthetic waveform data is proposed.
The extracellular matrix phenome across species
Authors: Statzer Cyril , Ewald Collin Y.
Published: March 2020

Extracellular matrices are essential for cellular and organismal function. Recent genome-wide and phenome-wide association studies started to reveal a broad spectrum of phenotypes associated with genetic variants. However, the phenome or spectrum of all phenotypes associated with genetic variants in extracellular matrix genes is unknown. Here, we analyzed over two million recorded genotype-to-phenotype relationships across hundreds of species to define their extracellular matrix phenomes. By using previously defined matrisomes of humans, mice, zebrafish,Drosophila, andC. elegans, we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (COL1A1, COL2A1) and fibrillin (FBN1) are each associated with more than 150 distinct phenotypes in humans, whereas collagenCOL4A1, Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found thatMSTN, CTSD, LAMB2, HSPG2, andCOL11A2 and their correspondingorthologues have the most phenotypes across species. Out of the 42’558 unique matrisome genotype-to-phenotype relationships across the five species with defined matrisomes, we have constructed interaction networks to identify the underlying molecular components connecting with orthologues phenotypes and with novel phenotypes. Thus, our networks provide a framework to predict unassessed phenotypes and their potential underlying molecular interactions. These frameworks inform on matrisome genotype-to-phenotype relationships and potentially provide a sophisticated choice of biological model system to study human phenotypes and diseases.

Highlights

7.6% of the human phenome originates from variations in matrisome genes

11’671 phenotypes are linked to matrisome genes of humans, mice, zebrafish,Drosophila, andC. elegans

Expected top ECM phenotypes are developmental, morphological and structural phenotypes

Nonobvious top ECM phenotypes include immune system, stress resilience, and age-related phenotypes
Typicality of Functional Connectivity robustly captures motion artifacts in rs-fMRI across datasets, atlases and preprocessing pipelines
Authors: Kopal Jakub , Pidnebesna Anna , Tomeček David , Tintěra Jaroslav , Hlinka Jaroslav
Published: March 2020

Functional connectivity analysis of resting state fMRI data has recently become one of the most common approaches to characterizing individual brain function. It has been widely suggested that the functional connectivity matrix, calculated by correlating signals from regions of interest, is a useful approximate representation of the brain’s connectivity, potentially providing behaviorally or clinically relevant markers. However, functional connectivity estimates are known to be detrimentally affected by various artifacts, including those due to in-scanner head motion. Treatment of such artifacts poses a standing challenge because of their high variability. Moreover, as individual functional connections generally covary only very weakly with head motion estimates, motion influence is difficult to quantify robustly, and prone to be neglected in practice. Although the use of individual estimates of head motion, or group-level correlation of motion and functional connectivity has been suggested, a sufficiently sensitive measure of individual functional connectivity quality has not yet been established. We propose a new intuitive summary index, the Typicality of Functional Connectivity, to capture deviations from normal brain functional connectivity pattern. Based on results of resting state fMRI for 245 healthy subjects we show that this measure is significantly correlated with individual head motion metrics. The results were further robustly reproduced across atlas granularity and preprocessing options, as well as other datasets including 1081 subjects from the Human Connectome Project. The Typicality of Functional Connectivity provides individual proxy measure of motion effect on functional connectivity and is more sensitive to inter-individual variation of motion than individual functional connections. In principle it should be sensitive also to other types of artifacts, processing errors and possibly also brain pathology, allowing wide use in data quality screening and quantification in functional connectivity studies as well as methodological investigations.