bluuebunny/crossref_metadata_2025 huggingface dataset:
Upper limb rehabilitation in facioscapulohumeral dystrophy (FSHD): a patients perspective
Authors: Kulshrestha Richa , Emery Nicholas , Faux-Nightingale Alice , Willis Tracey , Philp Fraser
Published: May 2020

Purpose: The study aims to identify exercise programmes used by Facioscapulohumeral dystrophy (FSHD) patients in the community, along with barriers and perceptions. Methods: A web based survey, distributed to patients on the UK FSHD registry, and focus groups were conducted. Thematic analysis was conducted on answers to survey questions supported by focus group notes, from seven FSHD patients. Results: A response rate of 43.6% was achieved with 232 out of 532 patients completing the survey. Only 44.4% engaged with exercises targeting the upper body. The themes from the data were: 1) Understanding of disease mechanism shaping exercise choice 2) Lack of understanding about the condition and how exercise interacts with it 3) Support from professionals 4) Barriers to exercise and 5) Thoughts about future research. Conclusion: Exercise selection was variable amongst FSHD patients. Lack of information, pain, fatigue, availability and access to facilities, cost and time were identified as barriers to exercise. Participants (92.2%) agreed additional research into upper limb exercises is needed and felt a 3-month arm cycling intervention with monthly clinical visits and MRI imaging would be appropriate. Further research is needed to develop evidence based exercise interventions and guidance for upper limb exercise prescription in FSHD.
Systemic corticosteroids show no benefit in severe and critical COVID-19 patients in Wuhan, China: A retrospective cohort study
Authors: Wu Jianfeng , Huang Jianqiang , Zhu Guochao , Liu Yihao , Xiao Han , Zhou Qian , Si Xiang , Yi Hui , Wang Cuiping , Yang Daya , Chen Shuling , Liu Xin , Liu Zelong , Wang Qiongya , Lv Qingquan , Huang Ying , Yu Yang , Guan Xiangdong , Li Yanbing , Nirantharakumar Krishnarajah , Cheng KarKeung , Peng Sui , Xiao Haipeng
Published: May 2020

Background: Systemic corticosteroids are recommended by some treatment guidelines and used in severe and critical COVID-19 patients, though evidence supporting such use is limited.
Methods: From December 26, 2019 to March 15, 2020, 1514 severe and 249 critical hospitalized COVID-19 patients were collected from two medical centers in Wuhan, China. We performed multivariable Cox models, Cox model with time-varying exposure and propensity score analysis (both inverse-probability-of-treatment-weighting (IPTW) and propensity score matching (PSM)) to estimate the association of corticosteroid use with the risk of in-hospital mortality among severe and critical cases.
Results: Corticosteroids were administered in 531 (35.1%) severe and 159 (63.9%) critical patients. Compared to no corticosteroid use group, systemic corticosteroid use showed no benefit in reducing in-hospital mortality in both severe cases (HR=1.77, 95% CI: 1.08-2.89, p=0.023), and critical cases (HR=2.07, 95% CI: 1.08-3.98, p=0.028). In the time-varying Cox analysis that with time varying exposure, systemic corticosteroid use still showed no benefit in either population (for severe patients, HR=2.83, 95% CI: 1.72-4.64, p< 0.001; for critical patients, HR=3.02, 95% CI: 1.59-5.73, p=0.001). Baseline characteristics were matched after IPTW and PSM analysis. For severe COVID-19 patients at admission, corticosteroid use was not associated with improved outcome in either the IPTW analysis. For critical COVID-19 patients at admission, results were consistent with former analysis that corticosteroid use did not reduce in-hospital mortality.
Conclusions: Corticosteroid use showed no benefit in reducing in-hospital mortality for severe or critical cases. The routine use of systemic corticosteroids among severe and critical COVID-19 patients was not recommended.
Comparative Safety of Therapies for Hyperthyroidism Planning Pregnancy: A Network Meta-analysis
Authors: Fang Xiaohua , Huang Huibin , Lin Wei , Liang Jixing , Wen Junping , Chen Gang
Published: May 2020

Objective: Our intention was to compare the pregnancy safety in women with hyperthyroidism seeking future pregnancy after ATD, RAI or thyroidectomy treatment and to explore the optimum treatment strategy. We hope the results will guide the choice for endocrinologists and patients, and be beneficial for promoting eugenics.
Methods: We searched multiple databases though December 2019. The outcome indicators were abortion, preterm birth, IUGR and birth defect. We conducted a frequency-framework network meta-analysis by using Stata and R software. The results of the intervention comparison were expressed as OR with 95%CI, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.
Results: The network meta-analysis included 4 retrospective cohort studies with a total enrollment of 480 patients. 1)Thyroidectomy had a lower risk of abortion than RAI [OR=0.77, 95%CI (0.23, 2.56)] and ATD [OR=0.68, 95%CI (0.21, 2.21)]. RAI had a lower risk of abortion than ATD [OR=0.88, 95%CI (0.45, 1.75)]. Based on SUCRA results, thyroidectomy (0.698) was followed by RAI (0.494), ATD (0.308). Thyroidectomy (60.7%) had the highest probability of being first compared to RAI (27.0%) and ATD (12.4%). 2)Thyroidectomy had a lower risk of preterm birth than RAI [OR=0.80, 95%CI (0.26, 2.44)] and ATD [OR=0.79, 95%CI (0.39, 1.59)]. RAI had a lower risk of preterm birth than ATD [OR=0.98, 95%CI (0.42, 2.33)]. Based on SUCRA results, thyroidectomy (0.703) was followed by RAI (0.430), ATD (0.367). Thyroidectomy (57.8%) had the highest probability of being first compared with RAI (30.5%) and ATD (11.8%). 3)Thyroidectomy had a lower risk of IUGR than RAI [OR=0.28, 95%CI (0.03, 3.02)] and ATD [OR=0.83, 95%CI (0.14, 4.86)]. RAI had a higher risk of IUGR than ATD [OR=3.02, 95%CI (0.60, 15.27)]. Based on SUCRA results, thyroidectomy (0.717) was followed by ATD (0.663), RAI (0.120). Thyroidectomy (56.6%) had the highest probability of being first compared with RAI (5.4%) and ATD (37.9%). 4)Thyroidectomy had a lower risk of birth defect than RAI [OR=0.70, 95%CI (0.02, 30.34)] and ATD [OR=0.23, 95%CI (0.01, 4.52)]. RAI had a lower risk of birth defect than ATD [OR=0.32, 95%CI (0.03, 3.12)] (Table 2). Based on SUCRA results, thyroidectomy (0.70) was followed by RAI (0.629), ATD (0.171). Thyroidectomy (55.9%) had the highest probability of being first compared with RAI (41.3%) and ATD (2.8%).
Conclusion: Thyroidectomy was the optimum option for women with hyperthyroidism seeking near future pregnancy. The future research direction is to include more samples to conduct head-to-head randomized controlled trials or prospective cohort studies, establish inclusion criteria for various pre-pregnancy conditions or further subgroup analysis, and develop more acceptable, safer, and more manageable treatments that allow for the remission of both thyroid function and autoimmune abnormalities.
Online COVID-19 diagnosis with chest CT images: Lesion-attention deep neural networks
Authors: Liu Bin , Gao Xiaoxue , He Mengshuang , Lv Fengmao , Yin Guosheng
Published: May 2020

Chest computed tomography (CT) scanning is one of the most important technologies for COVID-19 diagnosis and disease monitoring, particularly for early detection of coronavirus. Recent advancements in computer vision motivate more concerted efforts in developing AI-driven diagnostic tools to accommodate the enormous demands for the COVID-19 diagnostic tests globally. To help alleviate burdens on medical systems, we develop a lesion-attention deep neural network (LA-DNN) to predict COVID-19 positive or negative with a richly annotated chest CT image dataset. Based on the textual radiological report accompanied with each CT image, we extract two types of important information for the annotations: One is the indicator of a positive or negative case of COVID-19, and the other is the description of five lesions on the CT images associated with the positive cases. The proposed data-efficient LA-DNN model focuses on the primary task of binary classification for COVID-19 diagnosis, while an auxiliary multi-label learning task is implemented simultaneously to draw the model’s attention to the five lesions associated with COVID-19. The joint task learning process makes it a highly sample-efficient deep neural network that can learn COVID-19 radiology features more effectively with limited but high-quality, rich-information samples. The experimental results show that the area under the curve (AUC) and sensitivity (recall), precision, and accuracy for COVID-19 diagnosis are 94.0%, 88.8%, 87.9%, and 88.6% respectively, which reach the clinical standards for practical use. A free online system is currently alive for fast diagnosis using CT images at the websitehttps://www.covidct.cn/, and all codes and datasets are freely accessible at our github address.
Patterns of COVID-19 related excess mortality in the municipalities of Northern Italy
Authors: Gibertoni Dino , Adja Kadjo Yves Cedric , Golinelli Davide , Reno Chiara , Regazzi Luca , Fantini Maria Pia
Published: May 2020

The Coronavirus Disease 2019 (COVID-19) spatial distribution in Italy is inhomogeneous, because of its ways of spreading from the initial hotspots. The impact of COVID-19 on mortality has been described at the regional level, while less is known about mortality in demographic subgroups within municipalities.
We aimed to describe the excess mortality (EM) due to COVID-19 in the three most affected Italian regions, by estimating EM in subgroups defined by gender and age classes within each municipality from February 23 to March 31, 2020.
EM varied widely among municipalities even within the same region; it was similar between genders for the ≥75 age group, while in the other age groups it was higher in males. Thus, nearby municipalities may show a different mortality burden despite being under common regional health policies, possibly as a result of policies adopted both at the regional and at the municipality level.
The roles of stewardship and socioeconomic status in geographic variation in antibiotic prescribing: an observational study
Authors: Kissler Stephen M , Klevens R Monina , Barnett Michael L , Grad Yonatan H
Published: May 2020

Importance

Reducing geographic disparities in antibiotic prescribing is a central public health priority to combat antibiotic resistance, but the drivers of this variation have been unclear.

Objective

To measure how differences in outpatient visit rates per 1,000 individuals (‘observed disease’) and in antibiotic prescribing rates per outpatient visit (‘stewardship’) each contributed to a gap in monthly antibiotic prescriptions per 1,000 individuals in Boston vs. the rest of Massachusetts, and to identify spatial correlates of the medical conditions that contributed most to the gap.

Design

We conducted an observational study of medical insurance claims collected between January 2011 and September 2015.

Setting

Outpatient visits in Massachusetts.

Participants

5,028,609 Massachusetts residents under the age of 65 with at least one full month of primary medical insurance during the study period.

Exposures

Residence in Boston vs. the rest of Massachusetts.

Main outcomes

(1) The proportion of the gap in antibiotic prescribing rate between Boston and the rest of Massachusetts attributable to observed disease vs. stewardship for 20 medical conditions previously associated with antibiotic prescribing; and (2) geographic correlations between childhood vaccination, air pollution, density of children, and social deprivation index with the medical conditions that best explain the gap in prescribing.

Results

The average monthly antibiotic prescribing rate per 1,000 individuals in Boston was 51.8 (IQR 43.4, 57.5) vs. 65.2 (IQR 54.8, 74.5) in the rest of Massachusetts. Geographic differences in outpatient visit rates accounted for 56.0% of the gap in antibiotic prescribing between Boston and the rest of the state, while differences in stewardship accounted for just 19.8% of the gap. Geographic differences in outpatient visit rates for sinusitis, pharyngitis, and suppurative otitis media accounted for 43.3% of the gap in prescribing between Boston and the rest of Massachusetts. Social deprivation index best explains the geographic variation in outpatient visit rates for respiratory illness, with fewer visits in census tracts with higher social deprivation index.

Conclusions and relevance

Interventions aimed at reducing geographic disparities in antibiotic prescribing should target the drivers of outpatient visits for respiratory illness and should account for possible under-utilization of health services in areas with the lowest antibiotic consumption. Our findings challenge the conventional wisdom that prescribing practices are the main driver of geographic disparities in antibiotic use.
FSC-Q: A CryoEM map-to-atomic model quality validation based on the local Fourier Shell Correlation
Authors: Ramírez-Aportela Erney , Maluenda David , Fonseca Yunior C. , Conesa Pablo , Marabini Roberto , Heymann J. Bernard , Carazo Jose Maria , Sorzano Carlos Oscar S.
Published: May 2020

In recent years, advances in cryoEM have dramatically increased the resolution of Coulomb potential maps and, with it, the number of solved atomic models. It is widely accepted that the quality of cryoEM maps varies locally; therefore, the evaluation of the maps-derived structural models must be done locally as well. In this article, a method for the local analysis of the map-to-model fit is presented. The algorithm uses a comparison of two local resolution maps. The first is the local FSC (Fourier shell correlation) between the full map and the model, while the second is calculated between the half maps normally used in typical single particle analysis workflows. We call the new quality measure “FSC-Q”, and it is a quantitative estimation of how much of the model is supported by the signal content of the map. Furthermore, we show that FSC-Q may be helpful to avoid overfitting. It can be used to complement other methods, such as the Q-score method that estimates the resolvability of atoms.
Single Trial Decoding of Movement Intentions Using Functional Ultrasound Neuroimaging
Authors: Norman Sumner L. , Maresca David , Christopoulos Vasileios N. , Griggs Whitney S. , Demene Charlie , Tanter Mickael , Shapiro Mikhail G. , Andersen Richard A.
Published: May 2020

Brain-machine interfaces (BMI) are powerful devices for restoring function to people living with paralysis. Leveraging significant advances in neurorecording technology, computational power, and understanding of the underlying neural signals, BMI have enabled severely paralyzed patients to control external devices, such as computers and robotic limbs. However, high-performance BMI currently require highly invasive recording techniques, and are thus only available to niche populations. Here, we show that a minimally invasive neuroimaging approach based on functional ultrasound (fUS) imaging can be used to detect and decode movement intention signals usable for BMI. We trained non-human primates to perform memory-guided movements while using epidural fUS imaging to record changes in cerebral blood volume from the posterior parietal cortex – a brain area important for spatial perception, multisensory integration, and movement planning. Using hemodynamic signals acquired during movement planning, we classified left-cued vs. right-cued movements, establishing the feasibility of ultrasonic BMI. These results demonstrate the ability of fUS-based neural interfaces to take advantage of the excellent spatiotemporal resolution, sensitivity, and field of view of ultrasound without breaching the dura or physically penetrating brain tissue.
SimBit: A high performance, flexible and easy-to-use population genetic simulator
Authors: Matthey-Doret Remi
Published: May 2020

SimBit is a general purpose and high performance forward-in-time population genetics simulator. SimBit has been designed to be able to model a wide diversity of complex scenarios from a simple set of commands that are very flexible. SimBit also comes with a R wrapper that simplifies the management of an entire research project from the creation of a grid of parameters and corresponding inputs, running simulations and gathering outputs for analysis. Implementing various representations of the individual’s genotype allows SimBit to sustain a high performance in a wide diversity of simulation scenarios. SimBit’s performance was extensively benchmarked in comparison to SLiM, Nemo and SFS_CODE. No single program systematically outperforms the others but SimBit is most often the highest performing program and maintains high performance in all scenarios considered.
Non-canonical role forLpar1-EGFPsubplate neurons in early postnatal somatosensory cortex
Authors: Ghezzi Filippo , Marques-Smith Andre , Anastasiades Paul , Lyngholm Daniel , Vagnoni Cristiana , Rowett Alexandra , Hoerder-Suabedissen Anna , Nakagawa Yasushi , Molnár Zoltán , Butt Simon
Published: May 2020

Subplate neurons (SPNs) are a transient neuronal population shown to play a key role in nascent sensory processing relaying thalamic information to the developing cerebral cortex. However there is little understanding of how heterogeneity within this population relates to emergent function. To address this question we employed optical and electrophysiological technologies to investigate the synaptic connectivity of SPNs defined by expression of theLpar1-EGFPtransgene through the first postnatal week in primary whisker somatosensory cortex (S1BF) in mouse. Our data identify that theLpar1-EGFPSPNs represent two morphological subtypes: (1) transient, fusiform SPNs with axons largely restricted to the subplate zone; (2) pyramidal SPNs with axon collaterals that traverse the overlying cortex to extend through the marginal zone. Laser scanning photostimulation of caged glutamate was used to determine columnar glutamatergic and GABAergic input onto both of these SPN subtypes. These experiments revealed that the former receive translaminar input from more superficial cortical layers up until the emergence of the whisker barrels (~postnatal (P)5). In contrast, pyramidal SPNs only receive local input from the adjacent subplate network at early ages but then at later ages can acquire varied input from the overlying cortex. Combined electrical stimulation of the ventral posterior nucleus of the thalamus and optogenetic activation of thalamic afferents in thalamocortical slice preparations revealed thatLpar1-EGFPSPNs only receive sparse thalamic innervation during early postnatal development. Taken together, these data reveal two components of the postnatal network that interpret sparse thalamic input to direct the emergent columnar structure of neonatal somatosensory cortex.
EpiDope: A Deep neural network for linear B-cell epitope prediction
Authors: Collatz Maximilian , Mock Florian , Hölzer Martin , Barth Emanuel , Sachse Konrad , Marz Manja
Published: May 2020

By binding to specific structures on antigenic proteins, the so-called epitopes, B-cell antibodies can neutralize pathogens. The identification of B-cell epitopes is of great value for the development of specific serodiagnostic assays and the optimization of medical therapy. However, identifying diagnostically or therapeutically relevant epitopes is a challenging task that usually involves extensive laboratory work. In this study, we show that the time, cost and labor-intensive process of epitope detection in the lab can be significantly shortened by usingin silicoprediction. Here we presentEpiDope, a python tool which uses a deep neural network to detect B-cell epitope regions on individual protein sequences (github.com/mcollatz/EpiDope). With an area under the curve (AUC) between 0.67 ± 0.07 in the ROC curve,EpiDopeexceeds all other currently used B-cell prediction tools. Moreover, for AUC10% (AUC for a false-positive rate < 0.1),EpiDopeimproves the prediction accuracy in comparison to other state-of-the-art methods. Our software is shown to reliably predict linear B-cell epitopes of a given protein sequence, thus contributing to a significant reduction of laboratory experiments and costs required for the conventional approach.
Comparing fMRI responses measured at 3 versus 7 Tesla across human cortex, striatum, and brainstem
Authors: Colizoli Olympia , de Gee Jan Willem , van der Zwaag Wietske , Donner Tobias H.
Published: May 2020

Significant progress has been made in ultra-high field functional magnetic resonance imaging (fMRI) at 7 Tesla (T). While fMRI at 7 T promises a general increase in sensitivity compared to lower field strengths, the benefits may be most pronounced for specific applications. The current study aimed to evaluate the relative benefit of 7 T over 3 T fMRI for the assessment of task-evoked fMRI responses in different brain regions. We compared the amplitude of task-evoked responses between 3 T and 7 T measured from the same human participants. Participants performed a challenging random dot motion discrimination task with delayed monetary feedback, which animal physiology has linked to several cortical and subcortical structures including extrastriate (dorsal) visual cortical areas, the striatum, and the brainstem including dopaminergic midbrain nuclei. We quantified the evoked fMRI responses in each of these brain regions during the decision interval and the post-feedback interval of the task, and compared them between brain regions and field strengths. The dependence of response amplitudes on field strength during the decision interval differed between cortical, striatal, and brainstem regions, with a generally bigger 7 T vs. 3 T benefit in subcortical (in particular brainstem) structures. We also found stronger differential responses during easy than hard decisions at 7 T for the dopaminergic nuclei, possibly reflecting reward expectation. Our results demonstrate the potential of 7 T fMRI for illuminating the contribution of small brainstem nuclei to the orchestration of cognitive computations in the human brain.

Highlights

We compared 7 T to 3 T fMRI during perceptual decision-making under uncertainty.

Differences between 7 T and 3 T evoked responses and tSNR varied across the brain.

Evoked responses in dopaminergic brainstem nuclei were bigger at 7 T than 3 T.

The responses of dopaminergic nuclei are consistent with reward expectation.

Results highlight the potential of 7 T fMRI for imaging small brainstem nuclei.
Coexistence of long and short DNA constructs within adhesion plaques
Authors: Li Long , Kamal Mohammad Arif , Stumpf Henning , Thibaudau Franck , Sengupta Kheya , Smith Ana-Sunčana
Published: May 2020

Adhesion domains forming at the membrane interfaces between two cells or a cell and the ex-tracellular matrix commonly involve multiple proteins bridges. However, the physical mechanisms governing the domain structures are not yet fully resolved. Here we present a joint experimental and theoretical study of a mimetic model-system, based on giant unilammelar vesicles interacting with supported lipid bilayers, with which the underlying physical effects can be clearly identified. In our case, adhesion is induced by simultaneous action of DNA linkers with two different lengths. We study the organization of bridges into domains as a function of relative fraction of long and short DNA constructs. Irrespective of the composition, we systematically find adhesion domains with coexisting DNA bridge types, despite their relative differences in length of 9 nm. However, at short length scales, below the optical resolution of the microscope, simulations suggest the formation of nanodomains by the minority fraction. The nano-aggregation is more significant for long bridges, which are also more stable, even though the enthalpy of membrane insertion is the same for both species.
Electrophysiological correlates of visual backward masking in patients with bipolar disorder
Authors: Garobbio Simona , Roinishvili Maya , Favrod Ophélie , da Cruz Janir Ramos , Chkonia Eka , Brand Andreas , Herzog Michael H.
Published: May 2020

Background

In visual backward masking (VBM), a target is followed by a mask that decreases target discriminability. Schizophrenia patients (SZ) show strong and reproducible masking impairments, which are associated with reduced EEG amplitudes. Patients with bipolar disorder (BP) show masking deficits, too. Here, we investigated the neural EEG correlates of VBM in BP.

Methods

122 SZ, 94 unaffected controls, and 38 BP joined a standard VBM experiment. 123 SZ, 94 unaffected controls and 16 BP joined a corresponding EEG experiment, analyzed in terms of the global field power.

Results

As in previous studies, SZ and BP show strong masking deficits. Importantly and similarly to SZ, BP show decreased global field power amplitudes at approximately 200 ms after the target onset, compared to controls.

Conclusions

These results suggest that VBM deficits are not specific for schizophrenia but for a broader range of functional psychoses. Potentially, both SZ and BP show deficient target enhancement.
A cyclin-dependent kinase 5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
Authors: Seo Jinsoo , Pao Ping-Chieh , Kritskiy Oleg , Lee Audrey , Patnaik Debasis , Watson L. Ashely , Bula Michael , Barker Scarlett J. , Penney Jay , Silva M. Catarina , Haggarty Stephen J. , Tsai Li-Huei
Published: May 2020

Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage of the Cdk5 activator p35 to produce the truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit of blocking p25 production has been demonstrated in various rodent and human neurodegenerative models. However, important Cdk5/p35 functions in the developing and adult brain have made it challenging to selectively target the detrimental effects of Cdk5/p25 while sparing the physiological functions of Cdk5/p35. Here, we report a 12-amino acid-long peptide fragment derived from Cdk5 (the Cdk5 inhibitory (Cdk5i) peptide) that shows a high binding affinity toward the Cdk5/p25 complex and can efficiently and selectively inhibit Cdk5/p25 kinase activity. Using cellular assays, mouse neurodegeneration models and human cerebral organoids generated from patient-derived iPSCs, we demonstrate beneficial effects of the Cdk5i peptide on various pathological phenotypes including gliosis, DNA damage, and Tau hyperphosphorylation.
Skin conductance rise time and amplitude discern between different degrees of emotional arousal induced by affective pictures presented on a computer screen
Authors: Jindrová Miroslava , Kocourek Martin , Telenský Petr
Published: May 2020

Skin Conductance Response (SCR) is a phasic change in electric conductivity of the skin, occurring either non-specifically, or in response to a stimulus (event-related, or ER-SCR). It has long been understood that ER-SCR amplitudes are greater when associated with unpleasant or high-arousal stimuli; however, the relationship between emotional valence and arousal to other ER-SCR measures such as ER-SCR latency (interval between stimulus onset and ER-SCR onset) and ER-SCR rise time (interval between ER-SCR onset and peak amplitude) is less well-established. Here, we presented 60 emotive pictures from IAPS and NAPS affective picture systems to a group of 100 young, healthy adults (50 male and 50 female) and recorded their electrodermal activity. We found that higher emotional arousal was associated with greater ER-SCR amplitudes and shorter ER-SCR rise times. Interestingly, while the increase in ER-SCR amplitudes was only observed for a subset of high-arousal stimuli (score 7-9 on a 9 point scale), the effect on ER-SCR rise times was more graded and particularly sensitive to the difference between low (score 1-3) and medium-arousal (score 4-6) categories. Next, we found that while ER-SCR amplitudes were greater in response to unpleasant stimuli (valence score 1-3 on a 9-point scale), none of the ER-SCR measures could distinguish between neutral (score 4-6) and positive stimuli (score 7-9). We suggest that the increase in ER-SCR amplitudes for unpleasant stimuli is primarily driven by the inherent association between unpleasantness and high arousal. In conclusion, we demonstrate that ER-SCR rise time conveys valuable information about emotional arousal and represents a useful complementary measure to ER-SCR amplitude in order to discern between multiple degrees of emotional arousal. Furthermore, this study confirms the cross-cultural validity of the IAPS and NAPS databases in a sample of young adult Czechs.
Integrated technology platform for accelerated discovery of antiviral antibody therapeutics
Authors: Gilchuk Pavlo , Bombardi Robin G. , Erasmus Jesse H. , Tan Qing , Nargi Rachel , Soto Cinque , Abbink Peter , Suscovich Todd J , Durnell Lorellin A. , Khandhar Amit , Archer Jacob , Liang Jenny , Fouch Mallorie E. , Davidson Edgar , Doranz Benjamin J. , Jones Taylor , Larson Elise , Ertel Stacey , Granger Brian , Fuerte-Stone Jasmine , Roy Vicky , Broge Thomas , Linnekin Thomas C. , Linde Caitlyn H. , Gorman Matthew J. , Nkolola Joseph , Alter Galit , Reed Steven G. , Barouch Dan H. , Diamond Michael S. , Crowe James E. , Van Hoeven Neal , Thackray Larissa , Carnahan Robert
Published: May 2020

The emergence and reemergence of highly virulent viral pathogens with pandemic potential has created an urgent need for accelerated discovery of antiviral therapeutics. Antiviral human monoclonal (mAbs) are promising drug candidates to prevent or treat severe viral diseases, but the long timelines needed for discovery limits their rapid deployment and use. Here, we report the development of an integrated sequence of technologies incorporating advances in single-cell mRNA sequence analysis, bioinformatics, synthetic biology, and high-throughput functional analysis that allowed us to discover highly potent antiviral human mAbs and validate their activityin vivoat an unprecedented scale, speed, and efficiency. In a 78-day study, modeling deployment of a rapid response platform to an outbreak, we isolated >100 individual Zika virus (ZIKV) specific human mAbs, assessed their function, identified 29 broadly-neutralizing mAbs, and verified therapeutic potency of lead candidates with antibody-encoding mRNA formulation and/or IgG protein delivery in mice and nonhuman primates. Our work provides a roadmap for the rapid antibody discovery programs against viral pathogens of global concern.
Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant
Authors: Yammine Lucie , Picatoste Belén , Abdullah Nazish , Leahey Rosemary A. , Johnson Emma F. , Gómez-Banoy Nicolás , Rosselot Carolina , Wen Jennifer , Hossain Tahmina , Goncalves Marcus D. , Lo James C. , Garcia-Ocaña Adolfo , McGraw Timothy E.
Published: May 2020

Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant (GIPR-Q350 mice). Female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulatedex vivoduring glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in β-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Consequently, our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.
Control of RNA polymerase II promoter-proximal pausing by DNA supercoiling
Authors: Herrero-Ruiz A. , Martínez-García P. , Terrón-Bautista J. , Lieberman J.A. , Jimeno-González S. , Cortés-Ledesma F.
Published: May 2020

The accumulation of topological stress in the form of DNA supercoiling is inherent to the advance of RNA polymerase II (Pol II) complexes, and needs to be resolved by DNA topoisomerases to sustain productive transcriptional elongation. Topoisomerases are therefore considered general positive facilitators of transcription. Here we show that, in contrast to this general assumption, human topoisomerase IIa accumulates at gene promoters, where it removes transcription-associated negative DNA supercoiling and represses transcription by enforcing promoter-proximal pausing of Pol II. We demonstrate that this topological balance is essential to maintain Immediate Early Genes under basal repression conditions, and that its disruption creates a positive feedback loop that explains their typical bursting behavior in response to stimulus. We therefore describe the control of promoter DNA supercoiling by topoisomerases as a novel layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription.
Synergistic neural integration is greater downstream of recurrent information flow in organotypic cortical cultures
Authors: Sherrill Samantha P. , Timme Nicholas M. , Beggs John M. , Newman Ehren L.
Published: May 2020

The directionality of network information flow dictates how networks process information. A central component of information processing in both biological and artificial neural networks is their ability to perform synergistic integration–a type of computation. We established previously that synergistic integration varies directly with the strength of feedforward information flow. However, the relationships between both recurrent and feedback information flow and synergistic integration remain unknown. To address this, we analyzed the spiking activity of hundreds of neurons in organotypic cultures of mouse cortex. We asked how empirically observed synergistic integration varied with local functional network structure that was categorized into motifs with varying recurrent and feedback information flow. We found that synergistic integration was elevated in motifs with greater recurrent information flow beyond that expected from the local feedforward information flow. Feedback information flow was interrelated with feedforward information flow and was associated with decreased synergistic integration. Our results indicate that synergistic integration is distinctly influenced by the directionality of local information flow.

Author Summary

Networks compute information. That is, they modify inputs to generate distinct outputs. These computations are an important component of network information processing. Knowing how the routing of information in a network influences computation is therefore crucial. Here we asked how a key form of computation—synergistic integration—is related to the direction of local information flow in networks of spiking cortical neurons. Specifically, we asked how information flow between input neurons (i.e., recurrent information flow) and information flow from output neurons to input neurons (i.e., feedback information flow) was related to the amount of synergistic integration performed by output neurons. We found that greater synergistic integration occurred where there was more recurrent information flow. And, lesser synergistic integration occurred where there was more feedback information flow relative to feedforward information flow. These results show that computation, in the form of synergistic integration, is distinctly influenced by the directionality of local information flow. Such work is valuable for predicting where and how network computation occurs and for designing networks with desired computational abilities.
Combined pigment and metatranscriptomic analysis reveals synchronized diel patterns of phenotypic light response across domains in the open ocean
Authors: Becker Kevin W. , Harke Matthew J. , Mende Daniel R. , Muratore Daniel , Weitz Joshua S. , DeLong Edward F. , Dyhrman Sonya T. , Van Mooy Benjamin A.S.
Published: May 2020

Sunlight is the most important environmental control on diel fluctuations in phytoplankton activity, and understanding diel microbial processes is essential to the study of oceanic biogeochemical cycles. Yet, little is known about thein situfrequency of phytoplankton metabolic activities and their coordination across different populations. We investigated the diel orchestration of phytoplankton activity involved in photosynthesis, photoacclimation, and photoprotection by analyzing the pigment and quinone distribution in combination with metatranscriptomes in the surface waters of the North Pacific Subtropical Gyre (NPSG). We found diel cycles in pigment abundances resulting from the balance of their synthesis and consumption. The night represents a metabolic recovery phase to refill cellular pigment stores, while the photosystems are remodeled towards photoprotection during the day. Transcript levels of genes involved in photosynthesis and pigment metabolism had highly synchronized diel expression patterns among all taxa, suggesting that there are similar regulatory mechanisms for light and energy metabolism across domains, and that other environmental factors drive niche differentiation. Observed decoupling of diel oscillations in transcripts and related pigments in the NPSG indicates that pigment abundance is modulated by environmental factors extending beyond gene expression/regulation, showing that metatranscriptomes may provide only limited insights on real-time photophysiological metabolism.
Mu-opioids suppress GABAergic synaptic transmission onto orbitofrontal cortex pyramidal neurons with subregional selectivity
Authors: Lau Benjamin K. , Ambrose Brittany P. , Thomas Catherine S. , Qiao Min , Borgland Stephanie L.
Published: May 2020

The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion specific manner. However, it is unknown how mu-opioid signalling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist, DAMGO produced a concentration-dependant inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long-lasting and not reversed upon washout of DAMGO, or by application of the mu-opioid receptor antagonist, CTAP, suggesting an inhibitory long-term depression (iLTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/PKA signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Taken together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.

Significance Statement

Considering that both the OFC and the opioid system regulate reward, motivation, and food intake; understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Secondly, mu-opioids recruit PV+ inputs to suppress inhibitory synaptic transmission in the mOFC. Thirdly, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.
A deletion inGDF7is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats
Authors: Yu Yoshihiko , Creighton Erica K. , Buckley Reuben M. , Lyons Leslie A. ,   99 Lives Consortium
Published: May 2020

An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test, a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion ingrowth differentiation factor 7(GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing, and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. Obligate carrier cats were heterozygous. In mice,GDF7mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasizes the importance ofGDF7in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.
Multifractal signatures of perceptual processing on anatomical sleeves of the human body
Authors: Mangalam Madhur , Carver Nicole S. , Kelty-Stephen Damian G.
Published: May 2020

Research into haptic perception typically concentrates on mechanoreceptors and their supporting neuronal processes. This focus risks ignoring crucial aspects of active perception. For instance, bodily movements influence the information available to mechanoreceptors, entailing that movement facilitates haptic perception. Effortful manual wielding of an object prompts feedback loops at multiple spatiotemporal scales, rippling outwards from the wielding hand to the feet, maintaining an upright posture, and interweaving to produce a nonlinear web of fluctuations throughout the body. Here, we investigated whether and how this bodywide nonlinearity engenders a flow of multifractal fluctuations that could support perception of object properties via dynamic touch. Blindfolded participants manually wielded weighted dowels and reported judgments of heaviness and length. Mechanical fluctuations on the anatomical sleeves, from hand to the upper body, as well as to the postural center of pressure, showed evidence of multifractality arising from nonlinear temporal correlations across scales. The modeling of impulse-response functions obtained from vector autoregressive (VAR) analysis revealed that distinct sets of pairwise exchanges of multifractal fluctuations entailed accuracy in heaviness and length judgments. These results suggest that the accuracy of perception via dynamic touch hinges on specific flowing patterns of multifractal fluctuations that people wear on their anatomical sleeves.
Re-ranking of Computational Protein–Peptide Docking Solutions With Amino Acid Profiles of Rigid-Body Docking Results
Authors: Ohue Masahito
Published: May 2020

Protein–peptide interactions, in which one partner is a globular protein and the other is a flexible linear peptide, are important for understanding cellular processes and regulatory pathways, and are therefore targets for drug discovery. In this study, I combined rigid-body protein-protein docking software (MEGADOCK) and global flexible protein–peptide docking software (CABS-dock) to establish a re-ranking method with amino acid contact profiles using rigid-body sampling decoys. I demonstrate that the correct complex structure cannot be predicted (< 10 Å peptide RMSD) using the current version of CABS-dock alone. However, my newly proposed re-ranking method based on the amino acid contact profile using rigid-body search results (designated the decoy profile) demonstrated the possibility of improvement of predictions. Adoption of my proposed method along with continuous efforts for effective computational modeling of protein–peptide interactions can provide useful information to understand complex biological processes in molecular detail and modulate protein-protein interactions in disease treatment.
Comparison of SARS-CoV-2 Indirect and Direct Detection Methods
Authors: Pearson Joel D. , Trcka Daniel , Hyduk Sharon J. , Aynaud Marie-Ming , Hernández J. Javier , Peidis Filippos , Lu Suying , Chan Kin , Woodgett Jim , Mazzulli Tony , Attisano Liliana , Pelletier Laurence , Cybulsky Myron I. , Wrana Jeffrey L. , Bremner Rod
Published: May 2020

The COVID-19 pandemic caused by the SARS-CoV-2 virus has placed extensive strain on RNA isolation and RT-qPCR reagents. Rapid development of new test kits has helped to alleviate these shortages. However, comparisons of these new detection systems are largely lacking. Here, we compare indirect methods that require RNA extraction, and direct RT-qPCR on patient samples. For RNA isolation we compared four different companies (Qiagen, Invitrogen, BGI and Norgen Biotek). For detection we compared two recently developed Taqman-based modules (BGI and Norgen Biotek), a SYBR green-based approach (NEB Luna Universal One-Step Kit) with published and newly-developed primers, and clinical results (Seegene STARMag RNA extraction system and Allplex 2019-nCoV RT-qPCR assay). Most RNA isolation procedures performed similarly, and while all RT-qPCR modules effectively detected purified viral RNA, the BGI system proved most sensitive, generating comparable results to clinical diagnostic data, and identifying samples ranging from 65 copies – 2.1×105copies of viral Orf1ab/μl. However, the BGI detection system is ∼4x more expensive than other options tested here. With direct RT-qPCR we found that simply adding RNase inhibitor greatly improved sensitivity, without need for any other treatments (e.g. lysis buffers or boiling). The best direct methods were ∼10 fold less sensitive than indirect methods, but reduce sample handling, as well as assay time and cost. These studies will help guide the selection of COVID-19 detection systems and provide a framework for the comparison of additional systems.