bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractImportanceReducing geographic disparities in antibiotic prescribing is a central public health priority to combat antibiotic resistance, but the drivers of this variation have been unclear.ObjectiveTo 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.DesignWe conducted an observational study of medical insurance claims collected between January 2011 and September 2015.SettingOutpatient visits in Massachusetts.Participants5,028,609 Massachusetts residents under the age of 65 with at least one full month of primary medical insurance during the study period.ExposuresResidence 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.ResultsThe 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 relevanceInterventions 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

AbstractIn 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

AbstractBrain-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

AbstractSimBit 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

ABSTRACTSubplate 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

ABSTRACTBy 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

AbstractSignificant 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.HighlightsWe 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.
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

AbstractBackgroundIn 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.Methods122 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.ResultsAs 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.ConclusionsThese 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

AbstractAberrant 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

SummarySkin 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

AbstractThe 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

AbstractGlucose-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

SummaryThe 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.