bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin
Authors: Rohde John A. , Roopnarine Osha , Thomas David D. , Muretta Joseph M. 
Published: July 2018

Significance
Small-molecule allosteric effectors designed to target and modulate striated and smooth myosin isoforms for the treatment of disease show promise in preclinical and clinical trials. Beta-cardiac myosin is an especially important target, as heart disease remains a primary cause of death in the United States. One prevalent type of heart disease is hypertrophic cardiomyopathy (HCM), which is hypothesized to result from dysregulated force generation by cardiac myosin. Mavacamten is a potent cardiac myosin ATPase activity inhibitor that improves cardiac output in HCM animal models. Our results show that mavacamten selectively stabilizes a two-headed–dependent, autoinhibited state of cardiac myosin in solution. The kinetics and energetics of this state are consistent with the autoinhibited superrelaxed state previously observed only in intact sarcomeres.
Combined computational and experimental investigation of the La
2
CuO

4–
x

S

x

(0 ≤
x
≤ 4) quaternary system
Authors: He Hua , Yee Chuck-Hou , McNally Daniel E. , Simonson Jack W. , Zellman Shelby , Klemm Mason , Kamenov Plamen , Geschwind Gayle , Zebro Ashley , Ghose Sanjit , Bai Jianming , Dooryhee Eric , Kotliar Gabriel , Aronson Meigan C. 
Published: July 2018

Significance
Discovery of new materials enabling new technologies, from novel electronics to better magnets, has so far relied on serendipity. Computational advances show promise that new materials can be designed in a computer and not in the lab, a proposal called “Materials by Design.” We present here a detailed comparison between theory and experiment, carrying out the synthesis of a high-temperature superconductor in an X-ray beam to elucidate the sequence of chemical reactions as the compound forms. Parallel computations of the stabilities of possible compounds that could form from the selected elements accurately predict the observed reactions. Paired with our chemical intuition, this methodology provides understanding and potentially control of the essential chemical principles responsible for stabilizing virtually any compound.
Sex Drugs and Corporate Ventriloquism: How to Evaluate Science Policies Intended to Manage Industry-Funded Bias
Authors: Holman Bennett , Geislar Sally 
Published: July 2018

Abstract“Female sexual dysfunction” is the type of contested disease that has sparked concern about the role of the pharmaceutical industry in medical science. Many policies have been proposed to manage industry influence without carefully evaluating whether the proposed policies would be successful. We consider a proposal for incorporating citizen stakeholders into scientific research and show, via a detailed case study of the pharmaceutical regulation of flibanserin (misleadingly marketed as the “female Viagra”), that such programs can be co-opted. In closing, we use Holman’s asymmetric arms race framework as a tool for evaluating policies in industry-funded science.
Wishful Thinking and Values in Science
Authors: Steel Daniel 
Published: July 2018

AbstractThis article examines the concept of wishful thinking in philosophical literature on science and values. It suggests that this term tends to be used in an overly broad manner that fails to distinguish between separate types of bias, mechanisms that generate biases, and general theories that might explain those mechanisms. I explain how confirmation bias is distinct from wishful thinking and why it is more useful for examining the relationship between cognitive bias and beliefs about the existence of injustices.
What and How Do Cancer Systems Biologists Explain?
Authors: Plutynski Anya , Bertolaso Marta 
Published: July 2018

AbstractIn this article, we argue, first, that there are very different research projects that fall under the heading of “systems biology of cancer.” While they share some general features, they differ in their aims and theoretical commitments. Second, we argue that some explanations in systems biology of cancer are concerned with properties of signaling networks (such as robustness or fragility) and how they may play an important causal role in patterns of vulnerability to cancer. Further, some systems biological explanations are compelling illustrations of how “top-down” and “bottom-up” approaches to the same phenomena may be integrated.
Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial
Authors: Byrd James Brian , Newby David E , Anderson Julie A , Calverley Peter M A , Celli Bartolome R , Cowans Nicholas J , Crim Courtney , Martinez Fernando J , Vestbo Jørgen , Yates Julie , Brook Robert D ,   the SUMMIT Investigators
Published: July 2018

Abstract

Aims
To characterize the relationship between blood pressure (BP) or heart rate and mortality and morbidity in chronic obstructive pulmonary disease (COPD).

Methods and results
We performedpost hoc analysis of baseline BP or heart rate and all-cause mortality and cardiovascular events in the SUMMIT trial. SUMMIT was a randomized double-blind outcome trial of 16 485 participants (65 ± 8 years, 75% male, and 47% active smokers) enrolled at 1368 sites in 43 countries. Participants with moderate COPD with or at risk for cardiovascular disease (CVD) were randomized to placebo, long-acting beta agonist, inhaled corticosteroid, or their combination. All-cause mortality increased in relation to high systolic [≥140 mmHg; hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12–1.45] or diastolic (≥90 mmHg; HR 1.35, 95% CI 1.14–1.59) BP and low systolic (&lt;120 mmHg; HR 1.36, 95% CI 1.13–1.63) or diastolic (&lt;80 mmHg; HR 1.15, 95% CI 1.00–1.32) BP. Higher heart rates (≥80 per minute; HR 1.39, 95% CI 1.21–1.60) and pulse pressures (≥80 mmHg; HR 1.39, 95% CI 1.07–1.80) were more linearly related to increases in all-cause mortality. The risks of cardiovascular events followed similar patterns to all-cause mortality. Similar findings were observed in subgroups of patients without established CVD.

Conclusion
A ‘U-shaped’ relationship between BP and all-cause mortality and cardiovascular events exists in patients with COPD and heightened cardiovascular risk. A linear relationship exists between heart rate and all-cause mortality and cardiovascular events in this population. These findings extend the prognostic importance of BP to this growing group of patients and raise concerns that both high and low BP may pose health risks.
Weak-lensing mass calibration of the Sunyaev–Zel’dovich effect using APEX-SZ galaxy clusters
Authors: Nagarajan A , Pacaud F , Sommer M , Klein M , Basu K , Bertoldi F , Lee A T , Ade P A R , Bender A N , Ferrusca D , Halverson N W , Horellou C , Johnson B R , Kennedy J , Kneissl R , Menten K M , Reichardt C L , Tucker C , Westbrook B 
Published: July 2018

ABSTRACT
The use of galaxy clusters as precision cosmological probes relies on an accurate determination of their masses. However, inferring the relationship between cluster mass and observables from direct observations is difficult and prone to sample selection biases. In this work, we use weak lensing as the best possible proxy for cluster mass to calibrate the Sunyaev–Zel’dovich (SZ) effect measurements from the APEX-SZ experiment. For a well-defined (ROSAT) X-ray complete cluster sample, we calibrate the integrated Comptonization parameter, YSZ, to the weak-lensing derived total cluster mass, M500. We employ a novel Bayesian approach to account for the selection effects by jointly fitting both the SZ Comptonization, YSZ–M500, and the X-ray luminosity, Lx–M500, scaling relations. We also account for a possible correlation between the intrinsic (lognormal) scatter of Lx and YSZ at fixed mass. We find the corresponding correlation coefficient to be $r= 0.47_{-0.35}^{+0.24}$, and at the current precision level our constraints on the scaling relations are consistent with previous works. For our APEX-SZ sample, we find that ignoring the covariance between the SZ and X-ray observables biases the normalization of the YSZ–M500 scaling high by 1–2σ and the slope low by ∼1σ, even when the SZ effect plays no role in the sample selection. We conclude that for higher precision data and larger cluster samples, as anticipated from on-going and near-future cluster cosmology experiments, similar biases (due to intrinsic covariances of cluster observables) in the scaling relations will dominate the cosmological error budget if not accounted for correctly.
Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Evaluation and Treatment of Patients With Thoracolumbar Spine Trauma: Novel Surgical Strategies
Authors: Chi John H , Eichholz Kurt M , Anderson Paul A , Arnold Paul M , Dailey Andrew T , Dhall Sanjay S , Harrop James S , Hoh Daniel J , Qureshi Sheeraz , Rabb Craig H , Raksin P B , Kaiser Michael G , O’Toole John E 
Published: July 2018

Abstract

BACKGROUND
Treatment of thoracolumbar burst fractures has traditionally involved spinal instrumentation with fusion performed with standard open surgical techniques. Novel surgical strategies, including instrumentation without fusion and percutaneous instrumentation alone, have been considered less invasive and more efficient treatments.

OBJECTIVE
To review the current literature and determine the role of fusion in instrumented fixation, as well as the role of percutaneous instrumentation, in the treatment of patients with thoracolumbar burst fractures.

METHODS
The task force members identified search terms/parameters and a medical librarian implemented the literature search, consistent with the literature search protocol (see Appendix I), using the National Library of Medicine PubMed database and the Cochrane Library for the period from January 1, 1946 to March 31, 2015.

RESULTS
A total of 906 articles were identified and 38 were selected for full-text review. Of these articles, 12 articles met criteria for inclusion in this systematic review.

CONCLUSION
There is grade A evidence for the omission of fusion in instrumented fixation for thoracolumbar burst fractures. There is grade B evidence that percutaneous instrumentation is as effective as open instrumentation for thoracolumbar burst fractures.

RECOMMENDATIONS

QUESTION
Does the addition of arthrodesis to instrumented fixation improve outcomes in patients with thoracic and lumbar burst fractures?

RECOMMENDATION
It is recommended that in the surgical treatment of patients with thoracolumbar burst fractures, surgeons should understand that the addition of arthrodesis to instrumented stabilization has not been shown to impact clinical or radiological outcomes, and adds to increased blood loss and operative time.
Strength of Recommendation: Grade A

QUESTION
How does the use of minimally invasive techniques (including percutaneous instrumentation) affect outcomes in patients undergoing surgery for thoracic and lumbar fractures compared to conventional open techniques?

RECOMMENDATION
Stabilization using both open and percutaneous pedicle screws may be considered in the treatment of thoracolumbar burst fractures as the evidence suggests equivalent clinical outcomes.
Strength of Recommendation: Grade B
The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_12.
Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Evaluation and Treatment of Patients With Thoracolumbar Spine Trauma: Neurological Assessment
Authors: Harrop James S , Chi John H , Anderson Paul A , Arnold Paul M , Dailey Andrew T , Dhall Sanjay S , Eichholz Kurt M , Hoh Daniel J , Qureshi Sheeraz , Rabb Craig H , Raksin P B , Kaiser Michael G , O’Toole John E 
Published: July 2018

Abstract

QUESTION 1
Which neurological assessment tools have demonstrated internal reliability and validity in the management of patients with thoracic and lumbar fractures (ie, do these instruments provide consistent information between different care providers)?

RECOMMENDATION 1
Numerous neurologic assessment scales (Functional Independence Measure, Sunnybrook Cord Injury Scale and Frankel Scale for Spinal Cord Injury) have demonstrated internal reliability and validity in the management of patients with thoracic and lumbar fractures. Unfortunately, other contemporaneous measurement scales (ie, American Spinal Cord Injury Association Impairment Scale) have not been specifically studied in patients with thoracic and lumbar fractures.
Strength of Recommendation: Grade C

QUESTION 2
Are there any clinical findings (eg, presenting neurological grade/function) in patients with thoracic and lumbar fractures that can assist in predicting clinical outcomes?

RECOMMENDATION 2
Entry American Spinal Injury Association Impairment Scale grade, sacral sensation, ankle spasticity, urethral and rectal sphincter function, and AbH motor function can be used to predict neurological function and outcome in patients with thoracic and lumbar fractures (Table I https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_4_table1).
Strength of Recommendation: Grade B
The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_4.
Structural variation during dog domestication: insights from gray wolf and dhole genomes
Authors: Wang Guo-Dong , Shao Xiu-Juan , Bai Bing , Wang Junlong , Wang Xiaobo , Cao Xue , Liu Yan-Hu , Wang Xuan , Yin Ting-Ting , Zhang Shao-Jie , Lu Yan , Wang Zechong , Wang Lu , Zhao Wenming , Zhang Bing , Ruan Jue , Zhang Ya-Ping 
Published: July 2018

Abstract
Several processes like phenotypic evolution, disease susceptibility and environmental adaptations, which fashion the domestication of animals, are largely attributable to structural variations (SVs) in the genome. Here, we present high-quality draft genomes of the gray wolf (Canis lupus) and dhole (Cuon alpinus) with scaffold N50 of 6.04 Mb and 3.96 Mb, respectively. Sequence alignment comprising genomes of three canid species reveals SVs specific to the dog, particularly 16 315 insertions, 2565 deletions, 443 repeats, 16 inversions and 15 translocations. Functional annotation of the dog SVs associated with genes indicates their enrichments in energy metabolisms, neurological processes and immune systems. Interestingly, we identify and verify at population level an insertion fully covering a copy of the AKR1B1 (Aldo-Keto Reductase Family 1 Member B) transcript. Transcriptome analysis reveals a high level of expression of the new AKR1B1 copy in the small intestine and liver, implying an increase in de novo fatty acid synthesis and antioxidant ability in dog compared to gray wolf, likely in response to dietary shifts during the agricultural revolution. For the first time, we report a comprehensive analysis of the evolutionary dynamics of SVs during the domestication step of dogs. Our findings demonstrate that retroposition can birth new genes to facilitate domestication, and affirm the importance of large-scale genomic variants in domestication studies.
High Maternal Circulating Cotinine During Pregnancy is Associated With Persistently Shorter Stature From Birth to Five Years in an Asian Cohort
Authors: Ng Sharon , Aris Izzuddin M , Tint Mya Thway , Gluckman Peter D , Godfrey Keith M , Shek Lynette Pei-Chi , Yap Fabian , Tan Kok Hian , Lek Ngee , Teoh Oon Hoe , Chan Yiong Huak , Chong Mary Foong-Fong , Lee Yung Seng , Chong Yap-Seng , Kramer Michael S , Chan Shiao-Yng 
Published: July 2018

AbstractBackgroundSelf-reported maternal active smoking has been associated with reduced offspring birth length and shorter stature in early and late childhood.ObjectiveTo use circulating cotinine as an objective biomarker to investigate the association between smoking and environmental tobacco smoke (ETS) exposure in pregnancy and longitudinal measures of offspring length/height from birth to 60 months.MethodsIn 969 maternal-offspring dyads from the GUSTO cohort, maternal plasma cotinine at 26–28 weeks’ gestation was measured by LC/MS/MS and categorized into four groups: Group 1: cotinine <0.17 ng/mL (the assay’s detection limit) and no ETS exposure; Group 2: cotinine <0.17 ng/mL but self-reported ETS; Group 3: cotinine 0.17–13.99 ng/mL (ETS or light smoking); Group 4: cotinine ≥14 ng/mL (active smoking).ResultsAdjusting for infant sex, gestational age at birth, ethnicity, maternal age, education, parity, BMI, and height, Group 4 offspring were shorter at birth [z-score β = −0.42 SD units (SDs) (95% CI = −0.77 to −0.06)] than Group 1 offspring. Group 4 offspring continued to be shorter at older ages, with similar effect sizes at 3 months [−0.57 SDs (−0.95 to −0.20)], 36 months [−0.53 SDs (−0.92 to −0.15)], 48 months [−0.43 SDs (−0.81 to −0.04)], and 60 months [−0.57 SDs (−0.96 to −0.17)]. Associations were particularly marked in boys. No significant differences in stature were observed in Groups 2 or 3 compared with Group 1.ConclusionsThis Asian longitudinal study associated high prenatal cotinine with persistently shorter stature in offspring from birth and into early childhood, whilst low prenatal cotinine levels and ETS exposure showed no such association.ImplicationsLittle is known about the long-term effects of prenatal tobacco exposure on offspring stature in Asia where passive smoking is common. This study has used an objective biomarker to reveal that the association of prenatal tobacco exposure with offspring length/height mainly occurs at a high maternal cotinine level of greater than 14 ng/mL in pregnancy, consistent with active smoking, but no significant associations were found with lower cotinine levels, consistent with passive smoking. Encouraging women to quit smoking prior to or during pregnancy may avert the long-term negative impact on their child’s height despite appreciable prenatal ETS exposure.
The nature and scope of patient-sharing network research: a novel, important area for network science
Authors: Robbins Rebecca , Seixas Azizi , Schoenthaler Antoinette 
Published: July 2018

Abstract
A robust literature exists that draws on social network approaches to understand connections among individuals, and healthcare and behavior-related implications. This article offers commentary on the scoping review conducted by Dugoff et al. that examines “patient-sharing” networks, their characteristics, and various methodological approaches. The scoping review conducted by Dugoff et al. examines the characteristics and methods employed in patient-sharing network studies. It identified the most common measures used in patient-sharing network research, as well as theories used in patient-sharing network studies. Dugoff et al. also identified many studies that examined healthcare utilization considerations for patient sharing. Understanding the connections between providers and the flow of patients between providers could lend insight into barriers and enablers to efficient healthcare systems.
Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus
Authors: Mandelbaum Gil , Taranda Julian , Haynes Trevor M. , Hochbaum Daniel R. , Huang Kee Wui , Hyun Minsuk , Venkataraju Kannan Umadevi , Straub Christoph , Wang Wengang , Robertson Keiramarie , Osten Pavel , Sabatini Bernardo L. 
Published: July 2018

SUMMARYThe thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain-stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF forms the densest subcortical projection to the striatum. This projection arises from transcriptionally- and physiologically-distinct classes of PF neurons that are also reciprocally connected with functionally-distinct cortical regions, differentially innervate striatum neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and motor circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.
Short term depression shapes information transmission in a constitutively active GABAergic synapse
Authors: Lavian Hagar , Korngreen Alon 
Published: July 2018

AbstractShort-term depression is a low pass filter of synaptic information that reduces and flattens synaptic information transfer at high presynaptic firing frequencies. This view questions the relevance of spontaneous high firing rates in some networks. In the indirect pathway of the basal ganglia, spontaneously active neurons in the globus pallidus (GP) form depressing inhibitory synapses in the basal ganglia output nuclei. Using numerical modeling and whole-cell recordings from single entopeduncular nucleus (EP) neurons in rat brain slices we investigated the contribution of the different firing rates of GP neurons to information transmission in the indirect pathway. Wholecell recordings showed significant variability in steady-state depression which decreased as stimulation frequency increased. Modeling predicted that this variability would translate into different postsynaptic noise levels during constitutive presynaptic activity. Our simulations further predicted that individual GP-EP synapses mediate gain control. However, when we consider integration of multiple inputs, the large range of GP firing rates would enable different modes of information transmission in which the magnitude and temporal features of postsynaptic modulation would change as a function of present and past firing rates of GP neurons. Finally, we predict that changes in dopamine levels can shift the action of GP neurons from rate coding to gain modulation. Our results thus demonstrate how short-term synaptic depression shapes information transmission in the basal ganglia in particular and via GABAergic synapses in general.Significant statementSynapses displaying short-term depression are low-pass filters of synaptic input. Consequently, when presynaptic firing is high, little information passes to the postsynaptic neuron. However, many neurons fire at relatively high frequencies all the time. Are their synapses constantly silenced by depression? We tested this apparent contradiction in the indirect pathway of the basal ganglia, where neurons from the globus pallidus (GP) form constitutively active depressing synapses on basal ganglia output. We hypothesized that the different rates of ongoing activity underlie different modes of action for GP neurons. We show that the synaptic and structural properties of the indirect pathway map GP baseline frequencies to different postsynaptic signals, thus demonstrating how short-term synaptic depression shapes information transmission in the basal ganglia.