bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Evolution of Benzodiazepine Receptor Agonists
Authors: Hansen Jamie L. , Atkinson Timothy J. 
Published: November 2020

Abstract
Benzodiazepines have been touted as safer alternatives to their barbiturate predecessor since their arrival on the market in 1960. Their proposed improved safety is based on their reported reduced drug interactions, lower abuse potential, and decreased respiratory depression. Benzodiazepines bind to the GABAA receptor and positively modulate GABAergic transmission and hyperpolarization of neuronal membranes. Individual agents are utilized differently depending on their varying degrees of hypnotic, anxiolytic, antiepileptic, muscle relaxant, and amnestic properties. Benzodiazepines are frequently classified by their half-life (t½), a key pharmacokinetic parameter that dictates the agents’ ability to precipitate dangerous withdrawals. The majority of benzodiazepines undergo phase I hepatic metabolism via cytochrome p450 that introduce the potential for drug interactions. Following hepatic metabolism, almost all agents within this drug class have active metabolites that have extended half-lives beyond that of the parent drug that prolong the duration of activity. Urine drug screens are an essential component of medication monitoring and require a foundational understanding of the parent drug, its metabolites, and what the available immunoassay is designed to detect. A similar drug class that is frequently grouped with benzodiazepines are Z-drugs. These agents were developed in attempt to create a sleep aid that lacked the undesirable qualities of benzos with an improved safety profile. Z-drugs share the common characteristic of being short-acting in nature and are proposed to cause less disruption in the normal sleep cycle than benzodiazepines.
Benzodiazepine Therapy
Authors: Guina Jeffrey , Merrill Brian , LeQuang Jo Ann 
Published: November 2020

Abstract
Benzodiazepines are some of the most commonly prescribed medications worldwide. When used appropriately for the right condition, patient, dose, and duration, these drugs can provide rapid relief of the symptoms of anxiety and insomnia for some patients, but they are also linked to a variety of adverse effects (whether used long-term, short-term, or as needed). Many patients are prescribed, and take, benzodiazepines long-term without ever receiving evidence-based first-line treatments such as psychotherapy, relaxation techniques, sleep hygiene education, or serotonergic agents. This chapter discusses the risks and benefits of, and alternatives to, benzodiazepines. The evidence-based indications and contraindications are discussed, as are putative biopsychosocial bases for effectiveness, ineffectiveness, and harm. The known potential adverse effects and drug-drug interactions are summarized. Finally, alternative fast-acting/acute and chronic treatments for anxiety and/or insomnia are discussed. Response to treatment—whether benzodiazepines, other pharmacological agents, or psychotherapy—must be assessed.
Use of Benzodiazepines and Z-Drugs in the Geriatric Population
Authors: Kitzen Jan M. 
Published: November 2020

Abstract
The benzodiazepine (BZD) class of drugs has proven to be a useful addition to therapeutic management of anxiety and sleep disorders in the adult population. However, after many years of experience with BZDs in elderly patients (≥65 years), a large body of evidence indicates that BZDs are no longer recommended for use in this segment of the population, except under special conditions. Several aging-related changes in physiology such as decreases in renal and hepatic function, altered central nervous system function and changes in body composition can lead to impaired excretion of drug, higher plasma levels and accumulation of these drugs in the body. Side effects such as sedation, dizziness, cognitive impairment, and diminished control of gait and balance functions place the elderly at greater risk of various adverse events, especially falls and fractures, compared to younger adults. Another class of drugs, known as Z-drugs is structurally dissimilar from the BZDs but able to bind to GABAA, receptors making them useful for management of insomnia. These drugs have also been found to pose significant hazards to the elderly and are also not recommended for use in elderly patients. Both of these classes of drugs are currently included in the AGS Beers Criteria® of potentially inappropriate medications for use in the elderly. Alternative pharmacologic approaches to managing these conditions include use of either serotonin-norepinephrine reuptake inhibitors or buspirone for anxiety and the use of either low doses of doxepin, melatonin, or the melatonin agonist ramelteon for management of insomnia. Cognitive behavioral therapy and other relaxation techniques offer non-pharmacologic approaches to managing these conditions, thereby decreasing the need for prescribing BZDs or Z-drugs in the elderly.
Benzodiazepine Receptors in the Periphery
Authors: Raffa Robert B. 
Published: November 2020

Abstract
The benzodiazepines are almost universally thought to produce one and only one pharmacologic effect: positive allosteric modulation of GABAA receptors located in the brain. This results in an increased Cl−ion influx, greater negative transmembrane potential difference, and neurons that are less likely to fire in response to anxiety-producing stimulation. Unfortunately, the simplicity and success of this mono-target belief has distracted researchers and clinicians from studying and appreciating their other pharmacology. A glaring example is the general lack of awareness of the peripheral benzodiazepine receptor. The peripheral benzodiazepine receptor alters mitochondrial function (energy supply), cholesterol transport, and immune function. A patient who is on long-term benzodiazepine therapy (or withdrawing from them) will have these sites affected, just as are the sites located in the brain. One can easily imagine that the adverse effects associated with the peripheral sites would be fundamental, varied, and potentially profound—involving lack of energy, altered cholesterol metabolism, and aberrant immune function.
Drug Withdrawal
Authors: Koob George F. 
Published: November 2020

Abstract
Drug withdrawal has long been considered a key symptom in the diagnosis of alcohol and substance use disorders. In this chapter, it is also conceptualized as a major motivational factor that drives compulsive drug taking. Drawing from the negative emotional components of withdrawal, termed hyperkatifeia (i.e., the negative emotional and motivational signs of withdrawal), the hypothesis here is that withdrawal sets up another major source of reinforcement—namely, negative reinforcement—for drug seeking in substance use disorders. From the perspective of the hyperkatifeia phenotype, withdrawal then returns to being a key part of moderate to severe alcohol and substance use disorders to become the primary factor that motivates sustained drug seeking. Such hyperkatifeia is mediated by a multidetermined neurocircuitry that compromises within-system neurochemical systems that are involved in the rewarding effects of drugs and promotes the activation of pro-stress neuromodulators that combine with a weakening or inadequate anti-stress response. Altogether, these neurocircuitry, neurochemical, and molecular changes lead to a negative emotional state (hyperkatifeia) that sets up an allostatic hedonic load that drives negative reinforcement. Under this framework, strong multidetermined buffers, if activated and sufficient to allow the reward and pro-stress systems to recover, may help return the organism to homeostasis.
The Y dwarf population with HST: unlocking the secrets of our coolest neighbours – I. Overview and first astrometric results
Authors: Fontanive C , Bedin L R , Bardalez Gagliuffi D C 
Published: November 2020

ABSTRACT
In this paper, we present our project that aims at determining accurate distances and proper motions for the Y brown dwarf population using the Hubble Space Telescope. We validate the program with our first results, using a single new epoch of observations of the Y0pec dwarf WISE J163940.83−684738.6. These new data allowed us to refine its proper motion and improve the accuracy of its parallax by a factor of three compared to previous determinations, now constrained to ϖ = 211.11 ± 0.56 mas. This newly derived absolute parallax corresponds to a distance of 4.737 ± 0.013 pc, an exquisite and unprecedented precision for faint ultracool Y dwarfs.
Structural properties and anticoagulant/cytotoxic activities of heterochiral enantiomeric thrombin binding aptamer (TBA) derivatives
Authors: Virgilio Antonella , Esposito Veronica , Pecoraro Annalisa , Russo Annapina , Vellecco Valentina , Pepe Antonietta , Bucci Mariarosaria , Russo Giulia , Galeone Aldo 
Published: November 2020

Abstract
The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its development as an anticancer agent is drastically impaired by its concomitant anticoagulant activity. Therefore, suitable chemical modifications in the TBA sequence would be required in order to preserve its antiproliferative over anticoagulant activity. In this paper, we report structural investigations, based on circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR), and biological evaluation of four pairs of enantiomeric heterochiral TBA analogues. The four TBA derivatives of the d-series are composed by d-residues except for one l-thymidine in the small TT loops, while their four enantiomers are composed by l-residues except for one d-thymidine in the same TT loop region. Apart from the left-handedness for the l-series TBA derivatives, CD and NMR measurements have shown that all TBA analogues are able to adopt the antiparallel, monomolecular, ‘chair-like’ G-quadruplex structure characteristic of the natural D-TBA. However, although all eight TBA derivatives are endowed with remarkable cytotoxic activities against colon and lung cancer cell lines, only TBA derivatives of the l-series show no anticoagulant activity and are considerably resistant in biological environments.
Optogenetic control of Neisseria meningitidis Cas9 genome editing using an engineered, light-switchable anti-CRISPR protein
Authors: Hoffmann Mareike D , Mathony Jan , Upmeier zu Belzen Julius , Harteveld Zander , Aschenbrenner Sabine , Stengl Christina , Grimm Dirk , Correia Bruno E , Eils Roland , Niopek Dominik 
Published: November 2020

Abstract
Optogenetic control of CRISPR–Cas9 systems has significantly improved our ability to perform genome perturbations in living cells with high precision in time and space. As new Cas orthologues with advantageous properties are rapidly being discovered and engineered, the need for straightforward strategies to control their activity via exogenous stimuli persists. The Cas9 from Neisseria meningitidis (Nme) is a particularly small and target-specific Cas9 orthologue, and thus of high interest for in vivo genome editing applications. Here, we report the first optogenetic tool to control NmeCas9 activity in mammalian cells via an engineered, light-dependent anti-CRISPR (Acr) protein. Building on our previous Acr engineering work, we created hybrids between the NmeCas9 inhibitor AcrIIC3 and the LOV2 blue light sensory domain from Avena sativa. Two AcrIIC3-LOV2 hybrids from our collection potently blocked NmeCas9 activity in the dark, while permitting robust genome editing at various endogenous loci upon blue light irradiation. Structural analysis revealed that, within these hybrids, the LOV2 domain is located in striking proximity to the Cas9 binding surface. Together, our work demonstrates optogenetic regulation of a type II-C CRISPR effector and might suggest a new route for the design of optogenetic Acrs.
Protein carbamylation and chronic kidney disease progression in the Chronic Renal Insufficiency Cohort Study
Authors: Kalim Sahir , Berg Anders H , Karumanchi Subbian Ananth , Thadhani Ravi , Allegretti Andrew S , Nigwekar Sagar , Zhao Sophia , Srivastava Anand , Raj Dominic , Deo Rajat , Frydrych Anne , Chen Jing , Sondheimer James , Shafi Tariq , Weir Matthew , Lash James P ,   the CRIC Study Investigators, Appel Lawrence J , Feldman Harold I , Go Alan S , He Jiang , Nelson Robert G , Rahman Mahboob , Rao Panduranga S , Shah Vallabh O , Townsend Raymond R , Unruh Mark L 
Published: November 2020

Abstract

Background
Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea’s dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established.

Methods
We conducted two nested case–control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study.

Results
At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9–32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0–11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN.

Conclusions
Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation’s association with mortality was smaller in this limited sample size.
Overexpression and Inhibition of 3-Hydroxy-3-Methylglutaryl-CoA Synthase Affect Central Metabolic Pathways in Tobacco
Authors: Liao Pan , Lung Shiu-Cheung , Chan Wai Lung , Hu Menglong , Kong Geoffrey Kwai-Wai , Bach Thomas J , Hao Quan , Lo Clive , Chye Mee-Len 
Published: November 2020

Abstract
Little has been established on the relationship between the mevalonate (MVA) pathway and other metabolic pathways except for the sterol and glucosinolate biosynthesis pathways. In the MVA pathway, 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS) catalyzes the condensation of acetoacetyl-CoA and acetyl-CoA to form 3-hydroxy-3-methylglutaryl-coenzyme A. Our previous studies had shown that, while the recombinant Brassica juncea HMGS1 (BjHMGS1) mutant S359A displayed 10-fold higher enzyme activity than wild-type (wt) BjHMGS1, transgenic tobacco overexpressing S359A (OE-S359A) exhibited higher sterol content, growth rate and seed yield than OE-wtBjHMGS1. Herein, untargeted proteomics and targeted metabolomics were employed to understand the phenotypic effects of HMGS overexpression in tobacco by examining which other metabolic pathways were affected. Sequential window acquisition of all theoretical mass spectra quantitative proteomics analysis on OE-wtBjHMGS1 and OE-S359A identified the misregulation of proteins in primary metabolism and cell wall modification, while some proteins related to photosynthesis and the tricarboxylic acid cycle were upregulated in OE-S359A. Metabolomic analysis indicated corresponding changes in carbohydrate, amino acid and fatty acid contents in HMGS-OEs, and F-244, a specific inhibitor of HMGS, was applied successfully on tobacco to confirm these observations. Finally, the crystal structure of acetyl-CoA-liganded S359A revealed that improved activity of S359A likely resulted from a loss in hydrogen bonding between Ser359 and acyl-CoA, which is evident in wtBjHMGS1. This work suggests that regulation of plant growth by HMGS can influence the central metabolic pathways. Furthermore, this study demonstrates that the application of the HMGS-specific inhibitor (F-244) in tobacco represents an effective approach for studying the HMGS/MVA pathway.
Real-time simulation of (2+1)-dimensional lattice gauge theory on qubits
Authors: Yamamoto Arata 
Published: November 2020

Abstract
We study the quantum simulation of $Z_2$ lattice gauge theory in 2+1 dimensions. The dual variable formulation, the so-called Wegner duality, is utilized for reducing redundant gauge degrees of freedom. The problem of artificial charge unconservation is resolved for any charge distribution. As a demonstration, we simulate the real-time evolution of the system with two static electric charges, i.e. with two temporal Wilson lines. Some results obtained by a simulator (with no hardware noise) and a real quantum computing device (with sizable hardware noise) are shown.
Quantitative Evaluation of Embolic Load in Femoral and Tibial Shaft Fractures Treated With Reamed Intramedullary Fixation
Authors: Lee Christopher , O'Hara Nathan N. , Conti Bianca , Hyder Mary , Sepehri Aresh , Rudnicki Joshua , Hannan Zachary , Connelly Daniel , Baker Mitchell , Pollak Andrew N. , O'Toole Robert V. 
Published: November 2020

Objectives:
To compare the volume of embolic load during intramedullary fixation of femoral and tibial shaft fractures. Our hypothesis was that tibial intramedullary nails (IMNs) would be associated with less volume of intravasation of marrow than IM nailing of femur fractures.

Design:
Prospective observational study.

Setting:
Urban Level I trauma center.

Patients/Participants:
Twenty-three patients consented for the study: 14 with femoral shaft fractures and 9 with tibial shaft fractures.

Intervention:
All patients underwent continuous transesophageal echocardiography, and volume of embolic load was evaluated during 5 distinct stages: postinduction, initial guide wire, reaming (REAM), nail insertion, and postoperative.

Main Outcome Measurements:
Volume of embolic load was measured based on previously described luminosity scores. The embolic load based on fracture location and procedure stage was evaluated using a mixed effects model.

Results:
The IMN procedure increased the embolic load by 215% (−12% to 442%, P = 0.07) in femur patients relative to tibia patients after adjusting for baseline levels. Of the 5 steps measured, REAM was associated with the greatest increase in embolic load relative to the guide wire placement and controlling for fracture location (421%, 95% confidence interval: 169%–673%, P < 0.01).

Conclusions:
Femoral shaft IMN fixation was associated with a 215% increase in embolic load in comparison with tibial shaft IMN fixation, with the greatest quantitative load during the REAM stage; however, both procedures produce embolic load.

Level of Evidence:
Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Validation of Relative Motion Measurement Method of Lateral Compression Pelvic Fractures During Examination Under Anesthesia
Authors: Jacobs Robert , Kleweno Conor , Wallace Stephen , Elliott Iain , Patterson Joseph , Agel Julie , Firoozabadi Reza 
Published: November 2020

Objectives:
To determine if the relative distance between the acetabular teardrops on unstressed and lateral compressive stress examination under anesthesia (EUA) pelvic fluoroscopic images is reproducible between independent reviewers.

Design:
Retrospective database review.

Setting:
Level 1 trauma center.

Patients/Intervention:
Fifty-eight patients with a lateral compression type 1 pelvic ring injury who underwent EUA.

Main Outcome Measure:
Validation of EUA objective measurements between blinded, independent reviewers using interclass and intraclass correlation coefficients.

Results:
There was excellent interobserver and intraobserver reliability between all reviewers. Values for each intraclass correlation coefficients (including 95% confidence intervals) were between 0.96 (0.95–0.098) and 0.99 (0.99–0.99) for all measurements. P values were <0.0001 for all measured parameters.

Conclusions:
The relative change in distance between the acetabular tear drops during lateral compressive EUA of lateral compression type 1 pelvic injuries is reliable between independent reviewers. This allows for accurate, objective measurement of pelvic motion independent of patient size or body habitus.

Level of Evidence:
Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Prospective Randomized Trial on Smoking Cessation in Orthopaedic Trauma Patients: Results From the Let’s STOP (Smoking in Trauma Orthopaedic Patients) Now Trial
Authors: Matuszewski Paul E. , Joseph Katherine , O'Hara Nathan N. , DiClemente Carlo , O'Toole Robert V. 
Published: November 2020

Objectives:
Determine if extended inpatient counseling increases smoking cessation.

Design:
Prospective randomized trial.

Setting:
Level I trauma center.

Patients/Participants:
Current smokers with an operative fracture.

Intervention:
Randomly assigned to control (no counseling), brief counseling (inpatient counseling), or extended counseling (brief counseling plus follow-up counseling) groups in a 1:3:3 ratio.

Main Outcome Measurements:
Smoking cessation confirmed by exhaled carbon monoxide at 3 and 6 months. Secondary outcomes are proportion accepting services from a nationally based quitline.

Results:
Overall, 266 patients participated, with 40, 111, and 115 patients in the control and 2 treatment groups, respectively. At 3 months, 17% of control patients versus 11% in the brief counseling and 10% in the extended counseling groups quit smoking, respectively (P = 0.45, 0.37). At 6 months, 15% of control, and 10% and 5% of the respective counseling groups quit (P = 0.45, 0.10). Extended counseling patients were 3 times more likely to accept referral to a quitline [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.4-6.9], and brief counseling patients were more than 2 times as likely to accept referral (OR, 2.3; 95% CI, 1.0-5.1) than the control group. Extended counseling (OR, 8.2; 95% CI, 1.0-68.5) and brief counseling (OR, 5.3; 95% CI, 0.6-44.9) patients were more likely to use quitline services than the control group.

Conclusion:
Increasing levels of inpatient counseling can improve successful referral to a smoking quitline, but it does not seem to influence quit rates among orthopaedic trauma patients. Extended counseling does not appear to provide substantial benefit over brief counseling.

Level of Evidence:
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.