bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revealing capture sites and movements by strontium isotope analyses in bones of Caiman yacare in the Beni river floodplain, Bolivia
Authors: Pouilly Marc , Gomez Sergio , Pécheyran Christophe , Bérail Sylvain , Alvarez Gustavo , Miranda-Chumacero Guido 
Published: April 2021

ABSTRACTStudying the distribution of organisms and their movements is fundamental to understand population dynamics. Most studies indicated that crocodilians do not move around much but several studies demonstrated that some species showed movement patterns. Detection of these movements along the individual life is still a challenge. In this study we analyzed the variation of strontium isotopic ratio (87Sr/86Sr) in the femur bones of 70 Caimanya care individuals caught in 16 sites located in five hydrological sectors of the Beni river floodplain in Bolivia. Our results demonstrated for the first time that such a methodology could yield indications about the capture sites and reconstruct individual life history. Analyses of the outer part of the femur of 70 individuals showed that capture sites could be differentiated between sectors and even between sites or groups of sites in each sector. Studies of complete 87Sr/86Sr profiles along the femur, representing the individual’s entire life, were performed on 33 yacares. We found that most of the individuals did not show any significant isotopic variation throughout their lives. This absence of variation could result from a high fidelity to the birth site, and/or from an insignificant isotopic variation between the water bodies through which the animal has potentially moved. However, 24% of the analyzed individuals presented significant variations that can be considered as movements between different habitats. Based on the observed low proportion of moving yacares, we advocated that each water body should be considered an individual management unit.
Targeting Adaptation to Cancer Treatment by Drug Combinations
Authors: Wang Heping , Luna Augustin , Yan Gonghong , Li Xubin , Babur Ozgun , Mills Gordon B. , Sander Chris , Korkut Anil 
Published: April 2021

ABSTRACTAdaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of anti-apoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress.
How faculty define quality, prestige, and impact in research
Authors: Morales Esteban , McKiernan Erin , Niles Meredith T. , Schimanski Lesley , Alperin Juan Pablo 
Published: April 2021

AbstractDespite the calls for change, there is significant consensus that when it comes to evaluating publications, review, promotion, and tenure processes should aim to reward research that is of high “quality,” has an “impact,” and is published in “prestigious” journals. Nevertheless, such terms are highly subjective and present challenges to ascertain precisely what such research looks like. Accordingly, this article responds to the question: how do faculty from universities in the United States and Canada define the terms quality, prestige, and impact? We address this question by surveying 338 faculty members from 55 different institutions. This study’s findings highlight that, despite their highly varied definitions, faculty often describe these terms in overlapping ways. Additionally, results shown that marked variance in definitions across faculty does not correspond to demographic characteristics. This study’s results highlight the need to more clearly implement evaluation regimes that do not rely on ill-defined concepts.Financial DisclosureFunding for this project was provided to JPA, MTN, ECM, and LAS from the OpenSociety Foundations (OR2017-39637). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Related MaterialsOther publications related to this project, including a series of infographics summarizing findings, can be found at:https://www.scholcommlab.ca/research/rpt-project/Survey responses can be found at the following publication:Niles, Meredith T.; Schimanski, Lesley A.; McKiernan, Erin C.; Alperin, Juan Pablo,2020, “Data for: Why we publish where we do”,https://doi.org/10.7910/DVN/MRLHNO,Harvard Dataverse, V1Data regarding RPT documents can be found at the following data publication:Alperin, Juan Pablo; Muñoz Nieves, Carol; Schimanski, Lesley; McKiernan, Erin C.;Niles, Meredith T., 2018, “Terms and Concepts found in Tenure and Promotion Guidelines from the US and Canada”,https://doi.org/10.7910/DVN/VY4TJE,Harvard Dataverse, V3, UNF:6:PQC7QoilolhDrokzDPxxyQ== [fileUNF]
Monosodium Urate Crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response
Authors: Cobo Isidoro , Cheng Anyan , Murillo-Saich Jessica , Coras Roxana , Torres Alyssa , Lana Addison J. , Schlachetzki Johannes , Liu-Bryan Ru , Terkeltaub Robert , Sanchez-Lopez Elsa , Glass Christopher K. , Guma Monica 
Published: April 2021

ABSTRACTHow macrophages are programmed to respond to monosodium urate crystals (MSUc) is incompletely understood partly due to the use of a toll-like receptor-induced priming step. Here, using genome wide transcriptomic analysis and biochemical assays we demonstrate that MSUc alone induces anin vitrometabolic-inflammatory transcriptional program in both human and murine macrophages markedly distinct from that induced by LPS. Genes uniquely up-regulated in response to MSUc belonged to lipids, glycolysis, and transport of small molecules via SLC transporters pathways. Sera from individuals and mice with acute gouty arthritis provided further evidence for this metabolic rewiring. This distinct macrophage activation may explain the initiating mechanisms in acute gout flares and is regulated through JUN binding to the promoter of target genes through activation of JNK –but not by P38-in a process that is independent of inflammasome activation. Finally, pharmacological JNK inhibition limited MSUc-induced inflammation in animal models of acute gouty inflammation.
Characterization of five purine riboswitches in cellular and cell-free expression systems
Authors: Lins Milca Rachel da Costa Ribeiro , Correa Graciely Gomes , Amorim Laura Araujo da Silva , Franco Rafael Augusto Lopes , Ribeiro Nathan Vinicius , de Jesus Victor Nunes , Pedrolli Danielle Biscaro 
Published: April 2021

ABSTRACTBacillus subtilisemploys five purine riboswitches for the control of purinede novosynthesis and transport at the transcription level. All of them are formed by a structurally conserved aptamer, and a variable expression platform harboring a rho-independent transcription terminator. In this study, we characterized all five purine riboswitches under the context of active gene expression processes bothin vitroandin vivo. We identified transcription pause sites located in the expression platform upstream of the terminator of each riboswitch. Moreover, we defined a correlation betweenin vitrotranscription readthrough andin vivogene expression. Ourin vitroassay demonstrated that the riboswitches operate in the micromolar range of concentration for the cognate metabolite. Ourin vivoassay showed the dynamics of control of gene expression by each riboswitch. This study deepens the knowledge of the regulatory mechanism of purine riboswitches.
Speech-related auditory salience detection in the posterior superior temporal region
Authors: Brown Erik C. , Stedelin Brittany , Raslan Ahmed M. , Selden Nathan R. 
Published: April 2021

AbstractProcessing auditory human speech requires both detection (early and transient) and analysis (sustained). We analyzed high gamma (70-110Hz) activity of intracranial electroencephalography waveforms acquired during an auditory task that paired forward speech, reverse speech, and signal correlated noise. We identified widespread superior temporal sites with sustained activity responding only to forward and reverse speech regardless of paired order. More localized superior temporal auditory onset sites responded to all stimulus types when presented first in a pair and responded in recurrent fashion to the second paired stimulus in select conditions even in the absence of interstimulus silence; a novel finding. Auditory onset activity to a second paired sound recurred according to relative salience, with evidence of partial suppression during linguistic processing. We propose that temporal lobe auditory onset sites facilitate a salience detector function with hysteresis of 200ms and are influenced by cortico-cortical feedback loops involving linguistic processing and articulation.
Salt-induced first-order structural transition in a DNA-interacting protein
Authors: Lu Yue , Lu Ying , Ma Jianbing , Li Jinghua , Huang Xingyuan , Jia Qi , Ma Dongfei , Liu Ming , Zhang Hao , Yu Xuan , Hu Shuxin , Li Yunliang , Xu Chunhua , Li Ming 
Published: April 2021

AbstractThermodynamics and structural transitions on protein surfaces remain relatively understudied and poorly understood. Wrapping of DNA on proteins provides a paradigm for studying protein surfaces. We used magnetic tweezers to investigate a prototypical DNA-interacting protein, i.e., the single-stranded DNA binding protein (SSB). SSB binds DNA with distinct binding modes the mechanism of which is still elusive. The measured thermodynamic parameters relevant to the SSB-DNA complex are salt-dependent and discontinuous at the bind-mode transitions. Our data indicate that free SSB undergoes salt-induced first-order structural transitions. The conclusion was supported by the infrared spectroscopy of SSB in salt solutions. Ultrafast infrared spectroscopy further suggests that the transitions are correlated with surface salt bridges. Our work not only unravels a long-standing mystery of the different binding site sizes of SSB, but also would inspire interests in thermodynamics of protein surfaces.
Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications
Authors: Henning Nathaniel J. , Manford Andrew G. , Spradlin Jessica N. , Brittain Scott M. , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Rape Michael , Nomura Daniel K. 
Published: April 2021

AbstractProteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularity of TPD approaches in drug discovery, only a small number of E3 ligase recruiters are available for the >600 E3 ligases that exist in human cells. Here, we have discovered a cysteine-reactive covalent ligand, EN106, that targets FEM1B, an E3 ligase recently discovered as the critical component of the cellular response to reductive stress. By targeting Cys186 in FEM1B, EN106 disrupts recognition of the key reductive stress substrate of FEM1B, FNIP1. We further establish that EN106 can be used as a covalent recruiter for FEM1B in TPD applications, in which we demonstrate that a PROTAC linking EN106 to the BET Bromodomain inhibitor JQ1 leads to specific FEM1B- and proteasome-dependent degradation of BRD4 in cells. Our study showcases a covalent ligand that targets a natural E3 ligase-substrate binding site and highlights the utility of covalent ligand screening in expanding the arsenal of E3 ligase recruiters that can be deployed for TPD applications.
Dendritic inhibition by Shh signaling-dependent stellate cell pool is critical for motor learning
Authors: Li Wen , Chen Lei , Fleming Jonathan T. , Brignola Emily , Zavalin Kirill , Lagrange Andre H. , Rex Tonia S. , Heiney Shane A. , Wojaczynski Gregory J. , Medina Javier F. , Chiang Chin 
Published: April 2021

SUMMARYCerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and non-motor functions. The molecular layer interneurons (MLI), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons which migrate from the prospective white matter to the ML of the cortex. However, little is known as to how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well understood. Here, we show that GABAergic progenitors fated to generate both BCs and SCs respond to the Shh signal. Conditional abrogation of Shh signaling inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early-born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+cells settle into their laminar positions in an inside-out sequence. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.
Short‐term multimodal prehabilitation improves functional capacity for colorectal cancer patients prior to surgery
Authors: Suen Michael , Liew Andre , Turner Jane D. , Khatri Sonia , Lin Yanlan , Raso Kristy L. , Vardy Janette L. 
Published: April 2021

AbstractAimEvaluate feasibility and outcomes of a multimodal prehabiliation program in patients with stage I‐III colorectal cancer (CRC) awaiting surgery.MethodsPatients scheduled for elective CRC resection at Concord Repatriation General Hospital were recruited from pre‐admission clinic between January and November 2018. Participants received a 2‐4 week prehabilitation program consisting of supervised exercise sessions, nurse‐led phone support, and written nutritional information. Participants were assessed at baseline, pre‐surgery, and 4 weeks post‐surgery.ResultsTwenty‐two patients participated in the program: 55% male; median age 73 (56‐86) years. Six (28%) required an interpreter. At baseline, 19 of 22 (86%) had at least one comorbidity. Median intervention length was 11.5 days (range 7‐29). Participants attended 79% of scheduled exercise sessions (range 33‐100%, mean 3.5 sessions) and 66% of nurse support calls (range 0‐100%, mean 2.6 sessions). Between baseline and pre‐surgery, participants reported increasing mean unsupervised moderate‐intensity aerobic exercise from 17 (range 0‐210) to 73 minutes/week (range 0–276) and mean vigorous‐intensity aerobic exercise from 0 to 24 minutes/week (range 0‐300). Resistance exercise sessions increased from 0.6 to 2.6 times/week. Mean 6‐minute walk test distance increased by 48 meters (435‐483 m) and 30‐second "sit to stand" by 1.6 repetitions. Small improvements were seen in global quality of life and fatigue. Nutritional status and body composition remained unchanged. All participants were satisfied/strongly satisfied with the program and would recommend it to others.ConclusionOur multimodal prehabilitation program was feasible in CRC patients inclusive of those from non‐English speaking backgrounds, with improvement in functional capacity before CRC surgery.
Incorporation of eribulin in the systemic treatment of metastatic breast cancer patients in Australia
Authors: Chan Arlene , Lomma Christopher , Chih HuiJun , Blackely Elizabeth , Woodward Natasha , Tsoi Daphne , Cheong Kerry , Chipman Mitchell , Redfern Andrew 
Published: April 2021

AbstractPurposeReview of utilization and efficacy of eribulin in Australian metastatic breast cancer (MBC) patients.MethodsRetrospective review of consecutive MBC patients treated with eribulin in tertiary Australian BC centers. Key inclusion criteria included eribulin administration in nonclinical trial setting from October 2014 onwards, known duration of MBC systemic treatments administered and known follow‐up date after eribulin. Cox regression model was used to assess survival.ResultsStudy population comprised 266 patients from eight centers treated between October 2014 and May 2018. Median age at time of MBC diagnosis was 54 years with 18% of patients having de novo MBC. Seventy‐six percent had hormone receptor positive (HRp) disease, 19% triple negative (TN) and 5% HER2‐positive. CNS involvement was present in 36% of patients. Eribulin was most frequently given as third‐line chemotherapy (36%), with no prior anthracycline exposure in 14% of total population. Eribulin was given more frequently as ≤third‐line chemotherapy than > third‐line in patients with TN disease, ≥ two metastatic sites or CNS disease. Median overall survival (OS) from eribulin administration was 9.2 (95% CI [8.0, 10.3]) months.ConclusionSimilar efficacy was demonstrated for eribulin when given in the first‐line to beyond the fifth line of chemotherapy in all subtypes of MBC.
A prospective, real‐world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE‐02)
Authors: Kalaria Shamir N. , Armahizer Michael , McCarthy Paul , Badjatia Neeraj , Gobburu Jogarao V. , Gopalakrishnan Mathangi 
Published: April 2021

AimsAlthough the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice‐based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH).MethodsSeven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre‐filter, post‐filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post‐administration. Patient‐specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high‐performance liquid chromatography with ultraviolet radiation detection (HPLC‐UV) bioanalytical method. Non‐compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide.ResultsThe observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5–12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was −2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate‐based dosing regimens could be used to individualize lacosamide therapeutics.ConclusionsCVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.
Economic evaluation of remdesivir for the treatment of severe COVID‐19 patients in China under different scenarios
Authors: Jiang Yawen , Cai Dan , Chen Daqin , Jiang Shan , Si Lei , Wu Jing 
Published: April 2021

AimsThe present study aimed to evaluate the cost‐effectiveness of the 5‐day remdesivir regimen compared with standard of care among severe COVID‐19 patients in China, the evidence on which is essential to inform the necessity of securing access to remdesivir.MethodsA dynamic transmission model that extended the susceptible–exposed–infected–recovered framework by incorporating asymptomatic, presymptomatic and waiting‐to‐be‐diagnosed patients was constructed to conduct the cost‐effectiveness analysis from the healthcare system perspective. To estimate epidemic parameters, the model was first calibrated to the observed epidemic curve in Wuhan from 23 January to 19 March 2020. Following the calibration, the infected compartment was replaced by 3 severity‐defined health states to reflect differential costs and quality of life associated with disease gravity. Costs and quality‐adjusted life year (QALY) outcomes of 9 million simulated people were accrued across time to evaluate the incremental cost‐effectiveness ratio of remdesivir. As robustness checks, an alternative modelling technique using decision tree, additional epidemic scenarios representing different epidemic intensities, and 1‐way parameter variations were also analysed.ResultsRemdesivir treatment cost CN¥97.93 million more than standard of care. Also, the net QALY gain from 5‐day remdesivir treatment was 6947 QALYs. As such, the incremental cost‐effectiveness ratio was CN¥14 098/QALY, substantially lower than the gross domestic product per capita threshold. The peak daily number of severe cases was 19% lower in the remdesivir treatment strategy. Overall, results were robust in alternative scenarios and sensitivity analyses.ConclusionGiven the cost‐effectiveness profile, access to remdesivir for severe COVID‐19 patients in China should be considered.