bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Examination of the Extensor Pollicis Brevis: Anatomical Study and Description of a Novel Clinical Sign
Authors: Lonne Michael , Sparks David S. , Stephan Carl , Wagels Michael , Berger Anthony 
Published: October 2018

Background: The Extensor Pollicis Brevis (EPB) is an extrinsic thumb muscle whose main function is extension of the first metacarpophalangeal joint (MCPJ). It is subject to significant anatomical variation and may be absent, vestigial or have an anomalous distal attachment. Clinical examination of EPB is notoriously difficult and no reliable test has yet been described. We propose a novel test for the accurate examination of EPB. We sought to clarify the anatomical variations of EPB and to validate our clinical test using human cadaveric anatomical tests. Methods: A structured literature review of all human cadaveric anatomical studies describing the attachments of EPB was performed using MEDLINE and Embase with the key words “Extensor Pollicis Brevis”. A cadaveric anatomical study was performed using 18 unembalmed upper limbs. Positive and negative tests were simulated by manipulating the tendons of EPB, Extensor Pollicis Longus (EPL) and Flexor Pollicis Longus (FPL). Changes in tendon tension and joint position were measured and recorded. The EPB anatomy was then determined by dissection. Results: Anatomical variations were present in the majority of wrists, with only 35% of EPB tendons having a distal attachment to the proximal phalanx alone. EPB was absent in 5% of specimens. There was a significant difference between the change in MCPJ position between a positive (36 degrees; 95% CI 25 to 47 degrees) and negative (19 degrees; 95% CI 14 to 25 degrees) clinical test (p = 0.002). Conclusions: The functional importance of EPB depends on its congenital architecture in addition to the functional demands of the patient. We report a novel clinical test which is effective in demonstrating the integrity of the EPB. A positive test result is observed when a change in MCPJ position that occurs while the interphalangeal joint is brought into flexion from full thumb extension is 25 degrees or more.
Serotonin regulates dynamics of cerebellar granule cell activity by modulating tonic inhibition
Authors: Fleming Elizabeth , Hull Court 
Published: October 2018

Understanding how afferent information is integrated by cortical structures requires identifying the factors shaping excitation and inhibition within their input layers. The input layer of the cerebellar cortex integrates diverse sensorimotor information to enable learned associations that refine the dynamics of movement. Specifically, mossy fiber afferents relay sensorimotor input into the cerebellum to excite granule cells, whose activity is regulated by inhibitory Golgi cells. To test how this integration can be modulated, we have used an acute brain slice preparation from young adult rats and found that encoding of mossy fiber input in the cerebellar granule cell layer can be regulated by serotonin (5-hydroxytryptamine, 5-HT) via a specific action on Golgi cells. We find that 5-HT depolarizes Golgi cells, likely by activating 5-HT2A receptors, but does not directly act on either granule cells or mossy fibers. As a result of Golgi cell depolarization, 5-HT significantly increases tonic inhibition onto both granule cells and Golgi cells. 5-HT-mediated Golgi cell depolarization is not sufficient, however, to alter the probability or timing of mossy fiber-evoked feed-forward inhibition onto granule cells. Together, increased granule cell tonic inhibition paired with normal feed-forward inhibition acts to reduce granule cell spike probability without altering spike timing. Hence, these data provide a circuit mechanism by which 5-HT can reduce granule cell activity without altering temporal representations of mossy fiber input. Such changes in network integration could enable flexible, state-specific suppression of cerebellar sensorimotor input that should not be learned or enable reversal learning for unwanted associations. NEW & NOTEWORTHY Serotonin (5-hydroxytryptamine, 5-HT) regulates synaptic integration at the input stage of cerebellar processing by increasing tonic inhibition of granule cells. This circuit mechanism reduces the probability of granule cell spiking without altering spike timing, thus suppressing cerebellar input without altering its temporal representation in the granule cell layer.
Organ of Corti vibration within the intact gerbil cochlea measured by volumetric optical coherence tomography and vibrometry
Authors: Dong Wei , Xia Anping , Raphael Patrick D. , Puria Sunil , Applegate Brian , Oghalai John S. 
Published: October 2018

There is indirect evidence that the mammalian cochlea in the low-frequency apical and the more commonly studied high-frequency basal regions function in fundamentally different ways. Here, we directly tested this hypothesis by measuring sound-induced vibrations of the organ of Corti (OoC) at three turns of the gerbil cochlea using volumetric optical coherence tomography vibrometry (VOCTV), an approach that permits noninvasive imaging through the bone. In the apical turn, there was little frequency selectivity, and the displacement-vs.-frequency curves had low-pass filter characteristics with a corner frequency of ~0.5–0.9 kHz. The vibratory magnitudes increased compressively with increasing stimulus intensity at all frequencies. In the middle turn, responses were similar except for a slight peak in the response at ~2.5 kHz. The gain was ~50 dB at the peak and 30–40 dB at lower frequencies. In the basal turn, responses were sharply tuned and compressively nonlinear, consistent with observations in the literature. These data demonstrated that there is a transition of the mechanical response of the OoC along the length of the cochlea such that frequency tuning is sharper in the base than in the apex. Because the responses are fundamentally different, it is not appropriate to simply frequency shift vibratory data measured at one cochlear location to predict the cochlear responses at other locations. Furthermore, this means that the number of hair cells stimulated by sound is larger for low-frequency stimuli and smaller for high-frequency stimuli for the same intensity level. Thus the mechanisms of central processing of sounds must vary with frequency. NEW & NOTEWORTHY A volumetric optical coherence tomography and vibrometry system was used to probe cochlear mechanics within the intact gerbil cochlea. We found a gradual transition of the mechanical response of the organ of Corti along the length of the cochlea such that tuning at the base is dramatically sharper than that at the apex. These data help to explain discrepancies in the literature regarding how the cochlea processes low-frequency sounds.
mTORC1/2 and Protein Translation Regulate Levels of CHK1 and the Sensitivity to CHK1 Inhibitors in Ewing Sarcoma Cells
Authors: Koppenhafer Stacia L. , Goss Kelli L. , Terry William W. , Gordon David J. 
Published: October 2018

Abstract
The treatment of Ewing sarcoma has changed very little in the past two decades and novel treatment approaches are needed. We recently identified that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides. We subsequently found that the inhibition of checkpoint kinase 1 (CHK1) increases the sensitivity of Ewing sarcoma cells to inhibitors of RNR, such as gemcitabine. However, Ewing sarcoma cells exhibit high levels of the CHK1 protein, which may represent an adaptive response to elevated levels of endogenous DNA replication stress. Consequently, we began this work with the aim of determining the impact of CHK1 levels on drug sensitivity, as well as identifying the mechanisms and pathways that regulate CHK1 levels in Ewing sarcoma cells. In this report, we show that the high levels of the CHK1 protein in Ewing sarcoma cells limit the efficacy of CHK1 inhibitors. However, inhibition of mTORC1/2 activates the translational repressor 4E-BP1, reduces protein synthesis, and decreases levels of the CHK1 protein in Ewing sarcoma cells. Similarly, we identified that the CHK1 inhibitor prexasertib also activates 4E-BP1, inhibits protein synthesis, and reduces CHK1 protein levels in Ewing sarcoma cells. Moreover, the combination of prexasertib and gemcitabine was synergistic in vitro, caused tumor regression in vivo, and significantly prolonged mouse survival in a Ewing sarcoma xenograft experiment. Overall, our results provide insight into Ewing sarcoma biology and support further investigation of the CHK1 pathway as a therapeutic target in Ewing sarcoma tumors.
Association of Imatinib Plasma Concentration and Single-nucleotide Polymorphisms with Adverse Drug Reactions in Patients with Gastrointestinal Stromal Tumors
Authors: Zhang Qiang , Xu Jianghao , Qian Yi , Chen Liang , Li Qingya , Xu Kangjing , Chen Ming , Sun Luning , He Zhongyuan , Yang Li , Zhang Diancai , Wang Linjun , Sun Xiaofeng , Wang Yongqing , Xu Hao , Xu Zekuan 
Published: October 2018

Abstract
Gastrointestinal stromal tumors (GIST) are the most prevalent mesenchymal tumors of the digestive tract. To investigate the association of imatinib mesylate plasma concentration with adverse drug reactions (ADRs) and influences of genetic polymorphisms on ADRs in GIST patients taking imatinib, a cohort of GIST patients consecutively treated with imatinib were included in the observational study. Clinical, pathologic and genotype information was recorded at enrollment and blood samples were collected at time as design. The plasma concentration of the imatinib was detected by LC-MS/MS. A questionnaire was used to evaluate the ADRs at each visit. SNPs in 13 genes were analyzed for a possible association with ADRs. The mean plasma trough concentration of 129 patients taking imatinib was 1.45 ± 0.79 μg/ml, average peak concentration was 2.63 ± 1.07 μg/ml. The imatinib concentration in patients treated with 600 mg/day was significantly higher than other dosage groups (P &lt; 0.05). The ADRs were mostly mild. Edema, vomiting, and fatigue were significantly correlated with imatinib concentration (P &lt; 0.05). Mutations of IL13 rs1800925 and CXCL14 rs7716492 were related with the incidence of leukopenia and rash in our research, separately (P &lt; 0.05). We confirmed that with the increase of imatinib concentration, the incidence of edema, vomiting, and fatigue rises as well. Mutations of IL13 rs1800925 and CXCL14 rs7716492 may be the promising biomarkers to predict the ADRs of imatinib. The results of the study are of guiding significance for the use of imatinib in patients with GIST.
A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells
Authors: Hoang Trish T. , Tanrikulu I. Caglar , Vatland Quinn A. , Hoang Trieu M. , Raines Ronald T. 
Published: October 2018

AbstractPancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells. A human ptRNase variant that is resistant to inhibition by RI is a cytotoxin that is undergoing a clinical trial as a cancer chemotherapeutic agent. We find that the ptRNase and protein kinases in the ERK pathway exhibit strongly synergistic toxicity toward lung cancer cells (including a KRASG12C variant) and melanoma cells (including BRAFV600E variants). The synergism arises from inhibiting the phosphorylation of RI and thereby diminishing its affinity for the ptRNase. These findings link seemingly unrelated cellular processes, and suggest that the use of a kinase inhibitor to unleash a cytotoxic enzyme could lead to beneficial manifestations in the clinic.
Proteasome Biology Is Compromised in White Matter After Asphyxic Cardiac Arrest in Neonatal Piglets
Authors: Santos Polan T. , O'Brien Caitlin E. , Chen May W. , Hopkins C. Danielle , Adams Shawn , Kulikowicz Ewa , Singh Rashmi , Koehler Raymond C. , Martin Lee J. , Lee Jennifer K. 
Published: October 2018

Background
Neurological deficits in hypoxic‐ischemic encephalopathy, even with therapeutic hypothermia, are partially attributed to white matter injury. We theorized that proteasome insufficiency contributes to white matter injury.

Methods and Results

Neonatal piglets received hypoxia‐ischemia (
HI
) or sham procedure with normothermia, hypothermia, or hypothermia+rewarming. Some received a proteasome activator drug (oleuropein) or white matter–targeted, virus‐mediated proteasome knockdown. We measured myelin oligodendrocyte glycoprotein, proteasome subunit 20S (P20S), proteasome activity, and carbonylated and ubiquitinated protein levels in white matter and cerebral cortex.
HI
reduced myelin oligodendrocyte glycoprotein levels regardless of temperature, and myelin oligodendrocyte glycoprotein loss was associated with increased ubiquitinated and carbonylated protein levels. Ubiquitinated and carbonyl‐damaged proteins increased in white matter 29 hours after
HI
during hypothermia to exceed levels at 6 to 20 hours. In cortex, ubiquitinated proteins decreased. Ubiquitinated and carbonylated protein accumulation coincided with lower P20S levels in white matter; P20S levels also decreased in cerebral cortex. However, proteasome activity in white matter lagged behind that in cortex 29 hours after
HI
during hypothermia. Systemic oleuropein enhanced white matter P20S and protected the myelin, whereas proteasome knockdown exacerbated myelin oligodendrocyte glycoprotein loss and ubiquitinated protein accumulation after
HI
. At the cellular level, temperature and
HI
interactively affected macroglial P20S enrichment in subcortical white matter. Rewarming alone increased macroglial P20S immunoreactivity, but this increase was blocked by
HI
.

Conclusions

Oxidized and ubiquitinated proteins accumulate with
HI
‐induced white matter injury. Proteasome insufficiency may drive this injury. Hypothermia did not prevent myelin damage, protect the proteasome, or preserve oxidized and ubiquitinated protein clearance after
HI
.
Underutilization of Evidence‐Based Smoking Cessation Support Strategies Despite High Smoking Addiction Burden in Peripheral Artery Disease Specialty Care: Insights from the International PORTRAIT Registry
Authors: Patel Krishna K. , Jones Philip G. , Ellerbeck Edward F. , Buchanan Donna M. , Chan Paul S. , Pacheco Christina M. , Moneta Gregory , Spertus John A. , Smolderen Kim G. 
Published: October 2018

Background

Smoking is the most important risk factor for peripheral artery disease (
PAD
). Smoking cessation is key in
PAD
management. We aimed to examine smoking rates and smoking cessation interventions offered to patients with
PAD
consulting a vascular specialty clinic; and assess changes in smoking behavior over the year following initial visit.

Methods and Results

A total of 1272 patients with
PAD
and new or worsening claudication were enrolled at 16 vascular specialty clinics (2011–2015, PORTRAIT (Patient‐Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories) registry). Interviews collected smoking status and cessation interventions at baseline, 3, 6, and 12 months. Among smokers, transition state models analyzed smoking transitions at each time point and identified factors associated with quitting and relapse. On presentation, 474 (37.3%) patients were active, 660 (51.9%) former, and 138 (10.8%) never smokers. Among active smokers, only 16% were referred to cessation counseling and 11% were prescribed pharmacologic treatment. At 3 months, the probability of quitting smoking was 21%; among those continuing to smoke at 3 months, the probability of quitting during the next 9 months varied between 11% and 12% (
P
<0.001). The probability of relapse among initial quitters was 36%. At 12 months, 72% of all smokers continued to smoke.

Conclusions

More than one third of patients with claudication consulting a
PAD
provider are active smokers and few received evidence‐based cessation interventions. Patients appear to be most likely to quit early in their treatment course, but many quickly relapse and 72% of all patients smoking at baseline are still smoking at 12 months. Better strategies are needed to provide continuous cessation support.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01419080.
Agro-Climate Projections for a Warming Alaska
Authors: Lader Rick , Walsh John E. , Bhatt Uma S. , Bieniek Peter A. 
Published: October 2018

AbstractClimate warming is expected to disproportionately affect crop yields in the southern United States due to excessive heat stress, while presenting new farming opportunities through a longer growing season farther north. Few studies have investigated the impact of this warming on agro-climate indices that link meteorological data with important field dates in northern regions. This study employs regional dynamical downscaling using the Weather Research and Forecasting (WRF) Model to assess changes in growing season length (GSL), spring planting dates, and occurrences of plant heat stress (PHS) for five regions in Alaska. Differences between future representative concentration pathway 8.5 (RCP8.5; 2011–40, 2041–70, 2071–2100) and historical (1981–2010) periods are obtained using boundary forcing from the Geophysical Fluid Dynamics Laboratory Climate Model, version 3, and the NCAR Community Climate System Model, version 4. The model output is bias corrected using ERA-Interim. Median GSL shows increases of 48–87 days by 2071–2100, with the largest changes in northern Alaska. Similarly, by 2071–2100, planting dates advance 2–4 weeks, and PHS days increase from near 0 to 5–10 instances per summer in the hottest areas. The largest GSL changes occur in the mid- (2041–70) and late century (2071–2100), when a warming signal emerges from the historical interannual variability. These periods coincide with the greatest divergence of the RCPs, suggesting that near-term decision-making may affect substantial future changes. Early-century (2011–40) projections show median GSL increases of 8–27 days, which is close to the historical standard deviation of GSL. Thus, internal variability will remain an important source of uncertainty into the midcentury, despite a trend for longer growing seasons.
Application of a Physical Ensemble Method in the POD-4DEnVar
Authors: Yang Yuxuan , Zhang Lifeng , Zhang Bin , You Wei , Zhang Mingyang , Xie Binpeng 
Published: October 2018

Abstract
The sensitivity of the proper orthogonal decomposition (POD)-based ensemble four-dimensional variational assimilation (4DVar) method (referred to as POD-4DEnVar) to cumulus and microphysics schemes was investigated using the Weather Research and Forecasting (WRF) Model for heavy rainfall in South China. Results show that the choice of the cumulus and microphysics schemes for ensemble samples significantly impacts precipitation prediction and that Doppler radar data assimilation using POD-4DEnVar is sensitive to the parameterization schemes used for the ensemble samples. The cumulus and microphysics schemes primarily affect the vertical velocity and rainwater mixing ratio of the ensemble forecasts. Variations in the ensemble samples caused by different parameterization schemes are introduced into the four-dimensional ensemble variational assimilation by the radar data observation operator. These variations affect the analysis fields and result in variations in precipitation prediction. To obtain the optimal result (smallest forecast error), three methods are designed based on the physical ensemble technique, which can filter out the effects of different parameterization schemes for the ensemble samples through averaging. The results show that the precipitation forecasts from the three assimilation experiments are improved compared with a control experiment, but each physical ensemble method leads to a unique precipitation forecast.
The Political Economy of the New Left
Authors: Pickup Megan 
Published: October 2018

New Left regimes have been underpinned by a reliance both on labor and nontraditional social groups and on capital interests related to the primary commodity sector, and the state has played an important overseer role in these relationships. These states have attempted to accommodate all these groups by pursuing incompatible populist and pragmatic policies. Study of the particular configuration of these regimes is important because they have become simultaneously more inclusive and closed off, generating heightened social fragmentation. Divisions among the left, the hardening of the right, and economic frailty render these governments unstable. Los regímenes de Nueva Izquierda se han fundamentado por una dependencia tanto de los trabajadores y grupos sociales no tradicionales como de los intereses del capital relacionados con el sector de los productos primarios, y el Estado ha desempeñado un importante papel de supervisor en estas relaciones. Estos estados han intentado acomodar a todos estos grupos persiguiendo políticas populistas y pragmáticas incompatibles. El estudio de la configuración particular de estos regímenes es importante porque se han vuelto simultáneamente más inclusivos y cerrados, generando una mayor fragmentación social. Las divisiones en la izquierda, el endurecimiento de la derecha y la fragilidad económica hacen que estos gobiernos sean inestables.
Is exposure to personal music players a confounder in adolescent mobile phone use and hearing health studies?
Authors: Benke Geza , Dimitriadis Christina , Zeleke Berihun M. , Inyang Imo , McKenzie Dean , Abramson Michael J. 
Published: October 2018

Objective This study was performed to determine whether exposure to personal music players (PMPs) in the immediate morning prior to hearing testing confounds the association between mobile phone use and hearing thresholds of adolescents. Design In this cohort study of cognitive function in year 7 students (median age 13 years, range 11–14), information regarding the weekly use of mobile phones and the use of PMPs was assessed by a questionnaire. Pure-tone audiometry was used to establish hearing thresholds for all participants. Results Among a cohort of 317 adolescents (60.9% females), 130 were unexposed to PMP use while 33 were exposed to PMP use in the morning prior to hearing testing. No statistically significant difference in hearing threshold shifts was found between adolescents who were and were not exposed to PMP use prior to hearing testing. Likewise, the difference in the use of mobile phones according to the PMP use status was not statistically significant. Conclusion Exposure to PMPs prior to hearing testing did not introduce confounding in the present study of mobile phone use and hearing loss among adolescents.