bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopamine D1 receptor activation contributes to light-adapted changes in retinal inhibition to rod bipolar cells
Authors: Flood Michael D. , Moore-Dotson Johnnie M. , Eggers Erika D. 
Published: May 2018

Dopamine modulation of retinal signaling has been shown to be an important part of retinal adaptation to increased background light levels, but the role of dopamine modulation of retinal inhibition is not clear. We previously showed that light adaptation causes a large reduction in inhibition to rod bipolar cells, potentially to match the decrease in excitation after rod saturation. In this study, we determined how dopamine D1 receptors in the inner retina contribute to this modulation. We found that D1 receptor activation significantly decreased the magnitude of inhibitory light responses from rod bipolar cells, whereas D1 receptor blockade during light adaptation partially prevented this decline. To determine what mechanisms were involved in the modulation of inhibitory light responses, we measured the effect of D1 receptor activation on spontaneous currents and currents evoked from electrically stimulating amacrine cell inputs to rod bipolar cells. D1 receptor activation decreased the frequency of spontaneous inhibition with no change in event amplitudes, suggesting a presynaptic change in amacrine cell activity in agreement with previous reports that rod bipolar cells lack D1 receptors. Additionally, we found that D1 receptor activation reduced the amplitude of electrically evoked responses, showing that D1 receptors can modulate amacrine cells directly. Our results suggest that D1 receptor activation can replicate a large portion but not all of the effects of light adaptation, likely by modulating release from amacrine cells onto rod bipolar cells. NEW & NOTEWORTHY We demonstrated a new aspect of dopaminergic signaling that is involved in mediating light adaptation of retinal inhibition. This D1 receptor-dependent mechanism likely acts through receptors located directly on amacrine cells, in addition to its potential role in modulating the strength of serial inhibition between amacrine cells. Our results also suggest that another D2/D4 receptor-dependent or dopamine-independent mechanism must also be involved in light adaptation of inhibition to rod bipolar cells.
Effects of V1 surround modulation tuning on visual saliency and the tilt illusion
Authors: Keemink Sander W. , Boucsein Clemens , van Rossum Mark C. W. 
Published: May 2018

Neurons in the primary visual cortex respond to oriented stimuli placed in the center of their receptive field, yet their response is modulated by stimuli outside the receptive field (the surround). Classically, this surround modulation is assumed to be strongest if the orientation of the surround stimulus aligns with the neuron’s preferred orientation, irrespective of the actual center stimulus. This neuron-dependent surround modulation has been used to explain a wide range of psychophysical phenomena, such as biased tilt perception and saliency of stimuli with contrasting orientation. However, several neurophysiological studies have shown that for most neurons surround modulation is instead center dependent: it is strongest if the surround orientation aligns with the center stimulus. As the impact of such center-dependent modulation on the population level is unknown, we examine this using computational models. We find that with neuron-dependent modulation the biases in orientation coding, commonly used to explain the tilt illusion, are larger than psychophysically reported, but disappear with center-dependent modulation. Therefore we suggest that a mixture of the two modulation types is necessary to quantitatively explain the psychophysically observed biases. Next, we find that under center-dependent modulation average population responses are more sensitive to orientation differences between stimuli, which in theory could improve saliency detection. However, this effect depends on the specific saliency model. Overall, our results thus show that center-dependent modulation reduces coding bias, while possibly increasing the sensitivity to salient features. NEW & NOTEWORTHY Neural responses in the primary visual cortex are modulated by stimuli surrounding the receptive field. Most earlier studies assume this modulation depends on the neuron’s tuning properties, but experiments have shown that instead it depends mostly on the stimulus characteristics. We show that this simple change leads to neural coding that is less biased and under some conditions more sensitive to salient features.
Interference between competing motor memories developed through learning with different limbs
Authors: Kumar Neeraj , Kumar Adarsh , Sonane Bhoomika , Mutha Pratik K. 
Published: May 2018

Learning from motor errors that occur across different limbs is essential for effective tool use, sports training, and rehabilitation. To probe the neural organization of error-driven learning across limbs, we asked whether learning opposing visuomotor mappings with the two arms would interfere. Young right-handers first adapted to opposite visuomotor rotations A and B with different arms and were then reexposed to A 24 h later. We observed that relearning of A was never faster nor were initial errors smaller than prior A learning, which would be expected if there was no interference from B. Rather, errors were greater than or similar to, and learning rate was slower than or comparable to, previous A learning depending on the order in which the arms learned. This indicated robust interference between the motor memories of A and B when they were learned with different arms in close succession. We then proceeded to uncover that the order-dependent asymmetry in performance upon reexposure resulted from asymmetric transfer of learning from the left arm to the right but not vice versa and that the observed interference was retrograde in nature. Such retrograde interference likely occurs because the two arms require the same neural resources for learning, a suggestion consistent with that of our past work showing impaired learning following left inferior parietal damage regardless of the arm used. These results thus point to a common neural basis for formation of new motor memories with different limbs and hold significant implications for how newly formed motor memories interact. NEW & NOTEWORTHY In a series of experiments, we demonstrate robust retrograde interference between competing motor memories developed through error-based learning with different arms. These results provide evidence for shared neural resources for the acquisition of motor memories across different limbs and also suggest that practice with two effectors in close succession may not be a sound approach in either sports or rehabilitation. Such training may not allow newly acquired motor memories to be stabilized.
A Comparison of Direct and Indirect Analytical Approaches to Measuring Total Nicotine Equivalents in Urine
Authors: Taghavi Taraneh , Novalen Maria , Lerman Caryn , George Tony P. , Tyndale Rachel F. 
Published: May 2018

Abstract
Background: Total nicotine equivalents (TNE), the sum of nicotine and metabolites in urine, is a valuable tool for evaluating nicotine exposure. Most methods for measuring TNE involve two-step enzymatic hydrolysis for indirect quantification of glucuronide metabolites. Here, we describe a rapid, low-cost direct LC/MS assay.
Methods: In 139 smokers' urine samples, Bland–Altman, correlation, and regression analyses were used to investigate differences in quantification of nicotine and metabolites, TNE, and nicotine metabolite ratio (NMR) between direct and indirect LC/MS methods. DNA from a subset (n = 97 smokers) was genotyped for UGT2B10*2 and UGT2B17*2, and the known impact of these variants was evaluated using urinary ratios determined by the direct versus indirect method.
Results: The direct method showed high accuracy (0%–9% bias) and precision (3%–14% coefficient of variation) with similar distribution of nicotine metabolites to literary estimates and good agreement between the direct and indirect methods for nicotine, cotinine, and 3-hydroxycotinine (ratios 0.99–1.07), but less agreement for their respective glucuronides (ratios 1.16–4.17). The direct method identified urinary 3HC+3HC-GLUC/COT as having the highest concordance with plasma NMR and provided substantially better estimations of the established genetic impact of glucuronidation variants compared with the indirect method.
Conclusions: Direct quantification of nicotine and metabolites is less time-consuming and less costly, and provides accurate estimates of nicotine intake, metabolism rate, and the impact of genetic variation in smokers.
Impact: Lower cost and maintenance combined with high accuracy and reproducibility make the direct method ideal for smoking biomarker, NMR, and pharmacogenomics studies. Cancer Epidemiol Biomarkers Prev; 27(8); 882–91. ©2018 AACR.
Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
Authors: Tiriac Hervé , Belleau Pascal , Engle Dannielle D. , Plenker Dennis , Deschênes Astrid , Somerville Tim D. D. , Froeling Fieke E. M. , Burkhart Richard A. , Denroche Robert E. , Jang Gun-Ho , Miyabayashi Koji , Young C. Megan , Patel Hardik , Ma Michelle , LaComb Joseph F. , Palmaira Randze Lerie D. , Javed Ammar A. , Huynh Jasmine C. , Johnson Molly , Arora Kanika , Robine Nicolas , Shah Minita , Sanghvi Rashesh , Goetz Austin B. , Lowder Cinthya Y. , Martello Laura , Driehuis Else , LeComte Nicolas , Askan Gokce , Iacobuzio-Donahue Christine A. , Clevers Hans , Wood Laura D. , Hruban Ralph H. , Thompson Elizabeth , Aguirre Andrew J. , Wolpin Brian M. , Sasson Aaron , Kim Joseph , Wu Maoxin , Bucobo Juan Carlos , Allen Peter , Sejpal Divyesh V. , Nealon William , Sullivan James D. , Winter Jordan M. , Gimotty Phyllis A. , Grem Jean L. , DiMaio Dominick J. , Buscaglia Jonathan M. , Grandgenett Paul M. , Brody Jonathan R. , Hollingsworth Michael A. , O'Kane Grainne M. , Notta Faiyaz , Kim Edward , Crawford James M. , Devoe Craig , Ocean Allyson , Wolfgang Christopher L. , Yu Kenneth H. , Li Ellen , Vakoc Christopher R. , Hubert Benjamin , Fischer Sandra E. , Wilson Julie M. , Moffitt Richard , Knox Jennifer , Krasnitz Alexander , Gallinger Steven , Tuveson David A. 
Published: May 2018

Abstract
Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient–derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.
Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112–29. ©2018 AACR.
See related commentary by Collisson, p. 1062.
This article is highlighted in the In This Issue feature, p. 1047
Spatial Assessment of the Association between Long-Term Exposure to Environmental Factors and the Occurrence of Amyotrophic Lateral Sclerosis in Catalonia, Spain: A Population-Based Nested Case-Control Study
Authors: Povedano Mònica , Saez Marc , Martínez-Matos Juan-Antonio , Barceló Maria Antònia 
Published: May 2018

<b><i>Background:</i></b> It is believed that an interaction between genetic and non-genetic factors may be involved in the development of amyotrophic lateral sclerosis (ALS). With the exception of exposure to agricultural chemicals like pesticides, evidence of an association between environmental risk factors and ALS is inconsistent. Our objective here was to investigate the association between long-term exposure to environmental factors and the occurrence of ALS in Catalonia, Spain, and to provide evidence that spatial clusters of ALS related to these environmental factors exist. <b><i>Methods:</i></b> We carried out a nested case-control study constructed from a retrospective population-based cohort, covering the entire region. Environmental variables were the explanatory variables of interest. We controlled for both observed and unobserved confounders. <b><i>Results:</i></b> We have found some spatial clusters of ALS. The results from the multivariate model suggest that these clusters could be related to some of the environmental variables, in particular agricultural chemicals. In addition, in high-risk clusters, besides corresponding to agricultural areas, key road infrastructures with a high density of traffic are also located. <b><i>Conclusion:</i></b> Our results indicate that some environmental factors, in particular those associated with exposure to pesticides and air pollutants as a result of urban traffic, could be associated with the occurrence of ALS.
Notch2 and Proteomic Signatures in Mouse Neointimal Lesion Formation
Authors: Peterson Sarah M. , Turner Jacqueline E. , Harrington Anne , Davis-Knowlton Jessica , Lindner Volkhard , Gridley Thomas , Vary Calvin P.H. , Liaw Lucy 
Published: May 2018

Objective—
Vascular remodeling is associated with complex molecular changes, including increased Notch2, which promotes quiescence in human smooth muscle cells. We used unbiased protein profiling to understand molecular signatures related to neointimal lesion formation in the presence or absence of Notch2 and to test the hypothesis that loss of Notch2 would increase neointimal lesion formation because of a hyperproliferative injury response.

Approach and Results—

Murine carotid arteries isolated at 6 or 14 days after ligation injury were analyzed by mass spectrometry using a data-independent acquisition strategy in comparison to uninjured or sham injured arteries. We used a tamoxifen-inducible, cell-specific Cre recombinase strain to delete the
Notch2
gene in smooth muscle cells. Vessel morphometric analysis and immunohistochemical staining were used to characterize lesion formation, assess vascular smooth muscle cell proliferation, and validate proteomic findings. Loss of Notch2 in smooth muscle cells leads to protein profile changes in the vessel wall during remodeling but does not alter overall lesion morphology or cell proliferation. Loss of smooth muscle Notch2 also decreases the expression of enhancer of rudimentary homolog, plectin, and annexin A2 in vascular remodeling.

Conclusions—
We identified unique protein signatures that represent temporal changes in the vessel wall during neointimal lesion formation in the presence and absence of Notch2. Overall lesion formation was not affected with loss of smooth muscle Notch2, suggesting compensatory pathways. We also validated the regulation of known injury- or Notch-related targets identified in other vascular contexts, providing additional insight into conserved pathways involved in vascular remodeling.
Sex Differences at the Time of Myectomy in Hypertrophic Cardiomyopathy
Authors: Nijenkamp Louise L.A.M. , Bollen Ilse A.E. , van Velzen Hannah G. , Regan Jessica A. , van Slegtenhorst Marjon , Niessen Hans W.M. , Schinkel Arend F.L. , Krüger Martina , Poggesi Corrado , Ho Carolyn Y. , Kuster Diederik W.D. , Michels Michelle , van der Velden Jolanda 
Published: May 2018

Background:
One of the first clinically detectable alterations in heart function in hypertrophic cardiomyopathy (HCM) is a decline in diastolic function. Diastolic dysfunction is caused by changes in intrinsic properties of cardiomyocytes or an increase in fibrosis. We investigated whether clinical and cellular parameters of diastolic function are different between male and female patients with HCM at the time of myectomy.

Methods and Results:
Cardiac tissue from the interventricular septum of patients with HCM (27 women and 44 men) was obtained during myectomy preceded by echocardiography. At myectomy, female patients were 7 years older than male patients and showed more advanced diastolic dysfunction than men evident from significantly higher values for E/e′ ratio, left ventricular filling pattern, tricuspid regurgitation velocity, and left atrial diameter indexed for body surface. Whereas most male patients (56%) showed mild (grade I) diastolic dysfunction, 50% of female patients showed grade III diastolic dysfunction. Passive tension in HCM cardiomyocytes was comparable with controls, and myofilament calcium sensitivity was higher in HCM compared with controls, but no sex differences were observed in myofilament function. In female patients with HCM, titin was more compliant, and more fibrosis was present compared with men. Differences between female and male patients with HCM remained significant after correction for age.

Conclusions:
Female patients with HCM are older at the time of myectomy and show greater impairment of diastolic function. Furthermore, left ventricular and left atrial remodeling is increased in women when corrected for body surface area. At a cellular level, HCM women showed increased compliant titin and a larger degree of interstitial fibrosis.
Beclin-1-Dependent Autophagy Protects the Heart During Sepsis
Authors: Sun Yuxiao , Yao Xiao , Zhang Qing-Jun , Zhu Min , Liu Zhi-Ping , Ci Bo , Xie Yang , Carlson Deborah , Rothermel Beverly A. , Sun Yuxiang , Levine Beth , Hill Joseph A. , Wolf Steven E. , Minei Joseph P. , Zang Qun S. 
Published: May 2018

Background:
Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed.

Methods:
Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis.

Results:

LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mammalian target of rapamycin activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mammalian target of rapamycin signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for
beclin 1
resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial danger-associated molecular patterns, and promoted mitophagy via PTEN-induced putative kinase 1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by
beclin 1
deficiency in LPS-challenged mice.

Conclusions:
These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential.
Clinical Outcome of Degenerative Mitral Regurgitation
Authors: Antoine Clemence , Benfari Giovanni , Michelena Hector I. , Maalouf Joseph F. , Nkomo Vuyisile T. , Thapa Prabin , Enriquez-Sarano Maurice 
Published: May 2018

Background:
Echocardiographic quantitation of degenerative mitral regurgitation (DMR) is recommended whenever possible in clinical guidelines but is criticized and its scalability to routine clinical practice doubted. We hypothesized that echocardiographic DMR quantitation, performed in routine clinical practice by multiple practitioners, predicts independently long-term survival and thus is essential to DMR management.

Methods:
We included patients diagnosed with isolated mitral valve prolapse from 2003 to 2011 and any degree of mitral regurgitation quantified by any physician/sonographer in routine clinical practice. Clinical/echocardiographic data acquired at diagnosis were retrieved electronically. The end point was mortality under medical treatment analyzed by Kaplan-Meier method and proportional hazard models.

Results:

The cohort included 3914 patients (55% male) mean age (±standard deviation) 62±17 years with left ventricular ejection fraction 63±8% and median after routinely-measured effective regurgitant orifice area (EROA) [interquartile range], 19 [0–40] mm
2
. During follow-up (6.7±3.1 years), 696 patients died under medical management, and 1263 underwent mitral surgery. In multivariate analysis, routinely-measured EROA was associated with mortality (adjusted hazard ratio, 1.19; 95% confidence interval, 1.13–1.24;
P
<0.0001 per 10 mm
2
) independently of left ventricular ejection fraction and end-systolic diameter, symptoms, and age/comorbidities. The association between routinely-measured EROA and mortality persisted with competitive risk modeling (adjusted hazard ratio, 1.15; 95% confidence interval, 1.10–1.20;
P
<0.0001 per 10 mm
2
), or in patients without guideline-based class I/II surgical triggers (adjusted hazard ratio, 1.19; 95% confidence interval, 1.10–1.28;
P
<0.0001 per 10 mm
2
) and in all subgroups examined (all
P
<0.01). Spline curve analysis showed that, compared with general population mortality, excess mortality appears for moderate DMR (EROA ≥20 mm
2
), becomes notable at EROA ≥30 mm
2
, and steadily increases with higher EROA levels (eg, higher EROA levels beyond the 40 mm
2
threshold).

Conclusions:
Echocardiographic DMR quantitation is scalable to routine practice and is independently associated with clinical outcome. Routinely-measured EROA is strongly associated with long-term survival under medical treatment. Excess mortality versus the general population appears in the moderate DMR range and steadily increases with higher EROA. Hence, individual EROA values should be integrated into therapeutic considerations, in addition to categorical DMR grading.
Anthropology and Hebrew Bible Studies: Modes of Interchange and Interpretation
Authors: Goldberg Harvey E. 
Published: May 2018

AbstractInteraction between anthropology and biblical scholarship began because of perceived similarities between “simpler” societies and the practices and ideas seen in the Bible. After some disengagement in the first half of the twentieth century, new cross-disciplinary possibilities were envisioned as the structuralist approach emerged in anthropology. Ritual and mythology were major topics that received attention and structuralist methods were partially adopted by some biblical scholars. Anthropological research itself extended to complex societies and also affected historical studies, yielding models of inquiry that engaged a range of disciplines. Among the issues explored in this essay are ritual and notions of purity in the Bible, and the place of literacy in Israelite society and culture. These discussions are followed by three examples of structuralist-inspired analysis that partially take into account historical and literacy-based facets of the Bible.