bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental consistency modulation of error sensitivity during motor adaptation is explicitly controlled
Authors: Avraham Guy , Keizman Matan , Shmuelof Lior 
Published: November 2019

Motor adaptation, the adjustment of a motor output in face of changes in the environment, may operate at different rates. When human participants encounter repeated or consistent perturbations, their corrections for the experienced errors are larger compared with when the perturbations are new or inconsistent. Such modulations of error sensitivity were traditionally considered to be an implicit process that does not require attentional resources. In recent years, the implicit view of motor adaptation has been challenged by evidence showing a contribution of explicit strategies to learning. These findings raise a fundamental question regarding the nature of the error sensitivity modulation processes. We tested the effect of explicit control on error sensitivity in a series of experiments, in which participants controlled a screen cursor to virtual targets. We manipulated environmental consistency by presenting rotations in random (low consistency) or random walk (high consistency) sequences and illustrated that perturbation consistency affects the rate of adaptation, corroborating previous studies. When participants were instructed to ignore the cursor and move directly to the target, thus eliminating the contribution of explicit strategies, consistency-driven error sensitivity modulation was not detected. In addition, delaying the visual feedback, a manipulation that affects implicit learning, did not influence error sensitivity under consistent perturbations. These results suggest that increases of learning rate in consistent environments are attributable to an explicit rather than implicit process in sensorimotor adaptation. NEW & NOTEWORTHY The consistency of an external perturbation modulates error sensitivity and the motor response. The roles of explicit and implicit processes in this modulation are unknown. We show that when humans are asked to ignore the perturbation, they do not show increased error sensitivity in consistent environments. When the implicit system is manipulated by delaying feedback, sensitivity to a consistent perturbation does not change. Overall, our results suggest that consistency affects adaptation mainly through explicit control.
GABAA receptors contribute more to rate than temporal coding in the IC of awake mice
Authors: Gourévitch Boris , Mahrt Elena J. , Bakay Warren , Elde Cameron , Portfors Christine V. 
Published: November 2019

Speech is our most important form of communication, yet we have a poor understanding of how communication sounds are processed by the brain. Mice make great model organisms to study neural processing of communication sounds because of their rich repertoire of social vocalizations and because they have brain structures analogous to humans, such as the auditory midbrain nucleus inferior colliculus (IC). Although the combined roles of GABAergic and glycinergic inhibition on vocalization selectivity in the IC have been studied to a limited degree, the discrete contributions of GABAergic inhibition have only rarely been examined. In this study, we examined how GABAergic inhibition contributes to shaping responses to pure tones as well as selectivity to complex sounds in the IC of awake mice. In our set of long-latency neurons, we found that GABAergic inhibition extends the evoked firing rate range of IC neurons by lowering the baseline firing rate but maintaining the highest probability of firing rate. GABAergic inhibition also prevented IC neurons from bursting in a spontaneous state. Finally, we found that although GABAergic inhibition shaped the spectrotemporal response to vocalizations in a nonlinear fashion, it did not affect the neural code needed to discriminate vocalizations, based either on spiking patterns or on firing rate. Overall, our results emphasize that even if GABAergic inhibition generally decreases the firing rate, it does so while maintaining or extending the abilities of neurons in the IC to code the wide variety of sounds that mammals are exposed to in their daily lives. NEW & NOTEWORTHY GABAergic inhibition adds nonlinearity to neuronal response curves. This increases the neuronal range of evoked firing rate by reducing baseline firing. GABAergic inhibition prevents bursting responses from neurons in a spontaneous state, reducing noise in the temporal coding of the neuron. This could result in improved signal transmission to the cortex.
Dysregulation of Glutamate Transport Enhances Treg Function That Promotes VEGF Blockade Resistance in Glioblastoma
Authors: Long Yu , Tao Haipeng , Karachi Aida , Grippin Adam J. , Jin Linchun , Chang Yifan (Emily) , Zhang Wang , Dyson Kyle A. , Hou Alicia Y. , Na Meng , Deleyrolle Loic P. , Sayour Elias J. , Rahman Maryam , Mitchell Duane A. , Lin Zhiguo , Huang Jianping 
Published: November 2019

Abstract

Anti-VEGF therapy prolongs recurrence-free survival in patients with glioblastoma but does not improve overall survival. To address this discrepancy, we investigated immunologic resistance mechanisms to anti-VEGF therapy in glioma models. A screening of immune-associated alterations in tumors after anti-VEGF treatment revealed a dose-dependent upregulation of regulatory T-cell (Treg) signature genes. Enhanced numbers of Tregs were observed in spleens of tumor-bearing mice and later in tumors after anti-VEGF treatment. Elimination of Tregs with CD25 blockade before anti-VEGF treatment restored IFNγ production from CD8+ T cells and improved antitumor response from anti-VEGF therapy. The treated tumors overexpressed the glutamate/cystine antiporter SLC7A11/xCT that led to elevated extracellular glutamate in these tumors. Glutamate promoted Treg proliferation, activation, suppressive function, and metabotropic glutamate receptor 1 (mGlutR1) expression. We propose that VEGF blockade coupled with glioma-derived glutamate induces systemic and intratumoral immunosuppression by promoting Treg overrepresentation and function, which can be pre-emptively overcome through Treg depletion for enhanced antitumor effects.

Significance:
Resistance to VEGF therapy in glioblastoma is driven by upregulation of Tregs, combined blockade of VEGF, and Tregs may provide an additive antitumor effect for treating glioblastoma.
Novel Mechanisms of Cancer Emerge When Accounting for Sex as a Biological Variable
Authors: Wilson Melissa A. , Buetow Kenneth H. 
Published: November 2019

Abstract

There is a large gap between the aspiration of considering sex as biological variable and the execution of such studies, particularly in genomic studies of human cancer. This represents a lost opportunity to identify sex-specific molecular etiologies that may underpin the dramatic sex differences in cancer incidence and outcome. There are conceptual and practical challenges associated with considering sex as a biological variable, including the definition of sex itself and the need for novel study designs. A better understanding of cancer mechanisms, resulting in improved outcomes, will reward the effort invested in incorporating sex as a biological variable.
Let-7e Suppresses DNA Damage Repair and Sensitizes Ovarian Cancer to Cisplatin through Targeting PARP1
Authors: Xiao Man , Guo Jianfeng , Xie Lisha , Yang Chun , Gong Lanqing , Wang Zehua , Cai Jing 
Published: November 2019

Abstract

Increased DNA damage repair is one of the mechanisms implicated in cisplatin resistance. Our previous study indicated that the deregulation of let-7e promoted cisplatin resistance and that let-7e could suppress DNA double-strand break repair in ovarian cancer. In this study, we further characterized the role of let-7e in DNA damage repair and cisplatin resistance in ovarian cancer, and investigated the underlying mechanisms. The alkaline and neutral comet assay indicated that let-7e impeded both DNA single- and double-strand break repairs through downregulating its target gene PARP1. In vitro and in vivo experiments provided evidence that the let-7e–PARP1–DNA repair axis was involved in the modulation of cisplatin sensitivity in ovarian cancer. Contrary to let-7e, PARP1 was overexpressed in cisplatin-resistant ovarian cancer tissues, and patients with high PARP1 expression exhibited poor progression-free survival (PFS) and overall survival (OS). Multivariate logistic and Cox regression analyses showed that let-7e and FIGO stage were independent prognostic factors for PFS and OS, whereas let-7e and PARP1 were able to independently predict chemotherapy response. Taken together, our results indicated that low expression of let-7e promoted DNA single- and double-strand break repairs and subsequently contributed to cisplatin resistance by relieving the suppression on PARP1 in ovarian cancer.

Implications:
Targeting the let-7e–PARP1–DNA repair axis might be an effective strategy for the treatment of chemoresistant ovarian cancer.
Cardiomyocyte‐Specific
Snrk
Prevents Inflammation in the Heart
Authors: Thirugnanam Karthikeyan , Cossette Stephanie M. , Lu Qiulun , Chowdhury Shreya R. , Harmann Leanne M. , Gupta Ankan , Spearman Andrew D. , Sonin Dmitry L. , Bordas Michelle , Kumar Suresh N. , Pan Amy Y. , Simpson Pippa M. , Strande Jennifer L. , Bishop Erin , Zou Ming‐Hui , Ramchandran Ramani 
Published: November 2019

Background

The
SNRK
(sucrose‐nonfermenting–related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in
Snrk
cardiac conditional knockout mouse is unknown.

Methods and Results

Previously, 6‐month adult mice knocked out for
Snrk
in cardiomyocytes (
CM
s) displayed left ventricular dysfunction. Here, 4‐month adult mice, on angiotensin
II
(Ang
II
) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (
NF
‐κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang
II
infusion, mice knocked out for
Snrk
in endothelial cells did not show significant systolic or diastolic dysfunction. Although an
NF
‐κB inflammation signaling pathway was increased in
Snrk
knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for
Snrk
in
CM
s, we also observed
NF
‐κB pathway activation in
CM
s, and an increased presence of Mac2
+
macrophages was observed in basal and Ang
II
–infused states. In vitro analysis of
Snrk
knockdown
HL
‐1
CM
s revealed similar upregulation of the
NF
‐κB signaling proteins and proinflammatory proteins that was exacerbated on Ang
II
treatment. The Ang
II
–induced
NF
‐κB pathway–mediated proinflammatory effects were mediated in part through protein kinase B or
AKT
, wherein
AKT
inhibition restored the proinflammatory signaling protein levels to baseline in
Snrk
knockdown
HL
‐1
CM
s.

Conclusions

During heart failure,
SNRK
acts as a cardiomyocyte‐specific repressor of cardiac inflammation and fibrosis.
Sphingomyelin Synthase 2 Inhibition Ameliorates Cerebral Ischemic Reperfusion Injury Through Reducing the Recruitment of Toll‐Like Receptor 4 to Lipid Rafts
Authors: Xue Jing , Yu Yang , Zhang Xiangjian , Zhang Cong , Zhao Yanan , Liu Boyan , Zhang Lan , Wang Lina , Chen Rong , Gao Xuan , Jiao Peng , Song Guohua , Jiang Xian‐Cheng , Qin Shucun 
Published: November 2019

Background

Inflammation is recognized as an important contributor of ischemia/reperfusion (I/R) damage after ischemic stroke. Sphingomyelin synthase 2 (
SMS
2), the key enzyme for the biosynthesis of sphingomyelin, can function as a critical mediator of inflammation. In the present study, we investigated the role of
SMS
2 in a mouse model of cerebral I/R.

Methods and Results

Cerebral I/R was induced by 60‐minute transient middle cerebral artery occlusion in
SMS
2 knockout (
SMS
2
‐/‐
) mice and wild‐type mice. Brain injury was determined by neurological deficits and infarct volume at 24 and 72 hours after transient middle cerebral artery occlusion. Microglia activation and inflammatory factors were detected by immunofluorescence staining, flow cytometry, western blot, and
RT
‐
PCR
.
SMS
2 deficiency significantly improved neurological function and minimized infarct volume at 72 hours after transient middle cerebral artery occlusion. The neuroprotective effects of
SMS
2 deficiency were associated with (1) suppression of microglia activation through Toll‐like receptor 4/nuclear factor kappa‐light‐chain‐enhancer of activated B cells pathway and (2) downregulation of the level of galactin‐3 and other proinflammatory cytokines. The mechanisms underlying the beneficial effects of
SMS
2 deficiency may include altering sphingomyelin components in lipid raft fractions, thus impairing the recruitment of Toll‐like receptor 4 to lipid rafts and subsequently reducing Toll‐like receptor 4/myeloid differentiation factor 2 complex formation on the surface of microglia.

Conclusions

SMS
2 deficiency ameliorated inflammatory injury after cerebral I/R in mice, and
SMS
2 may be a key modulator of Toll‐like receptor 4/nuclear factor kappa‐light‐chain‐enhancer of activated B cells activation by disturbing the membrane component homeostasis during cerebral I/R.
Pigment Epithelium–Derived Factor Increases Native Collateral Blood Flow to Improve Cardiac Function and Induce Ventricular Remodeling After Acute Myocardial Infarction
Authors: Liu Xiucheng , Liu Zhiwei , Chen Jiali , Zhu Lidong , Zhang Hao , Quan Xiaoyu , Yuan Yanliang , Miao Haoran , Huang Bing , Dong Hongyan , Zhang Zhongming 
Published: November 2019

Background

We previously found that the structural defects of the coronary collateral microcirculation reserve (
CCMR
) prevent these preformed collateral vessels from continuously delivering the native collateral blood and supporting the ischemic myocardium in rats. Here, we tested whether these native collaterals can be remodeled by artificially increasing pigment epithelium–derived factor (
PEDF
) expression and demonstrated the mechanism for this stimulation.

Methods and Results

We performed intramyocardial gene delivery (
PEDF
‐lentivirus, 2×10
7
TU) along the left anterior descending coronary artery to artificially increase the expression of
PEDF
in the tissue of the region for 2 weeks. By blocking the left anterior descending coronary artery, we examined the effects of
PEDF
on native collateral blood flow and
CCMR
. The results of positron emission tomography perfusion imaging showed that
PEDF
increased the native collateral blood flow and significantly inhibited its decline during acute myocardial infarction. In addition, the number of
CCMR
vessels decreased and the size increased. Similar results were obtained from in vitro experiments. We tested whether
PEDF
induces
CCMR
remodeling in a fluid shear stress–like manner by detecting proteins and signaling pathways that are closely related to fluid shear stress. The nitric oxide pathway and the Notch‐1 pathway participated in the process of
CCMR
remodeling induced by
PEDF
.

Conclusions

PEDF
treatment activates the nitric oxide pathway, and the Notch‐1 pathway enabled
CCMR
remodeling. Increasing the native collateral blood flow can promote the ventricular remodeling process and improve prognosis after acute myocardial infarction.
Differences in Inpatient Outcomes After Surgical Aortic Valve Replacement at Transcatheter Aortic Valve Replacement (TAVR) and Non‐TAVR Centers
Authors: Jack Godly , Arora Sameer , Strassle Paula D. , Sitammagari Kranthi , Gangani Kishorbhai , Yeung Michael , Cavender Matthew A. , O'Gara Patrick T. , Vavalle John P. 
Published: November 2019

Background
Transcatheter aortic valve replacement (TAVR) has solidified the importance of a heart team and revolutionized patient selection for surgical aortic valve replacement (SAVR). It is unknown if hospital ability to offer TAVR impacts SAVR outcomes. We investigated outcomes after SAVR between TAVR and non‐TAVR centers.

Methods and Results
Hospitalizations of patients aged ≥50 years, undergoing elective SAVR between January 2012 and September 2015, in the National Readmission Database (NRD) were included. Multivariable logistic, linear, and generalized logistic regression models were used to adjust for patient and hospital characteristics and estimate association between undergoing SAVR at a TAVR center, compared with a non‐TAVR center. The association between TAVR volumes and these outcomes were also assessed. SAVR hospitalizations (n = 32 198) were identified; 22 066 (69%) at TAVR and 10 132 (31%) at non‐TAVR centers. SAVRs at TAVR centers had lower odds of inpatient mortality (odds ratio 0.67, 95% CI 0.55–0.82) and discharge to skilled nursing facility (odds ratio 0.92, 95% CI 0.85–0.99), compared with non‐TAVR centers. There was no difference in LOS (change in estimate −0.09, 95% CI −0.26 to 0.08) or 30‐day re‐admission (odds ratio 0.95, 95% CI 0.88–1.03). SAVRs performed at the highest TAVR volume centers had the lowest inpatient mortality, compared with non‐TAVR centers (odds ratio 0.43 95% CI 0.29–0.63).

Conclusions
Patients undergoing SAVR at TAVR centers are more likely to survive and have better discharge disposition than patients undergoing SAVR at non‐TAVR centers. Whether this represents benefits of a heart‐team approach to care or differences in patient selection for SAVR when TAVR is unavailable requires further study.
Building Social Enterprises Identity: A Comparative Analysis of Social Enterprises Certification Practice in China’s Mainland, Hong Kong and Taiwan
Authors: Luo Wenen , Huang Ying 
Published: November 2019

Abstract
Social enterprises (SE) certification is a process of labeling SE and distinguishing them from other types of organizations. This article centers on the SE certification practices in China’s Mainland, Hong Kong and Taiwan, analyzes their development conditions and compares them in the three areas. The research has found that there are many similarities in certification organizers, essential criteria, SE qualifications, government role, the application of certification results in such areas. Meanwhile, evident differences have also been found, which can be explained from the institutional contexts within which social enterprises grow and the maturity of non-profit sectors in these regions. Through the analysis of SE certification practice in the three areas, this article points out that SE certification practice varies in different institutional contexts, but in general it helps social enterprises to construct a unique and distinct identity so as to better acquire support from the market, government and other entities. At the same time, we should be alert to the “fence effect” when endorsing social enterprises, and avoid setting fine-grained indicators which may bring damage to the diversified ecology of social entrepreneurship.
Use of the Progressive Return to Activity Guidelines May Expedite Symptom Resolution After Concussion for Active Duty Military
Authors: Bailie Jason M. , Remigio-Baker Rosemay A. , Cole Wesley R. , McCulloch Karen L. , Ettenhofer Mark L. , West Therese , Ahrens Angelica , Sargent Paul , Cecchini Amy , Malik Saafan , Mullins Lynita , Stuessi Keith , Qashu Felicia M. , Gregory Emma 
Published: November 2019

Background: Clinical recommendations for concussion management encourage reduced cognitive and physical activities immediately after injury, with graded increases in activity as symptoms resolve. Empirical support for the effectiveness of such recommendations is needed. Purpose: To examine whether training medical providers on the Defense and Veterans Brain Injury Center’s Progressive Return to Activity Clinical Recommendation (PRA-CR) for acute concussion improves patient outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: This study was conducted from 2016 to 2018 and compared patient outcomes before and after medical providers received an educational intervention (ie, provider training). Patients, recruited either before or after intervention, were assessed at ≤72 hours, 1 week, 1 month, 3 months, and 6 months after a concussion. The participant population included 38 military medical providers and 106 military servicemembers with a diagnosed concussion and treated by one of the military medical providers: 58 patient participants received care before the intervention (ie, provider training) and 48 received care after intervention. The primary outcome measure was the Neurobehavioral Symptom Inventory. Results: The patients seen before and after the intervention were predominantly male (89.7% and 93.8%, respectively) of military age (mean ± SD, 26.62 ± 6.29 years and 25.08 ± 6.85 years, respectively) and a mean ± SD of 1.92 ± 0.88 days from injury. Compared with patients receiving care before intervention, patients receiving care after intervention had smaller increases in physical activities (difference in mean change; 95% CI, 0.39 to 6.79) and vestibular/balance activities (95% CI, 0.79 to 7.5) during the first week of recovery. Although groups did not differ in symptoms at ≤72 hours of injury ( d = 0.22; 95% CI, –2.21 to 8.07), the postintervention group reported fewer symptoms at 1 week ( d = 0.61; 95% CI, 0.52 to 10.92). Postintervention patients who completed the 6-month study had improved recovery both at 1 month ( d = 1.55; 95% CI, 5.33 to 15.39) and 3 months after injury ( d = 1.10; 95% CI, 2.36 to 11.55), but not at 6 months ( d = 0.35; 95% CI, 5.34 to 7.59). Conclusion: Training medical providers on the PRA-CR for management of concussion resulted in expedited recovery of patients.
Cerebral Palsy in Children With Congenital Zika Syndrome: A 2-Year Neurodevelopmental Follow-up
Authors: Carvalho Alessandra Lemos de , Ventura Paloma , Taguchi Tânia , Brandi Ivar , Brites Carlos , Lucena Rita 
Published: November 2019

Objective: To describe the 2-year neurodevelopmental outcome in children with cerebral palsy associated with congenital Zika (CZ) and explore variables associated with a more severe presentation. Methods: Data on 69 children with cerebral palsy associated with CZ, followed in a neurorehabilitation hospital, who consecutively attended the neurodevelopmental assessment at 2 years of age, were collected. Bayley III Scales of Infant and Toddler Development, Hammersmith Infant Neurological Examination, and Gross Motor Function Classification System were used for the outcome evaluation. Descriptive and inferential statistical analysis were performed. Results: The median age at follow-up was of 24.0 (23-32) months. Only 3 (4.3%) children were not microcephalic. The majority presented with bilateral (94.2%), spastic (100.0%), Gross Motor Function Classification System grade IV or V (92.8%) cerebral palsy, epilepsy (73.1%), extremely low performances on cognitive (94.2%), language (95.7%), and motor (95.7%) Bayley-III Scales of Infant and Toddler Development Test scores. The median Hammersmith Infant Neurological Examination score was of 21.0 (range 9-75). There was a correlation between birth head circumference with the cognitive ( r = 0.3, P < .01), language ( r = 0.3, P < .01), and motor ( r = 0.3, P < .01) Bayley-III Scales of Infant and Toddler Development Test scores, as well as with the Hammersmith Infant Neurological Examination score ( r = 0.2, P < .03). An association was observed between an inferior median Hammersmith Infant Neurological Examination score with congenital microcephaly ( P = .04), arthrogryposis ( P = .02), and epilepsy in the first year ( P < .01). Conclusion: Cerebral palsy related to CZ presents with a severe global impairment at a 2-year follow-up. Birth head circumference, arthrogryposis, and early epilepsy are associated with a worse outcome and may be considered as prognostic markers. These findings are important for the neurorehabilitation planning, parents’ guiding, and future prognostic studies.