bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variance in exposed perturbations impairs retention of visuomotor adaptation
Authors: Canaveral Cesar Augusto , Danion Frédéric , Berrigan Félix , Bernier Pierre-Michel 
Published: August 2017

Sensorimotor control requires an accurate estimate of the state of the body. The brain optimizes state estimation by combining sensory signals with predictions of the sensory consequences of motor commands using a forward model. Given that both sensory signals and predictions are uncertain (i.e., noisy), the brain optimally weights the relative reliance on each source of information during adaptation. In support, it is known that uncertainty in the sensory predictions influences the rate and generalization of visuomotor adaptation. We investigated whether uncertainty in the sensory predictions affects the retention of a new visuomotor relationship. This was done by exposing three separate groups to a visuomotor rotation whose mean was common at 15° counterclockwise but whose variance around the mean differed (i.e., SD of 0°, 3.2°, or 4.5°). Retention was assessed by measuring the persistence of the adapted behavior in a no-vision phase. Results revealed that mean reach direction late in adaptation was similar across groups, suggesting it depended mainly on the mean of exposed rotations and was robust to differences in variance. However, retention differed across groups, with higher levels of variance being associated with a more rapid reversion toward nonadapted behavior. A control experiment ruled out the possibility that differences in retention were accounted for by differences in success rates. Exposure to variable rotations may have increased the uncertainty in sensory predictions, making the adapted forward model more labile and susceptible to change or decay. NEW & NOTEWORTHY The brain predicts the sensory consequences of motor commands through a forward model. These predictions are subject to uncertainty. We use visuomotor adaptation and modulate uncertainty in the sensory predictions by manipulating the variance in exposed rotations. Results reveal that variance does not influence the final extent of adaptation but selectively impairs the retention of motor memories. These results suggest that a more uncertain forward model is more susceptible to change or decay.
Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas?
Authors: Sannino Giuseppina , Marchetto Aruna , Kirchner Thomas , Grünewald Thomas G.P. 
Published: August 2017

Abstract
The epithelial-to-mesenchymal transition (EMT) is a reversible process comprised of various subprograms via which epithelial cells reduce their intercellular adhesions and proliferative capacity while gaining a mesenchymal phenotype with increased migratory and invasive properties. This process has been well described in several carcinomas, which are cancers of epithelial origin, and is crucial to metastatic tumor cell dissemination and drug resistance. In contrast, the precise role of EMT-related processes in tumors originating from mesenchymal tissues, such as bone and soft-tissues sarcomas, is still largely unclear. In fact, although the existence of the EMT in sarcomas appears paradoxical because these cancers are, by definition, mesenchymal ab initio, accumulating evidence suggests that many sarcomas can undergo EMT-related processes, which may be associated with aggressive clinical behavior. These processes may be especially operative in certain sarcoma subtypes, such as carcinosarcomas displaying a biphenotypic morphology with characteristics of both mesenchymal and epithelial tumors. In this review, we discuss findings regarding the potential existence of EMT-related processes in sarcomas and propose that sarcomas can reside in a metastable state, enabling them to become either more mesenchymal or epithelial under specific conditions, which likely has important clinical implications. Cancer Res; 77(17); 4556–61. ©2017 AACR.
PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers
Authors: Chen Luxi , Yuan Yi , Kar Shreya , Kanchi Madhu M. , Arora Suruchi , Kim Ji E. , Koh Pei F. , Yousef Einas , Samy Ramar P. , Shanmugam Muthu K. , Tan Tuan Z. , Shin Sung W. , Arfuso Frank , Shen Han M. , Yang Henry , Goh Boon C. , Park Joo I. , Gaboury Louis , Lobie Peter E. , Sethi Gautam , Lim Lina H.K. , Kumar Alan P. 
Published: August 2017

Abstract
Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPARγ. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPARγ both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPARγ ligands. Mechanistically, we show for the first time PPARγ-induced ANXA1 protein directly interacts with receptor interacting protein-1 (RIP1), promoting its deubiquitination and thereby activating the caspase-8–dependent death pathway. We further identified this underlying mechanism also involved a PPARγ-induced ANXA1-dependent autoubiquitination of cIAP1, the direct E3 ligase of RIP1, shifting cIAP1 toward proteosomal degradation. Collectively, our study provides first insight for the suitability of using drug-induced expression of ANXA1 as a new player in RIP1-induced death machinery in TNBCs, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPARγ chemotherapy trials. Mol Cancer Ther; 16(11); 2528–42. ©2017 AACR.
Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities
Authors: Magani Fiorella , Peacock Stephanie O. , Rice Meghan A. , Martinez Maria J. , Greene Ann M. , Magani Pablo S. , Lyles Rolando , Weitz Jonathan R. , Burnstein Kerry L. 
Published: August 2017

Abstract
Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels.
Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469–80. ©2017 AACR.
Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells
Authors: Kubo Hiroshi , Mensurado Sofia , Gonçalves-Sousa Natacha , Serre Karine , Silva-Santos Bruno 
Published: August 2017

AbstractMetastases are responsible for the vast majority of cancer-related deaths. Although tumor cells can become invasive early during cancer progression, metastases formation typically occurs as a late event. How the immune response to primary tumors may dictate this outcome remains poorly understood, which hampers our capacity to manipulate it therapeutically. Here, we used a two-step experimental model, based on the highly aggressive B16F10 melanoma, that temporally segregates the establishment of primary tumors (subcutaneously) and the formation of lung metastases (from intravenous injection). This allowed us to identify a protective innate immune response induced by primary tumors that inhibits experimental metastasis. We found that in the presence of primary tumors, increased numbers of natural killer (NK) cells with enhanced IFNγ, granzyme B, and perforin production were recruited to the lung upon metastasis induction. These changes were mirrored by a local accumulation of patrolling monocytes and macrophages with high expression of MHC class II and NOS2. Critically, the protective effect on metastasis was lost upon patrolling monocyte or NK cell depletion, IL15 neutralization, or IFNγ ablation. The combined analysis of these approaches allowed us to establish a hierarchy in which patrolling monocytes, making IL15 in response to primary tumors, activate NK cells and IFNγ production that then inhibit lung metastasis formation. This work identifies an innate cell network and the molecular determinants responsible for “metastasis immunosurveillance,” providing support for using the key molecular mediator, IL15, to improve immunotherapeutic outcomes. Cancer Immunol Res; 5(9); 812–20. ©2017 AACR.
Analysis of the Heat Index in the Mesoamerica and Caribbean Region
Authors: Ramirez-Beltran Nazario D. , Gonzalez Jorge E. , Castro Joan M. , Angeles Moises , Harmsen Eric W. , Salazar Cesar M. 
Published: August 2017

AbstractHourly data collected from ground stations were used to study the maximum daytime heat index Hi in the Mesoamerica and Caribbean Sea (MAC) region for a 35-yr period (1980–2014). Observations of Hi revealed larger values during the rainy season and smaller values during the dry season. The Hi climatology exhibits the largest values in Mesoamerica, followed by the Greater Antilles and then by the Lesser Antilles. The trend in Hi indicates a notable increasing pattern of 0.05°C yr−1 (0.10°F yr−1), and the trends are more prominent in Mesoamerica than in Caribbean countries. This work also includes the analysis of heat index extreme events (HIEE). Usually the extreme values of the heat index are used for advising heat warning events, and it was found that 45 HIEEs occurred during the studied period. The average duration of HIEE was 2.4 days, and the average relative intensity (excess over the threshold) was 2.4°C (4.3°F). It was found that 82% of HIEE lasted 2 or 2.5 days and 80% exhibited relative intensity of 3°C (5.4°F) or less. It was also found that the frequency of extreme events has intensified since 1991, with the highest incidences occurring in 1995, 1998, 2005 and 2010, and these years coincide with the cool phase of El Niño–Southern Oscillation (ENSO). Therefore, the occurrences of HIEE in the MAC region appear to be at least partially influenced by ENSO episodes.
Using Systems Science to Inform Population Health Strategies in Local Health Departments: A Case Study in San Antonio, Texas
Authors: Li Yan , Padrón Norma A. , Mangla Anil T. , Russo Pamela G. , Schlenker Thomas , Pagán José A. 
Published: August 2017

Objectives: Because of state and federal health care reform, local health departments play an increasingly prominent role leading and coordinating disease prevention programs in the United States. This case study shows how a local health department working in chronic disease prevention and management can use systems science and evidence-based decision making to inform program selection, implementation, and assessment; enhance engagement with local health systems and organizations; and possibly optimize health care delivery and population health. Methods: The authors built a systems-science agent-based simulation model of diabetes progression for the San Antonio Metropolitan Health District, a local health department, to simulate health and cost outcomes for the population of San Antonio for a 20-year period (2015-2034) using 2 scenarios: 1 in which hemoglobin A1c (HbA1c) values for a population were similar to the current distribution of values in San Antonio, and the other with a hypothetical 1-percentage-point reduction in HbA1c values. Results: They projected that a 1-percentage-point reduction in HbA1c would lead to a decrease in the 20-year prevalence of end-stage renal disease from 1.7% to 0.9%, lower extremity amputation from 4.6% to 2.9%, blindness from 15.1% to 10.7%, myocardial infarction from 23.8% to 17.9%, and stroke from 9.8% to 7.2%. They estimated annual direct medical cost savings (in 2015 US dollars) from reducing HbA1c by 1 percentage point ranging from $6842 (myocardial infarction) to $39 800 (end-stage renal disease) for each averted case of diabetes complications. Conclusions: Local health departments could benefit from the use of systems science and evidence-based decision making to estimate public health program effectiveness and costs, calculate return on investment, and develop a business case for adopting programs.
Combined analysis of the safety of intra-coronary drug delivery during primary percutaneous coronary intervention for acute myocardial infarction: A study of three clinical trials
Authors: Rathod Krishnaraj S , Hamshere Stephen , Khambata Rayomand S , Andiapen Mervyn , Westwood Mark , Mathur Anthony , Ahluwalia Amrita , Jones Daniel A 
Published: August 2017

Background The local injection of novel cardioprotective study drugs prior to percutaneous coronary intervention could cause embolisation of thrombus, resulting in increased reperfusion injury and subsequent infarct size. The aim of this study was to assess the safety of the delivery of an intracoronary therapy delivered during primary percutaneous coronary intervention for acute myocardial infarction prior to the re-establishment of thrombolysis in myocardial infarction III flow. Methods One hundred sixty-seven patients with acute myocardial infarction successfully reperfused through primary percutaneous coronary intervention and undergoing Cardiac MRI within the first week after reperfusion were studied. Patients either underwent the delivery of an intracoronary agent (IMP or placebo) prior to balloon dilatation ( n = 80) or standard primary percutaneous coronary intervention procedure ( n = 117). Results Baseline characteristics were similar between the two groups. There were a similar number of successful procedures (IC IMP 75 (93.8%) vs. No IMP 114, (97.4%), p = 0.374), rates of no-reflow (IC IMP 1 (1.3%) vs. No IMP 2 (1.7%), p = 0.99) and levels of ST segment resolution (88.5% IC IMP vs. No IC IMP 87.0%, p = 0.669) between the two groups. Similar levels of microvascular obstruction were seen between the two groups with a trend to reduced infarct size, and improved ejection fractions in the IMP group. Lower MACE rates were seen in the IMP group. Conclusion The local intracoronary infusion of potential cardioprotective agents prior to the restoration of TIMI flow in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction appears to be safe and does not increase microvascular damage. This route should be considered when testing novel cardioprotective agents.
Increased Neuronal DNA/RNA Oxidation in the Frontal Cortex of Mice Subjected to Unpredictable Chronic Mild Stress
Authors: Maluach Alfred M. , Misquitta Keith A. , Prevot Thomas D. , Fee Corey , Sibille Etienne , Banasr Mounira , Andreazza Ana C. 
Published: August 2017

Background Chronic stress is implicated in the development of various psychiatric illnesses including major depressive disorder. Previous reports suggest that patients with major depressive disorder have increased levels of oxidative stress, including higher levels of DNA/RNA oxidation found in postmortem studies, especially within brain regions responsible for the cognitive and emotional processes disrupted in the disorder. Here, we aimed to investigate whether unpredictable chronic mild stress in mice induces neuronal DNA/RNA oxidation in the prelimbic, infralimbic, and cingulate cortices of the frontal cortex and the basolateral amygdala and to explore potential associations with depressive-like behaviors. We expected that animals subjected to unpredictable chronic mild stress will present higher levels of DNA/RNA oxidation, which will be associated with anxiety-/depressive-like behaviors. Methods C57BL/6J mice were assigned to unpredictable chronic mild stress or nonstress conditions (n = 10/group, 50% females). Following five weeks of unpredictable chronic mild stress exposure, mice were tested in a series of behavioral tests measuring anxiety- and depressive-like behaviors. Frontal cortex and amygdala sections were then immunolabeled for neuronal nuclei, a marker of post-mitotic neurons and anti-8-hydroxy-2-deoxyguanosine/8-oxo-7,8-dihydroguanosine, which reflects both DNA and RNA oxidation. Results Levels of neuronal DNA/RNA oxidation were increased in the frontal cortex of mice subjected to unpredictable chronic mild stress ( p = 0.0207). Levels of neuronal DNA/RNA oxidation in the frontal cortex were positively correlated with z-emotionality scores for latency to feed in the novelty-suppressed feeding test ( p = 0.0031). Statistically significant differences were not detected in basolateral amygdala levels of neuronal DNA/RNA oxidation between nonstress- and unpredictable chronic mild stress-exposed mice, nor were correlations found with behavioral performances for this region. Conclusion Our results demonstrate that unpredictable chronic mild stress induces a significant increase in neuronal DNA/RNA oxidation in the frontal cortex that correlate with behavioral readouts of the stress response. A lack of DNA/RNA oxidation alterations in the basolateral amygdala suggests greater vulnerability of frontal cortex neurons to DNA/RNA oxidation in response to unpredictable chronic mild stress. These findings add support to the hypothesis that chronic stress-induced damage to DNA/RNA may be an additional molecular mechanism underlying cellular dysfunctions associated with chronic stress and present in stress-related disorders.
Selectin catch-bonds mechanotransduce integrin activation and neutrophil arrest on inflamed endothelium under shear flow
Authors: Morikis Vasilios A. , Chase Shannon , Wun Ted , Chaikof Elliot L. , Magnani John L. , Simon Scott I. 
Published: August 2017

Key PointsNeutrophils rolling on E-selectin form catch-bonds with L-selectin that mechanosignal β2-integrin bond formation with intracellular adhesion molecule 1. Rivipansel blocks E-selectin recognition of sLex on L-selectin, thereby antagonizing outside-in signaling of high-affinity β2-integrin.
Maternal iAMP21 acute lymphoblastic leukemia detected on prenatal cell-free DNA genetic screening
Authors: Luskin Marlise R. , Discenza Marie N. , Easter Sarah Rae , Dal Cin Paola , Owen Renius , Ilagan Bernard , Masiello Meredith , Lane Andrew A. 
Published: August 2017

Key Points
cfDNA sequencing for fetal aneuploidy may detect chromosomal abnormalities representative of maternal malignancy. Maternal malignancy must be considered when abnormal cfDNA sequencing for fetal aneuploidy is associated with normal fetal karyotype.
Septal contributions to olfactory bulb interneuron diversity in the embryonic mouse telencephalon: role of the homeobox gene Gsx2
Authors: Qin Shenyue , Ware Stephanie M. , Waclaw Ronald R. , Campbell Kenneth 
Published: August 2017

Abstract

Background
Olfactory bulb (OB) interneurons are known to represent diverse neuronal subtypes, which are thought to originate from a number of telencephalic regions including the embryonic dorsal lateral ganglionic eminence (dLGE) and septum. These cells migrate rostrally toward the OB, where they then radially migrate to populate different OB layers including the granule cell layer (GCL) and the outer glomerular layer (GL). Although previous studies have attempted to investigate regional contributions to OB interneuron diversity, few genetic tools have been used to address this question at embryonic time points when the earliest populations are specified.

Methods
In this study, we utilized Zic3-lacZ and Gsx2e-CIE transgenic mice as genetic fate-mapping tools to study OB interneuron contributions derived from septum and LGE, respectively. Moreover, to address the regional (i.e. septal) requirements of the homeobox gene Gsx2 for OB interneuron diversity, we conditionally inactivated Gsx2 in the septum, leaving it largely intact in the dLGE, by recombining the Gsx2 floxed allele using Olig2

Cre/+
mice.

Results
Our fate mapping studies demonstrated that the dLGE and septum gave rise to OB interneuron subtypes differently. Notably, the embryonic septum was found to give rise largely to the calretinin+ (CR+) GL subtype, while the dLGE was more diverse, generating all major GL subpopulations as well as many GCL interneurons. Moreover, Gsx2 conditional mutants (cKOs), with septum but not dLGE recombination, showed impaired generation of CR+ interneurons within the OB GL. These Gsx2 cKOs exhibited reduced proliferation within the septal subventricular zone (SVZ), which correlated well with the reduced number of CR+ interneurons observed.

Conclusions
Our findings indicate that the septum and LGE contribute differently to OB interneuron diversity. While the dLGE provides a wide range of OB interneuron subtypes, the septum is more restricted in its contribution to the CR+ subtype. Gsx2 is required in septal progenitors for the correct expansion of SVZ progenitors specified toward the CR+ subtype. Finally, the septum has been suggested to be the exclusive source of CR+ interneurons in postnatal studies. Our results here demonstrate that dLGE progenitors in the embryo also contribute to this OB neuronal subtype.