bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered tactile sensitivity in children with attention-deficit hyperactivity disorder
Authors: Puts Nicolaas A. J. , Harris Ashley D. , Mikkelsen Mark , Tommerdahl Mark , Edden Richard A. E. , Mostofsky Stewart H. 
Published: August 2017

Attention-deficit hyperactivity disorder (ADHD) is characterized by an inability to concentrate, heightened activity, and hypermotoric behavior, but sensory (e.g., tactile) problems are common. The literature on tactile impairments in ADHD is limited, with most work employing clinical observations or questionnaires. We studied tactile processing in children with ADHD and hypothesized that children with ADHD would show reduced performance in tasks closely linked to inhibition. Sixty-seven children with ADHD and 62 typically developing children (TDC) performed a battery of tasks grouped in domains: simple and choice reaction time; static and dynamic detection threshold (probing feedforward inhibition); amplitude discrimination without adaptation and with dual and single-site adaptation (probing lateral inhibition and adaptation); sequential and simultaneous frequency discrimination (previously linked to GABA); and temporal order judgment with and without a synchronous carrier stimulus. Children with ADHD could discriminate different amplitudes without adaptation, suggesting lateral inhibition is intact, but were negatively affected in all adaptation conditions, whereas TDC were only affected during single-site adaptation. Children with ADHD also showed normal frequency discrimination. Children with ADHD showed slower reaction times and higher detection threshold, likely driven by IQ and inattention, because reaction time and detection thresholds correlated with IQ and subtle motor signs. Children with ADHD showed a pattern of altered tactile processing on specific tasks, suggesting that higher cognitive function and cortical mechanisms related to adaptation are affected in ADHD, but no clear conclusion can be drawn toward impaired inhibition. NEW & NOTEWORTHY This manuscript presents the first tactile psychophysical study testing different aspects of tactile processing in attention-deficit hyperactivity disorder (ADHD), using large cohort sizes of 67 children with ADHD and 65 Typically Developing Children. This study demonstrates impaired tactile processing in children with ADHD, on some, but not all tasks (showing this is not just due to attention), related to impaired cortical mechanisms. Furthermore, both IQ and soft motor skill abnormalities (common in ADHD) are correlated with tactile abnormalities.
Theta-frequency selectivity in the somatic spike-triggered average of rat hippocampal pyramidal neurons is dependent on HCN channels
Authors: Das Anindita , Narayanan Rishikesh 
Published: August 2017

The ability to distill specific frequencies from complex spatiotemporal patterns of afferent inputs is a pivotal functional requirement for neurons residing in networks receiving frequency-multiplexed inputs. Although the expression of theta-frequency subthreshold resonance is established in hippocampal pyramidal neurons, it is not known if their spike initiation dynamics manifest spectral selectivity, or if their intrinsic properties are tuned to process gamma-frequency inputs. Here, we measured the spike-triggered average (STA) of rat hippocampal pyramidal neurons through electrophysiological recordings and quantified spectral selectivity in their spike initiation dynamics and their coincidence detection window (CDW). Our results revealed strong theta-frequency selectivity in the STA, which was also endowed with gamma-range CDW, with prominent neuron-to-neuron variability that manifested distinct pairwise dissociations and correlations with different intrinsic measurements. Furthermore, we demonstrate that the STA and its measurements substantially adapted to the state of the neuron defined by its membrane potential and to the statistics of its afferent inputs. Finally, we tested the effect of pharmacologically blocking the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels on the STA and found that the STA characteristic frequency reduced significantly to the delta-frequency band after HCN channel blockade. This delta-frequency selectivity in the STA emerged in the absence of subthreshold resonance, which was abolished by HCN channel blockade, thereby confirming computational predictions on the dissociation between these two forms of spectral selectivity. Our results expand the roles of HCN channels to theta-frequency selectivity in the spike initiation dynamics, apart from underscoring the critical role of interactions among different ion channels in regulating neuronal physiology. NEW & NOTEWORTHY We had previously predicted, using computational analyses, that the spike-triggered average (STA) of hippocampal neurons would exhibit theta-frequency (4–10 Hz) spectral selectivity and would manifest coincidence detection capabilities for inputs in the gamma-frequency band (25–150 Hz). Here, we confirmed these predictions through direct electrophysiological recordings of STA from rat CA1 pyramidal neurons and demonstrate that blocking HCN channels reduces the frequency of STA spectral selectivity to the delta-frequency range (0.5–4 Hz).
Multiple spatial representations interact to increase reach accuracy when coordinating a saccade with a reach
Authors: Vazquez Yuriria , Federici Laura , Pesaran Bijan 
Published: August 2017

Reaching is an essential behavior that allows primates to interact with the environment. Precise reaching to visual targets depends on our ability to localize and foveate the target. Despite this, how the saccade system contributes to improvements in reach accuracy remains poorly understood. To assess spatial contributions of eye movements to reach accuracy, we performed a series of behavioral psychophysics experiments in nonhuman primates ( Macaca mulatta). We found that a coordinated saccade with a reach to a remembered target location increases reach accuracy without target foveation. The improvement in reach accuracy was similar to that obtained when the subject had visual information about the location of the current target in the visual periphery and executed the reach while maintaining central fixation. Moreover, we found that the increase in reach accuracy elicited by a coordinated movement involved a spatial coupling mechanism between the saccade and reach movements. We observed significant correlations between the saccade and reach errors for coordinated movements. In contrast, when the eye and arm movements were made to targets in different spatial locations, the magnitude of the error and the degree of correlation between the saccade and reach direction were determined by the spatial location of the eye and the hand targets. Hence, we propose that coordinated movements improve reach accuracy without target foveation due to spatial coupling between the reach and saccade systems. Spatial coupling could arise from a neural mechanism for coordinated visual behavior that involves interacting spatial representations. NEW & NOTEWORTHY How visual spatial representations guiding reach movements involve coordinated saccadic eye movements is unknown. Temporal coupling between the reach and saccade system during coordinated movements improves reach performance. However, the role of spatial coupling is unclear. Using behavioral psychophysics, we found that spatial coupling increases reach accuracy in addition to temporal coupling and visual acuity. These results suggest that a spatial mechanism to couple the reach and saccade systems increases the accuracy of coordinated movements.
The temporal stability of visuomotor adaptation generalization
Authors: Zhou Weiwei , Fitzgerald Justin , Colucci-Chang Katrina , Murthy Karthik G. , Joiner Wilsaan M. 
Published: August 2017

Movement adaptation in response to systematic motor perturbations exhibits distinct spatial and temporal properties. These characteristics are typically studied in isolation, leaving the interaction largely unknown. Here we examined how the temporal decay of visuomotor adaptation influences the spatial generalization of the motor recalibration. First, we quantified the extent to which adaptation decayed over time. Subjects reached to a peripheral target, and a rotation was applied to the visual feedback of the unseen motion. The retention of this adaptation over different delays (0–120 s) 1) decreased by 29.0 ± 6.8% at the longest delay and 2) was represented by a simple exponential, with a time constant of 22.5 ± 5.6 s. On the basis of this relationship we simulated how the spatial generalization of adaptation would change with delay. To test this directly, we trained additional subjects with the same perturbation and assessed transfer to 19 different locations (spaced 15° apart, symmetric around the trained location) and examined three delays (~4, 12, and 25 s). Consistent with the simulation, we found that generalization around the trained direction (±15°) significantly decreased with delay and distance, while locations >60° displayed near-constant spatiotemporal transfer. Intermediate distances (30° and 45°) showed a difference in transfer across space, but this amount was approximately constant across time. Interestingly, the decay at the trained direction was faster than that based purely on time, suggesting that the spatial transfer of adaptation is modified by concurrent passive (time dependent) and active (movement dependent) processes. NEW & NOTEWORTHY Short-term motor adaptation exhibits distinct spatial and temporal characteristics. Here we investigated the interaction of these features, utilizing a simple motor adaptation paradigm (recalibration of reaching arm movements in response to rotated visual feedback). We examined the changes in the spatial generalization of motor adaptation for different temporal manipulations and report that the spatiotemporal generalization of motor adaptation is generally local and is influenced by both passive (time dependent) and active (movement dependent) learning processes.
Altered modulation of sensorimotor rhythms with chronic paralysis
Authors: Foldes Stephen T. , Weber Douglas J. , Collinger Jennifer L. 
Published: August 2017

After paralysis, the disconnection between the cortex and its peripheral targets leads to neuroplasticity throughout the nervous system. However, it is unclear how chronic paralysis specifically impacts cortical oscillations associated with attempted movement of impaired limbs. We hypothesized that μ- (8–13 Hz) and β- (15–30 Hz) event-related desynchronization (ERD) would be less modulated for individuals with hand paralysis due to cervical spinal cord injury (SCI). To test this, we compared the modulation of ERD from magnetoencephalography (MEG) during attempted and imagined grasping performed by participants with cervical SCI ( n = 12) and able-bodied controls ( n = 13). Seven participants with tetraplegia were able to generate some electromyography (EMG) activity during attempted grasping, whereas the other five were not. The peak and area of ERD were significantly decreased for individuals without volitional muscle activity when they attempted to grasp compared with able-bodied subjects and participants with SCI,with some residual EMG activity. However, no significant differences were found between subject groups during mentally simulated tasks (i.e., motor imagery) where no muscle activity or somatosensory consequences were expected. These findings suggest that individuals who are unable to produce muscle activity are capable of generating ERD when attempting to move, but the characteristics of this ERD are altered. However, for people who maintain volitional muscle activity after SCI, there are no significant differences in ERD characteristics compared with able-bodied controls. These results provide evidence that ERD is dependent on the level of intact muscle activity after SCI. NEW & NOTEWORTHY Source space MEG was used to investigate sensorimotor cortical oscillations in individuals with SCI. This study provides evidence that individuals with cervical SCI exhibit decreased ERD when they attempt to grasp if they are incapable of generating muscle activity. However, there were no significant differences in ERD between paralyzed and able-bodied participants during motor imagery. These results have important implications for the design and evaluation of new therapies, such as motor imagery and neurofeedback interventions.
Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy
Authors: Mapuskar Kranti A. , Flippo Kyle H. , Schoenfeld Joshua D. , Riley Dennis P. , Strack Stefan , Hejleh Taher Abu , Furqan Muhammad , Monga Varun , Domann Frederick E. , Buatti John M. , Goswami Prabhat C. , Spitz Douglas R. , Allen Bryan G. 
Published: August 2017

Abstract
Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%–80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%–20% killing) and adult fibroblasts (20 years old; ∼10%–30% killing). Old fibroblasts also displayed significantly increased (2–4-fold) steady-state levels of O2•−, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%–50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5–7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•− in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•− and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054–67. ©2017 AACR.
Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
Authors: Engstrom Lars D. , Aranda Ruth , Lee Matthew , Tovar Elizabeth A. , Essenburg Curt J. , Madaj Zachary , Chiang Harrah , Briere David , Hallin Jill , Lopez-Casas Pedro P. , Baños Natalia , Menendez Camino , Hidalgo Manuel , Tassell Vanessa , Chao Richard , Chudova Darya I. , Lanman Richard B. , Olson Peter , Bazhenova Lyudmilla , Patel Sandip Pravin , Graveel Carrie , Nishino Mizuki , Shapiro Geoffrey I. , Peled Nir , Awad Mark M. , Jänne Pasi A. , Christensen James G. 
Published: August 2017

Abstract
Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.
Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.
Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.
Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.
Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation
Authors: Shi Puyu , Oh You-Take , Deng Liang , Zhang Guojing , Qian Guoqing , Zhang Shuo , Ren Hui , Wu Grant , Legendre Benjamin , Anderson Emily , Ramalingam Suresh S. , Owonikoko Taofeek K. , Chen Mingwei , Sun Shi-Yong 
Published: August 2017

Abstract
Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non–small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.
Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA.
Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo.
Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567–79. ©2017 AACR.
In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation
Authors: Borras Ester , Chang Kyle , Pande Mala , Cuddy Amanda , Bosch Jennifer L. , Bannon Sarah A. , Mork Maureen E. , Rodriguez-Bigas Miguel A. , Taggart Melissa W. , Lynch Patrick M. , You Y. Nancy , Vilar Eduardo 
Published: August 2017

Abstract
Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580–7. ©2017 AACR.
Effect of Green Tea Supplements on Liver Enzyme Elevation: Results from a Randomized Intervention Study in the United States
Authors: Yu Zheming , Samavat Hamed , Dostal Allison M. , Wang Renwei , Torkelson Carolyn J. , Yang Chung S. , Butler Lesley M. , Kensler Thomas W. , Wu Anna H. , Kurzer Mindy S. , Yuan Jian-Min 
Published: August 2017

Abstract
Liver injury effects of green tea–based products have been reported in sporadic case reports. However, no study has examined systematically such adverse effects in an unbiased manner. We examined the potential effects of a high, sustained oral dose of green tea extract (GTE) on liver injury measures in a randomized, placebo-controlled, double-blinded phase II clinical trial, which enrolled 1,075 women with the original aim to assess the effect of daily GTE consumption for 12 months on biomarkers of breast cancer risk. The current analysis examined the effect of GTE consumption on liver injury in 1,021 participants (513 in GTE and 508 in placebo arm) with normal baseline levels of liver enzymes. Among women in the GTE arm, alanine aminotransferase (ALT) increased by 5.4 U/L [95% confidence interval (CI), 3.6–7.1] and aspartate aminotransferase increased by 3.8 U/L (95% CI, 2.5–5.1), which were significantly higher than those among women in the placebo arm (both P &lt; 0.001). Overall, 26 (5.1%) women in GTE developed moderate or more severe abnormalities in any liver function measure during the intervention period, yielding an OR of 7.0 (95% CI, 2.4–20.3) for developing liver function abnormalities as compared with those in the placebo arm. ALT returned to normal after dechallenge and increased again after one or more rechallenges with GTE. The rise–fall pattern of liver enzyme values following the challenge–dechallenge cycles of GTE consumption strongly implicates the effect of high-dose GTE on liver enzyme elevations. Cancer Prev Res; 10(10); 571–9. ©2017 AACR.