bluuebunny/crossref_metadata_2025_split huggingface dataset:
Store-Operated Calcium Channel Complex in Postsynaptic Spines: A New Therapeutic Target for Alzheimer's Disease Treatment
Authors: Zhang Hua , Sun Suya , Wu Lili , Pchitskaya Ekaterina , Zakharova Olga , Fon Tacer Klementina , Bezprozvanny Ilya 
Published: November 2016

Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca2+influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca2+channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.SIGNIFICANCE STATEMENTMushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). This study demonstrated that Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 form stromal interaction molecule 2 (STIM2)-regulated neuronal-store-operated Ca2+influx (nSOC) channel complex in hippocampal synapse and the resulting Ca2+influx is critical for long-term maintenance of mushroom spines in hippocampal neurons. A novel nSOC-positive modulator, NSN21778 (NSN), rescues mushroom spine loss and synaptic plasticity impairment in AD mice models. The TRPC6/Orai2 nSOC channel complex is a new therapeutic target and NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
Time Is Not Space: Core Computations and Domain-Specific Networks for Mental Travels
Authors: Gauthier Baptiste , van Wassenhove Virginie 
Published: November 2016

Humans can consciously project themselves in the future and imagine themselves at different places. Do mental time travel and mental space navigation abilities share common cognitive and neural mechanisms? To test this, we recorded fMRI while participants mentally projected themselves in time or in space (e.g., 9 years ago, in Paris) and ordered historical events from their mental perspective. Behavioral patterns were comparable for mental time and space and shaped by self-projection and by the distance of historical events to the mental position of the self, suggesting the existence of egocentric mapping in both dimensions. Nonetheless, self-projection in space engaged the medial and lateral parietal cortices, whereas self-projection in time engaged a widespread parietofrontal network. Moreover, while a large distributed network was found for spatial distances, temporal distances specifically engaged the right inferior parietal cortex and the anterior insula. Across these networks, a robust overlap was only found in a small region of the inferior parietal lobe, adding evidence for its role in domain-general egocentric mapping. Our findings suggest that mental travel in time or space capitalizes on egocentric remapping and on distance computation, which are implemented in distinct dimension-specific cortical networks converging in inferior parietal lobe.SIGNIFICANCE STATEMENTAs humans, we can consciously imagine ourselves at a different time (mental time travel) or at a different place (mental space navigation). Are such abilities domain-general, or are the temporal and spatial dimensions of our conscious experience separable? Here, we tested the hypothesis that mental time travel and mental space navigation required the egocentric remapping of events, including the estimation of their distances to the self. We report that, although both remapping and distance computation are foundational for the processing of the temporal and spatial dimensions of our conscious experience, their neuroanatomical implementations were clearly dissociable and engaged distinct parietal and parietofrontal networks for mental space navigation and mental time travel, respectively.
Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles forAsefduring Development and after Injury
Authors: Chaboub Lesley S. , Manalo Jeanne M. , Lee Hyun Kyoung , Glasgow Stacey M. , Chen Fengju , Kawasaki Yoshihiro , Akiyama Tetsu , Kuo Chay T. , Creighton Chad J. , Mohila Carrie A. , Deneen Benjamin 
Published: November 2016

Lineage development is a stepwise process, governed by stage-specific regulatory factors and associated markers. Astrocytes are one of the principle cell types in the CNS and the stages associated with their development remain very poorly defined. To identify these stages, we performed gene-expression profiling on astrocyte precursor populations in the spinal cord, identifying distinct patterns of gene induction during their development that are strongly correlated with human astrocytes. Validation studies identified a new cohort of astrocyte-associated genes during development and demonstrated their expression in reactive astrocytes in human white matter injury (WMI). Functional studies on one of these genes revealed that mice lackingAsefexhibited impaired astrocyte differentiation during development and repair after WMI, coupled with compromised blood–brain barrier integrity in the adult CNS. These studies have identified distinct stages of astrocyte lineage development associated with human WMI and, together with our functional analysis ofAsef, highlight the parallels between astrocyte development and their reactive counterparts associated with injury.SIGNIFICANCE STATEMENTAstrocytes play a central role in CNS function and associated diseases. Yet the mechanisms that control their development remain poorly defined. Using the developing mouse spinal cord as a model system, we identify molecular changes that occur in developing astrocytes. These molecular signatures are strongly correlated with human astrocyte expression profiles and validation in mouse spinal cord identifies a host of new genes associated with the astrocyte lineage. These genes are present in reactive astrocytes in human white matter injury, and functional studies reveal that one of these genes,Asef, contributes to reactive astrocyte responses after injury. These studies identify distinct stages of astrocyte lineage development and highlight the parallels between astrocyte development and their reactive counterparts associated with injury.
Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory
Authors: Pearson-Leary Jiah , McNay Ewan C. 
Published: November 2016

The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin- and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues.SIGNIFICANCE STATEMENTThe role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long-term inhibition of GluT4 impaired long-term memory, short-term memory was enhanced. These data further our understanding of the molecular mechanisms of memory and have particular significance for type 2 diabetes (in which GluT4 activity in the periphery is impaired) and Alzheimer's disease (which is linked to impaired brain insulin signaling and for which type 2 diabetes is a key risk factor). Both diseases cause marked impairment of hippocampal memory linked to hippocampal hypometabolism, suggesting the possibility that brain GluT4 dysregulation may be one cause of cognitive impairment in these disease states.
Consolidation of Goal-Directed Action Depends on MAPK/ERK Signaling in Rodent Prelimbic Cortex
Authors: Hart Genevra , Balleine Bernard W. 
Published: November 2016

The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2–3 and 5–6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning. Rats were given either a single session of training to press a lever for a pellet reward or yoked reward deliveries without instrumental training and assessed 5 or 60 min after training for pERK expression. Relative to yoked training, instrumental training produced an increase in pERK expression in all regions of the PL both at 5 and 60 min, and this was accompanied by an increase in nuclear pERK expression in the posterior PL in rats given instrumental training. pDMS-projecting neurons showed a transient increase in pERK expression in posterior layer 5–6 projection neurons after 5 min, and a delayed increase in anterior layer 2–3 neurons after 60 min, suggesting that ERK expression in the PL is necessary for the consolidation of goal-directed learning. Consistent with this claim, we found that rats trained on two lever press actions for distinct outcomes and then infused with the MEK inhibitor PD98059 into the PL immediately after training failed to acquire specific action–outcome associations, suggesting that persistent pERK signaling in the PL is necessary for goal-directed learning.SIGNIFICANCE STATEMENTThe prelimbic cortex is implicated in goal-directed learning in rodents; however, it is unclear whether it is involved in the consolidation of this learning, and what cellular processes are involved. We used pERK as a marker of activity-related synaptic plasticity to assess learning-induced changes in distinct layers and neuronal populations of the prelimbic prefrontal cortex (PL). Training produced long-lasting upregulation of pERK throughout the PL and specifically within neurons that project to the pDMS, another region critical for goal-directed learning. Next, we demonstrated that pERK signaling in the PL was necessary for the consolidation of goal-directed learning. Together, these results indicate that instrumental training induces ERK signaling in distinct layers and populations in the PL and this signaling underlies the consolidation of goal-directed learning.
Attentive Motion Discrimination Recruits an Area in Inferotemporal Cortex
Authors: Stemmann Heiko , Freiwald Winrich A. 
Published: November 2016

Attentional selection requires the interplay of multiple brain areas. Theoretical accounts of selective attention predict different areas with different functional properties to support endogenous covert attention. To test these predictions, we devised a demanding attention task requiring motion discrimination and spatial selection and performed whole-brain imaging in macaque monkeys. Attention modulated the early visual cortex, motion-selective dorsal stream areas, the lateral intraparietal area, and the frontal eye fields. This pattern of activation supports early selection, feature-based, and biased-competition attention accounts, as well as the frontoparietal theory of attentional control. While high-level motion-selective dorsal stream areas did not exhibit strong attentional modulation, ventral stream areas V4d and the dorsal posterior inferotemporal cortex (PITd) did. The PITd in fact was, consistently across task variations, the most significantly and most strongly attention-modulated area, even though it did not exhibit signs of motion selectivity. Thus the recruitment of the PITd in attention tasks involving different kinds of motion analysis is not predicted by any theoretical account of attention. These functional data, together with known anatomical connections, suggest a general and possibly critical role of the PITd in attentional selection.SIGNIFICANCE STATEMENTAttention is the key cognitive function that selects sensory information relevant to the current goals, relegating other information to the shadows of consciousness. To better understand the neural mechanisms of this interplay between sensory processing and internal cognitive state, we must learn more about the brain areas supporting attentional selection. Here, to test theoretical accounts of attentional selection, we used a novel task requiring sustained attention to motion. We found that, surprisingly, among the most strongly attention-modulated areas is one that is neither selective for the sensory feature relevant for current goals nor one hitherto thought to be involved in attentional control. This discovery suggests a need for an extension of current theoretical accounts of the brain circuits for attentional selection.
Brain Network Mechanisms Underlying Motor Enhancement by Transcranial Entrainment of Gamma Oscillations
Authors: Moisa Marius , Polania Rafael , Grueschow Marcus , Ruff Christian C. 
Published: November 2016

Gamma and beta oscillations are routinely observed in motor-related brain circuits during movement preparation and execution. Entrainment of gamma or beta oscillations via transcranial alternating current stimulation (tACS) over primary motor cortex (M1) has opposite effects on motor performance, suggesting a causal role of these brain rhythms for motor control. However, it is largely unknown which brain mechanisms characterize these changes in motor performance brought about by tACS. In particular, it is unclear whether these effects result from brain activity changes only in the targeted areas or within functionally connected brain circuits. Here we investigated this issue by applying gamma-band and beta-band tACS over M1 in healthy humans during a visuomotor task and concurrent functional magnetic resonance imaging (fMRI). Gamma tACS indeed improved both the velocity and acceleration of visually triggered movements, compared with both beta tACS and sham stimulation. Beta tACS induced a numerical decrease in velocity compared with sham stimulation, but this was not statistically significant. Crucially, gamma tACS induced motor performance enhancements correlated with changed BOLD activity in the stimulated M1. Moreover, we found frequency- and task-specific neural compensatory activity modulations in the dorsomedial prefrontal cortex (dmPFC), suggesting a key regulatory role of this region in motor performance. Connectivity analyses revealed that the dmPFC interacted functionally with M1 and with regions within the executive motor system. These results suggest a role of the dmPFC for motor control and show that tACS-induced behavioral changes not only result from activity modulations underneath the stimulation electrode but also reflect compensatory modulation within connected and functionally related brain networks. More generally, our results illustrate how combined tACS–fMRI can be used to resolve the causal link between cortical rhythms, brain systems, and behavior.SIGNIFICANCE STATEMENTRecent research has suggested a causal role for gamma oscillations during movement preparation and execution. Here we combine transcranial alternating current stimulation (tACS) with functional magnetic resonance imaging (fMRI) to identify the neural mechanisms that accompany motor performance enhancements triggered by gamma tACS over the primary motor cortex. We show that the tACS-induced motor performance enhancements correlate with changed neural activity in the stimulated area and modulate, in a frequency- and task-specific manner, the neural activity in the dorsomedial prefrontal cortex. This suggests a regulatory role of this region for motor control. More generally, we show that combined tACS–fMRI can elucidate the causal link between brain oscillations, neural systems, and behavior.
Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease
Authors: Nazarpour Sima , Ramezani Tehrani Fahimeh , Simbar Masoumeh , Tohidi Maryam , Alavi Majd Hamid , Azizi Fereidoun 
Published: November 2016

Background
Despite some studies indicating that thyroid antibody positivity during pregnancy has been associated with adverse pregnancy outcomes, evidence regarding the effects of levothyroxine (LT4) treatment of euthyroid/subclinical hypothyroid pregnant women with autoimmune thyroid disease on pregnancy outcome is limited. We aimed to assess whether pregnant women with autoimmune thyroid disease, but without overt thyroid dysfunction are affected by higher rates of adverse pregnancy outcomes. In addition, we aimed to explore whether LT4 treatment improves the pregnancy outcome of affected women.

Methods
A prospective study was carried out on pregnant women from the first trimester to delivery. The study was conducted among pregnant women receiving prenatal care in centers under coverage of Shahid Beheshti University of Medical Sciences. Of a total of 1746 pregnant women, screened for thyroid dysfunction, 1028 euthyroid TPOAb-negative (TPOAb−) and 131 thyroid peroxidase antibody-positive (TPOAb+) women without overt thyroid dysfunction entered the second phase of the study. TPOAb+ women were randomly divided into two groups: group A (n = 65), treated with LT4 and group B (n = 66), received no treatment. The 1028 TPOAb− women (group C) served as a normal population control group. Primary outcomes were preterm delivery and miscarriage and secondary outcomes included placenta abruption, still birth, neonatal admission and neonatal TSH levels.

Results
Groups A and C displayed a lower rate of preterm deliveries compared with group B (RR = 0.30, 95% CI: 0.1–0.85, P = 0.0229) and (RR = 0.23, 95% CI: 0.14–0.40, P < 0.001) respectively. There was no statistically significant difference in the rates of preterm labor between groups A and C (RR = 0.79, 95% CI: 0.30–2.09, P = 0.64). The number needed to treat (NNT) for preterm birth was 5.9 (95% CI: 3.33–25.16)

Conclusions
Treatment with LT4 decreases the risk of preterm delivery in women who are positive for TPOAb.
A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B
Authors: Gurung Ritika , Ono Yosuke , Baxendale Sarah , Lee Samantha Lin Chiou , Moore Steven , Calvert Meredith , Ingham Philip W 
Published: November 2016

Abstract
Myosin 18B is an unconventional myosin that has been implicated in tumor progression in humans. In addition, loss-of-function mutations of the MYO18B gene have recently been identified in several patients exhibiting symptoms of nemaline myopathy. In mouse, mutation of Myo18B results in early developmental arrest associated with cardiomyopathy, precluding analysis of its effects on skeletal muscle development. The zebrafish, frozen (fro) mutant was identified as one of a group of immotile mutants in the 1996 Tübingen genetic screen. Mutant embryos display a loss of birefringency in their skeletal muscle, indicative of disrupted sarcomeric organization. Using meiotic mapping, we localized the fro locus to the previously unannotated zebrafish myo18b gene, the product of which shares close to 50% identity with its human ortholog. Transcription of myo18b is restricted to fast-twitch myocytes in the zebrafish embryo; consistent with this, fro mutant embryos exhibit defects specifically in their fast-twitch skeletal muscles. We show that sarcomeric assembly is blocked at an early stage in fro mutants, leading to the disorganized accumulation of actin, myosin, and α-actinin and a complete loss of myofibrillar organization in fast-twitch muscles.
Impact of Planting Date and Seeding Rate on Forage and Grain Yields of Dual‐Purpose Wheat in Central Texas
Authors: Darapuneni Murali K. , Morgan Gaylon D. , Shaffer Oliver J. , Dodla Syam 
Published: November 2016

Core Ideas
Planting date is more important than the seeding rate for maximizing forage and grain yields in a dual‐use system.
Optimum planting date for maximizing forage yield is September to early October, whereas optimum planting date for maximizing grain yield is early November in central Texas.
Optimum planting date for maximum returns is early to late September.
Producers of central Texas can drop the seeding rate to 30 lb ac−1 without sacrificing forage and grain yield potential of dual purpose wheat.
Planting date and seeding rate are important considerations for maximizing the forage and grain yields of dual‐purpose wheat (Triticum aestivum L.). A 3‐year study was conducted to evaluate the effect of six planting dates (September through November in 2‐week intervals) and four seeding rates (30, 60, 90, and 120 lb acre−1) on forage and grain yields of dual‐purpose winter wheat. Earlier planting dates maximized forage yield and declined when planting date was delayed in all tested years (R2 = 0.9646). However, optimum planting date for maximum grain yield was early November. Based on economic analysis, optimum planting date for maximum returns was early to late September. Forage and grain yields of dual‐purpose wheat were unaffected by different seeding rates (P > 0.05). Based on the results, producers in central Texas can sow at 30 lb acre−1 without sacrificing forage and grain yield potential of dual‐purpose wheat. Growers of dual‐purpose wheat operating under different grazing requirements to central Texas may be able to maximize returns by planting at an appropriate time and reducing seeding rates.