bluuebunny/crossref_metadata_2025 huggingface dataset:
First‐line therapy with dacomitinib, an orally available pan‐HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open‐label, single‐arm, single‐centre, phase 2 study
Authors: Necchi Andrea , Lo Vullo Salvatore , Perrone Federica , Raggi Daniele , Giannatempo Patrizia , Calareso Giuseppina , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Togliardi Elena , Colecchia Maurizio , Busico Adele , Gloghini Annunziata , Testi Adele , Mariani Luigi , Salvioni Roberto
Published: September 2017

Objective

To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan‐epidermal growth factor receptor (HER) inhibitor.

Patients and Methods

In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2–3 or M1 (Tumour‐Node‐Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set.

Results

From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0–43.0%). The median (interquartile range [IQR]) follow‐up duration was 19.8 (6.3–25.7) months; 12‐month progression‐free survival was 26.2% (95% confidence interval [CI] 13.2–51.9); 12‐month overall survival (OS) was 54.9% (95% CI 36.4–82.8). The median (IQR) OS of locally advanced patients was 20 (11.1–not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high‐risk human papillomavirus‐positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non‐responders) and it was confirmed in all post‐dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non‐responders.

Conclusion

Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies.
Palaeoceanographic evolution of the SW Svalbard shelf over the last 14 000 years
Authors: Telesiński Maciej M. , Przytarska Joanna E. , Sternal Beata , Forwick Matthias , Szczuciński Witold , Łącka Magdalena , Zajączkowski Marek
Published: September 2017

The palaeoceanographic evolution of the SW Svalbard shelf west of Hornsund over the last 14 000 years was reconstructed using benthic foraminiferal assemblages, stable oxygen and carbon isotopes, and grain‐size and ice‐rafted debris data. The results reveal the complexity of the feedbacks influencing the shelf environment: the inflow of Atlantic and Arctic waters (AW and ArW, respectively), and the influence of sea ice and tidewater glaciers. The inflow of subsurface AW onto the shelf gradually increased with the first major intrusion at the end of the Bølling‐Allerød. During the Younger Dryas, the shelf was affected by fresh water originating from sea ice and glacier discharge. Glaciomarine conditions prevailed until the earliest Holocene with the intense deliveries of icebergs and meltwater from retreating glaciers and the occasional penetration of AW onto the shelf. Other major intrusions of AW occurred before and after the Preboreal oscillation (early Holocene), which resulted in more dynamic and open‐water conditions. Between 10.5 and 9.7 cal. ka BP, the shelf environment transformed from glaciomarine to open marine conditions. Between c. 9.7 and 6.1 cal. ka BP the AW advection reached its maximum, resulting in a highly dynamic and productive environment. At c. 6.1 cal. ka BP, the inflow of AW onto the Svalbard shelf decreased due to the intensification of the Greenland Gyre and the subduction of AW under the sea‐ice‐bearing ArW. Bioproductivity decreased over the next c. 5500 years. During the Little Ice Age, bioproductivity increased due to favourable conditions in the marginal sea‐ice zone despite the effects of cooling. The renewed advection of AW after AD 1850 started the climate warming trend observed presently. Our findings show that δ18O can be used to reconstruct the dominances of different water‐masses and, with some caution, as a proxy for the presence of sea ice in frontal areas over the northwestern Eurasian shelves.
Gα12 facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3‐kinase‐mediated activation in a RhoA‐dependent manner
Authors: Yoo Edwin J , Cao Gaoyuan , Koziol‐White Cynthia J , Ojiaku Christie A , Sunder Krishna , Jude Joseph A , Michael James V , Lam Hong , Pushkarsky Ivan , Damoiseaux Robert , Di Carlo Dino , Ahn Kwangmi , An Steven S , Penn Raymond B , Panettieri Reynold A
Published: September 2017

Background and Purpose

PI3K‐dependent activation of Rho kinase (ROCK) is necessary for agonist‐induced human airway smooth muscle cell (HASMC) contraction, and inhibition of PI3K promotes bronchodilation of human small airways. The mechanisms driving agonist‐mediated PI3K/ROCK axis activation, however, remain unclear. Given that G12 family proteins activate ROCK pathways in other cell types, their role in M3 muscarinic acetylcholine receptor‐stimulated PI3K/ROCK activation and contraction was examined.

Experimental Approach

Gα12 coupling was evaluated using co‐immunoprecipitation and serum response element (SRE)‐luciferase reporter assays. siRNA and pharmacological approaches, as well as overexpression of a regulator of G‐protein signaling (RGS) proteins were applied in HASMCs. Phosphorylation levels of Akt, myosin phosphatase targeting subunit‐1 (MYPT1), and myosin light chain‐20 (MLC) were measured. Contraction and shortening were evaluated using magnetic twisting cytometry (MTC) and micro‐pattern deformation, respectively. Human precision‐cut lung slices (hPCLS) were utilized to evaluate bronchoconstriction.

Key Results

Knockdown of M3 receptors or Gα12 attenuated activation of Akt, MYPT1, and MLC phosphorylation. Gα12 coimmunoprecipitated with M3 receptors, and p115RhoGEF‐RGS overexpression inhibited carbachol‐mediated induction of SRE‐luciferase reporter. p115RhoGEF‐RGS overexpression inhibited carbachol‐induced activation of Akt, HASMC contraction, and shortening. Moreover, inhibition of RhoA blunted activation of PI3K. Lastly, RhoA inhibitors induced dilation of hPCLS.

Conclusions and Implications

Gα12 plays a crucial role in HASMC contraction via RhoA‐dependent activation of the PI3K/ROCK axis. Inhibition of RhoA activation induces bronchodilation in hPCLS, and targeting Gα12 signaling may elucidate novel therapeutic targets in asthma. These findings provide alternative approaches to the clinical management of airway obstruction in asthma.
How Unequal Is the United States? Adolescents’ Images of Social Stratification
Authors: Flanagan Constance A. , Kornbluh Mariah
Published: September 2017

This study highlights the use of pictorial images to understand adolescents’ views on social stratification. A continuum of five visual images of social stratification were presented to a diverse sample of five hundred ninety‐eight 8th–12th graders (14–18 years old). Adolescents selected which image best represented the United States (today, in 20 years, how it ought to be). Images ranged from inequitable to egalitarian. Results supported reference group and possible selves theories. Adolescents in higher status families chose a more egalitarian image for how the United States is today and how it ought to be. African Americans considered the United States today more unequal. Differences in adolescents’ commitment to an egalitarian ideal depended on their reactions to inequality and their beliefs about government responsiveness, bolstering the measure's validity.
Kidney allograft failure in the steroid‐free immunosuppression era: A matched case‐control study
Authors: Alkadi Mohamad M. , Kim Jim , Aull Meredith J. , Schwartz Joseph E. , Lee John R. , Watkins Anthony , Lee Jun B. , Dadhania Darshana M. , Seshan Surya V. , Serur David , Kapur Sandip , Suthanthiran Manikkam , Hartono Choli , Muthukumar Thangamani
Published: September 2017

We studied the causes and predictors of death‐censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid‐free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1‐1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18‐51). Physician‐validated and biopsy‐confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus‐associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody‐mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28‐63.45) and urine protein ≥1 g/d within the first year post‐transplantation (5.85, 2.37‐14.45). Serum creatinine ≤1.5 mg/dL within the first year post‐transplantation reduced the odds (0.29, 0.13‐0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure.
Using a novel model approach to assess the distribution and conservation status of the endangered Baird's tapir
Authors: Schank Cody J. , Cove Michael V. , Kelly Marcella J. , Mendoza Eduardo , O'Farrill Georgina , Reyna‐Hurtado Rafael , Meyer Ninon , Jordan Christopher A. , González‐Maya Jose F. , Lizcano Diego J. , Moreno Ricardo , Dobbins Michael T. , Montalvo Victor , Sáenz‐Bolaños Carolina , Jimenez Eduardo Carillo , Estrada Nereyda , Cruz Díaz Juan Carlos , Saenz Joel , Spínola Manuel , Carver Andrew , Fort Jessica , Nielsen Clayton K. , Botello Francisco , Pozo Montuy Gilberto , Rivero Marina , de la Torre Jesús Antonio , Brenes‐Mora Esteban , Godínez‐Gómez Oscar , Wood Margot A. , Gilbert Jessica , Miller Jennifer A.
Published: September 2017

Aim

We test a new species distribution modelling (SDM) framework, while comparing results to more common distribution modelling techniques. This framework allows for the combination of presence‐only (PO) and presence‐absence (PA) data and accounts for imperfect detection and spatial bias in presence data. The new framework tested here is based on a Poisson point process model, which allows for predictions of population size. We compared these estimates to those provided by experts on the species.

Species and Location

Presence data on Baird's tapir (Tapirus bairdii) throughout its range from southern México to northern Colombia were used in this research, primarily from the years 2000 to 2016.

Methods

Four SDM frameworks are compared as follows: (1) Maxent, (2) a presence‐only (PO) SDM based on a Poisson point process model (PPM), (3) a presence‐absence (PA) SDM also based on a PPM and (4) an Integrated framework which combines the previous two models. Model averaging was used to produce a single set of coefficient estimates and predictive maps for each model framework. A hotspot analysis (Gi*) was used to identify habitat cores from the predicted intensity of the Integrated model framework.

Results

Important variables to model the distribution of Baird's tapir included land cover, human pressure and topography. Accounting for spatial bias in the presence data affected which variables were important in the model. Maxent and the Integrated model produced predictive maps with similar patterns and were considered to be more in agreement with expert knowledge compared to the PO and PA models.

Main conclusions

Total abundance as predicted by the model was higher than expert opinion on the species, but local density estimates from our model were similar to available independent assessments. We suggest that these results warrant further validation and testing through collection of independent test data, development of more precise predictor layers and improvements to the model framework.
The need for large‐scale distribution data to estimate regional changes in species richness under future climate change
Authors: Titeux Nicolas , Maes Dirk , Van Daele Toon , Onkelinx Thierry , Heikkinen Risto K. , Romo Helena , García‐Barros Enrique , Munguira Miguel L. , Thuiller Wilfried , van Swaay Chris A. M. , Schweiger Oliver , Settele Josef , Harpke Alexander , Wiemers Martin , Brotons Lluís , Luoto Miska
Published: September 2017

Aim

Species distribution models built with geographically restricted data often fail to capture the full range of conditions experienced by species across their entire distribution area. Using such models to predict distribution shifts under future environmental change may, therefore, produce biased projections. However, restricted‐scale models have the potential to include a larger sample of taxa for which distribution data are available and to provide finer‐resolution projections that are better applied to conservation planning than the forecasts of broad‐scale models. We examine the circumstances under which the projected shifts in species richness patterns derived from restricted‐scale and broad‐scale models are most likely to be similar.

Location

Europe.

Methods

The distribution of butterflies in Finland, Belgium/Netherlands and Spain was modelled based on restricted‐scale (local) and broad‐scale (continental) distribution and climate data. Both types of models were projected under future climate change scenarios to assess potential changes in species richness.

Results

In Finland, species richness was projected to increase strongly based on restricted‐scale models and to decrease slightly with broad‐scale models. In Belgium/Netherlands, restricted‐scale models projected a larger decrease in richness than broad‐scale models. In Spain, both models projected a slight decrease in richness. We obtained similar projections based on restricted‐scale and broad‐scale models only in Spain because the climatic conditions available here covered the warm part of the distributions of butterflies better than in Finland and Belgium/Netherlands.

Main conclusions

Restricted‐scale models that fail to capture the warm part of species distributions produce biased estimates of future changes in species richness when projected under climatic conditions with no modern analogue in the study area. We recommend the use of distribution data beyond the boundaries of the study area to capture the part of the species response curves reflecting the climatic conditions that will prevail within that area in the future.
Encoding seasonal information in a two‐oscillator model of the multi‐oscillator circadian clock
Authors: Myung Jihwan , Pauls Scott D.
Published: September 2017

The suprachiasmatic nucleus (SCN) is a collection of about 10 000 neurons, each of which functions as a circadian clock with slightly different periods and phases, that work in concert with form and maintain the master circadian clock for the organism. The diversity among neurons confers on the SCN the ability to robustly encode both the 24‐h light pattern as well as the seasonal time. Cluster synchronization brings the different neurons into line and reduces the large population to essentially two oscillators, coordinated by a macroscopic network motif of asymmetric repulsive‐attractive coupling. We recount the steps leading to this simplification and rigorously examine the two‐oscillator case by seeking an analytical solution. Through these steps, we identify physiologically relevant parameters that shape the behaviour of the SCN network and delineate its ability to store past details of seasonal variation in photoperiod.
Temporal alignment of anticipatory motor cortical beta lateralisation in hidden visual‐motor sequences
Authors: Heideman Simone G. , van Ede Freek , Nobre Anna C.
Published: September 2017

Performance improves when participants respond to events that are structured in repeating sequences, suggesting that learning can lead to proactive anticipatory preparation. Whereas most sequence‐learning studies have emphasised spatial structure, most sequences also contain a prominent temporal structure. We used MEG to investigate spatial and temporal anticipatory neural dynamics in a modified serial reaction time (SRT) task. Performance and brain activity were compared between blocks with learned spatial‐temporal sequences and blocks with new sequences. After confirming a strong behavioural benefit of spatial‐temporal predictability, we show lateralisation of beta oscillations in anticipation of the response associated with the upcoming target location and show that this also aligns to the expected timing of these forthcoming events. This effect was found both when comparing between repeated (learned) and new (unlearned) sequences, as well as when comparing targets that were expected after short vs. long intervals within the repeated (learned) sequence. Our findings suggest that learning of spatial‐temporal structure leads to proactive and dynamic modulation of motor cortical excitability in anticipation of both the location and timing of events that are relevant to guide action.
Processing of temporally patterned sounds in the auditory cortex of Seba's short‐tailed bat,Carollia perspicillata
Authors: Martin Lisa M. , García‐Rosales Francisco , Beetz M. Jerome , Hechavarría Julio C.
Published: September 2017

This article presents a characterization of cortical responses to artificial and natural temporally patterned sounds in the bat species Carollia perspicillata, a species that produces vocalizations at rates above 50 Hz. Multi‐unit activity was recorded in three different experiments. In the first experiment, amplitude‐modulated (AM) pure tones were used as stimuli to drive auditory cortex (AC) units. AC units of both ketamine‐anesthetized and awake bats could lock their spikes to every cycle of the stimulus modulation envelope, but only if the modulation frequency was below 22 Hz. In the second experiment, two identical communication syllables were presented at variable intervals. Suppressed responses to the lagging syllable were observed, unless the second syllable followed the first one with a delay of at least 80 ms (i.e., 12.5 Hz repetition rate). In the third experiment, natural distress vocalization sequences were used as stimuli to drive AC units. Distress sequences produced by C. perspicillata contain bouts of syllables repeated at intervals of ~60 ms (16 Hz). Within each bout, syllables are repeated at intervals as short as 14 ms (~71 Hz). Cortical units could follow the slow temporal modulation flow produced by the occurrence of multisyllabic bouts, but not the fast acoustic flow created by rapid syllable repetition within the bouts. Taken together, our results indicate that even in fast vocalizing animals, such as bats, cortical neurons can only track the temporal structure of acoustic streams modulated at frequencies lower than 22 Hz.
Effects of the availability of accurate proprioceptive information on older adults' postural sway and muscle co‐contraction
Authors: Craig Chesney E. , Calvert Glenn H. M. , Doumas Michail
Published: September 2017

During conditions of increased postural instability, older adults exhibit greater lower limb muscle co‐contraction. This response has been interpreted as a compensatory postural strategy, which may be used to increase proprioceptive information from muscle spindles or to stiffen the lower limb as a general response to minimise postural sway. The current study aimed to test these two hypotheses by investigating use of muscle co‐contraction during sensory transitions that manipulated proprioceptive input. Surface EMG was recorded from the bilateral tibialis anterior and gastrocnemius medialis muscles, in young (aged 18–30) and older adults (aged 68–80) during blind‐folded postural assessment. This commenced on a fixed platform (baseline: 2 min), followed by 3 min on a sway‐referenced platform (adaptation) and a final 3 min on a fixed platform again (reintegration). Sensory reweighting was slower in older adults, as shown by a significantly larger and longer postural sway after‐effect once a stable platform was restored. Muscle co‐contraction showed similar after‐effects, whereby older adults showed a larger increase in co‐contraction once the stable platform had been restored, compared to young adults. This co‐contraction after‐effect did not return to baseline until after 1 min. Our evidence for high muscle co‐contraction during the reintroduction of veridical proprioceptive input suggests that increased co‐contraction in older adults is not dependent on contemporaneous proprioceptive input. Rather, it is more likely that co‐contraction is a general postural strategy used to minimise postural sway, which is increased during this sensory transition. Future research should examine whether muscle co‐contraction is typically a reactive or anticipatory response.
Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities
Authors: Ehlinger Daniel G. , Commons Kathryn G.
Published: September 2017

Polymorphism in the geneCACNA1C, encoding the pore‐forming subunit of Cav1.2 L‐type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain‐of‐function mutation inCACNA1Cis responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2‐neo) mouse, which displays behavioral features consistent with the core triad ofASD. We find thatTS2‐neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor‐dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain‐of‐function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across severalASDmouse models, and the capacity for Cav1.2 L‐type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions.
Corticospinal responses following strength training: a systematic review and meta‐analysis
Authors: Kidgell Dawson J. , Bonanno Daniel R. , Frazer Ashlyn K. , Howatson Glyn , Pearce Alan J.
Published: September 2017

Strength training results in changes in skeletal muscle; however, changes in the central nervous system also occur. Over the last 15 years, non‐invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been used to study the neural adaptations to strength training. This review explored the hypothesis that the neural adaptations to strength training may be due to changes in corticospinal excitability and inhibition and, such changes, contribute to the gain in strength following strength training. A systematic review, according to PRISMA guidelines, identified studies by database searching, hand‐searching and citation tracking between January 1990 and the first week of February 2017. Methodological quality of included studies was determined using the Downs and Black quality index. Data were synthesised and interpreted from meta‐analysis. Nineteen studies investigating the corticospinal responses following strength training were included. Meta‐analysis found that strength training increased strength [standardised mean difference (SMD) 0.84, 95% CI 0.55 to 1.13], decreased short‐interval intracortical inhibition (SMD −1.00, 95% CI −1.84 to −0.17) and decreased the cortical silent period (SMD −0.66, 95% CI −1.00 to −0.32). Strength training had no effect on motor threshold (SMD −0.12, 95% CI −0.49 to 0.25), but a borderline effect for increased corticospinal excitability (SMD 0.27, 95% CI 0.00 to 0.54). In untrained healthy participants, the corticospinal response to strength training is characterised by reduced intracortical inhibition and cortical silent period duration, rather than changes in corticospinal excitability. These data demonstrate that strength training targets intracortical inhibitory networks within the primary motor cortex (M1) and corticospinal pathway, characterising an important neural adaptation to strength training.
Inflammation alters AMPA‐stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons
Authors: Winland Carissa D. , Welsh Nora , Sepulveda‐Rodriguez Alberto , Vicini Stefano , Maguire‐Zeiss Kathleen A.
Published: September 2017

Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of AMPARs. The preferential trafficking of calcium‐permeable versus impermeable AMPARs can result in disruptions of [Ca2+]i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca2+]i and L‐type voltage‐gated calcium channels (VGCCs) have been reported. Therefore, this study sought to determine whether a proinflammatory environment alters AMPA‐stimulated [Ca2+]i through calcium‐permeable AMPARs and/or L‐type VGCCs in dopamine‐2‐ and dopamine‐1‐expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum. Mice expressing the calcium indicator protein, GCaMP in D2 or D1 SPNs, were utilized for calcium imaging. Microglial activation was assessed by morphology analyses. To induce inflammation, acute mouse striatal slices were incubated with lipopolysaccharide (LPS). Here we report that LPS treatment potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA‐stimulated calcium fluorescence in D2 but not D1 SPNs. The remaining agonist‐induced [Ca2+]i was mediated by calcium‐permeable AMPARs because the responses were completely blocked by a selective calcium‐permeable AMPAR antagonist. We used isradipine, the highly selective L‐type VGCC antagonist to determine the role of L‐type VGCCs in SPNs treated with LPS. Isradipine decreased AMPA‐stimulated responses selectively in D2 SPNs after LPS treatment. Our findings suggest that dorsal striatal D2 SPNs are specifically targeted in proinflammatory conditions and that L‐type VGCCs and calcium‐permeable AMPARs are important mediators of this effect.
The effects of dynamical synapses on firing rate activity: a spiking neural network model
Authors: Khalil Radwa , Moftah Marie Z. , Moustafa Ahmed A.
Published: September 2017

Accumulating evidence relates the fine‐tuning of synaptic maturation and regulation of neural network activity to several key factors, including GABAA signaling and a lateral spread length between neighboring neurons (i.e., local connectivity). Furthermore, a number of studies consider short‐term synaptic plasticity (STP) as an essential element in the instant modification of synaptic efficacy in the neuronal network and in modulating responses to sustained ranges of external Poisson input frequency (IF). Nevertheless, evaluating the firing activity in response to the dynamical interaction between STP (triggered by ranges of IF) and these key parameters in vitro remains elusive. Therefore, we designed a spiking neural network (SNN) model in which we incorporated the following parameters: local density of arbor essences and a lateral spread length between neighboring neurons. We also created several network scenarios based on these key parameters. Then, we implemented two classes of STP: (1) short‐term synaptic depression (STD) and (2) short‐term synaptic facilitation (STF). Each class has two differential forms based on the parametric value of its synaptic time constant (either for depressing or facilitating synapses). Lastly, we compared the neural firing responses before and after the treatment with STP. We found that dynamical synapses (STP) have a critical differential role on evaluating and modulating the firing rate activity in each network scenario. Moreover, we investigated the impact of changing the balance between excitation (E) and inhibition (I) on stabilizing this firing activity.
FoxP expression identifies a Kenyon cell subtype in the honeybee mushroom bodies linking them to fruit fly αβc neurons
Authors: Schatton Adriana , Scharff Constance
Published: September 2017

The arthropod mushroom bodies (MB) are a higher order sensory integration centre. In insects, they play a central role in associative olfactory learning and memory. In Drosophila melanogaster (Dm), the highly ordered connectivity of heterogeneous MB neuron populations has been mapped using sophisticated molecular genetic and anatomical techniques. The MB‐core subpopulation was recently shown to express the transcription factor FoxP with relevance for decision‐making. Here, we report the development and adult distribution of a FoxP‐expressing neuron population in the MB of honeybees (Apis mellifera, Am) using in situ hybridisation and a custom‐made antiserum. We found the same expression pattern in adult bumblebees (Bombus terrestris, Bt). We also designed a new Dm transgenic line that reports FoxP transcriptional activity in the MB‐core region, clarifying previously conflicting data of two other reporter lines. Considering developmental, anatomical and molecular similarities, our data are consistent with the concept of deep homology of FoxP expression in neuron populations coding reinforcement‐based learning and habit formation.
Randomized controlled trial evaluating the temporal effects of high‐intensity exercise on learning, short‐term and long‐term memory, and prospective memory
Authors: Frith Emily , Sng Eveleen , Loprinzi Paul D.
Published: September 2017

The broader purpose of this study was to examine the temporal effects of high‐intensity exercise on learning, short‐term and long‐term retrospective memory and prospective memory. Among a sample of 88 young adult participants, 22 were randomized into one of four different groups: exercise before learning, control group, exercise during learning, and exercise after learning. The retrospective assessments (learning, short‐term and long‐term memory) were assessed using the Rey Auditory Verbal Learning Test. Long‐term memory including a 20‐min and 24‐hr follow‐up assessment. Prospective memory was assessed using a time‐based procedure by having participants contact (via phone) the researchers at a follow‐up time period. The exercise stimulus included a 15‐min bout of progressive maximal exertion treadmill exercise. High‐intensity exercise prior to memory encoding (vs. exercise during memory encoding or consolidation) was effective in enhancing long‐term memory (for both 20‐min and 24‐h follow‐up assessments). We did not observe a differential temporal effect of high‐intensity exercise on short‐term memory (immediate post‐memory encoding), learning or prospective memory. The timing of high‐intensity exercise may play an important role in facilitating long‐term memory.
Soil microbial communities drive the resistance of ecosystem multifunctionality to global change in drylands across the globe
Authors: Delgado‐Baquerizo Manuel , Eldridge David J. , Ochoa Victoria , Gozalo Beatriz , Singh Brajesh K. , Maestre Fernando T.
Published: September 2017

The relationship between soil microbial communities and the resistance of multiple ecosystem functions linked to C, N and P cycling (multifunctionality resistance) to global change has never been assessed globally in natural ecosystems. We collected soils from 59 dryland ecosystems worldwide to investigate the importance of microbial communities as predictor of multifunctionality resistance to climate change and nitrogen fertilisation. Multifunctionality had a lower resistance to wetting–drying cycles than to warming or N deposition. Multifunctionality resistance was regulated by changes in microbial composition (relative abundance of phylotypes) but not by richness, total abundance of fungi and bacteria or the fungal: bacterial ratio. Our results suggest that positive effects of particular microbial taxa on multifunctionality resistance could potentially be controlled by altering soil pH. Together, our work demonstrates strong links between microbial community composition and multifunctionality resistance in dryland soils from six continents, and provides insights into the importance of microbial community composition for buffering effects of global change in drylands worldwide.
Plant resistance to drought depends on timely stomatal closure
Authors: Martin‐StPaul Nicolas , Delzon Sylvain , Cochard Hervé
Published: September 2017

Stomata play a significant role in the Earth's water and carbon cycles, by regulating gaseous exchanges between the plant and the atmosphere. Under drought conditions, stomatal control of transpiration has long been thought to be closely coordinated with the decrease in hydraulic capacity (hydraulic failure due to xylem embolism). We tested this hypothesis by coupling a meta‐analysis of functional traits related to the stomatal response to drought and embolism resistance with simulations from a soil–plant hydraulic model. We report here a previously unreported phenomenon: the existence of an absolute limit by which stomata closure must occur to avoid rapid death in drought conditions. The water potential causing stomatal closure and the xylem pressure at the onset of embolism formation were equal for only a small number of species, and the difference between these two traits (i.e. safety margins) increased continuously with increasing embolism resistance. Our findings demonstrate the need to revise current views about the functional coordination between stomata and hydraulic traits and provide a mechanistic framework for modeling plant mortality under drought conditions.
Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation
Authors: Konno T. , Yoshida K. , Mizuta I. , Mizuno T. , Kawarai T. , Tada M. , Nozaki H. , Ikeda S.‐I. , Onodera O. , Wszolek Z. K. , Ikeuchi T.
Published: September 2017

Background and purpose

To establish and validate diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony‐stimulating factor 1 receptor (CSF1R) mutation.

Methods

We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation‐negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations.

Results

Among the CSF1R mutation‐positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation‐negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria.

Conclusions

These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.
The role of pre‐morbid diabetes on developing amyotrophic lateral sclerosis
Authors: D'Ovidio F. , d'Errico A. , Carnà P. , Calvo A. , Costa G. , Chiò A.
Published: September 2017

Background and purpose

The literature on the association between diabetes and amyotrophic lateral sclerosis (ALS) consists of a limited number of studies. This cohort study was developed in order to assess the role of diabetes on the risk of developing ALS.

Methods

The study population was represented by all residents in Turin (Italy) at the beginning of 1996 who participated in the 1991 census, over 14 years of age (n = 727 977) and followed up for ALS occurrence from 1998 to 2014. Presence of diabetes at baseline or during follow‐up was ascertained through two Piedmont regional sources: the Diabetes Registry and the Anatomical Therapeutic Chemical Drug Prescription Archive. The risk of ALS was estimated using the Piedmont and Valle d'Aosta ALS Registry (PARALS). The association of diabetes, treated as a time‐dependent variable, with ALS onset was estimated through Cox proportional hazard regression models adjusted for age, gender, education and marital status.

Results

During follow‐up, 397 subjects developed ALS, 24 of whom were already diabetic before ALS onset. Diabetes was associated with a significantly decreased risk of ALS [hazard ratio, 0.30 (95% confidence interval, 0.19–0.45)] without differences in risk by gender, age class or ALS phenotype.

Conclusion

The results support the protective role of diabetes toward ALS.
Growth options and firm valuation
Authors: Kraft Holger , Schwartz Eduardo , Weiss Farina
Published: September 2017

This paper studies the relationship between firm value and a firm's growth options. We find strong empirical evidence that Tobin's Q increases with firm‐level volatility. The significance mainly comes from R&D firms, which have more growth options than non‐R&D firms. By decomposing firm‐level volatility into its systematic and unsystematic part, we document that only idiosyncratic volatility has a significant effect on valuation. Second, we analyze the relation of stock returns to realized contemporaneous idiosyncratic volatility and R&D expenses. Sorting on idiosyncratic volatility yields a significant negative relationship between portfolio alphas and contemporaneous idiosyncratic volatility for non‐R&D portfolios.
The nexus of fun and nutrition: Recreational fishing is also about food
Authors: Cooke Steven J , Twardek William M , Lennox Robert J , Zolderdo Aaron J , Bower Shannon D , Gutowsky Lee F G , Danylchuk Andy J , Arlinghaus Robert , Beard Douglas
Published: September 2017

Recreational fishing is a popular activity in aquatic ecosystems around the globe using a variety of gears including rod and line and to a lesser extent handlines, spears, bow and arrow, traps and nets. Similar to the propensity to engage in voluntary catch‐and‐release, the propensity to harvest fishes strongly varies among cultures, locations, species and fisheries. There is a misconception that because recreational fishing happens during non‐work (i.e. leisure) time, the nutritional motivation is negligible; therefore, the role of recreational fishing in supporting nutrition (and thus food security) at regional, national or global scales is underappreciated. We consider the factors that influence whether fish will be harvested or released by examining the motives that underlie recreational fishing. Next, we provide an overview of the magnitude and role of recreational fishing harvest in supporting nutrition using regional case‐studies. Then, we address issues such as contaminants and parasites that constrain the ability of fish harvested by recreational fishers to be consumed. Although recreational fishing is foremost a leisure activity, the harvest of fish for personal consumption by recreational fishers has contributed and will continue to contribute to human nutrition by providing an accessible, affordable and generally highly sustainable food source, notwithstanding concerns about food safety and possibly overfishing. Attempts to better quantify the role of fish harvested by recreational fishers and the relative contribution to overall food security and personal nutrition will provide resource managers and policymakers the information needed to guide management activities and policy development.
A visual approach of care pathways from the French nationwide SNDS database – from population to individual records: the ePEPS toolbox
Authors: Happe André , Drezen Erwan
Published: September 2017

Secondary use of medical and administrative databases has become a powerful tool for epidemiological studies. In that respect, the recent access opening of French nationwide health record database or Système National des Données de Santé is a great opportunity to carry out comprehensive health studies at the country level. However, using this database is far from being straightforward for nonexpert data scientists; so, dedicated tools needed to be developed. Our contribution is focused on data management and visualization tools able to query and cope with the complexity of care pathways of patients. The scope of the toolbox presented below goes from interactive tools for building groups of patients to timeline representations of individual patient healthcare trajectories.
Structural characterization and functional analysis of cystathionine β‐synthase: an enzyme involved in the reverse transsulfuration pathway of Bacillus anthracis
Authors: Devi Suneeta , Abdul Rehman Syed A. , Tarique Khaja F. , Gourinath Samudrala
Published: September 2017

The reverse transsulfuration pathway has been reported to produce cysteine from homocysteine in eukaryotes ranging from protozoans to mammals while bacteria and plants produce cysteine via a de novo pathway. Interestingly, the bacterium Bacillus anthracis includes enzymes of the reverse transsulfuration pathway viz. cystathionine β‐synthase [BaCBS, previously annotated to be an O‐acetylserine sulfhydrylase (OASS)] and cystathionine γ‐lyase. Here, we report the structure of BaCBS at a resolution of 2.2 Å. The enzyme was found to show CBS activity only with activated serine (O‐acetylserine) and not with serine, and was also observed to display OASS activity but not serine sulfhydrylase activity. BaCBS was also found to produce hydrogen sulfide (H2S) upon reaction of cysteine and homocysteine. A mutational study revealed Glu 220, conserved in CBS, to be necessary for generating H2S. Structurally, BaCBS display a considerably more open active site than has been found for any other CBS or OASS, which was attributed to the presence of a helix at the junction of the C‐ and N‐terminal domains. The root‐mean‐square deviation (RMSD) between the backbone Cα carbon atoms of BaCBS and those of other CBSs and OASSs were calculated to be greater than 3.0 Å. The pyridoxal 5′‐phosphate at the active site was not traced, and appeared to be highly flexible due to the active site being wide open. Phylogenetic analysis revealed the presence of an O‐acetylserine‐dependent CBS in the bacterial domain and making separate clade from CBS and OASS indicating its evolution for specific function.

Database

Structural data are available in the PDB under the accession number 5XW3.
A large‐area, spatially continuous assessment of land cover map error and its impact on downstream analyses
Authors: Estes Lyndon , Chen Peng , Debats Stephanie , Evans Tom , Ferreira Stefanus , Kuemmerle Tobias , Ragazzo Gabrielle , Sheffield Justin , Wolf Adam , Wood Eric , Caylor Kelly
Published: September 2017

Land cover maps increasingly underlie research into socioeconomic and environmental patterns and processes, including global change. It is known that map errors impact our understanding of these phenomena, but quantifying these impacts is difficult because many areas lack adequate reference data. We used a highly accurate, high‐resolution map of South African cropland to assess (1) the magnitude of error in several current generation land cover maps, and (2) how these errors propagate in downstream studies. We first quantified pixel‐wise errors in the cropland classes of four widely used land cover maps at resolutions ranging from 1 to 100 km, and then calculated errors in several representative “downstream” (map‐based) analyses, including assessments of vegetative carbon stocks, evapotranspiration, crop production, and household food security. We also evaluated maps’ spatial accuracy based on how precisely they could be used to locate specific landscape features. We found that cropland maps can have substantial biases and poor accuracy at all resolutions (e.g., at 1 km resolution, up to ∼45% underestimates of cropland (bias) and nearly 50% mean absolute error (MAE, describing accuracy); at 100 km, up to 15% underestimates and nearly 20% MAE). National‐scale maps derived from higher‐resolution imagery were most accurate, followed by multi‐map fusion products. Constraining mapped values to match survey statistics may be effective at minimizing bias (provided the statistics are accurate). Errors in downstream analyses could be substantially amplified or muted, depending on the values ascribed to cropland‐adjacent covers (e.g., with forest as adjacent cover, carbon map error was 200%–500% greater than in input cropland maps, but ∼40% less for sparse cover types). The average locational error was 6 km (600%). These findings provide deeper insight into the causes and potential consequences of land cover map error, and suggest several recommendations for land cover map users.