Characteristics of long-duration inhibitory postsynaptic potentials in rat neocortical neurons in vitro

1. The characteristics of long-duration inhibitory postsynaptic potentials (l-IPSPs) which are evoked in rat frontal neocortical neurons by local electrical stimulation were investigated with intracellular recordings from anin vitro slice preparation. 2. Stimulation with suprathreshold intensities evoked l-IPSPs with typical durations of 600–900 msec at resting membrane potential. Conductance increases of 15–60% were measured at the peak amplitude of l-IPSPs (150–250 msec poststimulus). 3. The duration of the conductance increases during l-IPSPs displayed a significant voltage dependence, decreasing as the membrance potential was depolarized and increasing with hyperpolarization. 4. The reversal potential of l-IPSPs is significantly altered by reductions in the extracellular potassium concentration. Therefore it is concluded that l-IPSPs in rat neocortical neurons are generated by the activation of a potassium conductance. 5. l-IPSPs exhibit stimulation fatigue. Stimulation with a frequency of 1 Hz produces a complete fatigue of the conductance increases during l-IPSPs after approximately 20 consecutive stimuli. Recovery from this fatigue requires minutes. 6. l-IPSPs are not blocked by bicuculline but are blocked by baclofen

Assessing the impact of a joint human-porcine intervention package for Taenia solium control:Results of a pilot study from northern Lao PDR

Following confirmation that a remote village of approximately 300 inhabitants in northern Lao PDR was hyperendemic for the Neglected Tropical Disease Taenia solium, a pilot human-porcine therapeutic control intervention was implemented between October 2013 and November 2014. Mass drug administration with a three day albendazole 400 mg protocol was offered to all eligible humans in October 2013 and March 2014. At these times, and again in October 2014, eligible village pigs received the anti-cysticercosis TSOL18 vaccination and an oral dose of oxfendazole anthelmintic at 30 mg/kg, both repeated one month later. Community and individual human taeniasis prevalences were estimated via copro-antigen ELISA of volunteered human faecal samples prior to October 2013, and again in January 2015, in order to examine the short term impact of the intervention.</p

Cluster Abell 520: a perspective based on member galaxies. A cluster forming at the crossing of three filaments?

The connection of cluster mergers with the presence of extended, diffuse radio sources in galaxy clusters is still debated. An interesting case is the rich, merging cluster Abell 520, containing a radio halo. A recent gravitational analysis has shown in this cluster the presence of a massive dark core suggested to be a possible problem for the current cold dark matter paradigm. We aim to obtain new insights into the internal dynamics of Abell 520 analyzing velocities and positions of member galaxies. Our analysis is based on redshift data for 293 galaxies in the cluster field obtained combining new redshift data for 86 galaxies acquired at the TNG with data obtained by CNOC team and other few data from the literature. We also use new photometric data obtained at the INT telescope. We combine galaxy velocities and positions to select 167 cluster members around z~0.201. We analyze the cluster structure using the weighted gap analysis, the KMM method, the Dressler-Shectman statistics and the analysis of the velocity dispersion profiles. We compare our results with those from X-ray, radio and gravitational lensing analyses. We find that Abell 520 is definitely a very complex system. Our results suggest that we are looking at a cluster forming at the crossing of three filaments of the large scale structure. In particular, we detect a filament aligned with the LOS and projected onto the center of the forming cluster. It might explain the apparent massive dark core shown by gravitational lensing analysis.Comment: 18 pages, 16 figures, 4 tables. Accepted for publication on A&

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells\u27 inflammatory phenotype may impact obesity and its complications

Avapritinib versus regorafenib in locally advanced unresectable or metastatic GI stromal tumor: A randomized, open-label phase III study

PURPOSE Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V–mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS Four hundred seventy-six patients were randomly assigned (avapritinib, n 5 240; regorafenib, n 5 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P 5 .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade $ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST

Endoskeletal structure in Cheirolepis (Osteichthyes, Actinopterygii), An early ray-finned fish

As the sister lineage of all other actinopterygians, the Middle to Late Devonian (Eifelian–Frasnian) Cheirolepis occupies a pivotal position in vertebrate phylogeny. Although the dermal skeleton of this taxon has been exhaustively described, very little of its endoskeleton is known, leaving questions of neurocranial and fin evolution in early ray‐finned fishes unresolved. The model for early actinopterygian anatomy has instead been based largely on the Late Devonian (Frasnian) Mimipiscis, preserved in stunning detail from the Gogo Formation of Australia. Here, we present re‐examinations of existing museum specimens through the use of high‐resolution laboratory‐ and synchrotron‐based computed tomography scanning, revealing new details of the neuro‐cranium, hyomandibula and pectoral fin endoskeleton for the Eifelian Cheirolepis trailli. These new data highlight traits considered uncharacteristic of early actinopterygians, including an uninvested dorsal aorta and imperforate propterygium, and corroborate the early divergence of Cheirolepis within actinopterygian phylogeny. These traits represent conspicuous differences between the endoskeletal structure of Cheirolepis and Mimipiscis. Additionally, we describe new aspects of the parasphenoid, vomer and scales, most notably that the scales display peg‐and‐socket articulation and a distinct neck. Collectively, these new data help clarify primitive conditions within ray‐finned fishes, which in turn have important implications for understanding features likely present in the last common ancestor of living osteichthyans

How individuals change language

Languages emerge and change over time at the population level though interactions between individual speakers. It is, however, hard to directly observe how a single speaker's linguistic innovation precipitates a population-wide change in the language, and many theoretical proposals exist. We introduce a very general mathematical model that encompasses a wide variety of individual-level linguistic behaviours and provides statistical predictions for the population-level changes that result from them. This model allows us to compare the likelihood of empirically-attested changes in definite and indefinite articles in multiple languages under different assumptions on the way in which individuals learn and use language. We find that accounts of language change that appeal primarily to errors in childhood language acquisition are very weakly supported by the historical data, whereas those that allow speakers to change incrementally across the lifespan are more plausible, particularly when combined with social network effects