Miracle-dz/UniFAR-FTUs huggingface dataset:
BDNF attenuates hippocampal LTD via activation of phospholipase C: implications for a vertical shift in the frequency–response curve of synaptic plasticity

Recent evidence shows that neurotrophins are not only involved in neuronal survival and differentiation during development but also in modulating synaptic strength in the mature brain. To understand how neurotrophins alter this synaptic modification, we have investigated the effect of brain‐derived neurotrophic factor (BDNF) on long‐term depression (LTD) at Schaffer collateral–CA1 synapses in rat hippocampal slices. The slices treated with BDNF for 5 min showed significantly less LTD in response to a 1‐Hz tetanus compared with controls but displayed normal LTD when the afferents were tetanized at 10 Hz. Because BDNF enhanced long‐term potentiation (LTP) induced by a 30‐Hz tetanus, the synaptic modification threshold (θm) as defined in the ‘BCM’ theory of Bienenstock Cooper & Monroe [Bienenstock et al. (1982), J. Neurosci. , 2, 32–48] was not shifted. BNDF is likely to alter the capability of the plastic changes in synaptic efficacy, i.e. to produce an upward shift in the BCM curve. The suppressive effect of BDNF on LTD was prevented by either the tyrosine kinase (Trk) receptor inhibitor K252a or the phospholipase C inhibitor U73122. Thus, TrkB activation may attenuate LTD through phospholipase C signalling pathway.
ObStruct: A Method to Objectively Analyse Factors Driving Population Structure Using Bayesian Ancestry Profiles

Bayesian inference methods are extensively used to detect the presence of population structure given genetic data. The primary output of software implementing these methods are ancestry profiles of sampled individuals. While these profiles robustly partition the data into subgroups, currently there is no objective method to determine whether the fixed factor of interest (e.g. geographic origin) correlates with inferred subgroups or not, and if so, which populations are driving this correlation. We present ObStruct, a novel tool to objectively analyse the nature of structure revealed in Bayesian ancestry profiles using established statistical methods. ObStruct evaluates the extent of structural similarity between sampled and inferred populations, tests the significance of population differentiation, provides information on the contribution of sampled and inferred populations to the observed structure and crucially determines whether the predetermined factor of interest correlates with inferred population structure. Analyses of simulated and experimental data highlight ObStruct's ability to objectively assess the nature of structure in populations. We show the method is capable of capturing an increase in the level of structure with increasing time since divergence between simulated populations. Further, we applied the method to a highly structured dataset of 1,484 humans from seven continents and a less structured dataset of 179 Saccharomyces cerevisiae from three regions in New Zealand. Our results show that ObStruct provides an objective metric to classify the degree, drivers and significance of inferred structure, as well as providing novel insights into the relationships between sampled populations, and adds a final step to the pipeline for population structure analyses.
Non-invasive estimation of prostate cancer aggressiveness using diffusion-weighted MRI and 3D proton MR spectroscopy at 3.0 T

Background Clinical management of prostate cancer increasingly aims to distinguish aggressive types that require immediate and radical treatment from indolent tumors that are candidates for watchful waiting. This requires reliable and reproducible parameters to effectively control potential cancer progression. Magnetic resonance imaging (MRI) may provide a non-invasive means for this purpose. Purpose To assess the value of diffusion-weighted imaging and proton MR spectroscopy for the prediction of prostate cancer (PCa) aggressiveness. Material and Methods In 39 of 64 consecutive patients who underwent endorectal 3-T MRI prior to radical prostatectomy, prostate specimens were analyzed as whole-mount step sections. Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor/healthy tissue), choline/citrate (CC), and (choline + creatine)/citrate (CCC) ratios were correlated with Gleason scores (GS) from histopathological results. The power to discriminate low (GS ≤ 6) from higher-risk (GS ≥ 7) tumors was assessed with receiver operating characteristics (area under the curve [AUC]). Resulting threshold values were used by a blinded reader to distinguish between aggressive and indolent tumors. Results Ninety lesions (1 × GS = 5, 41 × GS = 6, 36 × GS = 7, 12 × GS = 8) were considered. nADC (AUC = 0.90) showed a higher discriminatory power than ADC (AUC = 0.79). AUC for CC and CCC were 0.73 and 0.82, respectively. Using either nADC < 0.46 or CCC > 1.3, as well as both criteria for aggressive PCa, the reader correctly identified aggressive and indolent tumors in 31 (79%), 28 (72%), and 33 of 39 patients (85%), respectively. Predictions of tumor aggressiveness from TRUS-guided biopsies were correct in 27 of 36 patients (75%). Conclusion The combination of a highly sensitive normalized ADC with a highly specific CCC was found to be well suited to prospectively estimate PCa aggressiveness with a similar diagnostic accuracy as biopsy results.
Effect of nitrogen mustard on natural history of right-sided streptococcal endocarditis in rabbits: role for cellular host defenses

Cellular host defenses are considered to be ineffective in bacterial endocarditis; the microorganisms in infected vegetations are protected from phagocytic cells by dense layers of fibrin. To test this hypothesis, nitrogen mustard-induced agranulocytosis and leukopenia were produced in rabbits with right-sided streptococcal endocarditis. The spontaneous sterilization of tricuspid infection observed in the control animals was not present in the granulocytopenic, leukopenic animals. Since the bacterium Streptococcus intermedius is not sensitive to the complement-mediated bactericidal effect of serum and since the animals were not bacteremic during the time of agranulocytosis, an inhibitory effect of the drug on local cellular host defense mechanisms is postulated. We suggest that the spontaneous sterilization of infective endocarditis in the right side of the heart in rabbits is mediated by cellular host defenses.
Gestures, Vocalizations, and Memory in Language Origins

This article discusses the possible homologies between the human language networks and comparable auditory projection systems in the macaque brain, in an attempt to reconcile two existing views on language evolution: one that emphasizes hand control and gestures, and the other that emphasizes auditory–vocal mechanisms. The capacity for language is based on relatively well defined neural substrates whose rudiments have been traced in the non-human primate brain. At its core, this circuit constitutes an auditory–vocal sensorimotor circuit with two main components, a “ventral pathway” connecting anterior auditory regions with anterior ventrolateral prefrontal areas, and a “dorsal pathway” connecting auditory areas with parietal areas and with posterior ventrolateral prefrontal areas via the arcuate fasciculus and the superior longitudinal fasciculus. In humans, the dorsal circuit is especially important for phonological processing and phonological working memory, capacities that are critical for language acquisition and for complex syntax processing. In the macaque, the homolog of the dorsal circuit overlaps with an inferior parietal–premotor network for hand and gesture selection that is under voluntary control, while vocalizations are largely fixed and involuntary. The recruitment of the dorsal component for vocalization behavior in the human lineage, together with a direct cortical control of the subcortical vocalizing system, are proposed to represent a fundamental innovation in human evolution, generating an inflection point that permitted the explosion of vocal language and human communication. In this context, vocal communication and gesturing have a common history in primate communication.
KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy

KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti‐EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti‐EGFR treatment in a small proportion of patients.
Closed-Cell Stent-Assisted Coiling of Intracranial Aneurysms: Evaluation of Changes in Vascular Geometry Using Digital Subtraction Angiography

Background Stent-assisted coil embolization (SACE) plays an important role in the treatment of intracranial aneurysms. The purpose of this study was to investigate geometrical changes caused by closed-cell design stents in bifurcation and sidewall aneurysms. Methods 31 patients with 34 aneurysms underwent SACE with closed-cell design stents. Inflow angle α, determined by aneurysm neck and afferent vessel, and angle between afferent and efferent vessel close to (δ1), respectively, more remote from the aneurysm neck (δ2) were graphically determined in 2D angiography projections. Results Stent assisted coiling resulted in a significant increase of all three angles from a mean value (±SEM) of α = 119° (±6.5°) pretreatment to 130° (±6.6°) posttreatment (P ≤ .001), δ1 = 129° (±6.4°) to 139° (±6.1°), (P ≤ .001) and δ2 = 115° (±8.4°) to 126° (±7.5°), (P ≤ .01). Angular change of δ1 in AcomA aneurysms was significant greater compared to sidewall aneurysms (26°±4.9° versus 8°± 2.3°, P ≤ .05). The initial angle of δ1 and δ2 revealed a significantly inverse relationship to the angle increase (δ1: r = -0.41, P ≤ .05 and δ2: r = -0.47, P ≤ .01). Moreover, angle δ1 was significantly higher in unruptured compared to ruptured aneurysms (135°±7.1° versus 103°±10.8°, P ≤ .05). Conclusion Stent deployment modulates the geometry of the aneurysm-vessel complex, which may lead to favorable hemodynamic changes more similar to unruptured than to ruptured aneurysms. Our findings also suggest that the more acute-angled aneurysm-vessel anatomy, the larger the angular change. Further studies are needed to investigate whether these changes improve the clinical outcome.
The influence of local sea surface temperatures on Australian east coast cyclones

Cyclones are a major cause of rainfall and extreme weather in the midlatitudes and have a preference for genesis and explosive development in areas where a warm western boundary current borders a continental landmass. While there is a growing body of work on how extratropical cyclones are influenced by the Gulf Stream and Kuroshio Current in the Northern Hemisphere, there is little understanding of similar regions in the Southern Hemisphere including the Australian east coast, where cyclones that develop close to the coast are the main cause of severe weather and coastal flooding. This paper quantifies the impact of east Australian sea surface temperatures (SSTs) on local cyclone activity and behavior, using three different sets of sea surface temperature boundary conditions during the period 2007–2008 in an ensemble of Weather Research and Forecasting Model physics parameterizations. Coastal sea surface temperatures are demonstrated to have a significant impact on the overall frequency of cyclones in this region, with warmer SSTs acting as a trigger for the intensification of weak or moderate cyclones, particularly those of a subtropical nature. However, sea surface temperatures play only a minor role in the most intense cyclones, which are dominated by atmospheric conditions.
The chemokine CXCL13 (BLC): A putative diagnostic marker for neuroborreliosis

Using protein expression profiling, the authors identified an upregulation of the chemokine B lymphocyte chemoattractant (BLC) in the CSF of patients with neuroborreliosis but not in patients with noninflammatory and various other inflammatory neurologic diseases. This upregulation was confirmed by ELISA, showing increased BLC levels in every neuroborreliosis patient while being undetectable in patients with noninflammatory neurologic diseases. These results point to BLC as a putative additional diagnostic marker for neuroborreliosis.
Clinical Features of Right-Sided Infective Endocarditis Occurring in Non-Drug Users

Right-sided infective endocarditis (RIE) occurs predominantly in intravenous drug users in western countries, and it has a relatively good prognosis. Clinical features and prognosis of RIE occurring in non-drug users are not well known. We investigated the clinical findings of RIE in non-drug users. We retrospectively reviewed 345 cases diagnosed with IE. Cases with RIE or left-sided infective endocarditis (LIE) defined by the vegetation site were included and cases having no vegetation or both-side vegetation were excluded. Clinical findings and in-hospital outcome of RIE were compared to those of LIE. Among the 245 cases, 39 (16%) cases had RIE and 206 (84%) cases had LIE. RIE patients were younger (40±19 yr vs 50±18 yr, P=0.004), and had a higher incidence of congenital heart disease (CHD) (36% vs 13%, P<0.001) and central venous catheter (CVC) (21% vs 4%, P=0.001) compared to LIE patients. A large vegetation was more common in RIE (33% vs 9%, P<0.001). Staphylococcus aureus was the most common cause of RIE, while Streptococcus viridans were the most common cause of LIE. In-hospital mortality and cardiac surgery were not different between the two groups. CHD and use of CVC were common in non-drug users with RIE. The short-term clinical outcome of RIE is not different from that of LIE. Graphical Abstract
Clean up or mess up: the effect of sampling biases on measurements of degree distributions in mobile phone datasets

Mobile phone data have been extensively used in the recent years to study social behavior. However, most of these studies are based on only partial data whose coverage is limited both in space and time. In this paper, we point to an observation that the bias due to the limited coverage in time may have an important influence on the results of the analyses performed. In particular, we observe significant differences, both qualitatively and quantitatively, in the degree distribution of the network, depending on the way the dataset is pre-processed and we present a possible explanation for the emergence of Double Pareto LogNormal (DPLN) degree distributions in temporal data.
Weakly Supervised Natural Language Learning Without Redundant Views

We investigate single-view algorithms as an alternative to multi-view algorithms for weakly supervised learning for natural language processing tasks without a natural feature split. In particular, we apply co-training, self-training, and EM to one such task and find that both self-training and FS-EM, a new variation of EM that incorporates feature selection, outperform co-training and are comparatively less sensitive to parameter changes.
Comparison of agent oriented software methodologies to apply in cyber physical production systems

Cyber-Physical Systems (CPS) could be the most modern electronic development as yet, thanks to the integration of information and communication technology (ICT). CPS has associated with computer systems (cyber part) which are closely related to the real-world processes (physical part). A CPS is supported by the newest and foreseeable further advances of computer science, data and communication equipment on the one hand, and of manufacturing science and tools, on the other. On the contrary, within the multiple applications, there are CPS for manufacturing systems, called CPPS (Cyber-Physical Production Systems). The fourth industrial revolution regularly distinguished as I4.0 is based on CPPS. Considerable numbers of authors agree that paradigms agent-based as Multi-Agent Systems (MAS) converge or they make up some parts to apply CPPS. In general, this paper emphasizes that there are different important approaches in CPPS implementation which point near, in particular to MAS. The objective of this article is to provide general and specific concepts associated CPPS implementation through agents, considering the current multiples approaches and methods. A key result is that AgentOriented Software Engineering (AOSE) methodologies have been a highlight to comparisons leading benefits to apply in CPPS.
Depolarization of Mitochondria in Endothelial Cells Promotes Cerebral Artery Vasodilation by Activation of Nitric Oxide Synthase

Objective—Mitochondrial depolarization after ATP-sensitive potassium channel activation has been shown to induce cerebral vasodilation by the generation of calcium sparks in smooth muscle. It is unclear, however, whether mitochondrial depolarization in endothelial cells is capable of promoting vasodilation by releasing vasoactive factors. Therefore, we studied the effect of endothelial mitochondrial depolarization by mitochondrial ATP-sensitive potassium channel activators, BMS-191095 (BMS) and diazoxide, on endothelium-dependent vasodilation. Approach and Results—Diameter studies in isolated rat cerebral arteries showed BMS- and diazoxide-induced vasodilations that were diminished by endothelial denudation. Mitochondrial depolarization-induced vasodilation was reduced by inhibition of mitochondrial ATP-sensitive potassium channels, phosphoinositide-3 kinase, or nitric oxide synthase. Scavenging of reactive oxygen species, however, diminished vasodilation induced by diazoxide, but not by BMS. Fluorescence studies in cultured rat brain microvascular endothelial cells showed that BMS elicited mitochondrial depolarization and enhanced nitric oxide production; diazoxide exhibited largely similar effects, but unlike BMS, increased mitochondrial reactive oxygen species production. Measurements of intracellular calcium ([Ca2+]i) in cultured rat brain microvascular endothelial cells and arteries showed that both diazoxide and BMS increased endothelial [Ca2+]i. Western blot analyses revealed increased phosphorylation of protein kinase B and endothelial nitric oxide synthase (eNOS) by BMS and diazoxide. Increased phosphorylation of eNOS by diazoxide was abolished by phosphoinositide-3 kinase inhibition. Electron spin resonance spectroscopy confirmed vascular nitric oxide generation in response to diazoxide and BMS. Conclusions—Pharmacological depolarization of endothelial mitochondria promotes activation of eNOS by dual pathways involving increased [Ca2+]i as well as by phosphoinositide-3 kinase-protein kinase B–induced eNOS phosphorylation. Both mitochondrial reactive oxygen species–dependent and –independent mechanisms mediate activation of eNOS by endothelial mitochondrial depolarization.
Synaesthesia: A Case Study of Discordant Monozygotic Twins

We describe a study of 11-year-old twin sisters who are physically identical in appearance but who have considerably different conscious experiences. One twin appears to be a synaesthete in that she states that she has specific colour experiences (i.e. photisms) whenever she views, hears or thinks of digits. The other twin does not report such conscious experiences when viewing, hearing or thinking about digits. A genotypic analysis using eight microsatellite loci plus the gender of the twins and their parents confirmed that the twins are monozygotic. A phenotypic analysis using a modification of the Stroop task confirmed that only one twin is a synaesthete. We suggest that the discordance in synaesthesia may be due to either an epigenetic event, X chromosome inactivation, or a mutation of a synaesthesia gene.
Sequential tethering of Golgins and catalysis of SNAREpin assembly by the vesicle-tethering protein p115

p115 tethers coat protein (COP)I vesicles to Golgi membranes. The acidic COOH-terminal domain of p115 links the Golgins, Giantin on COPI vesicles, to GM130 on Golgi membranes. We now show that a SNARE motif-related domain within p115 stimulates the specific assembly of endogenous Golgi SNAREpins containing the t-SNARE, syntaxin 5. p115 catalyzes the construction of a cognate GOS-28–syntaxin-5 (v-/t-SNARE) complex by first linking the SNAREs to promote their direct interaction. These events are essential for NSF-catalyzed reassembly of postmitotic Golgi vesicles and tubules into mature cisternae. Staging experiments reveal that the linking of Golgins precedes SNAREpin assembly. Thus, p115 coordinates sequential tethering and docking of COPI vesicles by first using long tethers (Golgins) and then short tethers (SNAREs).
An innovative model for teaching complex clinical procedures: Integration of standardised patients into ward round training for final year students

Objectives: Ward rounds are an essential activity for doctors in hospital settings and represent complex tasks requiring not only medical knowledge but also communication skills, clinical technical skills, patient management skills and team-work skills. However, although the need for ward round training is emphasized in the published literature, there are currently no reports of ward round training in a simulated setting with standardized patients. Methods: 45 final year students participated in a ward round training session lasting two hours with three standardized patient scenarios and role-plays. Final year students assumed the role of either doctor, nurse or final year student with role-specific instructions and provided each other with peer-feedback during the training session. Training was assessed using final year student focus groups and semi-structured interviews of standardized patients. Written protocols of the focus group as well as the interviews of standardized patients were content analysed. Results: In the course of five focus groups, 204 individual statements were gathered from participating final year students. Ward round training proved to be a feasible tool, well accepted by final year students. It was seen to offer a valuable opportunity for reflection on the processes of ward rounds, important relevant feedback from standardized patients, peer group and tutors. Semi-structured standardized patient interviews yielded 17 central comments indicating that ward rounds are a novel and exciting experience for standardized patients. Conclusion: Ward round training with standardized patients is greatly appreciated by final year students and is viewed as an important part of their education, easing the transition from observing ward rounds to conducting them on their own.