Miracle-dz/UniFAR-FTUs huggingface dataset:
Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition of irrelevant information in people with multiple sclerosis

Background Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission. MS leads to cognitive impairment such as reduced information processing speed and impaired working memory (WM). Recent studies have suggested that the 1/f slope of EEG/MEG power spectra can be associated with the excitation/inhibition (E/I) balance. A normal E/I balance is crucial for normal information processing and working memory. Methods We analyzed magnetoencephalographic (MEG) recordings of 38 healthy control subjects and 79 people with multiple sclerosis (pwMS) while performing an n-back working task. We computed and compared the steepness of the 1/f spectral slope through the FOOOF algorithm in the time windows [-1 0] and [0 1] s peristimulus time for both target and distractor stimulus for each brain parcel and for different working memory loads (0-back, 1-back, 2-back). Results The spectral slope was significantly steeper after the stimulus onset and was correlated with reaction time. We also observed a steeper 1/f slope after distractor stimuli in healthy subjects compared to pwMS. Finally, we observed significant correlations between the 1/f spectral slope modulation and visuospatial working memory functioning in both healthy subjects and pwMS. Conclusion Our findings are consistent with an increased inhibition following stimulus onset. In pwMS, this increase is reduced, suggesting dysfunctional inhibition of irrelevant information. Finally, this impaired modulation is significantly associated with a pencil-paper test of visuospatial working memory. Highlights The flatter 1/f slope after distractor stimuli in people with multiple sclerosis (pwMS) compared to healthy subjects suggests a less pronounced inhibition of irrelevant information in pwMS. The significantly flatter 1/f slope was observed in the left inferior dorsal prefrontal cortex of pwMS in both 1-back and 2-back conditions. This particular brain parcel is known for its key role in motor planning, and the maintenance of sustained attention and working memory and executive functions. A steeper 1/f slope after target and distractor stimuli suggests an increase in inhibition following stimulus onset in both healthy controls (HCs) and people with MS (pwMS). The 1/f slope modulation correlates with visuospatial working memory performance.
Novel gramicidin-derived β-helical antimicrobial peptides

Combating the threat of multidrug resistance bacteria requires many different approaches. Using structural motifs and sequences from existing antibacterial compounds affords a fresh attack against such bacteria, while circumventing inherited resistance against the existing compound. Gramicidin is a 16 amino acid peptide with an alternating L- and D-motif with highly bacteriocidal effects in gram-positive membranes. In the membrane it assumes a β-helix form with two peptides aligned by their N-terminal interactions, and only conducts in such a form. Using gramicidin as a basis, this study employs molecular dynamics simulations as an initial design step and evaluates gramicidin-derived candidates based on their backbone hydrogen-bond interactions, capacity for conductance, profile of their RMSD over the course of the simulation, and how the peptide interacts with the phospholipid headgroups. There are twelve candidate systems with results comparable to gramicidin and the factors at play in their efficacy are examined.
KCNQ2/3 regulates efferent mediated slow excitation of vestibular afferents in mammals

Primary vestibular afferents transmit information from hair cells about head position and movement to the CNS, which is critical for maintaining balance, gaze stability and spatial navigation. The CNS, in turn, modulates hair cells and afferents via the efferent vestibular system (EVS) and its activation of several cholinergic signaling mechanisms. Electrical stimulation of EVS neurons gives rise to three kinetically– and mechanistically-distinct afferent responses including a slow excitation, a fast excitation, and a fast inhibition. EVS-mediated slow excitation is attributed to odd-numbered muscarinic acetylcholine receptors (mAChRs) on the afferent whose activation leads to the closure of a potassium conductance and increased afferent discharge. Likely effector candidates include low-threshold, voltage-gated potassium channels belonging to the KCNQ (Kv7.X) family, which are involved in neuronal excitability across the nervous system and are subject to mAChR modulation. Specifically, KCNQ2/3 heteromeric channels may be the molecular correlates for the M-current, a potassium current that is blocked following the activation of odd-numbered mAChRs. To this end, multiple members of the KCNQ channel family, including KCNQ2 and KCNQ3, are localized to several microdomains within vestibular afferent endings, where they influence afferent excitability and could be targeted by EVS neurons. Additionally, the relative expression of KCNQ subunits appears to vary across the sensory epithelia and among different afferent types. However, it is unclear which KCNQ channel subunits are targeted by mAChR activation and whether that also varies among different afferent classes. Here we show that EVS-mediated slow excitation is blocked and enhanced by the non-selective KCNQ channel blocker XE991 and opener retigabine, respectively. Using KCNQ subunit-selective drugs, we observed that a KCNQ2 blocker blocks the slow response in irregular afferents, while a KCNQ2/3 opener enhances slow responses in regular afferents. The KCNQ2 blockers did not appear to affect resting afferent discharge rates, while KCNQ2/3 or KCNQ2/4 openers decreased afferent excitability. Here, we show pharmacological evidence that KCNQ2/3 subunits are likely targeted by mAChR activation in mammalian vestibular afferents. Additionally, we show that KCNQ3 KO mice have altered resting discharge rate as well as EVS-mediated slow response. These data together suggest that KCNQ channels play a role in slow response and discharge rate of vestibular afferents, which can be modulated by EVS in mammals.
Structural Basis of Voltage-Dependent Gating in BK Channels and Its Coupling to the Calcium Sensor

The allosteric communication between pore domain, voltage sensors, and Ca2+ binding sites in the Ca2+-activated K+ channel (BK) shapes its multiple physiological roles as the preeminent signal integrator in excitable systems. BK displays shallow voltage sensitivity with very fast gating charge kinetics, yet little is known about the molecular underpinnings of this distinctive behavior. Here, we explore the mechanistic basis of coupling between voltage-sensing domains (VSDs) and calcium sensors in Aplysia BK by locking the VSDs in their resting (R196Q and R199Q) and activated (R202Q) states, with or without calcium. Cryo-EM structures of these mutants reveal unique tilts at the S4 C-terminal end, together with large side-chain rotameric excursions of the gating charges. Importantly, the VSD resting structure (R202Q) also revealed BK in its elusive fully closed state, highlighting the reciprocal relation between calcium and voltage sensors. These structures provide a plausible mechanism where voltage and Ca2+ binding converge physically and couple energetically to define the conformation of the pore domain and thus, BK’ full functional range.
Geomorphometric Controls on Mountain Glacier Changes Since the Little Ice Age in the Eastern Tien Shan, Central Asia

The linkage between glacier change and climate has garnered significant attention in recent decades, but little is known about the role of local geomorphometric factors on glacier changes since the Little Ice Age (LIA), approximately 100 to 700 years ago. This study examines the spatial pattern of changes in glacier area in the eastern Tien Shan based on geomorphological mapping of LIA glacial extents and contemporary glaciers from the Second Glacier Inventory of China. Partial least squares regression was applied to examine the correlations between geomorphometric factors, including glacier area, slope, aspect, shape, elevation, and hypsometry, and relative glacier area loss, both in the whole area and in three subregions (the Boro-Eren Range, the Bogda Range, and the Karlik Range). Our results show that the area of 640 mapped LIA glaciers decreased from 791.6 ± 18.7 km2 to 483.9 ± 31.2 km2 between 2006 and 2010, a loss of 38.9 ± 2.7 percent. The losses for three subregions are 43.4 ± 3.2 percent, 35.9 ± 2.4 percent, and 30.2 ± 1.8 percent, respectively. Elevation, slope, and area of a glacier are the three most significant geomorphometric factors to glacier area change, at both regional and subregional scales. The west–east decreasing trend of glacier retreat and different variances explained in subregional regressions might reflect the influence from the shifting dominance of the westerlies and the Siberian High.
Northern high latitude climate variability of the last millennium

Northern high latitude climate variability of the last millennium Heather J. Andres Doctor of Philosophy Graduate Department of Physics University of Toronto 2016 This work explores the causes of northern high-latitude climate variations over the last millennium, and industrial and future periods. Attribution studies are performed on a suite of global climate simulations, and four historical reconstructions of Greenland surface temperatures and precipitation (two of which are new to this work). The simulations followed the protocols of the Palaeoclimate Modelling Intercomparison Project 3 and Coupled Model Intercomparison Project 5. At least half of the multi-decadal variability in simulated Greenland climate variations over the last millennium is reproduced by a linear, empirically-generated model including terms for volcanic emissions, solar insolation changes (including total solar irradiance and orbital components) and an index associated with latitudinal shifts in the North Atlantic jet. Empirical model parameters are obtained by regressing simulated Greenland temperatures and precipitation against time series for each of the response variables. Greenhouse gas radiative forcing changes are unimportant to simulated Greenland conditions over the last millennium, although they dominate after the mid-20th century. Most of the historical Greenland climate reconstructions are restricted to the industrial period, due to a lack of spatially-comprehensive climate records. They exhibit substantial differences in the timing, phasing and amplitudes of past climate variations, due to regional sensitivities in the source data and the reconstruction methodologies. Reconstructions indicate that Greenland temperatures did not begin to follow hemispheric greenhouse gas warming patterns until the mid-1990s. This discrepancy indicates either
ASTARTE: Assessment Strategy and Risk Reduction for Tsunamis in Europe

for dissemination) This report focuses on preparedness skills, resources and attitudes within the communities of the ASTARTE test sites. It presents the main results achieved in the Task 9.2 of the WP9. The aim of this task is to assess the preparedness skills, including risk perception and attitudes of the tsunami risk among inhabitants. The risk perception of local stakeholders will be held in the Task 9.3. Based on a single questionnaire for all the test sites, such assessment allowed us: (1) to estimate how people consider the tsunami risk (multi-risk approach), how they are aware of the tsunamis recurrence and sources (links with WP2 and 3), and would people react in the future facing a tsunami threat; (2) estimate the needed level of customization and their modalities for awareness and preparedness material in each studied community; and to (3) provide data for agent-based evacuation modeling (age, reactivity, admissibility of an evacuation, etc.). The results of this report are based on a similar questionnaire which has been translated in 9 different languages. It is divided in 5 topics (see Methods section p. 5). The results of each test site are presented in a 4-pages individual report. These reports have been gathered together for the D9.7 deliverable. A comparative study is in process.
Project Selection and Success: Insights from the Drug Development Process

Effective R&D is essential for innovation and synonymous to choosing the right innovative ideas. Yet, selecting the right R&D projects is challenging because of the uncertainty and complexity inherent in making those selection decisions. We leverage a unique database comprising the drug development pipelines of the Top 15 pharmaceutical companies between 1999-2016 to examine how operational factors—technological uncertainty, competitive development projects, and the presence of project transaction costs—drive the selection decision. We find that firms continuously invest in development projects if they have previously had success in a domain, but that this decision is crucially moderated by the project development choices of their competitors. Early-stage competitive investments decrease the likelihood of the firm selecting to compete in the same domain, whereas late-stage project investments signal high technological feasibility and increase this likelihood. Still, entry into the same domain occurs only when the competitors do not have a large head-start in development. Moreover, the presence of project-level transaction costs manifested in in-licensed compounds makes them less likely to be selected than in-house ones, even though they exhibit above-average rates of success when selected. Finally, we provide evidence on how these selection factors meaningfully contribute to productivity.
Sierra del Colmenar 1A, a new late Messinian (Late Miocene) locality in the Bajo Segura Basin (SE Spain): biostratigraphic and palaeoenvironmental implications

Abstract In this paper, we have studied a new micromammal site from the Sierra del Colmenar section (Elche, SE Spain), named Sierra del Colmenar 1A (SCO-1A), representing the uppermost levels of Messinian age of the Bajo Segura Basin. The sedimentary context of this locality corresponds to a costal lagoon with marine influence. The fossil site has yielded remains of Apodemus aff. gorafensis, Paraethomys meini, Apocricetus alberti, Occitanomys alcalai, Ruscinomys sp. , Eliomys cf. truci, Muscardinus sp. , Parasorex ibericus, Prolagus michauxi and Soricidae indet. Based on this assemblage, we propose a Late Miocene age (MN13) for the locality SCO-1A, matching the previously inferred age for the stratigraphic unit in which the fossil site is situated. According to its faunal composition, we infer warm and humid climate conditions in the moment of formation of this locality, agreeing with the environmental conditions of the Messinian age in a parallic sedimentary context.
Unfolding government policies towards the development of climate smart agriculture in India

The main aim of this paper is to map agricultural policies and programmes, with components of climate smart agriculture, implemented by the Government of India (GoI). Although climate resilience is not the explicit goal of these, our analysis shows that the GoI has been spending 15% of the total expenditure for agriculture towards enhancing resilience on agriculture to climate change. This expenditure has been made through micro-irrigation, watershed development and conservation agriculture under National Food Security Mission (NFSM), National Mission for Sustainable Agriculture (NMSA), National Horticulture Mission (NHM), Rasthrya Krishi Vikas Yojana (RKVY), crop insurance, neem coated urea, and weather advisory systems. Moreover, the government of India is committed to invest Rs 838 billion towards development of climate smart agriculture in the coming five years. We can argue that the increase in public expenditure will also attract significant additional investments from farmers, private sectors and state governments. This large resource commitment by the central and state governments and the farmers of India will have a greater impact on agrarian economy and environment only if there is a greater convergence among different programmes and more farmers’ participation in these.
Facies analysis and depositional model of the Serravallian-age Neurath Sand, Lower Rhine Basin (W Germany)

Abstract The up to 60 m thick Neurath Sand (Serravallian, late middle Miocene) is one of several marine sands in the Lower Rhine Basin which were deposited as a result of North Sea transgressive activity in Cenozoic times. The shallow-marine Neurath Sand is well exposed in the Garzweiler open-cast mine, which is located in the centre of the Lower Rhine Basin. Detailed examination of three sediment profiles extending from the underlying Frimmersdorf Seam via the Neurath Sand and through to the overlying Garzweiler Seam, integrating both sedimentological and palaeontological data, has enabled the depositional setting of the area to be reconstructed. Six subenvironments are recognised in the Neurath Sand, commencing with the upper shoreface (1) sediments characterised by glauconite-rich sands and an extensive biota (Ophiomorpha ichnosp.). These are associated with the silt-rich sands of a transitional subenvironment (2), containing Skolithos linearis, Planolites ichnosp. and Teichichnus ichnosp. These silt-rich sands grade up to the upper shoreface subenvironment (1), which is indicative of an initial regressive trend. The overlying intertidal deposits can be subdivided into a lower breaker zone (3), characterised by ridge-and-runnel systems, and the swash zone (4) where the surge and backwash of waves resulted in the deposition of high-energy laminites. The intertidal deposits were capped by aeolian backshore sediments (5). Extensive root traces present in this latter subenvironment reflect the development of the overlying peatland (i.e. Garzweiler Seam). Within the Garzweiler Seam, restricted sand lenses indicate a lagoonal or estuarine depositional environment (6). Regional correlation with adjacent wells establishes that shallow-marine conditions were widespread across the Lower Rhine Basin in middle Serravallian times. The shoreline profile, characterised by both tidal and wave activity and influenced by fluvial input from the adjacent Rhenish Massif, is indicative of the complexity of the coastal depositional setting within the Lower Rhine Basin.
Projected Significant Increase in the Number of Extreme Extratropical Cyclones in the Southern Hemisphere

AbstractExtratropical cyclones are responsible for much of the extreme weather in the midlatitudes; thus, how these cyclones may change under increasing greenhouse gas forcing is of much general interest. Previous studies have suggested a poleward shift in the location of these cyclones, but how the intensity may change remains uncertain, especially in terms of maximum wind speed. In this study, projected changes in extreme cyclones in the Southern Hemisphere, based on 26 models participating in phase 5 of the Coupled Model Intercomparison Project (CMIP5), are presented. Multiple definitions of extreme cyclones have been examined, including intensity exceeding constant thresholds of sea level pressure perturbations, 850-hPa vorticity, and 850-hPa winds, as well as variable thresholds corresponding to a top-5 or top-1 cyclone per winter month in these three parameters and the near-surface winds. Results presented show that CMIP5 models project a significant increase in the frequency of extreme cyclones in .
Dysbiosis of the larval gut microbiota of Spodoptera frugiperda Strains feeding on different host-plants

The gut microbiota plays important roles in the bioecology of insects, including host plant adaptation and speciation. Spodoptera frugiperda has two well-established host-adapted strains with marked differences at the genetic and host plant utilization levels. We investigated whether differences in the gut microbiota would occur between the “corn” (CS) and “rice” (RS) strains of S. frugiperda when feeding on different crops. The gut microbiota of larvae fed on corn and millet was predominantly represented by Firmicutes followed by Proteobacteria, with an opposite pattern in larvae fed on cotton. No differences were observed between the CS and RS using PERMANOVA. PCoA analyses resulted in distinct bacterial clusters based on the host plant. Comparisons of strains gut microbiota at the phylum level resulted in differences only for larvae fed on cotton, but differences in the relative abundance of minor representatives at the genus level between strains were observed regardless of the food source used. We also found differences in the potential functional contribution of bacteria between the strains. In conclusion the gut microbiota of S. frugiperda is strongly modulated by the host plant while strains seemed to play a minor role in changing the abundance of members of the gut bacterial community.
Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers

Cell fate in response to an aberrant mitosis is governed by two competing networks: the spindle assembly checkpoint (SAC) and the intrinsic apoptosis pathway. The mechanistic interplay between these two networks is obscured by functional redundancy and the ability of cells to die either in mitosis or in the subsequent interphase. By coupling time-lapse microscopy with selective pharmacological agents, we systematically probe pro-survival Bcl-xL in response to various mitotic perturbations. Concentration matrices show that BH3-mimetic-mediated inhibition of Bcl-xL synergises with perturbations that induce an SAC-mediated mitotic block, including drugs that dampen microtubule dynamics, and inhibitors targeting kinesins and kinases required for spindle assembly. By contrast, Bcl-xL inhibition does not synergize with drugs which drive cells through an aberrant mitosis by overriding the SAC. This differential effect, which is explained by compensatory Mcl-1 function, provides opportunities for patient stratification and combination treatments in the context of cancer chemotherapy.