Miracle-dz/UniFAR-FTUs huggingface dataset:
Recurrent circuits amplify corticofugal signals and drive feedforward inhibition in the inferior colliculus

The inferior colliculus (IC) is a midbrain hub critical for perceiving complex sounds such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies imply that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons. Corticofugal inhibition of the IC may thus occur largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology in acute IC slices from fluorescent reporter mice of either sex. Using optogenetic stimulation of corticofugal axons, we find that excitation evoked with single light flashes is indeed stronger in presumptive glutamatergic neurons compared to GABAergic neurons. However, many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. Furthermore, a subset of glutamatergic IC neurons fire spikes during repetitive corticofugal activity, leading to polysynaptic excitation in IC GABA neurons owing to a dense intra-collicular connectivity. Consequently, recurrent excitation amplifies corticofugal activity, drives spikes in IC GABA neurons, and generates substantial local inhibition in the IC. Thus, descending signals engage intra-collicular inhibitory circuits despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons. Significance Statement Descending “corticofugal” projections are ubiquitous across mammalian sensory systems, and enable the neocortex to control subcortical activity in a predictive or feedback manner. Although corticofugal neurons are glutamatergic, neocortical activity often inhibits subcortical neuron spiking. How does an excitatory pathway generate inhibition? Here we study the corticofugal pathway from auditory cortex to inferior colliculus (IC), a midbrain hub important for complex sound perception. Surprisingly, cortico-collicular transmission was stronger onto IC glutamatergic compared to GABAergic neurons. However, corticofugal activity triggered spikes in IC glutamate neurons with local axons, thereby generating strong polysynaptic excitation and feed-forward spiking of GABAergic neurons. Our results thus reveal a novel mechanism that recruits local inhibition despite limited monosynaptic convergence onto inhibitory networks.
Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant Staphylococcus aureus to Human Group IIA-Secreted Phospholipase A2 and Daptomycin

Methicillin-resistant Staphylococcus aureus (MRSA) has been classified as a high priority pathogen by the World Health Organization underlining the high demand for new therapeutics to treat infections. Human group IIA secreted phospholipase A2 (hGIIA) is among the most potent bactericidal proteins against Gram-positive bacteria, including S. aureus. To determine hGIIA-resistance mechanisms of MRSA we screened the Nebraska Transposon Mutant Library using a sublethal concentration of recombinant hGIIA. We identified and confirmed the role of lspA, encoding the lipoprotein signal peptidase LspA, as a new hGIIA resistance gene in both in vitro assays and an infection model in hGIIA-transgenic mice. Increased susceptibility of the lspA mutant was associated with faster and increased cell wall penetration of hGIIA. Moreover, lspA deletion also increased susceptibility to daptomycin, a last-resort antibiotic to treat MRSA infections. Exposure of MRSA wild-type to the LspA-specific inhibitors globomycin and myxovirescin A1 induced a lspA mutant phenotype with regard to hGIIA and daptomycin killing. Analysis of >26,000 S. aureus genomes showed that LspA is highly sequence-conserved, suggesting that LspA inhibition could be applied universally. The role of LspA in hGIIA resistance was not restricted to MRSA since Streptococcus mutans and Enterococcus faecalis were also more hGIIA-susceptible after lspA deletion or LspA inhibition, respectively. Overall, our data suggest that pharmacological blocking of LspA may disarm Gram-positive pathogens, including MRSA, to enhance clearance by innate host defense molecules and clinically-applied antibiotics.
Large-scale biophysically detailed model of somatosensory thalamocortical circuits in NetPyNE

The primary somatosensory cortex (S1) of mammals is critically important in the perception of touch and related sensorimotor behaviors. In 2015, the Blue Brain Project developed a groundbreaking rat S1 microcircuit simulation with over 31,000 neurons with 207 morpho-electrical neuron types, and 37 million synapses, incorporating anatomical and physiological information from a wide range of experimental studies. We have implemented this highly-detailed and complex S1 model in NetPyNE, using the data available in the Neocortical Microcircuit Collaboration Portal. NetPyNE provides a Python high-level interface to NEURON and allows defining complicated multiscale models using an intuitive declarative standardized language. It also facilitates running parallel simulations, automates the optimization and exploration of parameters using supercomputers, and provides a wide range of built-in analysis functions. This will make the S1 model more accessible and simpler to scale, modify and extend in order to explore research questions or interconnect to other existing models. Despite some implementation differences, the NetPyNE model preserved the original cell morphologies, electrophysiological responses and spatial distribution for all 207 cell types; and the connectivity properties of all 1941 pathways, including synaptic dynamics and short-term plasticity (STP). The NetPyNE S1 simulations produced reasonable physiological firing rates and activity patterns across all populations. The network generated a 1 Hz oscillation comparable to the original model in vitro-like state. By then reducing the extracellular calcium concentration, the model reproduced the original S1 in vivo-like states with asynchronous activity. These results validate the original study using a new modeling tool. Simulated local field potentials (LFPs) exhibited realistic oscillatory patterns and features, including distance- and frequency-dependent attenuation. The model was extended by adding thalamic circuits, including 6 distinct thalamic populations with intrathalamic, thalamocortical and corticothalamic connectivity derived from experimental data. The thalamic model reproduced single known cell and circuit-level dynamics, including burst and tonic firing modes and oscillatory patterns, providing a more realistic input to cortex and enabling study of thalamocortical interactions. Overall, our work provides a widely accessible, data-driven and biophysically-detailed model of the somatosensory thalamocortical circuits that can be employed as a community tool for researchers to study neural dynamics, function and disease.
Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression

Epithelial-Mesenchymal Transition (EMT) and immunoevasion through upregulation of Programmed Death-Ligand 1 (PD-L1) are important drivers of cancer progression. While EMT has been proposed to facilitate PD-L1-mediated immunosuppression, the molecular mechanisms of their interaction remain obscure. Here we provide insight into these mechanisms by proposing a mathematical model that describes the crosstalk between EMT and Interferon gamma (IFNγ)-induced PD-L1 expression. Our model shows that via interaction with microRNA-200 (miR-200), the multistability of the EMT regulatory circuit is mirrored in the PD-L1 levels, which are further amplified by IFNγ stimulation. This IFNγ-mediated effect is most prominent for cells in a fully mesenchymal state, and less strong for those in an epithelial or partially mesenchymal state. Additionally, bi-directional crosstalk between miR-200 and PD-L1 implies that IFNγ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and that IFNγ presence accelerates EMT and decelerates Mesenchymal-Epithelial Transition (MET). Overall, our model agrees with published findings and provides insight into possible mechanisms behind EMT-mediated immune-evasion; and primary, adaptive, or acquired resistance to immunotherapy. Our model can be used as a starting point to explore additional crosstalk mechanisms, as an improved understanding of these mechanisms is indispensable for developing better diagnostic and therapeutic options for cancer patients. Graphical Abstract Schematic overview of the crosstalk between Epithelial-Mesenchymal Transition (EMT) and Interferon gamma (IFNγ)-induced Programmed Death-Ligand 1 (PD-L1) expression. IFNγ-induced PD-L1 expression promotes the occurrence of EMT. EMT, also induced by, for example, Transforming Growth Factor Beta (TGFβ), increases PD-L1 expression levels, facilitating tumor immunoevasion.
A year in the life of the Eastern Mediterranean: Monthly dynamics of phytoplankton and bacterioplankton in an ultra-oligotrophic sea

The Eastern Mediterranean Sea (EMS) is a poorly studied ultra-oligotrophic marine environment, dominated by small-size phyto- and bacterioplankton. Here, we describe the dynamics of a single annual cycle (2018-19) of phyto- and bacterioplankton (abundances, pigments and productivity) in relation to the physical and chemical conditions in the photic water column at an offshore EMS site (Station THEMO-2, ∼1,500m depth, 50km offshore). We show that phytoplankton biomass (as chlorophyll a), primary and bacterial productivity differed between the mixed winter (January-April) and the thermally stratified (May-December) periods. Prochlorococcus and Synechococcus numerically dominated the picophytoplankton populations, with each clade revealing different temporal and depth changes indicative to them, while pico-eukaryotes (primarily haptophytes) were less abundant, yet likely contributed significant biomass. Estimated primary productivity (∼32 gC m-2 y-1) was lower compared with other well-studied oligotrophic locations, including the north Atlantic and Pacific (BATS and HOT observatories), the western Mediterranean (DYFAMED observatory) and the Red Sea, and was on-par with the ultra-oligotrophic South Pacific Gyre. In contrast, integrated bacterial production (∼11 gC m-2 y-1) was similar to other oligotrophic locations. Phytoplankton seasonal dynamics were similar to those at BATS and the Red Sea, suggesting an observable effect of winter mixing in this ultra-oligotrophic location. These results highlight the ultra-oligotrophic conditions in the EMS and provide, for the first time in this region, a full-year baseline and context to ocean observatories in the region. Highlights Bacterioplankton dynamics were assessed monthly in the Eastern Mediterranean Sea Small-sized picophytoplankton numerically dominated the phytoplankton community Seasonal phytoplankton dynamics are similar to BATS and Red Sea, but not to HOT Annual primary productivity is among the lowest in the world’s oceans Bacterial to primary production ratio is higher than most oligotrophic seas
The distribution of /w/ and /ʍ/ in Scottish Standard English

Abstract The Scottish English phoneme inventory is generally claimed to have a /ʍ/-/w/ contrast, although several studies have suggested that this historical contrast is weakening for Scottish English speakers in the urban areas of Glasgow, Edinburgh and Aberdeen. Little is known about whether the /ʍ/-/w/ contrast is maintained in supraregional Scottish Standard English (SSE). This study sets out to explore, based on the phonemically transcribed ICE-Scotland corpus, the distribution of [ʍ] and [w] in SSE, their acoustic properties and potentially influencing social and language-internal factors. A total of 1,241 tokens were extracted from the corpus, together with a matching number of tokens, and the median of harmonicity was measured. The results show that [ʍ] and [w] produced for words beginning with are acoustically distinct from [w] produced for words beginning with . [ʍ] is relatively frequent in SSE, but most speakers use both [ʍ] and [w] interchangeably for and some never use [ʍ]. The realisation of as [ʍ] is determined by preceding phonetic context and speaker gender.
DETERMINING THE WORKING CONDITIONS OF HEAT PUMP COMPONENTS ACCORDING TO RUNNING MODES

In this study a detailed exergetic analysis is made of the components of heat pumps by changing the heat source and heat sink fluid as either water or air. To realize this aim a multifunctional heat pump test system was used, which can be run in four modes, air to air, air to water, water to air and water to water, using one compressor. When the system is run in water to air mode compressor exergy efficiency reaches its highest value. When the system is run in air to water mode the exergy efficiency of the compressor falls to its lowest value. In the heat pump’s water to air mode the exergy destruction rate of the compressor becomes minimal. Exergetic performance of the condenser is best when the system is run in water to air mode. When the system runs in air to air mode, the exergy destruction rate of the condenser is at maximum, and falls to minimum when the system runs in air to water mode. Water to water is the running mode in which evaporator exergy efficiency is the best. Exergy efficiency of the evaporator decreases when the temperature of the evaporator fluid increases. Maximum compressor exergy efficiency increases according to an increase of mass flow rate is seemed in the air to air mode. The heat pump mode in which the exergy destruction rate of the compressor is minimal, is water to air mode. The running modes in which the condenser and compressor work with maximum and minimum efficiency are the same: water to air, and air to water modes. The compressor is the component which has maximum exergy efficiency with an average of 61.04% for all tests. Exergy efficiency of the condenser is lowest for all tests with an average of 14.25%
Improving Road Surface Area Extraction via Semantic Segmentation with Conditional Generative Learning for Deep Inpainting Operations

The road surface area extraction task is generally carried out via semantic segmentation over remotely-sensed imagery. However, this supervised learning task is often costly as it requires remote sensing images labelled at the pixel level, and the results are not always satisfactory (presence of discontinuities, overlooked connection points, or isolated road segments). On the other hand, unsupervised learning does not require labelled data and can be employed for post-processing the geometries of geospatial objects extracted via semantic segmentation. In this work, we implement a conditional Generative Adversarial Network to reconstruct road geometries via deep inpainting procedures on a new dataset containing unlabelled road samples from challenging areas present in official cartographic support from Spain. The goal is to improve the initial road representations obtained with semantic segmentation models via generative learning. The performance of the model was evaluated on unseen data by conducting a metrical comparison where a maximum Intersection over Union (IoU) score improvement of 1.3% was observed when compared to the initial semantic segmentation result. Next, we evaluated the appropriateness of applying unsupervised generative learning using a qualitative perceptual validation to identify the strengths and weaknesses of the proposed method in very complex scenarios and gain a better intuition of the model’s behaviour when performing large-scale post-processing with generative learning and deep inpainting procedures and observed important improvements in the generated data.
Longer Nap Duration During Ramadan Observance Positively Impacts 5-m Shuttle Run Test Performance Performed in the Afternoon

It is well-documented that changes in the rhythm of life during Ramadan affect sleep schedules (i.e., interruption of night sleep patterns) and are likely to have negative effects on physical and cognitive performances. The aim of the present study was to examine the effect of different naps opportunities’ durations during Ramadan on performance of short-duration repetitive maximal exercise and perception of effort. Fifteen physically active men (age: 21 ± 3 years, height: 177 ± 6 cm, body-mass: 73 ± 10 kg) performed a 6 × 30-s shuttle run test after a 25-min nap (N25), a 45-min nap (N45), and in a no-nap condition (NN) during three experimental periods: ∼2 weeks before Ramadan (BR), the last ten days of Ramadan (ER), and ∼3 weeks after Ramadan (AR). During the shuttle run test performed in the late afternoon, the greatest distance (GD), the total distance (TD) and a fatigue index (FI) were assessed. Rating of perceived exertion (RPE) was determined after each 30-s effort. Dietary intake and sleep quality were assessed in each of the three periods. Compared to BR, GD and TD were lower in the ER testing period (p = 0.005; d = 0.54) but returned to BR levels in the AR period. During ER, carbohydrate intake was lower (p = 0.04; d = 0.2), and sleep duration and sleep quality were reduced (d = 0.27 and 0.54, respectively), although other aspects of dietary intake and sleep pattern were not affected. Compared to NN, GD and TD were higher after N25 (d = 0.57 and 0.34, respectively) and N45 (d = 0.93 and 0.88 respectively). RPE was lower in N45 (p = 0.035, d = 0.84). N45 resulted in higher TD (p = 0.021, d = 0.13) and lower RPE (p = 0.004; d = 0.57) compared to N25 during ER. Taking a daytime nap benefits subsequent performance in a shuttle run test, whether sleep the previous night was normal (as in BR) or compromised (as in ER). The benefits of napping were greater after a 45-min nap opportunity than after a 25-min nap opportunity.
“Tricking the Brain” Using Immersive Virtual Reality: Modifying the Self-Perception Over Embodied Avatar Influences Motor Cortical Excitability and Action Initiation

To offer engaging neurorehabilitation training to neurologic patients, motor tasks are often visualized in virtual reality (VR). Recently introduced head-mounted displays (HMDs) allow to realistically mimic the body of the user from a first-person perspective (i.e., avatar) in a highly immersive VR environment. In this immersive environment, users may embody avatars with different body characteristics. Importantly, body characteristics impact how people perform actions. Therefore, alternating body perceptions using immersive VR may be a powerful tool to promote motor activity in neurologic patients. However, the ability of the brain to adapt motor commands based on a perceived modified reality has not yet been fully explored. To fill this gap, we “tricked the brain” using immersive VR and investigated if multisensory feedback modulating the physical properties of an embodied avatar influences motor brain networks and control. Ten healthy participants were immersed in a virtual environment using an HMD, where they saw an avatar from first-person perspective. We slowly transformed the surface of the avatar (i.e., the “skin material”) from human to stone. We enforced this visual change by repetitively touching the real arm of the participant and the arm of the avatar with a (virtual) hammer, while progressively replacing the sound of the hammer against skin with stone hitting sound via loudspeaker. We applied single-pulse transcranial magnetic simulation (TMS) to evaluate changes in motor cortical excitability associated with the illusion. Further, to investigate if the “stone illusion” affected motor control, participants performed a reaching task with the human and stone avatar. Questionnaires assessed the subjectively reported strength of embodiment and illusion. Our results show that participants experienced the “stone arm illusion. ” Particularly, they rated their arm as heavier, colder, stiffer, and more insensitive when immersed with the stone than human avatar, without the illusion affecting their experienced feeling of body ownership. Further, the reported illusion strength was associated with enhanced motor cortical excitability and faster movement initiations, indicating that participants may have physically mirrored and compensated for the embodied body characteristics of the stone avatar. Together, immersive VR has the potential to influence motor brain networks by subtly modifying the perception of reality, opening new perspectives for the motor recovery of patients.
Additional Use of Prostacyclin Analogs in Patients With Pulmonary Arterial Hypertension: A Meta-Analysis

Background: Combination therapy has become an attractive option in pulmonary arterial hypertension (PAH) treatment. The aim of this study was to investigate whether additional use of prostacyclin analogs could exert any additional benefits over background targeted therapies in PAH patients. Methods: Searches were performed on PubMed, Embase, and ClinicalTrials.gov from inception to 1 October 2021. Randomized controlled trials were included if patients had been treated with prostacyclin analog-containing combination therapy and compared with the use of other PAH-specific background therapies. The bias risk and statistical analysis of the enrolled studies were performed with RevMan 5.1. Sensitivity analysis and funnel plot were used to evaluate the stability and publication bias, respectively. PROSPERO registered number CRD42021284196. Results: Ten trials involving 1828 patients were included. Prostacyclin analog treatment was associated with greater improvement in clinical worsening (risk ratio [RR], 0.70; 95% confidence interval [CI], 0.57–0.86), 6-min walk distance (mean difference [MD], 37.17 m; 95% CI, 3.01–71.33 m), NYHA/WHO functional class (RR, 1.58; 95% CI, 1.21–2.05), mean pulmonary artery pressure (MD, −9.23 mmHg; 95% CI, −17.44 to −1.03 mmHg), and cardiac index (MD, 0.41 L/min/m2; 95% CI, 0.26–0.55 L/min/m2) than the control group. No significant differences in pulmonary vascular resistance (MD, −137.22 dyn·s/cm5; 95% CI, −272.61 to −1.84 dyn·s/cm5) and all-cause mortality (RR, 0.96; 95% CI, 0.57–1.61) were found between the prostacyclin analog group and control group. Of note, more adverse events (RR, 1.07; 95% CI, 1.02–1.13) occurred in the prostacyclin analog group but no significant increase in serious adverse events (RR, 1.25; 95% CI, 0.75–2.11). Conclusion: Additional prostacyclin analog treatment exerted benefits on clinical worsening, exercise capacity, functional class, mean pulmonary artery pressure, and cardiac index in PAH patients, but it was associated with overall risk of adverse events. Clinical Trial Registration: https://www.crd. york.ac. uk/prospero/display_record. php? ID=CRD42021284196, identifier CRD42021284196.