Miracle-dz/UniFAR-FTUs huggingface dataset:
Fixational eye movements depend on task and target

Human fixational eye movements are so small and precise that they require high-speed, accurate tools to fully reveal their properties and functional roles. Where the fixated image lands on the retina and how it moves for different levels of visually demanding tasks is the subject of the current study. An Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) was used to image, track and present Maltese cross, disk, concentric circles, Vernier and tumbling-E letter fixation targets to healthy subjects. During these different passive (static) or active (discriminating) fixation tasks under natural eye motion, the landing position of the target on the retina was tracked in space and time over the retinal image directly. We computed both the eye motion and the exact trajectory of the fixated target’s motion over the retina. We confirmed that compared to passive fixation, active tasks elicited a partial inhibition of microsaccades, leading to longer drifts periods compensated by larger corrective saccades. Consequently the fixation stability during active tasks was larger overall than during passive tasks. The preferred retinal locus of fixation was the same for each task and did not coincide with the location of the peak cone density.
Analyzing Brain Morphology in Alzheimer’s Disease Using Discriminative and Generative Spiral Networks

Several patterns of atrophy have been identified and strongly related to Alzheimer’s disease (AD) pathology and its progression. Morphological changes in brain shape have been identified up to ten years before clinical diagnoses of AD, making its early detection more relevant. We propose novel geometric deep learning frameworks for the analysis of brain shape in the context of neurodegeneration caused by AD. Our deep neural networks learn low-dimensional shape descriptors of multiple neuroanatomical structures, instead of handcrafted features for each structure. A discriminative network using spiral convolution on 3D meshes is constructed for the in-vivo binary classification of AD from healthy controls (HCs) using a fast and efficient “spiral” convolution operator on 3D triangular mesh surfaces of human brain subcortical structures extracted from T1-weighted magnetic resonance imaging (MRI). Our network architecture consists of modular learning blocks using residual connections to improve overall classifier performance. In this work: (1) a discriminative network is used to analyze the efficacy of disease classification using input data from multiple brain structures and compared to using a single hemisphere or a single structure. It also outperforms prior work using spectral graph convolution on the same the same tasks, as well as alternative methods that operate on intermediate point cloud representations of 3D shapes. (2) Additionally, visual interpretations for regions on the surface of brain structures that are associated to true positive AD predictions are generated and fall in accordance with the current reports on the structural localization of pathological changes associated to AD. (3) A conditional generative network is also implemented to analyze the effects of phenotypic priors given to the model (i.e. AD diagnosis) in generating subcortical structures. The generated surface meshes by our model indicate learned morphological differences in the presence of AD that agrees with the current literature on patterns of atrophy associated to the disease. In particular, our inference results demonstrate an overall reduction in subcortical mesh volume and surface area in the presence of AD, especially in the hippocampus. The low-dimensional shape descriptors obtained by our generative model are also evaluated in our discriminative baseline comparisons versus our discriminative network and the alternative shape-based approaches.
Clinical efficacy of prebiotics and glycosaminoglycans versus placebo In dogs with food responsive enteropathy receiving a hydrolyzed diet: A pilot study

Induction of remission is easily achieved with dietary treatment in dogs diagnosed with Food Responsive Chronic Enteropathy (FRD). Administration of prebiotics and glycosaminoglycans (GAGs) may improve epithelial cell integrity and therefore be useful as adjunct treatment. This study evaluated whether the relapse rate of FRD dogs that are switched back to a normal diet can be influenced using supplemental treatment with prebiotics and GAGs. A randomized, controlled clinical trial (RCCT) was performed in dogs diagnosed with FRD. Dogs were diagnosed based on clinical exclusion diagnosis, endoscopic biopsies showing predominantly lymphoplasmacytic infiltration, and response to dietary treatment. Dogs were randomized to be fed a combination of prebiotics and GAGs (group 1) or placebo (group 2) in addition to a hydrolyzed diet. At week 10, a second endoscopy was performed and dogs were switched back to normal diet. Relapse rate was monitored every 2 weeks after that until week 18. Statistical analysis was performed for each outcome (Canine Chronic Enteropathy Clinical Activity Index (CCECAI), clinicopathological data, endoscopic scoring, mWSAVA histological scoring index (mWSAVA), and number of relapses following switch to normal diet) using a linear mixed effects model for group comparison. Time, group, and their interactions were included as a fixed effect, whereas each dog was treated as a random effect. Of the 35 dogs enrolled into the clinical trial, 10 in each group reached the point of second endoscopy. A total of 13 dogs (n=8 in group 1 and n=5 in group 2) reached the trial endpoint of 18 weeks. After switching back to normal diet, none of the dogs in either group relapsed. No significant differences were found over time or between groups for CCECAI, endoscopy scoring and histological scoring. Although there was a clinical worsening in the placebo group after switching back to the original diet, this was not statistically significant (CCECAI p=0.58). Post-hoc power calculation revealed that 63 dogs per group would have been needed to detect statistically significant differences in CIBDAI between treatment groups. Standard dietary treatment induced rapid clinical response in all cases, however, additional supplementation with prebiotics and GAGs did not significantly improve clinical outcome within 4 months after switching back to normal diet. Since there are very few RCCT published in CE in dogs, this pilot study provides important power analyses for planning of further studies.
The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

Transcription is essential for cells to respond to signaling cues and involves factors with multiple distinct activities. One such factor, TRRAP, functions as part of two large complexes, SAGA and TIP60, which have crucial roles during transcription activation. Structurally, TRRAP belongs to the PIKK family but is the only member classified as a pseudokinase. Recent studies established that a dedicated HSP90 co-chaperone, the TTT complex, is essential for PIKK stabilization and activity. Here, using endogenous auxin- inducible degron alleles, we show that the TTT subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 in human colorectal cancer cells (CRC). Transcriptomic analysis revealed that TELO2 contributes to TRRAP regulatory roles in CRC cells, most notably of MYC target genes. Surprisingly, TELO2 and TRRAP depletion also induced the expression of type I interferon genes. Using a combination of nascent RNA, antibody-targeted chromatin profiling (CUT&RUN) and kinetic analyses, we show that TRRAP directly represses the expression of IRF9, which is a master regulator of interferon stimulated genes. We have therefore uncovered a new, unexpected transcriptional repressor role for TRRAP, which may contribute to its tumorigenic activity.
GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, but not in Female Mice

Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freund’s Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not reduce thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hyper-sensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the periaqueductal gray. Treatment with MS15203 then rescued the protein levels of GPR171 in the periaqueductal gray of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.
Sleep Modulates Alcohol Toxicity in Drosophila

Study Objectives Alcohol abuse is a significant public health problem, particularly in populations in which sleep deprivation is common as such as shift workers and aged individuals. Although research demonstrates the effect of alcohol on sleep, little is known about the role of sleep in alcohol sensitivity and toxicity. We investigated sleep as a factor modulating alcohol toxicity using Drosophila melanogaster, a model system ideal for studies of sleep, alcohol and aging. Methods Following 24 hours of sleep deprivation using mechanical stimulation, Drosophila were exposed to binge-like alcohol exposures. Behavioral sensitivity, tolerance, and mortality were assessed. The effects of chronic sleep deprivation on alcohol toxicity were investigated using a short sleep mutant insomniac. Pharmacological induction of sleep for prior to alcohol exposure was accomplished using a GABAA-receptor agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) to determine if increased sleep mitigated the effects of alcohol toxicity on middle-aged flies and flies with environmentally disrupted circadian clocks mimicking groups more vulnerable to the effects of alcohol. Results Acute sleep deprivation increased alcohol-induced mortality following alcohol exposure. However, sleep deprivation had no effect on alcohol absorbance or clearance. Sleep deprivation also abolished functional tolerance measured 24 hours after the initial alcohol exposure, although tolerance at 4 h was observed. Pharmacologically increasing sleep prior to alcohol exposure decreased alcohol-induced mortality. Conclusions Sleep quantity prior to alcohol exposure affects alcohol toxicity with decreased sleep increasing alcohol toxicity and dampened 24-hour alcohol tolerance. In contrast, increased sleep mitigated alcohol-induced mortality even in vulnerable groups such as aging flies and those with circadian dysfunction. Statement of significance With the growing incidence of sleep deprivation and sleep disorders across adolescents and adults, it is important to understand the role of sleep in alcohol toxicity to develop future therapies for prevention and treatment of alcohol-induced pathologies. Using Drosophila melanogaster, an established model for both sleep and alcohol research, we found that acute and chronic sleep deprivation increased alcohol toxicity and eliminated long-term functional alcohol tolerance. In contrast, increased sleep prior to binge-like alcohol exposure mitigated alcohol-induced mortality even in vulnerable groups with higher susceptibility to alcohol toxicity.
Changes in regional white matter volumetry and microstructure during the post-adolescence period: a cross-sectional study of a cohort of 1,713 university students

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilised to study white matter changes during development and ageing. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18 to 26. We assessed the age and sex dependence, as well as hemispheric asymmetry of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterised by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. We also report a robust hemispheric asymmetry in both the volume and microstructural properties in many regions. These findings emphasise the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.
Longitudinal characterization of neuroanatomical changes in the Fischer 344 rat brain during normal aging and between sexes

Animal models are widely used to study the pathophysiology of disease and to evaluate the efficacy of novel interventions, crucial steps towards improving disease outcomes in humans. The Fischer 344 (F344) wildtype rat is a common experimental background strain for transgenic models of disease and is also one of the most frequently used models in aging research. Despite frequency of use, characterization of neuroanatomical change with age has not been performed in the F344 rat. To this end, we present a comprehensive longitudinal examination of morphometric change in 73 brain regions and at a voxel-wise level during normative aging in a mixed-sex cohort of F344 rats. We identified age- and sex-related changes in regions such as the cortex, hippocampus, cingulum, caudoputamen, and nucleus accumbens, which are implicated in memory and motor control circuits frequently affected by aging and neurodegenerative disease. These findings provide a baseline for neuroanatomical changes associated with aging in male and female F344 rats, to which data from transgenic models or other background strains can be compared. HIGHLIGHTS In vivo magnetic resonance imaging reveals altered neuroanatomy in aging Fischer rats Linear and curvilinear age effects exist in both grey and white matter structures Sex differences are primarily seen in grey matter structures This study clarifies normal aging trajectories across 73 brain regions in both sexes Improved understanding of normal aging will inform future pathological aging studies
The neural bases of program comprehension: a coordinate-based fMRI meta-analysis

The understanding of brain activity during program comprehension have advanced thanks to noninvasive neuroimaging techniques, such as functional magnetic resonance imaging (fMRI). However, individual neuroimaging studies of program comprehension often provided inconsistent results and made it difficult to identify the neural bases. To identify the essential brain regions, this study performed a small meta-analysis on recent fMRI studies of program comprehension using multilevel kernel density analysis (MKDA). Our analysis identified a set of brain regions consistently activated in various program comprehension tasks. These regions consisted of three clusters, each of which centered at the left inferior frontal gyrus pars triangularis (IFG Tri), posterior part of middle temporal gyrus (pMTG), and right middle frontal gyrus (MFG). Additionally, subsequent analyses revealed relationships among the activation patterns in the previous studies and multiple cognitive functions. These findings suggest that program comprehension mainly recycles the language-related networks and partially employs other domain-general resources in the human brain.
Towards a causal role of Broca’s area in language: A TMS-EEG study on syntactic prediction

Categorical predictions have been proposed as the key mechanism supporting the fast pace of syntactic composition in human language. Accordingly, grammar-based expectations facilitate the analysis of incoming syntactic information—e.g., hearing the determiner “the” enhances the prediction of a noun—which is then checked against a single or few other word categories. Previous functional neuroimaging studies point towards Broca’s area in the left inferior frontal gyrus (IFG) as one fundamental cortical region involved in categorical prediction during on-line language processing. Causal evidence for this hypothesis is however still missing. In this study, we combined Electroencephalography (EEG) and Transcranial Magnetic Stimulation (TMS) to test whether Broca’s area is functionally relevant in predictive mechanisms for language. Specifically, we transiently perturbed Broca’s area during the categorical prediction phase in two-word constructions, while simultaneously measuring the Event-Related Potential (ERP) correlates of syntactic composition. We reasoned that if Broca’s area is involved in predictive mechanisms for syntax, disruptive TMS during the processing of the first word (determiner/pronoun) would mitigate the difference in ERP responses for predicted and unpredicted categories when composing basic phrases and sentences. Contrary to our hypothesis, perturbation of Broca’s area at the predictive stage did not affect the ERP correlates of basic composition. The correlation strength between the electrical field induced by TMS and the magnitude of the EEG response on the scalp further confirmed this pattern. We discuss the present results in light of an alternative account of the role of Broca’s area in syntactic composition, namely the bottom-up integration of words into constituents.
Viral neuroinvasion and neurotropism without neuronal damage in the hACE2 mouse model of COVID-19

Coronavirus disease 2019 (COVID-19) is a primarily respiratory disease with variable clinical courses for which animal models are needed to gather insights into the pathogenesis of its causative virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), in human patients. SARS-CoV-2 not only affects the respiratory tract but also the central nervous system (CNS), leading to neurological symptoms such as loss of smell and taste, headache, fatigue or severe complications like cerebrovascular diseases. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a well-known model of SARS-CoV-2 infection. In the present study, it served to investigate the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with relatively low SARS-CoV-2 doses and after prior influenza A virus infection.In K18-hACE2 mice, SARS-CoV-2 was found to frequently spread to and within the CNS during the later phase (day 7) of infection. Infection was restricted to neurons and appeared to first affect the olfactory bulb and spread from there mainly in basally orientated regions in the brain and into the spinal cord, in a dose dependent manner and independent of ACE2 expression. Neuronal infection was not associated with cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed. This was accompanied by apoptotic death of endothelial, microglial and immune cells, without evidence of viral infection of glial cells, endothelial cells and leukocytes.Taken together, microgliosis and immune cell apoptosis indicate a potential important role of microglial cells for the pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.
Pore dynamics and asymmetric cargo loading in an encapsulin nanocompartment

Encapsulins are protein nanocompartments that house various cargo enzymes, including a family of decameric ferritin-like proteins. Here, we study a recombinant Haliangium ochraceum encapsulin:encapsulated ferritin complex using electron cryo-microscopy and hydrogen/deuterium exchange mass spectrometry to gain insight into the structural relationship between the encapsulin shell and its protein cargo. An asymmetric single particle reconstruction reveals four encapsulated ferritin decamers in a tetrahedral arrangement within the encapsulin nanocompartment. This leads to a symmetry mismatch between the protein cargo and the icosahedral encapsulin shell. The encapsulated ferritin decamers are offset from the interior face of the encapsulin shell. Using HDX-MS, we observed dynamic behavior of the major five-fold pore in the encapsulin shell and show the pore opening via the movement of the encapsulin A-domain. These data will accelerate efforts to engineer the encapsulation of heterologous cargo proteins and to alter the permeability of the encapsulin shell via pore modifications. Teaser Cryo-EM and HDX-MS analysis of an encapsulin nanocompartment shows that the pores at the five-fold icosahedral vertex of the shell are flexible.