Miracle-dz/UniFAR-FTUs huggingface dataset:
An Approach to Automatically Label & Order Brain Activity/Component Maps

Functional magnetic resonance imaging (fMRI) is a brain imaging technique which provides detailed in-sights into brain function and its disruption in various brain disorders. fMRI data can be analyzed using data-driven or region-of-interest based methods. The data-driven analysis of brain activity maps involves several steps, the first of which is identifying whether the maps capture what might be interpreted as intrinsic connectivity networks (ICNs) or artifacts. This is followed by linking the ICNs to known anatomical and/or functional parcellations. Optionally, as in the study of functional network connectivity (FNC), rearranging the connectivity graph is also necessary for systematic interpretation. Here we present a toolbox that automates all these processes under minimal or no supervision with high accuracy. We provide a pretrained cross-validated elastic-net regularized general linear model for the noisecloud toolbox to separate the ICNs from artifacts. We include several well-known anatomical and functional parcellations from which researchers can choose to label the activity maps. Finally, we integrate a method for maximizing the within-domain modularity to generate a more systematically structured FNC matrix. We improve upon and integrate existing techniques and new methods to design this toolbox which can take care of all the above needs. Specifically, we show that our pretrained model achieves 89% accuracy and 100% precision at classifying ICNs from artifacts in a validation dataset. Researchers are generating brain imaging data and analyzing brain activity at an ever-increasing rate. The Autolabeller toolbox can help automate such analyses for faster and reproducible research.
Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PLpro and Mpro in in vitro studies

Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage - a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and anti-viral assays. In this study, we screened a collection of 23 ebselen derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Our work shows that ebselen constitutes a promising platform for development of new antiviral agents targeting both SARS-CoV-2 PLpro and Mpro.
Emergence of Lyme disease on treeless islands in Scotland, UK

Lyme disease (LD) is typically associated with forested habitats but has recently emerged on treeless islands in the Western Isles of Scotland. This has created a need to understand the environmental and human components of LD risk in open habitats. This study quantified both elements of LD risk and compared these between treeless islands with high and low LD incidence. We found high LD incidence was linked to higher prevalence in ticks (6.4% vs 0.4%) and increased human tick bite exposure. Most reported tick bites (72.7%) were within 1km of the home address and commonly in gardens. Residents on islands with high LD incidence reported increasing problems with ticks and suggested changing deer distribution as a potential driver. This study highlights the benefits to public health of an integrated approach to understand the factors contributing to LD emergence and a need to evaluate LD ecology in treeless habitats more broadly.
DYRK2 is a ciliary kinase involved in vertebrate Hedgehog signal transduction

Primary cilia are organelles specialized for signaling. We previously defined the proteomes of sea urchin and sea anemone cilia to identify ciliary proteins that predate the origin of bilateria. This evolutionary perspective on cilia identified DYRK2, a kinase not been previously implicated in ciliary biology. We found that DYRK2 localizes to cilia and that loss of DYRK2 disrupts ciliary morphology. We also found that DYRK2 participates in ciliary Hh signal transduction, communicating between SMO and GLI transcription factors. Mutation of mouse Dyrk2 resulted in skeletal defects reminiscent of those caused by loss of Indian hedgehog (Ihh). Like Dyrk2 mutations, pharmacological inhibition of DYRK2 dysregulates ciliary length control and attenuates Hedgehog signaling. Thus, DYRK2 is required for ciliary morphology, for Hedgehog signaling in vitro, and for skeletal development. We propose that DYRK2 is part of the mechanism that transduces SMO to activate GLI transcription factors within cilia.
Response of Endolithic Chroococcidiopsis Strains From the Polyextreme Atacama Desert to Light Radiation

The Atacama Desert is known to be the place on Earth with one of the highest solar radiation limiting the presence of life to endolithic microhabitats and soil microbial ecosystems. Endolithic microbial communities are supported by photosynthetic primary producers, mainly cyanobacteria, which can be injured by UVR. Nevertheless, cyanobacteria exposed to high solar radiation and its harmful effects have developed a series of defense mechanisms: avoidance, antioxidant systems or production of photoprotective compounds such as scytonemin among others. Scytonemin is a liposoluble pigment whose absorption maxima are located in UVA and UVC range and highly absorbing in the UVB range. In order to elucidate the protection capacity of endolithic cyanobacteria against harmful radiation, two cyanobacterial strains from Chroococcidiopsis genus were isolated from different endolithic microhabitats in the Atacama Desert: UAM813 strain, originally from the cryptoendolithic microhabitat of halite (NaCl), and UAM816 strain from chasmoendolithic microhabitat of calcite (CaCO3). Both were exposed to PAR and UVR+PAR conditions studying their short-term response, as oxidative stress and long-term response, as scytonemin production, metabolic activity and ultrastructural damage. The observed response of both strains reveals a high sensitivity to direct light exposure, even to PAR. The differences in their acclimation suggest specific adaptation strategies related to their original microhabitat, revealing their protective potential and the strain specific environmental pressure selection to inhabit different microhabitats and exposed to different light conditions. Importance Cyanobacteria are photosynthetic prokaryotes that inhabit most types of illuminated environments, even the endolithic microhabitats in cold and hot deserts. The environmental pressure caused by the extreme solar irradiation in the Atacama Desert involve that only those cyanobacterial strains able to cope with it can be found in these endolithic communities, usually dominated by members belonging to the extremotolerant Chroococcidiopsis genus. Here, a comprehensive analysis of multiple lines of defense against harmful sun radiation was conducted to diagnose the response of two Chroococcidiopsis strains isolated from different endolithic microhabitats and lithic substrates, and identify its relation with the original microenvironmental conditions of each strain. Our results contribute to a better understanding of the acclimation strategies developed by these cyanobacterial strains and its potential protective role for the whole endolithic microbial community.
Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders

The mammalian neocortex develops from a single layer of neuroepithelial cells to form a six-layer heterogeneous mosaic of differentiated neurons and glial cells. This process requires a complex choreography of temporally and spatially restricted transcription factors and epigenetic regulators. Even subtle disruptions in this regulation can alter the way the neocortex forms and functions, leading to a neurodevelopmental disorder. One epigenetic regulator that is essential for the precise development of the neocortex is CITED2 (CBP/p300 Interacting Transactivator with ED-rich termini). Cited2 is highly expressed by intermediate progenitor cells in the subventricular zone during the generation of the superficial layers of the neocortex. A forebrain-specific conditional knockout of Cited2 (cKO) exhibits reduced proliferation of intermediate progenitor cells embryonically, leading to reduced thickness of the superficial layers and a specific reduction in the somatosensory neocortical length postnatally. Further, the Cited2 cKO displays decreased corpus callosum volume and dysregulation of precise neuronal connectivity within the somatosensory cortex. Here, we explore the behavioral consequences resulting from this aberrant neocortical development. We demonstrate that Cited2 cKO mice display decreased maternal separation-induced ultrasonic vocalizations as neonates, and an increase in the repetitive behavior of rearing and lack of habituation following repeated acoustic startle as adults. They do not display alterations in anxiety-like behavior, overall locomotor activity or social interactions. Together with the morphological, molecular, and connectivity disruptions, these results identify the Cited2 cKO neocortex as an ideal system to study mechanisms underlying neurodevelopmental and neuroanatomical disruptions with relevance to human neurodevelopmental disorders.
Calcium-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21, a member of the DHHC family of mammalian protein acyltransferases, mediates agonist-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice expressing a functionally deficient version of DHHC21, we show that DHHC21 is a calcium/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We found that disruption of the calcium/calmodulin binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2, and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity. Significance This study identifies DHHC21, a member of the DHHC family of mammalian protein acyltransferases, as a novel component of the TCR signaling pathway and demonstrates that this enzyme critically regulates activation and differentiation of CD4+ T cells by mediating rapid TCR-induced S-acylation of signaling proteins. This finding shows that protein acyltransferases can play a vital function in regulation of T cell-mediated immunity and thus serve as potential drug targets in diseases associated with altered immune system homeostasis.
Regression plane concept: analysing continuous cellular processes with machine learning

Biological processes are inherently continuous, and the chance of phenotypic discovery is significantly restricted by discretising them. Using multi-parametric active regression we introduce a novel concept to describe and explore biological data in a continuous manner. We have implemented Regression Plane (RP), the first user-friendly discovery tool enabling class-free phenotypic supervised machine learning.
L1PA2 transposons contribute abundant regulatory sequences in MCF7 breast cancer cell line

Transposons, a type of repetitive DNA elements, can contribute cis-regulatory sequences and regulate the expression of human genes. L1PA2 is a hominoid-specific subfamily of LINE1 transposons, with approximately 4,940 copies in the human genome. Individual transposons have been demonstrated to contribute specific biological functions, such as cancer-specific alternate promoter activity for the MET oncogene, which is correlated with enhanced malignancy and poor prognosis in cancer. Given the sequence similarity between L1PA2 elements, we hypothesise that transposons within the L1PA2 subfamily likely have a common regulatory potential and may provide a mechanism for global genome regulation. Here we show that in breast cancer, the regulatory potential of L1PA2 is not limited to single transposons, but is common within the subfamily. We demonstrate that the L1PA2 subfamily is an abundant reservoir of transcription factor binding sites, the majority of which cluster in the LINE1 5’UTR. In MCF7 breast cancer cells, over 27% of L1PA2 transposons harbour binding sites of functionally interacting, cancer-associated transcription factors. The ubiquitous and replicative nature of L1PA2 makes them an exemplary vector to disperse co-localised transcription factor binding sites, facilitating the co-ordinated regulation of genes. In MCF7 cells, L1PA2 transposons also supply transcription start sites to up-regulated transcripts. These transcriptionally active L1PA2 transposons display a cancer-specific active epigenetic profile, and likely play an oncogenic role in breast cancer aetiology. Overall, we show that the L1PA2 subfamily contributes abundant regulatory sequences in breast cancer cells, and likely plays a global role in modulating the tumorigenic state in breast cancer.
ACE2 and SARS-CoV-2 Expression in the Normal and COVID-19 Pancreas

Diabetes is associated with increased mortality from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of the key molecule for SARS-CoV-2 infection of cells, angiotensin-converting enzyme-2 (ACE2). Specifically, we analyzed five public scRNAseq pancreas datasets and performed fluorescence in situ hybridization, Western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) patients. These in silico and ex vivo analyses demonstrated pancreatic expression of ACE2 is prominent in pancreatic ductal epithelium and the microvasculature, with rare endocrine cell expression of this molecule. Pancreata from COVID-19 patients demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression primarily limited to ducts. SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, appears an unlikely central pathogenic feature of COVID-19 as it relates to diabetes.
Zinc dysregulation in slc30a8 (znt8) mutant zebrafish leads to blindness and disrupts bone mineralisation

Zinc is an essential cofactor for many cellular processes including gene transcription, insulin secretion and retinal function. Excessive free Zn2+ is highly toxic and consequently intracellular zinc is tightly controlled by a system of transporters, metallothioneins (MTs) and storage vesicles. Here we describe the developmental consequences of a missense allele of zinc efflux transporter slc30a8 (znt8) in zebrafish. Homozygous slc30a8hu1798 larvae are virtually blind and develop very little or no bone mineral. We show that zinc is stored in pigmented cells (melanophores) of healthy larvae but in slc30a8hu1798 mutants it instead accumulates in the bone and brain. Supporting a role for pigment cells in zinc homeostasis, nacre zebrafish, which lack melanophores, also show disrupted zinc homeostasis. The photoreceptors of slc30a8hu1798 fish are severely depleted while those of nacre fish are enriched with zinc. We propose that developing zebrafish utilise pigmented cells as a zinc storage organ, and that Slc30a8 is required for transport of zinc into these cells and into photoreceptors.
A new species, Stemonitis sichuanensis, and a newly recorded species, Stemonitis marjana (Myxogastria) from China

A new species, Stemonitis sichuanensis , collected in Gexigou National Natural Reserve, Sichuan province, China, is described herein. This new species has a columella that usually ends in an ovoid to triangular expansion at the apex of the sporotheca and small spores (about 6–7 μm in diam.). We present a scanning electron micrograph study of S. sichuanensis and a key to the species in the genus Stemonitis . Holotype specimens of S. sichuanensis are deposited in the Herbarium of the Mycological Institute of Jilin Agricultural University (HMJAU), Changchun, China. We also report a new record of another species of Stemonitis , S. marjana Y. Yamam. , in this paper, specimens of which are also deposited in the HMJAU.
Effects of an odor background on moth pheromone communication: constituent identity matters more than blend complexity

Olfaction allows insects to communicate with pheromones even in complex olfactory landscapes. It is generally admitted that, due to the binding selectivity of the receptors, general odorants should weakly interfere with pheromone detection. However, laboratory studies show that volatile plant compounds (VPCs) modulate responses to the pheromone in male moths. We used extracellular electrophysiology and calcium imaging to measure the responses to the pheromone of receptor and central neurons in males Agrotis ipsilon while exposed to simple or composite backgrounds of VPCs. Maps of activities were built using calcium-imaging to visualize which areas in antennal lobes (ALs) were affected by VPCs. To mimic a natural olfactory landscape short pheromone puffs were delivered over VPC backgrounds. We chose a panel of VPCs with different chemical structures and physicochemical properties representative of the odorant variety encountered by a moth. We evaluated the intrinsic activity of each VPC and compared the impact of VPC backgrounds at antenna and antennal lobe levels. Then, we prepared binary, ternary and quaternary combinations to determine whether blend activity could be deduced from that of its components. Our data confirm that a VPC background interfere with the moth pheromone system in a dose-dependent manner. Interference with the neuronal coding of pheromone signal starts at the periphery. VPCs showed differences in their capacity to elicit Phe-ORN firing response that cannot be explained by differences in stimulus intensities because we adjusted the source concentrations to vapor pressures. Thus, these differences must be attributed to the selectivity of ORs or any other olfactory proteins. The neuronal network in the ALs, which reformats the ORN-input, did not improve pheromone salience. We postulate that the AL network might have evolved to increase sensitivity and encode for fast changes over a wide range of concentrations, possibly at some cost for selectivity. Comparing three- or four-component blends to binary blends or single compound indicated that a blend showed the activity of its most active compound. Thus, although the diversity of a background might increase the probability of including a VPC interacting with the pheromone system, chemical diversity does not seem to be a prominent factor per se. Global warming is significantly affecting plant metabolism so that the emissions of VPCs and resulting odorscapes are modified. Increase in atmospheric mixing rates of VPCs will change olfactory landscapes which, as confirmed in our study, might impact pheromone communication.
Experimentally disambiguating models of sensory cue integration

Sensory cue integration is one of the primary areas in which a normative mathematical framework has been used to define the “optimal” way in which to make decisions based upon ambiguous sensory information and compare these predictions to behaviour. The conclusion from such studies is that sensory cues are integrated in a statistically optimal fashion. However, numerous alternative computational frameworks exist by which sensory cues could be integrated, many of which could be described as “optimal” based on different criteria. Existing studies rarely assess the evidence relative to different candidate models, resulting in an inability to conclude that sensory cues are integrated according to the experimenter’s preferred framework. The aims of the present paper are to summarise and highlight the implicit assumptions rarely acknowledged in testing models of sensory cue integration, as well as to introduce an unbiased and principled method by which to determine, for a given experimental design, the probability with which a population of observers behaving in accordance with one model of sensory integration can be distinguished from the predictions of a set of alternative models.
Spontaneous rate of clonal mutations in Daphnia galeata

Mutations are the ultimate source of heritable variation and therefore the fuel for evolution, but direct estimates exist only for few species. We estimated the spontaneous nucleotide mutation rate among clonal generations in the waterflea Daphnia galeata with a short term mutation accumulation approach. Individuals from eighteen mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing the parental genotype. We identified 12 new nucleotide mutations in 90 clonal generational passages. This resulted in an estimated haploid mutation rate of 0.745 x 10-9 (95% c.f. 0.39 x 10-9 − 1.26 x 10-9), which is slightly lower than recent estimates for other Daphnia species. We discuss the implications for the population genetics of Cladocerans.
Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients

Membrane protein biogenesis in the endoplasmic reticulum (ER) is complex and failure-prone. The ER membrane protein complex (EMC), comprising eight conserved subunits, has emerged as a central player in this process. Yet, we have limited understanding of how EMC enables insertion and integrity of diverse clients, from tail-anchored to polytopic transmembrane proteins. Here, yeast and human EMC cryo-EM structures reveal conserved intricate assemblies and human-specific features associated with pathologies. Structure-based functional studies revealed at least two separable EMC activities, as an insertase regulating tail-anchored protein levels and as a polytopic membrane protein holdase chaperone. These depend on mechanistically coupled yet spatially distinct regions including two lipid-accessible membrane cavities which confer client-specific regulation, and a novel, non-insertase EMC function mediated by the EMC lumenal domain. Our studies illuminate the structural and mechanistic basis of EMC’s multifunctionality and point to its role in differentially regulating the biogenesis of distinct client protein classes.
MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.