Miracle-dz/UniFAR-FTUs huggingface dataset:
Combined CTL and NK cell cytotoxicity against cancer cells

CTL and NK cells recognize and eliminate cancer cells. However, immune evasion, down regulation of immune function by the tumor microenvironment, or resistance of cancer cells are a major problem. While CTL and NK cells are both important to eliminate cancer, most studies address them individually. We used SK-Mel-5 melanoma cells as a cancer model to analyze combined CTL and NK cell cytotoxicity. At high effector-to-target ratios, MART-1-specific CTL or NK cells completely eradicated SK-Mel-5 cells within 24 hours indicating that SK-Mel-5 cells are initially not resistant. However, at lower effector-to-target ratios, which resemble conditions of the immune contexture in human cancer, a significant number of SK-Mel-5 cells survived. Whereas CTL pre-exposure induced resistance in surviving SK-Mel-5 cells to subsequent CTL or NK cell cytotoxicity, NK cell pre-exposure induced resistance in surviving SK-Mel-5 cells to NK cells but not to MART-1 specific CTL. In contrast, there was even a slight enhancement of CTL cytotoxicity against SK-Mel-5 cells following NK cell pre-exposure. In all other combinations, resistance to subsequent cytotoxicity was higher, if melanoma cells were pre-exposed to larger numbers of CTL or NK cells. Alterations in human leukocyte antigen class I expression correlated with resistance to NK cells, while reduction in MART-1 antigen expression correlated with reduced CTL cytotoxicity. CTL cytotoxicity was rescued beyond control levels by exogenous MART-1 antigen. This study quantifies combined CTL and NK cell cytotoxicity and may guide strategies for efficient CTL-NK cell anti-cancer therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/150672v1_ufig1. gif" ALT="Figure 1"> View larger version (36K): org.highwire. dtl.DTLVardef@5999c3org.highwire. dtl.DTLVardef@7dda9eorg.highwire. dtl.DTLVardef@9bd80borg.highwire. dtl.DTLVardef@184e27e_HPS_FORMAT_FIGEXP M_FIG C_FIG
DILS: Demographic Inferences with Linked Selection by using ABC

We present DILS, a deployable statistical analysis platform for conducting demographic inferences with linked selection from population genomic data using an Approximate Bayesian Computation framework. DILS takes as input single-population or two-population datasets (multilocus fasta sequences) and performs three types of analyses in a hierarchical manner, identifying: 1) the best demographic model to study the importance of gene flow and population size change on the genetic patterns of polymorphism and divergence, 2) the best genomic model to determine whether the effective size Ne and migration rate N.m are heterogeneously distributed along the genome (implying linked selection) and 3) loci in genomic regions most associated with barriers to gene flow. Also available via a web interface, an objective of DILS is to facilitate collaborative research in speciation genomics. Here, we show the performance and limitations of DILS by using simulations, and finally apply the method to published data on a divergence continuum composed by 28 pairs of Mytilus mussel populations/species.
Journal Pre-proofs

The recent outbreak of the respiratory ailment COVID-19 caused by novel coronavirus SARS-Cov2 is a severe and urgent global concern. In the absence of eﬀective treatments, the main containment strategy is to reduce the contagion by the isolation of infected individuals; however, isolation of unaﬀected individuals is highly undesirable. To help make rapid decisions on treatment and isolation needs, it would be useful to determine which features presented by suspected infection cases are the best predictors of a positive diagnosis. This can be done by analyzing patient characteristics, case trajectory, comorbidities, symptoms, diagnosis, and outcomes. We developed a model that employed supervised machine learning algorithms to identify the presentation features predicting COVID-19 disease diagnoses with high accuracy. Features examined included details of the individuals concerned, e.g., age, gender, observation of fever, history of travel, and clinical details such as the severity of cough and incidence of lung infection. We implemented and applied several machine learning algorithms to our collected data and found that the XGBoost algorithm performed with the highest accuracy (>85%) to predict and select features that correctly indicate COVID-19 status for all age groups. Statistical analyses revealed that the most frequent and signiﬁcant predictive symptoms are fever (41.1%), cough (30.3%), lung infection (13.1%) and runny nose (8.43%). While 54.4% of people examined did not develop any symptoms that could be used for diagnosis, our work indicates that for the remainder, our predictive model could signiﬁcantly improve the prediction of COVID-19 status, including at early stages of infection.
Exposure to artemisinin at the trophozoite stage increases sexual conversion rates in the malaria parasite Plasmodium falciparum

Malaria transmission is dependent on formation of gametocytes in the human blood. The sexual conversion rate, the proportion of asexual parasites that convert into gametocytes at each multiplication cycle, is variable and reflects the relative parasite investment between transmission and maintaining the infection. The impact of environmental factors such as drugs on sexual conversion rates is not well understood. We developed a robust assay using gametocyte-reporter parasite lines to accurately measure the impact of drugs on conversion rates, independently from their gametocytocidal activity. We found that exposure to subcurative doses of the frontline antimalarial drug dihydroartemisinin (DHA) at the trophozoite stage resulted in a ~4-fold increase in sexual conversion. In contrast, no increase was observed when ring stages were exposed or in cultures in which sexual conversion was stimulated by choline depletion. Our results reveal a complex relationship between antimalarial drugs and sexual conversion, with potential public health implications.
An Atlas of Phosphorylation and Proteolytic Processing Events During Excitotoxic Neuronal Death Reveals New Therapeutic Opportunities

Excitotoxicity, a neuronal death process in neurological disorders, is initiated by over-stimulation of neuronal ionotropic glutamate receptors. The over-stimulated receptors dysregulate proteases, protein kinases and phosphatases, which in turn modify target neuronal proteins to induce cell death. To decipher this cell death mechanism, we used quantitative proteomics, phosphoproteomics and N-terminomics to identify modified proteins in excitotoxic neurons. Data, available in ProteomeXchange (identifiers: PXD019527 and PXD019211), enabled us to identify over one thousand such proteins with calpains, cathepsins and over twenty protein kinases as their major modifiers. These protein modification events can potentially perturb signalling pathways governing cell survival, synaptogenesis, axonal guidance and mRNA processing. Importantly, blocking the modification of Src protein kinase, a signalling hub in excitotoxic neurons, protected against neuronal loss in vivo in a rat model of neurotoxicity. Besides offering new insights into excitotoxic neuronal death mechanism, our findings suggest potential neuroprotective therapeutic targets for treating neurological disorders. Graphical abstract Highlights Multi-dimensional proteomic analysis identified proteins modified by proteolysis and altered phosphorylation in neurons undergoing excitotoxic cell death. Calpains, cathepsins and over twenty protein kinases are major modifiers of these proteins. These protein modification events are predicted to impact cell survival, axonal guidance, synaptogenesis and mRNA processing. Blocking modification of an identified protein Src, which acts as a major signalling hub in neurons, was protective against excitotoxic injury in vivo. In Brief Using multidimensional proteomic approaches, Ameen, et al. mapped the changes of proteome, phosphoproteome and N-terminome of cultured primary neurons during excitotoxicity, a crucial neuronal death process in neurological disorders. These proteomic changes document new excitotoxicity-associated molecular events, and offer insights into how these events are organized to induce neuronal death. Potential therapeutic relevance of these molecular events is illustrated by the demonstration that in vivo blockade of one of these events could protect against excitotoxic neuronal loss.
Differences in movement and dynamic resource selection between breeders and floaters revealed with an Ornstein-Uhlenbeck space use model

In populations of many taxa, a large fraction of sexually mature individuals do not breed but are attempting to enter the breeding population. Such individuals, often referred to as “floaters” play critical roles in determining dynamics and stability of these populations. Floaters are difficult to study, however, so we lack data on the roles they play in population ecology and conservation status of many species. Here, we paired satellite telemetry and a new mechanistic space use model based on an Ornstein-Uhlenbeck process to study the differential habitat selection and space use of floater and territorial golden eagles Aquila chrysaetos. Our sample consisted of 49 individuals tracked over complete breeding seasons across four years, totalling 104 eagle breeding seasons. Modeling these data with the new mechanistic approach was required to parse key differences in movement and separate aspects of resource selection from central place behavior. We found that floaters generally had more expansive space use patterns and larger home ranges, partitioning space with territorial individuals seemingly on fine scales through differential habitat and resource selection. Floater and territorial eagle home ranges overlapped markedly, suggesting floaters use the interstices between territories. Further, floater and territorial eagles differed in how they selected for uplift variables, key components of soaring birds’ energy landscape, with territorial eagles apparently better able to find and use thermal uplift. We also found relatively low individual heterogeneity in resource selection, especially among territorial individuals, suggesting a narrow realized niche for breeding individuals. This work furthers our understanding of floaters’ potential roles in population ecology of territorial species, as well as suggests that conserving landscapes occupied by territorial eagles also protects floaters.
Instance-level contrastive learning yields human brain-like representation without category-supervision

Humans learn object categories without millions of labels, but to date the models with the highest correspondence to primate visual systems are all category-supervised. This paper introduces a new self-supervised learning framework: instance-prototype contrastive learning (IPCL), and compares the internal representations learned by this model and other instance-level contrastive learning systems to the structure of human brain responses. We present the ﬁrst evidence to date showing that self-supervised systems can show more brain-like representation than category-supervised models. Further, we ﬁnd that recent substantial gains in top-1 accuracy from instance-wise contrastive learning models do not result in more brain-like representation—instead we ﬁnd the architecture and normalization scheme are critical. Finally, this dataset reveals substantial representational structure in intermediate and late stages of the human visual system that is not accounted for by any model, whether self-supervised or category-supervised. Considering both neuroscience and machine vision perspectives, these results provide promise for instance-level representation as a key objective of visual system encoding, and highlight the room to grow towards more robust, efﬁcient, human-like object representation. scanner (Bruker) using an eight-channel head Functional were QX MATLAB. Standard preprocessing was performed and a general linear modeling framework was used to estimate the response of each voxel to each of the 72 images, using square-wave regressors for each image
Extensive individual differences of category information in ventral temporal cortex in the congenitally blind

Human ventral temporal cortex (VTC) is a cortical expanse that performs different functions and computations, but is especially critical for visual categorization. Nevertheless, accumulating evidence shows that category-selective regions persist in VTC in the absence of visual experience – for example, in congenitally blind (CB) participants. Despite this evidence, a large body of previous work comparing functional representations in VTC between sighted and CB participants performed univariate analyses at the group level, which assume a homogeneous population – an assumption that has not been formally tested until the present study. Specifically, using fMRI in CB and sighted participants (male and female), we empirically show that at the group level, distributed category representations in VTC are more reliable in the sighted (when viewing visual stimuli) compared to the CB (when hearing auditorily-substituted visual stimuli). Despite these group differences, there is extensive heterogeneity in VTC category representations in the CB to the point that VTC category representations in a subset of CB participants (some who were born without eyes, but not all) are more similar to sighted individuals compared to other CB participants. Together, our findings support a novel idea that driving factors contributing to the formation of VTC category representations in the blind are subject-specific, which complements factors that may generalize across group members. More broadly, the present findings caution conclusions of homogeneity across subjects within a group when performing group neuroimaging analyses without explicitly quantifying individual differences.
Ability of Salmonids to Ascend High Fishways

Abstract The ability and persistence of salmonids in ascending pool-and-overfall fishways was measured in experimental “endless” fishway structures in which fishways of any height could be simulated. Six chinook salmon (Oncorhynchus tshawytscha), four sockeye salmon (O. nerka), and four steelhead trout (Salmo gairdneri) were permitted to ascend 1,000 feet in the experimental fishways. One sockeye salmon was allowed to ascend an endless fishway for over 5 days, climbing 6,648 feet, a vertical ascent of more than a mile, before the test was discontinued. Rate of ascent of all fish tested increased following an initial period of experience in the fishway. The level of blood lactate in the exercised fish showed no evidence of fatigue. Practical significance of the data in relation to fishway design is discussed.
Pleistocene‐driven diversification in freshwater zooplankton: Genetic patterns of refugial isolation and postglacial recolonization in Leptodora kindtii (Crustacea, Cladocera)

In this study we investigate the extent to which successive range fragmentations, postglacial expansions, and recolonizations influenced intraspecific genetic diversity and patterns of diversification in freshwater zooplankton. Specifically, we explore the global phylogeography of the Holarctic predatory cladoceran Leptodora kindtii Focke, 1844. Phylogenetic analyses based on the mitochondrial cytochrome c oxidase subunit I recover seven deeply divergent lineages (11.8–20.0%) comprising two sister clades within the Nearctic and east Palearctic and three related clades within the west Palearctic. Strong continental endemism was also supported by the nuclear 18S ribosomal gene. Intra‐continental divergence levels (< 6%) suggest that many speciation events in Leptodora were initiated by glacial isolation. Demographic and network analyses indicate that in the Nearctic and west Palearctic, regions heavily affected by the Pleistocene glaciations, Leptodora persisted in both classic (e.g., Cascadia, Mississippi, southern Europe) and cryptic refugia (e.g., northeastern Europe, Carpathian basin). Strong signatures of late Pleistocene range expansions and secondary contact were observed in most clades. Deeper intraspecific phylogeographic structure occurs across much finer geographic scales in unglaciated regions of the east Palearctic than across glaciated Nearctic and west Palearctic regions. Leptodora's ecological and biological characteristics, such as a reliance on temperate, permanent lakes, weak dispersal ability, and specific geological settings likely shaped the complex pattern of diversification in this important planktonic predator. Our data suggest the Pleistocene glaciations were important in the diversification of Holarctic freshwater zooplankton.
The ribbon-helix-helix domain proteins CdrS and CdrL regulate cell division in archaea

Precise control of the cell cycle is central to the physiology of all cells. In prior work we demonstrated that archaeal cells maintain a constant size; however, the regulatory mechanisms underlying the cell cycle remain unexplored in this domain of life. Here we use genetics, functional genomics, and quantitative imaging to identify and characterize the novel CdrSL gene regulatory network in a model species of archaea. We demonstrate the central role of these ribbon-helix-helix family transcription factors in the regulation of cell division through specific transcriptional control of the gene encoding FtsZ2, a putative tubulin homolog. Using time lapse fluorescence microscopy in live cells cultivated in microfluidics devices, we further demonstrate that FtsZ2 is required for cell division but not elongation. The cdrS-ftsZ2 locus is highly conserved throughout the archaeal domain, and the central function of CdrS in regulating cell division is conserved across hypersaline adapted archaea. We propose that the CdrSL-FtsZ2 transcriptional network coordinates cell division timing with cell growth in archaea. Importance Healthy cell growth and division are critical for individual organism survival and species long-term viability. However, it remains unknown how cells of the domain Archaea maintain a healthy cell cycle. Understanding archaeal cell cycle is of paramount evolutionary importance given that an archaeal cell was the host of the endosymbiotic event that gave rise to eukaryotes. Here we identify and characterize novel molecular players needed for regulating cell division in archaea. These molecules dictate the timing of cell septation, but are dispensable for growth between divisions. Timing is accomplished through transcriptional control of the cell division ring. Our results shed light on mechanisms underlying the archaeal cell cycle, which has thus far remained elusive.
Systematic analysis of REBASE identifies numerous Type I restriction-modification systems that contain duplicated, variable hsdS specificity genes that randomly switch methyltransferase specificity by recombination

N6-adenine DNA methyltransferases associated with some Type I and Type III restriction-modification (R-M) systems are able to randomly switch expression by variation in the length of locus-encoded simple sequence repeats (SSRs). SSR tract-length variation causes ON/OFF switching of methyltransferase expression, resulting in genome-wide methylation differences, and global changes in gene expression. These epigenetic regulatory systems are called phasevarions, phase-variable regulons, and are widespread in bacteria. A distinct switching system has also been described in Type I R-M systems, based on recombination-driven changes in hsdS genes, which dictate the DNA target site. In order to determine the prevalence of recombination-driven phasevarions, we generated a program called RecombinationRepeatSearch to interrogate REBASE and identify the presence and number of inverted repeats of hsdS downstream of Type I R-M loci. We report that 5.9% of Type I R-M systems have duplicated variable hsdS genes containing inverted repeats capable of phase-variation. We report the presence of these systems in the major pathogens Enterococcus faecalis and Listeria monocytogenes, which will have important implications for pathogenesis and vaccine development. These data suggest that in addition to SSR-driven phasevarions, many bacteria have independently evolved phase-variable Type I R-M systems via recombination between multiple, variable hsdS genes. Importance Many bacterial species contain DNA methyltransferases that have random on/off switching of expression. These systems called phasevarions (phase-variable regulons) control the expression of multiple genes by global methylation changes. In every previously characterised phasevarion, genes involved in pathobiology, antibiotic resistance, and potential vaccine candidates are randomly varied in their expression, commensurate with methyltransferase switching. A systematic study to determine the extent of phasevarions controlled by invertible Type I R-M systems has never before been performed. Understanding how bacteria regulate genes is key to the study of physiology, virulence, and vaccine development; therefore it is critical to identify and characterize phase-variable methyltransferases controlling phasevarions.
The impacts of ski resorts on reptiles: a natural experiment

Alpine–subalpine areas are sensitive environments that support large numbers of endemic species. They are also popular for human recreation. Increasing demands for tourism means that infrastructure in alpine resorts is expanding. Consequently, habitat is being modified and fragmented, potentially adversely affecting fauna. However, research investigating the effects of ski resorts on wildlife, particularly reptiles, is limited, and the effectiveness of management strategies in mitigating adverse impacts is unknown. To quantify the effects of ski‐related disturbances on specialist and generalist reptile species, we surveyed sites in disturbed and undisturbed subalpine habitats. We also examined vegetation composition and habitat structure to determine whether structural or compositional habitat features were driving patterns of reptile occurrence. Our results indicate that the effects of ski‐related disturbance varied between species, but that adverse effects – particularly on ski runs – were more pronounced for specialists. Given that each species studied was positively associated with compositional or structural features of the environment, we argue that alterations to these habitat attributes when creating ski runs will suppress lizard abundances in these areas. However, while ski runs have an adverse effect on reptiles, the persistence of these animals in ski resorts can be facilitated by retaining habitat structure and minimizing disturbance to native vegetation.