Miracle-dz/UniFAR-FTUs huggingface dataset:
α‐Synuclein contributes to GSK‐3β‐catalyzed Tau phosphorylation in Parkinson's disease models

We have shown in the parknsonism‐inducing neurotoxin MPP+/MPTP model that α‐Synuclein (α‐Syn), a presynaptic protein causal in Parkinson's disease (PD), contributes to hyperphosphorylation of Tau (p‐Tau), a protein normally linked to tauopathies, such as Alzheimer's disease (AD). Here, we investigated the kinase involved and show that the Tau‐specific kinase, glycogen synthase kinase 3β (GSK‐3β), is robustly activated in various MPP+/MPTP models of Parkinsonism (SH‐SY5Y cotransfected cells, mesencephalic neurons, transgenic mice overexpressing α‐Syn, and postmortem striatum of PD patients). The activation of GSK‐3β was absolutely dependent on the presence of α‐Syn, as indexed by the absence of p‐GSK‐3β in cells lacking α‐Syn and in α‐Syn KO mice. MPP+ treatment induced translocation and accumulation of p‐GSK‐3β in nuclei of SHSY5Y cells and mesencephalic neurons. Through coimmunoprecipitation (co‐IP), we found that α‐Syn, pSer396/ 404‐Tau, and p‐GSK‐3β exist as a heterotrimeric complex in SH‐SY5Y cells. GSK‐3β inhibitors (lithium and TDZD‐8) protected against MPP+‐induced events in SHSY5Y cells, preventing cell death and p‐GSK‐3β formation, by reversing increases in α‐Syn accumulation and p‐Tau formation. These data unveil a previously unappreciated role of α‐Syn in the induction of p‐GSK‐3β, and demonstrate the importance of this kinase in the genesis and maintenance of neurodegenerative changes associated with PD. —Duka, T. , Duka, V. , Joyce, J. N. , Sidhu, A. α‐Synuclein contributes to GSK‐3β‐catalyzed Tau phosphorylation in Parkinson's disease models. FASEB J. 23, 2820–2830 (2009). www.fasebj. org
Exploit fully automatic low-level segmented PET data for training high-level deep learning algorithms for the corresponding CT data

We present an approach for fully automatic urinary bladder segmentation in CT images with artificial neural networks in this study. Automatic medical image analysis has become an invaluable tool in the different treatment stages of diseases. Especially medical image segmentation plays a vital role, since segmentation is often the initial step in an image analysis pipeline. Since deep neural networks have made a large impact on the field of image processing in the past years, we use two different deep learning architectures to segment the urinary bladder. Both of these architectures are based on pre-trained classification networks that are adapted to perform semantic segmentation. Since deep neural networks require a large amount of training data, specifically images and corresponding ground truth labels, we furthermore propose a method to generate such a suitable training data set from Positron Emission Tomography/Computed Tomography image data. This is done by applying thresholding to the Positron Emission Tomography data for obtaining a ground truth and by utilizing data augmentation to enlarge the dataset. In this study, we discuss the influence of data augmentation on the segmentation results, and compare and evaluate the proposed architectures in terms of qualitative and quantitative segmentation performance. The results presented in this study allow concluding that deep neural networks can be considered a promising approach to segment the urinary bladder in CT images.
Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

Na+/K+-ATPase transports Na+ and K+ ions across the cell membrane via an ion-binding site becoming alternatively accessible to the intra- and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free-energy perturbation approaches to identify probable protonation states of Na+- and K+-coordinating residues in E1P and E2P conformations of Na+/K+-ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na+-coordinating residue Asp926. This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion-binding stoichiometry and selectivity.
Spatially structured populations with a low level of cryptic diversity in European marine Gastrotricha

Species of the marine meiofauna such as Gastrotricha are known to lack dispersal stages and are thus assumed to have low dispersal ability and low levels of gene flow between populations. Yet, most species are widely distributed, and this creates a paradox. To shed light on this apparent paradox, we test (i) whether such wide distribution may be due to misidentification and lumping of cryptic species with restricted distributions and (ii) whether spatial structures exist for the phylogeography of gastrotrichs. As a model, we used the genus Turbanella in NW Europe. DNA taxonomy using a mitochondrial and a nuclear marker supports distinctness of four traditional species (Turbanella ambronensis, T. bocqueti, T. mustela and T. cornuta) and provides evidence for two cryptic species within T. hyalina. An effect of geography on the within‐species genetic structure is indeed present, with the potential for understanding colonization processes and for performing phylogeographic inference from microscopic animals. On the other hand, the occurrence of widely distributed haplotypes indicates long‐distance dispersal as well, despite the assumed low dispersal ability of gastrotrichs.
Carnivore diet analysis based on next‐generation sequencing: application to the leopard cat (Prionailurus bengalensis) in Pakistan

Diet analysis is a prerequisite to fully understand the biology of a species and the functioning of ecosystems. For carnivores, traditional diet analyses mostly rely upon the morphological identification of undigested remains in the faeces. Here, we developed a methodology for carnivore diet analyses based on the next‐generation sequencing. We applied this approach to the analysis of the vertebrate component of leopard cat diet in two ecologically distinct regions in northern Pakistan. Despite being a relatively common species with a wide distribution in Asia, little is known about this elusive predator. We analysed a total of 38 leopard cat faeces. After a classical DNA extraction, the DNA extracts were amplified using primers for vertebrates targeting about 100 bp of the mitochondrial 12S rRNA gene, with and without a blocking oligonucleotide specific to the predator sequence. The amplification products were then sequenced on a next‐generation sequencer. We identified a total of 18 prey taxa, including eight mammals, eight birds, one amphibian and one fish. In general, our results confirmed that the leopard cat has a very eclectic diet and feeds mainly on rodents and particularly on the Muridae family. The DNA‐based approach we propose here represents a valuable complement to current conventional methods. It can be applied to other carnivore species with only a slight adjustment relating to the design of the blocking oligonucleotide. It is robust and simple to implement and allows the possibility of very large‐scale analyses.
Cardiac aldosterone overexpression prevents harmful effects of diabetes in the mouse heart by preserving capillary density

Recent reports showed an unexpected worsening of endothelial function by aldosterone antagonism in diabetic patients, suggesting that aldosterone could interfere with the detrimental consequences of diabetes on microvasculature and thus on cardiac function. To test this hypothesis, diabetes (D) was induced using streptozotocin in transgenic (Tg) male mice overexpressing aldosterone‐synthase in the heart and in wild‐type (Wt) mice. Eight weeks after streptozotocin injection, impairment of left ventricular systolic function, measured by echocardiography (fractional shortening), was accompanied by a decrease in capillaries/cardiomyocyte ratio (—20%) and VEGFa expression (—40%) in Wt‐D mice compared with normoglycemic littermates. Furthermore, Wt‐D mice demonstrated an increase in superoxide production (+100%) and protein carbonylation (+33%), hallmarks of oxidative stress. Except for a slight increase in protein carbonylation, all of these diabetes‐associated cardiac alterations were undetectable in Tg‐D mice. Fibrosis was induced similarly in both diabetic groups. Eplerenone (an aldosterone antagonist) abolished all of the effects of aldosterone‐synthase overexpression but had no effect in Wt‐D mice. Thus, aldosterone prevents systolic dysfunction through a mineralocorticoid receptor‐dependent mechanism that may include preventing VEGFa down‐regulation and maintaining capillary density. Understanding how aldosterone prevents VEGFa down‐regulation in experimental diabetes could be important to define new strategies targeting the prevention of a decrease in capillary density. —Messaoudi, S. ,Milliez, P., Samuel, J.‐L. , Delcayre, C. Cardiac aldosterone overexpression prevents harmful effects of diabetes in the mouse heart by preserving capillary density. FASEB J. 23, 2176–2185 (2009)
Forest elephant mitochondrial genomes reveal that elephantid diversification in Africa tracked climate transitions

Among elephants, the phylogeographic patterns of mitochondrial (mt) and nuclear markers are often incongruent. One hypothesis attributes this to sex differences in dispersal and in the variance of reproductive success. We tested this hypothesis by examining the coalescent dates of genetic markers within elephantid lineages, predicting that lower dispersal and lower variance in reproductive success among females would have increased mtDNA relative to nuclear coalescent dates. We sequenced the mitochondrial genomes of two forest elephants, aligning them to mitogenomes of African savanna and Asian elephants, and of woolly mammoths, including the most divergent mitogenomes within each lineage. Using fossil calibrations, the divergence between African elephant F and S clade mitochondrial genomes (originating in forest and savanna elephant lineages, respectively) was estimated as 5.5 Ma. We estimated that the (African) ancestor of the mammoth and Asian elephant lineages diverged 6.0 Ma, indicating that four elephantid lineages had differentiated in Africa by the Miocene–Pliocene transition, concurrent with drier climates. The coalescent date for forest elephant mtDNAs was c. 2.4 Ma, suggesting that the decrease in tropical forest cover during the Pleistocene isolated distinct African forest elephant lineages. For all elephantid lineages, the ratio of mtDNA to nuclear coalescent dates was much greater than 0.25. This is consistent with the expectation that sex differences in dispersal and in variance of reproductive success would have increased the effective population size of mtDNA relative to nuclear markers in elephantids, contributing to the persistence of incongruent mtDNA phylogeographic patterns.
Cell‐surface thiols affect cell entry of disulfide‐conjugated peptides

Cell‐penetrating peptides (CPPs) can cross the cell membrane and are widely used to deliver bioactive cargoes inside cells. The cargo and the CPP are often conjugated through a disulfide bridge with the common acceptation that this linker is stable in the extracellular biological medium and should not perturb the internalization process. However, with the use of thiol‐specific reagents combined with mass spectrometry (as a quantitative method to measure intracellular concentrations of peptides) and confocal microscopy (as a qualitative method to visualize internalized pep‐tides) analyses, we could show that, depending on the peptide sequence, thiol/disulfide exchange reactions could happen at the cell surface. These exchange reactions lead to the reduction of disulfide conjugates. In addition, it was observed that not only disulfide‐ but also thiol‐containing peptides could cross‐react with cell‐surface thiols. The peptides cross‐linked by thiolcontaining membrane proteins were either trapped in the membrane or further internalized. Therefore, a new route of cellular uptake was unveiled that is not restricted to CPPs: a protein kinase C peptide inhibitor that is not cell permeant could cross cell membranes when an activated cysteine (with a 3‐nitro‐2‐pyridine‐sulfenyl moiety) was introduced in its sequence. — Aubry, S. , Burlina, F. , Dupont, E. , Delaroche, D. , Joliot, A. , Lavielle, S. , Chassaing, G. , Sagan, S. Cell‐surface thiols affect cell entry of disulfide‐conjugated peptides. FASEB J. 23, 2956–2967 (2009). www.fasebj. org
Post-transcriptional regulation of ERBB2 by miR26a/b and HuR confers resistance to tamoxifen in estrogen receptor-positive breast cancer cells

Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3′-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3′-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3′-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.
Robust and Communication-Efficient Federated Learning From Non-i.i.d. Data

Federated learning allows multiple parties to jointly train a deep learning model on their combined data, without any of the participants having to reveal their local data to a centralized server. This form of privacy-preserving collaborative learning, however, comes at the cost of a significant communication overhead during training. To address this problem, several compression methods have been proposed in the distributed training literature that can reduce the amount of required communication by up to three orders of magnitude. These existing methods, however, are only of limited utility in the federated learning setting, as they either only compress the upstream communication from the clients to the server (leaving the downstream communication uncompressed) or only perform well under idealized conditions, such as i.i. d. distribution of the client data, which typically cannot be found in federated learning. In this article, we propose sparse ternary compression (STC), a new compression framework that is specifically designed to meet the requirements of the federated learning environment. STC extends the existing compression technique of top- $k$ gradient sparsification with a novel mechanism to enable downstream compression as well as ternarization and optimal Golomb encoding of the weight updates. Our experiments on four different learning tasks demonstrate that STC distinctively outperforms federated averaging in common federated learning scenarios. These results advocate for a paradigm shift in federated optimization toward high-frequency low-bitwidth communication, in particular in the bandwidth-constrained learning environments.
Comprehensive sampling reveals circumpolarity and sympatry in seven mitochondrial lineages of the Southern Ocean crinoid species Promachocrinus kerguelensis (Echinodermata)

Sampling at appropriate spatial scales in the Southern Ocean is logistically challenging and may influence estimates of diversity by missing intermediate representatives. With the assistance of sampling efforts especially influenced by the International Polar Year 2007–2008, we gathered nearly 1500 specimens of the crinoid species Promachocrinus kerguelensis from around Antarctica. We used phylogeographic and phylogenetic tools to assess its genetic diversity, demographic history and evolutionary relationships. Six phylogroups (A–F) identified in an earlier study are corroborated here, with the addition of one new phylogroup (E2). All phylogroups are circumpolar, sympatric and eurybathic. The phylogeny of Promachocrinus phylogroups reveals two principal clades that may represent two different cryptic species with contrasting demographic histories. Genetic diversity indices vary dramatically within phylogroups, and within populations, suggesting multiple glacial refugia in the Southern Ocean: on the Kerguelen Plateau, in the East Weddell Sea and the South Shetland Islands (Atlantic sector), and on the East Antarctic continental shelf in the Dumont d’Urville Sea and Ross Sea. The inferences of gene flow vary among the phylogroups, showing discordant spatial patterns. Phylogroup A is the only one found in the Sub‐Antarctic region, although without evident connectivity between Bouvet and Kerguelen populations. The Scotia Arc region shows high levels of connectivity between populations in most of the phylogroups, and barriers to gene flow are evident in East Antarctica.
Mitogenomic sequences better resolve stock structure of southern Greater Caribbean green turtle rookeries

Analyses of mitochondrial control region polymorphisms have supported the presence of several demographically independent green turtle (Chelonia mydas) rookeries in the Greater Caribbean region. However, extensive sharing of common haplotypes based on 490‐bp control region sequences confounds assessment of the scale of natal homing and population structure among regional rookeries. We screened the majority of the mitochondrial genomes of 20 green turtles carrying the common haplotype CM‐A5 and representing the rookeries of Buck Island, St. Croix, United States Virgin Islands (USVI); Aves Island, Venezuela; Galibi, Suriname; and Tortuguero, Costa Rica. Five single‐nucleotide polymorphisms (SNPs) were identified that subdivided CM‐A5 among regions. Mitogenomic pairwise φST values of eastern Caribbean rookery comparisons were markedly lower than the respective pairwise FST values. This discrepancy results from the presence of haplotypes representing two divergent lineages in each rookery, highlighting the importance of choosing the appropriate test statistic for addressing the study question. Haplotype frequency differentiation supports demographic independence of Aves Island and Suriname, emphasizing the need to recognize the smaller Aves rookery as a distinct management unit. Aves Island and Buck Island rookeries shared mitogenomic haplotypes; however, frequency divergence suggests that the Buck Island rookery is sufficiently demographically isolated to warrant management unit status for the USVI rookeries. Given that haplotype sharing among rookeries is common in marine turtles with cosmopolitan distributions, mitogenomic sequencing may enhance inferences of population structure and phylogeography, as well as improve the resolution of mixed stock analyses aimed at estimating natal origins of foraging turtles.
Disentangling the genetic origins of a plant pathogen during disease spread using an original molecular epidemiology approach

The advent of molecular epidemiology has greatly improved our ability to identify the population sources and track the pathogen movement. Yet the wide spatial and temporal scales usually considered are useful only to infer historical migration pathways. In this study, Bayesian genetic assignments and a landscape epidemiology approach were combined to unravel genetic origin and annual spread during a single epidemic of a plant pathogen: the poplar rust fungus Melampsora larici‐populina. The study focused on a particular area—the Durance River valley—which enabled inoculum sources to be identified and channelled spread of the epidemic along a one‐dimensional corridor. Spatio‐temporal monitoring of disease showed that the epidemic began in the upstream part of the valley and spread out downstream. Using genetic assignment tests, individuals collected at the end of the epidemic were sorted into two genetic groups; very few hybrids were detected, although individuals from both groups coexisted locally downstream in the valley. The epidemic originated from two genetically distinct inoculum sources. Individuals of each group then dispersed southwards along the Durance River and became mixed in poplar riparian stands. These two genetic groups were found previously at a wider spatial scale and proved to result from distinct evolutionary histories on either wild or cultivated poplars. This study showed that the two groups can mix during an epidemic but do not hybridize because they then reproduce asexually. In general, the methods employed here could be useful for elucidating the genetic origin and retracing the colonization history and migration pathways of recent epidemics.
Thrombospondin‐1 modulates vascular endothelial growth factor activity at the receptor level

Vascular endothelial growth factor (VEGF) is a well‐established stimulator of vascular permeability and angiogenesis, whereas thrombospondin‐1 (TSP‐1) is a potent angiogenic inhibitor. In this study, we have found that the TSP‐1 receptors CD36 and ßl integrin associate with the VEGF receptor 2 (VEGFR2). The coclustering of receptors that regulate angiogenesis may provide the endothelial cell with a platform for integration of positive and negative signals in the plane of the membrane. Thus, this complex may represent a molecular switch that regulates angiogenesis and determines endothelial cell behavior. In this context, physiological levels of TSP‐1 appear to support VEGFR2 function on both the cellular and tissue level, because phosphorylation of VEGFR2 and vascular permeability in response to VEGF are decreased in TSP‐1‐null mice and isolated endothelial cells. A therapeutic agent based on the antiangiogenic domain of TSP‐1, designated 3TSR (for three TSP‐1 type 1 repeats), has significant antiangiogenic and antitumor efficacy. Systemic treatment of wild‐type mice with 3TSR significantly decreased VEGF‐induced permeability. Consistent with this result, VEGF‐stimulated phosphorylation of VEGFR2 was also significantly decreased in lung extracts from 3TSR‐treated mice. Moreover, 3TSR significantly decreased VEGF‐stimulated VEGFR2 phosphorylation in human dermal microvascular endothelial cells in culture. Taken together, the results indicate that TSP‐1 and 3TSR modulate the function of VEGFR2. —Zhang, X. , Kazerounian, S. , Duquette, M. , Perruzzi, C. , Nagy, J. A. , Dvorak, H. J., Parangi, S. , and Lawler, J. Thrombospondin‐1 modulates vascular endothelial growth factor activity at the receptor level. FASEB J. 23, 3368–3376 (2009). www.fasebj. org