Miracle-dz/UniFAR-FTUs huggingface dataset:
Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability

Lassa virus is endemic in large parts of West Africa and causes a hemorrhagic fever. Recent years have seen several serious outbreaks of Lassa fever with high mortality rates. A vaccine to curtail infection is urgently needed. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here we use two-component protein nanoparticles to stabilize GPC in a trimeric conformation and present twenty prefusion GPC trimers on the surface of an icosahedral nanoparticle. Cryo-EM studies of assembled GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against a lethal Lassa virus challenge in guinea pigs. We isolated a neutralizing antibody which was mapped to the putative receptor-binding site, revealing a novel site of vulnerability on GPC.
Hip osteoarthritis: A novel network analysis of subchondral trabecular bone structures

Hip osteoarthritis (HOA) is a degenerative joint disease that leads to the progressive destruction of subchondral bone and cartilage at the hip joint. Development of effective treatments for HOA remains an open problem, primarily due to the lack of knowledge of its pathogenesis and a typically late-stage diagnosis. We describe a novel network analysis methodology for micro-computed tomography (micro-CT) images of human trabecular bone. We explored differences between the trabecular bone microstructure of femoral heads with and without HOA. Large-scale automated extraction of the network formed by trabecular bone revealed significant network properties not previously reported for bone. Profound differences were discovered, particularly in the proximal third of the femoral head, where HOA networks demonstrated elevated numbers of edges, vertices and graph components. When further differentiating healthy joint and HOA networks, the latter showed fewer small-world network properties, due to decreased clustering coefficient and increased characteristic path length. Furthermore, we found that HOA networks had reduced length of edges, indicating the formation of compressed trabecular structures. In order to assess our network approach, we developed a deep learning model for classifying HOA and control cases, and we fed it with two separate inputs: (i) micro-CT images of the trabecular bone, and (ii) the network extracted from them. The model with plain micro-CT images achieves 74.63% overall accuracy while the trained model with extracted networks attains 96.47% accuracy. We anticipate our findings to be a starting point for a novel description of bone microstructure in HOA, by considering the phenomenon from a graph theory viewpoint.
Classification of Movement-Related Oscillations in sEEG Recordings with Machine Learning

Previous electrophysiological research has characterized canonical oscillatory patterns associated with movement mostly from recordings of primary sensorimotor cortex. Less work has attempted to decode movement based on electrophysiological recordings from a broader array of brain areas such as those sampled by stereoelectroencephalography (sEEG). Here we decoded movement using a linear support vector machine (SVM). We were able to accurately classify sEEG spectrograms during a keypress movement in a task versus those during the inter-trial interval. Furthermore, the important time-frequency patterns for this classification recapitulated findings from previous studies that used non-invasive electroencephalography (EEG) and electrocorticography (ECoG) and identified brain regions that were not associated with movement in previous studies. Specifically, we found these previously described patterns: beta (13 - 30 Hz) desynchronization, beta synchronization (rebound), pre-movement alpha (8 - 15 Hz) modulation, a post-movement broadband gamma (60 - 90 Hz) increase and an event-related potential. These oscillatory patterns were newly observed in a wide range of brain areas accessible with sEEG that are not accessible with other electrophysiology recording methods. For example, the presence of beta desynchronization in the frontal lobe was more widespread than previously described, extending outside primary and secondary motor cortices. We provide evidence for a system of putative motor networks that exhibit unique oscillatory patterns by describing the anatomical extent of the movement-related oscillations that were observed most frequently across all sEEG contacts. Significance Statement Several major motor networks have been previously delineated in humans, however, much less is known about the population-level oscillations that coordinate this neural circuitry, especially in cortex. Therapies that modulate brain circuits to treat movement disorders, such as deep brain stimulation (DBS), or use brain signals to control movement, such as brain-computer interfaces (BCIs), rely on our basic scientific understanding of this movement neural circuitry. In order to bridge this gap, we used stereoelectroencephalography (sEEG) collected in human patients being monitored for epilepsy to assess oscillatory patterns during movement.
Osmotic stress via calmodulin lead to the formation of stress granule in Drosophila S2 cells

Cellular stress of S2 cells leads to the formation of stress assemblies by phase separation of cytoplasmic components. We have shown that the cellular stresses of either high increase of the NaCl concentration in the extracellular medium, or a moderate one combined to amino acid starvation, leads to the formation of Sec bodies where components of the endoplasmic Reticulum exit sites (ERES) coalesce. These extracellular stresses lead to both the activation of salt inducible kinase (SIK), and to ER stress triggering the activation of the two downstream kinases IRE1 and PERK. Interestingly, the same stresses also result in the formation of a second stress assembly, the stress granules, which stores specific RNAs and RNA binding proteins. Here we asked whether stress granule formation is governed by the same pathways as Sec bodies. However, we found that the inhibition of SIK, IRE1 and PERK does not affect stress granule formation. Instead, we found that osmotic stress through the addition of either salts (including calcium chloride) or sucrose leads to the formation of stress granules. Interestingly, stress granule formation is partly modulated by calmodulin activation, suggesting the involvement of calcium signaling. Furthermore, as Sec body formation is driven by entirely different pathways, these results show that the same cells under the same stress, form two different stress assemblies by non-overlapping downstream pathway activation, perhaps explaining that they do not coalescence into a single structure.
NDR1/2 kinases regulate membrane trafficking, enable efficient autophagy and prevent neurodegeneration

Autophagy is essential for neuronal development and its deregulation contributes to neurodegenerative diseases. NDR1 and NDR2 are highly conserved kinases implicated in neuronal development, mitochondrial health and autophagy, but how they affect mammalian brain development in vivo is not known. Using single and double Ndr1/2 knockout mouse models we show that, dual, but not individual loss of Ndr1/2 in neurons causes neurodegeneration during brain development, but also in adult mice. Proteomic and phosphoproteomic comparisons between Ndr1/2 knockout and control brains revealed novel kinase substrates and indicated that endocytosis is significantly affected in the absence of NDR1/2. We validated the endocytic protein, Raph1/Lpd1 as a novel NDR1/2 substrate and showed that both NDR1/2 and Raph1 are critical for endocytosis and membrane recycling. In NDR1/2 knockout brains, we observed prominent accumulation of transferrin receptor, p62 and ubiquitinated proteins, indicative of a major impairment of protein homeostasis. Furthermore, the levels of LC3-positive autophagosomes were reduced in knockout neurons, implying that reduced autophagy efficiency mediates p62 accumulation and neurotoxicity. Mechanistically, pronounced mislocalisation of the transmembrane autophagy protein ATG9A at the neuronal periphery, impaired axonal ATG9A trafficking and increased ATG9A surface levels further confirm defects in membrane trafficking and could underlie the impairment in autophagy. We provide novel insight into the roles of NDR1/2 kinases in maintaining neuronal health. Highlights Dual neuronal Ndr1 and Ndr2 knockout during development or in adult mice causes neurodegeneration. Phosphoproteomics comparison of Ndr1/2 knockouts with control littermates shows endocytosis and membrane trafficking to be affected and reveals novel substrates. Raph1/Lamellipodin is a novel NDR1/2 substrate that is required for TfR endocytosis. Ndr1/2 knockout brains exhibit a severe defect in ubiquitinated protein clearance and reduced autophagy. NDR1/2 and Raph1 are required for the trafficking of the only transmembrane autophagy protein, ATG9A.
Cell type profiling in salamanders identifies innovations in vertebrate forebrain evolution

The evolution of advanced cognition in vertebrates is associated with two independent innovations in the forebrain: the six-layered neocortex in mammals and the dorsal ventricular ridge (DVR) in sauropsids (reptiles and birds). How these novelties arose in vertebrate ancestors remains unclear. To reconstruct forebrain evolution in tetrapods, we built a cell type atlas of the telencephalon of the salamander Pleurodeles waltl. Our molecular, developmental, and connectivity data indicate that parts of the sauropsid DVR trace back to tetrapod ancestors. In contrast, the salamander dorsal pallium is devoid of cellular and molecular characteristics of the mammalian neocortex, yet shares similarities with entorhinal cortex and subiculum. Our findings chart the series of innovations that resulted in the emergence of the sauropsid DVR, and the mammalian six-layered neocortex.
Effects of haemosporidian co-infection and parasitemia on reproductive strategies in a polymorphic species

Host-parasite interactions play a significant role in evolution. Parasite infections impose fitness costs that can trigger trade-off responses in host reproductive strategies. Individuals can invest limited resources in parasite defense, such as stimulating the immune system, or perform terminal reproductive investment. Here, we investigated how haemosporidian co-infection and parasitemia influence different reproductive strategies in a polymorphic bird species (the white-throated sparrow, Zonotrichia albicollis). We provided an account of the impacts of co-infection and parasitemia on host reproductive success and reproductive strategies in response to parasite infection. We tested the effect of co-infection and parasitemia on reproductive success (fledgling number, extra-pair paternity, ratio social/genetic offspring) and the effect of parental infection on nestling quality (mean nestling growth rate and body condition). We found that co-infection increases reproductive extra-pair paternity and nestling mean body condition. Parental high parasitemia positively impacts the ratio of genetic offspring belonging to the social father and has mixed results on nestling quality. We observed that co-infection in females and parasitemia in males might trigger a switch in reproductive strategy towards a terminal investment for co-infected individuals. In contrast, high parasitemia in females negatively impacted their offspring fitness, possibly due to the reallocation of resources for fighting the infection.
Social Learning of a Spatial Task by Observation Alone

Interactions between conspecifics are central to the acquisition of useful memories in the real world. Observational learning, i.e., learning a task by observing the success or failure of others, has been reported in many species, including rodents. However, previous work in rats with NMDA-receptor blockade has shown that even extensive observation of an unexplored space through a clear barrier is not sufficient to generate a stable hippocampal representation of that space. This raises the question of whether rats can learn a spatial task in a purely observed space from watching a conspecific, and if so, does this somehow stabilize their hippocampal representation? To address these questions, we designed an observational spatial task in a two-part environment that is nearly identical to that of the aforementioned electrophysiological study, in which an observer rat watches a demonstrator animal to learn the location of a hidden reward. Our results demonstrate that rats do not need to physically explore an environment to learn a reward location, provided a conspecific demonstrates where it is. We also show that the behavioral memory is not affected by NMDA receptor blockade, suggesting that the spatial representation underlying the behavior has been consolidated by observation alone.
Resistance of mitochondrial DNA to chemical-induced germline mutations is independent of mitophagy in C. elegans

Mitochondrial DNA (mtDNA) is prone to mutation in aging and over evolutionary time, yet the processes that regulate the accumulation of de novo mtDNA mutations and modulate mtDNA heteroplasmy are not fully elucidated. Mitochondria lack certain DNA repair processes, which could contribute to polymerase error-induced mutations and increase susceptibility to chemical-induced mtDNA mutagenesis. We conducted error-corrected, ultra-sensitive Duplex Sequencing to investigate the effects of two known nuclear genome mutagens, cadmium and Aflatoxin B1, on germline mtDNA mutagenesis in Caenorhabditis elegans. After 1,750 generations, we detected 2,270 single nucleotide mutations. Heteroplasmy is pervasive in C. elegans and mtDNA mutagenesis is dominated by C:G → A:T mutations generally attributed to oxidative damage, yet there was no effect of either exposure on mtDNA mutation frequency, spectrum, or trinucleotide context signature. Mitophagy may play a role in eliminating mtDNA damage or deleterious mutations, and mitophagy-deficient mutants pink-1 and dct-1 accumulated significantly higher levels of mtDNA damage compared to wild-type C. elegans after exposures. However, there were only small differences in overall mutation frequency, spectrum, or trinucleotide context signature compared to wild-type after 3,050 generations, across all treatments. These findings suggest mitochondria harbor additional previously uncharacterized mechanisms that regulate mtDNA mutational processes across generations.
The hidden intricacies of aquaporins: Remarkable details in a common structural scaffold

Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow through cell membranes at no expense of solute discrimination. In spite of a plethora of solved AQP structures, many structural details remain hidden. Here, by combining extensive sequence- and structural-based analysis of a unique set of 20 non-redundant high-resolution structures and molecular dynamics simulations of 4 representatives, we identify key aspects of AQP stability, gating, selectivity, pore geometry and oligomerization, with a potential impact on channel functionality. We challenge the general view of AQPs possessing a continuous open water pore and depict that AQPs selectivity is not exclusively shaped by pore lining residues but also by the relative arrangement of transmembrane helices. Moreover, our analysis reveals that hydrophobic interactions constitute the main determinant of protein thermal stability. Finally, we establish a novel numbering scheme of the conserved AQP scaffold facilitating direct comparison and prediction of potential structural effects of e.g. disease-causing mutations. Additionally, our results pave the way for the design of optimized AQP water channels to be utilized in biotechnological applications.
3’UTR-directed, kinase proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells

C/EBPβ is a potent regulator of RAS-induced senescence (RIS) and the SASP. C/EBPβ is post- translationally activated in RIS cells by the effector kinases ERK1/2 and CK2, but in tumor cells activation is suppressed by the CEBPB 3’UTR. 3′UTR regulation of protein activity (UPA) requires a G/U-rich element (GRE) and its cognate binding protein, HuR. These components segregate CEBPB transcripts away from a perinuclear compartment harboring ERK1/2 and CK2, restricting C/EBPβ from its activating kinases. We report here that the mRNA decay proteins UPF1 and Staufen1/2 are essential UPA factors enriched within the perinuclear cytoplasm. STAU1/2 colocalize with CK2 on perinuclear signaling endosomes where they promote localized CEBPB mRNA decay. UPF1 or STAU1/2 depletion in tumor cells increased CEBPB transcripts adjacent to CK2 foci, coinciding with C/EBPβ activation and senescence. The GRE and an adjacent STAU binding site act to suppress C/EBPβ-mediated senescence, while a separate 3’UTR region inhibits SASP induction. Accordingly, KrasG12D-driven lung tumors in mice carrying a Cebpb GRE deletion rarely progressed to malignant adenocarcinomas. Our findings identify kinase-proximal mRNA decay as a novel mechanism to inhibit C/EBPβ activating modifications in tumor cells to facilitate senescence bypass.
Herbivore life histories are altered by drought stress in their hosts plants

Drought associated with climate change can stress plants, altering their interactions with 20 phytophagous arthropods. Dryness not only impacts cultivated plants but also their parasites, which 21 in some cases are favoured by drought. Herbivorous arthropods feeding on drought-stressed plants 22 typically produce bigger offspring and develop faster. However, how much responses to abiotic 23 factors differ among populations of a species remains poorly documented. Here, we evaluate 24 variability among populations of a major agricultural pest, the two spotted spider mite, Tetranychus 25 urticae , in response to drought-stress. We compare key life-history parameters of twelve populations 26 that originate from climates ranging from wet and cool Atlantic locations to medium to dry hot 27 Mediterranean locations. We evaluated how plant drought stress affects four life history traits: 28 development time, fecundity, sex-ratio and emigration rate in an experiment comparing well- 29 watered and drought-stressed bean plants. Mites feeding on drought-stressed plants developed 30 faster and attempted to leave leaves less often, and young females were more fecund. The mites 31 from wet temperate climates exhibited greater plasticity between the two water regimes than mites 32 originating from dryer and hot climates. Thus, climate in the area of origin influences mite response 33 to drought. 34
Software process improvement programs: What are the pitfalls that lead to abandonment?

While many organizations successfully embrace and experience software process improvement (SPI) benefits, others abandon the effort before realizing the total potential result of an SPI initiative. Therefore, researchers' interest in understanding the reasons why software organizations that have a successful start in adopting SPI abandon improvement initiatives after evaluation has increased. Thus, this work aims to investigate how the abandonment of SPI programs based on maturity models occurs after the evaluation. The multiple case study method was used with eight organizations. Data were analyzed using Grounded Theory open and axial coding procedures. The results show that SPI initiatives failed because of internal factors (people, SPI project management, organizational aspects, and processes) and external factors to the organizational context (country economic crisis, outsourcing, governmental political influence, and external pressure from the client). As a contribution, we highlight the identification of these factors that organizations can use to learn about their initiatives and avoid pitfalls that can lead to the abandonment of SPI.
Cultivating User-ship? Developing a Circular System for the Acquisition and Use of Baby Clothing

Abstract This paper sets out to explore the significance of the production, sale and consumption of clothing as a product service system rather than as the more familiar “shop-window” product offered for individual sale. While there are a number of studies of occupational clothing systems, relatively little is known about clothing systems tailored for the private market. This article presents a case study of a recently launched subscription service for baby clothing, which offered a range of eco-certified garments for rent as more or less complete wardrobes. Drawing on fashion scholar Kate Fletcher’s concept of “techniques and processes of use” and on Actor-Network Theory, the study follows the company from its tentative beginnings through its first year in a process that provided an opportunity to study a clothing system “in the making. ” Particular interest is paid to how the leasing system and product design features are mutually constitutive and to how the system interconnects with practices of use and maintenance among subscribers with a special interest in laundry regimes and durability. Taking this empirical example as its point of departure, the article concludes with a discussion of how product qualities and processes of use are intertwined and co-constructed.