Miracle-dz/UniFAR-FTUs huggingface dataset:
Guidelines for Galileo Assisted Commercial Authentication Service Implementation

The European Global Navigation Satellite System (GNSS), Galileo, is currently developing and implementing new added-value services aiming to provide increased security and robustness against malicious attacks (e.g. spoofing), like Open Service Navigation Message Authentication (OSNMA), to authenticate the data symbols, or Commercial Authentication Service (CAS), to authenticate the ranging signal. This paper analyses the impact, from a signal-level performance, of the different parameters involved in the service definition of the Assisted Commercial Authentication Service (ACAS) mode, and presents some guidelines for the implementation of this new service, focusing on the acquisition procedure. We also offer some simulation results showing the performance in different scenarios.
A Deep Study of the Effects and Fixes of Server-Side Request Races in Web Applications

Server-side web applications are vulnerable to request races. While some previous studies of real-world request races exist, they primarily focus on the root cause of these bugs. To better combat request races in server-side web applications, we need a deep understanding of their characteristics. In this paper, we provide a complementary focus on race effects and fixes with an enlarged set of request races from web applications developed with Object-Relational Mapping (ORM) frameworks. We revisit characterization questions used in previous studies on newly included request races, distinguish the external and internal effects of request races, and relate requestrace fixes with concurrency control mechanisms in languages and frameworks for developing server-side web applications. Our study reveals that: (1) request races from ORM-based web applications share the same characteristics as those from raw-SQL web applications; (2) request races violating application semantics without explicit crashes and error messages externally are common, and latent request races, which only corrupt some shared resource internally but require extra requests to expose the misbehavior, are also common; and (3) various fix strategies other than using synchronization mechanisms are used to fix request races. We expect that our results can help developers better understand request races and guide the design and development of tools for combating request races.
Amyloid-β Oligomers Serve as Nucleation Sites for α-Synuclein Aggregation

Neurodegenerative diseases are associated with the formation of amyloids in the nervous system. An increasing number of cases where amyloids of the same protein are found in different dementias is being reported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the protein α-synuclein are traditionally considered hallmarks of Alzheimer’s and Parkinson’s diseases, respectively. However, the co-occurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we provide new evidence about the protein composition of aggregates formed when these two proteins are co-present. We show that soluble species of amyloid-β can induce the aggregation of α-synuclein. The amyloid fibrils formed under these conditions are solely composed of α-synuclein to which amyloid-β can be found associated, but not as part of the core of the fibrils. Our data take us one step closer to understanding the complex nature of heterogenous aggregation in disease contexts which may aid clinical diagnosis and the development of therapeutic interventions.
Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media

The dynamics of blood flow in the smallest vessels and passages of the human body, where the cellular character of blood becomes prominent, plays a dominant role in the transport and exchange of solutes. Recent studies have revealed that the micro-haemodynamics of a vascular network is underpinned by its interconnected structure, and certain structural alterations such as capillary dilation and blockage can substantially change blood flow patterns. However, for extravascular media with disordered microstructure (e.g., the porous intervillous space in the placenta), it remains unclear how the medium’s structure affects the haemodynamics. Here, we simulate cellular blood flow in simple models of canonical porous media representative of extravascular biological tissue, with corroborative microfluidic experiments performed for validation purposes. For the media considered here, we observe three main effects: first, the relative apparent viscosity of blood increases with the structural disorder of the medium; second, the presence of red blood cells (RBCs) dynamically alters the flow distribution in the medium; third, increased structural disorder of the medium can promote a more homogeneous distribution of RBCs. Our findings contribute to a better understanding of the cellscale haemodynamics that mediates the relationship linking the function of certain biological tissues to their microstructure.
Seasonal plasticity in morphology and metabolism differs between migratory North American and resident Costa Rican monarch butterflies

Environmental heterogeneity in temperate latitudes is expected to maintain seasonally plastic life-history strategies that include the tuning of morphologies and metabolism that support overwintering. For species that have expanded their ranges into tropical latitudes, it is unclear the extent to which the capacity for plasticity will be maintained or will erode with disuse. The migratory generations of the North American (NA) monarch butterfly Danaus plexippus lead distinctly different lives from their summer generation NA parents and their tropical descendants living in Costa Rica (CR). NA migratory monarchs postpone reproduction, travel thousands of kilometers south to overwinter in Mexico, and subsist on little food for months. Whether recently dispersed populations of monarchs such as those in Costa Rica, which are no longer subject to selection imposed by migration, retain ancestral seasonal plasticity is unclear. To investigate differences in seasonal plasticity, we reared NA and CR monarchs in summer and autumn in Illinois, USA, and measured seasonal reaction norms for aspects of morphology and metabolism related to flight. NA monarchs were seasonally plastic in forewing and thorax size, increasing wing area and thorax to body mass ratio in autumn. While CR monarchs increased thorax mass in autumn, they did not increase the area of the forewing. NA monarchs maintained similar resting and maximal flight metabolic rates across seasons. However, CR monarchs had elevated metabolic rates in autumn. Our findings suggest that the recent expansion of monarchs into habitats that support year-round breeding may be accompanied by (1) the loss of some aspects of morphological plasticity as well as (2) the underlying physiological mechanisms that maintain metabolic homeostasis in the face of temperature heterogeneity.
Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-Cov-2 Spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify local and global effects of mutations in the complexes, identify structural stability centers, characterize binding energy hotspots and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific structural stability signatures of the spike complexes that can dictate the pattern of mutational escape. By employing an integrated analysis of conformational dynamics and binding energetics, we found that the potent antibodies that efficiently neutralize Omicron spike variant can form the dominant binding energy hotpots with the conserved stability centers in which mutations may be restricted by the requirements of the folding stability and binding to the host receptor. The results show that protein stability and binding energetics of the SARS-CoV-2 spike complexes with the panel of cross-reactive ultrapotent antibodies are tolerant to the constellation of Omicron mutations. A network-based perturbation approach for mutational profiling of allosteric residues potentials revealed how antibody binding can modulate allosteric interactions and identified allosteric control points that can form vulnerable sites for mutational escape. This study suggested a mechanism in which the pattern of specific escape mutants for ultrapotent antibodies may not be solely determined by the binding interaction changes but are driven by a complex balance and tradeoffs between different local and global factors including the impact of mutations on structural stability, binding strength, long-range interactions and fidelity of allosteric signaling.
Two Types of Motor Inhibition after Action Errors in Humans

Adaptive behavior requires the ability to appropriately react to action errors. Post-error slowing (PES) of response times is one of the most reliable phenomena in human behavior. It has been proposed that PES is partially achieved through inhibition of the motor system. However, there is no direct evidence for this link, or indeed, that the motor system is physiologically inhibited after errors altogether. Here, we used transcranial magnetic stimulation and electromyography to measure corticospinal excitability (CSE) across four experiments using a Simon task, in which female and male human participants sometimes committed errors. Errors were followed by reduced CSE at two different time points and in two different modes. Shortly after error commission (250 ms), CSE was broadly suppressed (i.e., even task-unrelated motor effectors were inhibited). During the preparation of the subsequent response, CSE was specifically reduced at task-relevant effectors only. This latter effect was directly related to PES, with stronger CSE suppression accompanying greater PES. This suggests that PES is achieved through increased inhibitory control during post-error responses. To provide converging evidence, we then reanalyzed an openly available EEG dataset that contained both Simon- and Stop-signal tasks using independent component analysis. We found that the same neural source component that indexed action cancellation in the stop-signal task also showed clear PES-related activity during post-error responses in the Simon task. Together, these findings provide evidence that post-error adaptation is partially achieved through motor inhibition. Moreover, inhibition is engaged in two modes (first nonselective, then selective), aligning with recent multistage theories of error processing. SIGNIFICANCE STATEMENT It is a common observation that humans implement a higher degree of caution when repeating an action during which they just committed a mistake. In the laboratory, such increased “caution” is reflected in post-error slowing of response latencies. Many competing theories exist regarding the precise neural mechanisms underlying post-error slowing. Using transcranial magnetic stimulation, we show that, after error commission, the human corticomotor system is momentarily inhibited, both immediately after an error and during the preparation of the next action. Moreover, motor inhibition during the latter time period is directly predictive of post-error slowing. This shows that inhibitory control is a key mechanism humans engage to regulate their own behavior in the aftermath of error commission.
Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures

Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that result from impaired longitudinal growth of denervated muscles. This deficit in muscle growth is driven by increased proteasome-mediated protein degradation, suggesting a dysregulation of muscle proteostasis. The myostatin (MSTN) pathway, a prominent muscle-specific regulator of proteostasis, is a putative signaling mechanism by which neonatal denervation could impair longitudinal muscle growth, and thus a potential target to prevent NBPI-induced contractures. Through a mouse model of NBPI, our present study revealed that pharmacologic inhibition of MSTN signaling induces hypertrophy, restores longitudinal growth, and prevents contractures in denervated muscles of female but not male mice, despite inducing hypertrophy of normally innervated muscles in both sexes. Additionally, the MSTN-dependent impairment of longitudinal muscle growth after NBPI in female mice is associated with perturbation of 20S proteasome activity, but not through alterations in canonical MSTN signaling pathways. These findings reveal a sex dimorphism in the regulation of neonatal longitudinal muscle growth and contractures, thereby providing insights into contracture pathophysiology, identifying a potential muscle-specific therapeutic target for contracture prevention, and underscoring the importance of sex as a biological variable in the pathophysiology of neuromuscular disorders.
One model fits all: Combining inference and simulation of gene regulatory networks

The rise of single-cell data highlights the need for a nondeterministic view of gene expression, while offering new opportunities regarding gene regulatory network inference. We recently introduced two strategies that specifically exploit time-course data, where single-cell profiling is performed after a stimulus: HARISSA, a mechanistic network model with a highly efficient simulation procedure, and CARDAMOM, a scalable inference method seen as model calibration. Here, we combine the two approaches and show that the same model driven by transcriptional bursting can be used simultaneously as an inference tool, to reconstruct biologically relevant networks, and as a simulation tool, to generate realistic transcriptional profiles emerging from gene interactions. We verify that CARDAMOM quantitatively reconstructs causal links when the data is simulated from HARISSA, and demonstrate its performance on experimental data collected on in vitro differentiating mouse embryonic stem cells. Overall, this integrated strategy largely overcomes the limitations of disconnected inference and simulation. Author summary Gene regulatory network (GRN) inference is an old problem, to which single-cell data has recently offered new challenges and breakthrough potential. Many GRN inference methods based on single-cell transcriptomic data have been developed over the last few years, while GRN simulation tools have also been proposed for generating synthetic datasets with realistic features. However, except for benchmarking purposes, these two fields remain largely disconnected. In this work, building on a combination of two methods we recently described, we show that a particular GRN model can be used simultaneously as an inference tool, to reconstruct a biologically relevant network from time-course single-cell gene expression data, and as a simulation tool, to generate realistic transcriptional profiles in a non-trivial way through gene interactions. This integrated strategy demonstrates the benefits of using the same executable model for both simulation and inference.
Variation in symbiont density is linked to changes in constitutive immunity in the facultatively symbiotic coral, Astrangia poculata

Scleractinian corals are essential ecosystem engineers, forming the basis of coral reef ecosystems. However, these organisms are in decline globally, in part due to rising disease prevalence. Most corals are dependent on symbiotic interactions with single-celled algae from the family Symbiodiniaceae to meet their nutritional needs, however suppression of host immunity may be essential to this relationship. To explore immunological consequences of algal symbioses in scleractinian corals, we investigated constitutive immune activity in the facultatively symbiotic coral, Astrangia poculata. We compared immune metrics (melanin synthesis, antioxidant production, and antibacterial activity) between coral colonies of varying symbiont density. Symbiont density was positively correlated to both antioxidant activity and melanin concentration. Our results suggest that the relationship between algal symbiosis and host immunity may be more complex than originally hypothesized and highlight the need for nuanced approaches when considering these relationships.
Inhibited KdpFABC resides in an E1 off-cycle state

KdpFABC is a high-affinity prokaryotic K+ uptake system that forms a functional chimera between a channel-like subunit (KdpA) and a P-type ATPase (KdpB). At high K+ levels, KdpFABC needs to be inhibited to prevent excessive K+ accumulation to the point of toxicity. This is achieved by a phosphorylation of the serine residue in the TGES162 motif in the A domain of the pump subunit KdpB (KdpBS162-P). Here, we explore the structural basis of inhibition by KdpBS162 phosphorylation by determining the conformational landscape of KdpFABC under inhibiting and non-inhibiting conditions. Under turnover conditions, we identified a new inhibited KdpFABC conformation that we termed E1-P tight, which is not part of the canonical Post-Albers transport cycle of P-type ATPases. It likely represents the biochemically described stalled E1-P state adopted by KdpFABC upon KdpBS162 phosphorylation. The E1-P tight state exhibits a compact fold of the three cytoplasmic domains and is likely adopted when the transition from high-energy E1-P states to E2-P states is unsuccessful. This study represents a structural characterization of a biologically relevant off-cycle state in the P-type ATPase family and supports the emerging discussion of P-type ATPase regulation by such conformations.
Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptional repression during oogenesis

GLP (EHMT1) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with G9A (EHMT2). Here, we investigate the role of GLP in the oocyte in comparison to G9A using oocyte-specific conditional knockout mouse models (G9a cKO, Glp cKO, G9a-Glp cDKO). Loss of GLP in Glp cKO and G9a-Glp cDKO oocytes re-capitulated meiotic defects observed in the G9a cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Glp cKO and G9a-Glp cDKO oocytes beyond that observed in the G9a cKO. Consequently, loss of GLP in oogenesis results upon fertilisation in mid-gestation embryonic lethality. To assess the molecular functions of GLP and G9A, we applied a multi-omics approach, supported by immunofluorescence, to identify changes in epigenomic, transcriptomic and proteomic signatures in cKO oocytes. H3K9me2 was equally depleted in all cKO oocytes, whereas H3K9me1 was decreased only upon loss of GLP. The transcriptome, DNA methylome and proteome were markedly more affected in G9a-Glp cDKO than G9a cKO oocytes, with transcriptional de-repression associated with increased protein abundance and gains in genic DNA methylation in G9a-Glp cDKO oocytes. Together, our findings suggest that GLP contributes to transcriptional repression in the oocyte, independent of G9A, and is critical for oogenesis and oocyte developmental competence.
Mosacism in Cutaneous Disorders

Genetic mosaicism arises when a zygote harbors two or more distinct genotypes, typically due to de novo, somatic mutation during embryogenesis. The clinical manifestations largely depend on the differentiation status of the mutated cell; earlier mutations target pluripotent cells and generate more widespread disease affecting multiple organ systems. If gonadal tissue is spared—as in somatic genomic mosaicism—the mutation and its effects are limited to the proband, whereas mosaicism also affecting the gametes, such as germline or gonosomal mosaicism, is transmissible. Mosaicism is easily appreciated in cutaneous disorders, as phenotypically distinct mutant cells often give rise to lesions in patterns determined by the affected cell type. Genetic investigation of cutaneous mosaic disorders has identified pathways central to disease pathogenesis, revealing novel therapeutic targets. In this review, we discuss examples of cutaneous mosaicism, approaches to gene discovery in these disorders, and insights into molecular pathobiology that have potential for clinical translation.
ORALLY DELIVERED PHENCYCLIDINE: EFFECTS OF FEEDING CONDITIONS

Two experiments addressed the effects of food satiation and deprivation on oral self-administration of two concurrently available phencyclidine concentrations. In the first experiment, 8 rhesus monkeys self-administered either of two concentrations of phencyclidine ("PCP, angel dust") and water under concurrent fixed-ratio 16 schedules. One concentration was always held constant (0.25 mg/mL) while a series of other phencyclidine concentrations, ranging from 0 (water) to 1.0 mg/mL, was presented in a nonsystematic order. Initially the monkeys were tested while food satiated, and the procedure was then repeated during food deprivation. The monkeys usually selected the higher concentration within the first few minutes of the session, indicating that taste and/or other immediate postingestional effects were important factors. Contrary to a number of previous reports, there were no consistent differences across subjects in the mean number of liquid deliveries or mean drug intake (mg/kg) during food satiation and deprivation. However, for all monkeys the within-session time course of responding during food satiation consistently differed from that during deprivation. A second experiment assessed whether the failure to find consistent differences in drug intake during food satiation and deprivation had been due to the history of concurrent access to different phencyclidine concentrations or to the extended experience with phencyclidine under food-satiation conditions. Six additional monkeys (Group 2) were exposed to the phencyclidine self-administration procedure (during food satiation and deprivation) for the same length of time as the monkeys in Experiment 1 (Group 1), except they received only concurrent access to phencyclidine (0.25 mg/mL) and water. Both groups then received concurrent access to phencyclidine and water during five repeated cycles of food deprivation and satiation. There were also marked individual differences in Group 2: During food satiation, 2 of the monkeys' responding increased, 1 showed no change, and 3 decreased. Examination of a number of historical variables indicated that the greater the percentage of total sessions spent during food satiation with phencyclidine available (before these experiments began), the greater the amounts of phencyclidine consumed during food satiation and the smaller the differences in phencyclidine intake when the two feeding conditions were compared.