Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterizing, exploiting, and detecting DMA code injection vulnerabilities in the presence of an IOMMU

Direct memory access (DMA) renders a system vulnerable to DMA attacks, in which I/O devices access memory regions not intended for their use. Hardware input-output memory management units (IOMMU) can be used to provide protection. However, an IOMMU cannot prevent all DMA attacks because it only restricts DMA at page-level granularity, leading to sub-page vulnerabilities. Current DMA attacks rely on simple situations in which write access to a kernel pointer is obtained due to sub-page vulnerabilities and all other attack ingredients are available and reside on the same page. We show that DMA vulnerabilities are a deep-rooted issue and it is often the kernel design that enables complex and multistage DMA attacks. This work presents a structured top-down approach to characterize, exploit, and detect them. To this end, we first categorize sub-page vulnerabilities into four types, providing insight into the structure of DMA vulnerabilities. We then identify a set of three vulnerability attributes that are sufficient to execute code injection attacks. We built analysis tools that detect these sub-page vulnerabilities and analyze the Linux kernel. We found that 72% of the device drivers expose callback pointers, which may be overwritten by a device to hijack the kernel control flow. Aided by our tools' output, we demonstrate novel code injection attacks on the Linux kernel; we refer to these as compound attacks. All previously reported attacks are single-step, with the vulnerability attributes present in a single page. In compound attacks, the vulnerability attributes are initially incomplete. However, we demonstrate that they can be obtained by carefully exploiting standard OS behavior.
Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial

Neutralization of endothelial lipase with a monoclonal antibody raises functional HDL in both nonhuman primates and in healthy humans. Limiting lipase to control cholesterol Strategies to reduce low-density lipoprotein cholesterol (LDL-C) while promoting high-density lipoprotein cholesterol (HDL-C) are of interest for combating atherosclerosis. Le Lay et al. developed a monoclonal antibody that neutralizes endothelial lipase, an enzyme that hydrolyzes HDL. Antibody treatment in nonhuman primates increased plasma HDL-C, and pretreatment with a PCSK9-neutralizing antibody reduced LDL-C. Results from a phase 1 study showed that the endothelial lipase-neutralizing antibody was safe and elevated HDL-C. This approach may help reduce cardiovascular risk. Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.
Typifications and nomenclatural notes in the genus Photinia and Pyrus (Rosaceae)1

Abstract. Lectotypifications of Photinia beckii, Ph. chingiana, Ph. crassifolia, Ph. crassifolia var. denticulata (synonym of Ph. crassifolia), Ph. glomerata, Ph. serrulata var. congestiflora (synonym of Ph. glomerata), Ph. lindleyana var. yunnanensis (synonym of Ph. glomerata), Ph. mairei, Ph. serrulata var. prunifolia (synonym of Ph. prunifolia), Ph. serrulata var. obovata, Ph. stenophylla, Ph. undulata var. formosana (synonym of Ph. davidiana var. formosana), and Pyrus cavaleriei (synonym of Ph. davidiana) are designated here. The protologues of these names and the original materials are evaluated. Taxonomic notes discussing the selection or correction of type specimens are given for each name, and, when possible, known isolectotypes are also cited.
Effect of a single bout of morning or afternoon exercise on glucose fluctuation in young healthy men

The timing of exercise plays an important role in the effect of the exercise on physiological functions, such as substrate oxidation and circadian rhythm. Exercise exerts different effects on the glycemic response to exercise and meal intake depending on when the exercise performed. Here, we comprehensively investigated the effects of the timing (morning or afternoon) of exercise on glucose fluctuation on the basis of several indices: glycemic variability over 24 h (24‐h SD), J‐index, mean amplitude of glucose excursions (MAGE), continuous overall net glycemic action (CONGA), and detrended fluctuation analysis (DFA). Eleven young men participated in 3 trials in a repeated measures design in which they performed a single bout of exercise at 60% of their maximal oxygen uptake for 1 h beginning either at 7:00 (morning exercise), 16:00 (afternoon exercise), or no exercise (control). Glucose levels were measured using a continuous glucose monitoring system (CGMs). Glucose fluctuation was slightly less stable when exercise was performed in the afternoon than in the morning, indicated by higher CONGA at 2 h and α2 in DFA in the afternoon exercise trial than in the control trial. Additionally, decreased stability in glucose fluctuation in the afternoon exercise trial was supported by the descending values of the other glucose fluctuation indices in order from the afternoon exercise, morning exercise, and control trials. Meal tolerance following exercise was decreased after both exercise trials. Glucose levels during exercise were decreased only in the afternoon exercise trial, resulting in less stable glucose fluctuations over 24 h.
Behavior-dependent spatial maps enable efficient theta phase coding

Navigation through space involves learning and representing relationships between past, current and future locations. In mammals, this might rely on the hippocampal theta phase code, where in each cycle of the theta oscillation, spatial representations start behind the animal’s location and then sweep forward. However, the exact relationship between phase and represented and true positions remains unclear. Developing a quantitative framework for the theta phase code, we formalize two previous notions: in spatial sweeps, different phases of theta encode positions at fixed distances behind or ahead of the animal, whereas in temporal sweeps, they encode positions reached at fixed time intervals into the past or future. These two schemes predict very different position representations during theta depending on the animal’s running speed. Paradoxically, in some studies sweep length has been shown to increase proportionally with running speed, consistent with temporal sweeps, whereas in other studies individual place field parameters such as field size and phase precession slope were shown to remain constant with speed, consistent with spatial sweeps. Here, we introduce a third option: behavior-dependent sweeps, according to which sweep length and place field properties vary across the environment depending on the running speed characteristic of each location. Analyzing single-cell and population variables in parallel in recordings from rat CA1 place cells and comparing them to model simulations, we show that behavior-dependent sweeps uniquely account for all relevant variables. This coding scheme combines features and advantages of both spatial and temporal sweeps, revealing an efficient hippocampal code. Significance To learn the structure of the world and the consequences of our actions, information about the past must be carried through to the present and linked to what is currently happening. To plan, desired future states and the predicted outcomes of actions must be represented. In mammals, including humans, hippocampal neurons are thought to encode such representations of past, present and future states at different phases of the theta oscillation. However, the precise hippocampal phase code remains unknown. We show that two previous ideas are incompatible with each other and with rat experimental data. So, we propose a new coding scheme that synthesizes features from both ideas and accounts for all relevant observations.
Mucin-mimetic glycan arrays integrating machine learning for analyzing receptor pattern recognition by influenza A viruses

Influenza A viruses (IAVs) exploit host glycans in airway epithelial mucosa to gain entry and initiate infection. Rapid detection of changes in IAV specificity towards host glycan classes can provide early indication of virus transmissibility and infection potential. IAVs use hemagglutinins (HA) to bind sialic acids linked to larger glycan structures and a switch in HA specificity from α2,3-to α2,6-linked sialoglycans is considered a prerequisite for viral transmission from birds to humans. While the changes in HA structure associated with the evolution of binding phenotype have been mapped, the influence of glycan receptor presentation on IAV specificity remains obscured. Here, we describe a glycan array platform which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation in the mucinous glycocalyx, including glycan type and valency of the glycoconjugates and their surface density, impact IAV binding. We found that H1N1 virus produced in embryonated chicken eggs, which recognizes both receptor types, exclusively engaged mucin-mimetics carrying α2,3-linked sialic acids in their soluble form. The virus was able utilize both receptor structures when the probes were immobilized on the array; however, increasing density in the mucin-mimetic brush diminished viral adhesion. Propagation in mammalian cells produced a change in receptor pattern recognition by the virus, without altering its HA affinity, toward improved binding of α2,6-sialylated mucin mimetics and reduced sensitivity to surface crowding of the probes. Application of a support vector machine (SVM) learning algorithm as part of the glycan array binding analysis efficiently characterized this shift in binding preference and may prove useful to study the evolution of viral responses to a new host.
Protein visualization and manipulation in Drosophila through the use of epitope tags recognized by nanobodies

Expansion of the available repertoire of reagents for visualization and manipulation of proteins will help understand their function. Short epitope tags linked to proteins of interest and recognized by existing binders such as nanobodies facilitate protein studies by obviating the need to isolate new antibodies directed against them. Nanobodies have several advantages over conventional antibodies, as they can be expressed and used as tools for visualization and manipulation of proteins in vivo. Here, we characterize two short (<15 aa) NanoTag epitopes, 127D01 and VHH05) and their corresponding high-affinity nanobodies. We demonstrate their use in Drosophila for in vivo protein detection and re-localization, direct and indirect immunofluorescence, immunoblotting, and immunoprecipitation. We further show that CRISPR-mediated gene targeting provides a straightforward approach to tagging endogenous proteins with the NanoTags. Single copies of the NanoTags, regardless of their location, suffice for detection. This versatile and validated toolbox of tags and nanobodies will serve as a resource for a wide array of applications, including functional studies in Drosophila and beyond.
eIF2α integrates proteotoxic signals both from ER and cytoplasm: Hsp70-Bag3 module regulates HRI-dependent phosphorylation of eIF2α

The major heat shock protein Hsp70 has been implicated in many stages of cancer development. These effects are mediated by a scaffold protein Bag3 that binds to Hsp70 and links it to components of multiple cancer-related signaling pathways. Accordingly, the Hsp70-Bag3 complex has been targeted by small molecules, which showed strong anti-cancer effects. Here, our initial question was how JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3, causes cell death. Breast epithelial cells MCF10A transformed with a single oncogene Her2 showed higher sensitivity to JG-98 then parental MCF10A cells. RNA expression analysis showed that this enhanced sensitivity correlated with higher induction of the UPR genes. Indeed, depletion of the pro-apoptotic UPR responsive transcription factor CHOP significantly protected cells from JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated by JG-98, suggesting that the response was not related to the ER proteotoxicity. Indeed, it was dependent on activation of a distinct cytoplasmic eIF2α kinase HRI. HRI-dependent phosphorylation of eIF2α was also activated by the cytoplasmic proteotoxicity via Hsp70-Bag3 complex, which directly associates with HRI. Dissociation of Hsp70-Bag3 complex led to Bag3-dependent degradation of HRI via autophagy. Therefore, eIF2α integrates proteotoxicity signals from both ER and cytoplasm, and the cytoplasmic response mediates cytotoxicity of the Hsp70-Bag3 inhibitors.
Correction: pUL21 is a viral phosphatase adaptor that promotes herpes simplex virus replication and spread

The herpes simplex virus (HSV)-1 protein pUL21 is essential for efficient virus replication and dissemination. While pUL21 has been shown to promote multiple steps of virus assembly and spread, the molecular basis of its function remained unclear. Here we identify that pUL21 is a virus-encoded adaptor of protein phosphatase 1 (PP1). pUL21 directs the dephosphorylation of cellular and virus proteins, including components of the viral nuclear egress complex, and we define a conserved non-canonical linear motif in pUL21 that is essential for PP1 recruitment. In vitro evolution experiments reveal that pUL21 directly antagonises the activity of the virus-encoded kinase pUS3, with growth and spread of pUL21 PP1-binding mutant viruses being restored when pUS3 activity is disrupted. This study shows that virus-directed phosphatase activity is essential for efficient herpesvirus assembly and spread, highlighting the fine balance between kinase and phosphatase activity required for optimal virus replication.
Human adipose-derived mesenchymal stromal cells from face and abdomen undergo replicative senescence and loss of genetic integrity after long-term culture

Body fat depots are heterogeneous concerning their embryonic origin, structure, exposure to environmental stressors, and availability. Thus, investigating adipose-derived mesenchymal stromal cells (ASCs) from different sources is essential to standardization for future therapies. In vitro amplification is also critical because it may predispose cell senescence and mutations, reducing regenerative properties and safety. Here, we evaluated long-term culture of human facial ASCs (fASCs) and abdominal ASCs (aASCs) and showed that both met the criteria for MSCs characterization, but presented differences in their immunophenotypic profile, and differentiation and clonogenic potentials. The abdominal tissue yielded more ASCs, but facial cells displayed fewer mitotic errors at higher passages. However, both cell types reduced clonal efficiency over time and entered replicative senescence around P12, as evaluated by progressive morphological alterations, reduced proliferative capacity, and SA-β-galactosidase expression. Loss of genetic integrity was detected by a higher proportion of cells showing nuclear alterations and γ-H2AX expression. Our findings indicate that the source of ASCs can substantially influence their phenotype and therefore should be carefully considered in future cell therapies, avoiding, however, long-term culture to ensure genetic stability.
Revealing capture sites and movements by strontium isotope analyses in bones of Caiman yacare in the Beni river floodplain, Bolivia

Studying the distribution of organisms and their movements is fundamental to understand population dynamics. Most studies indicated that crocodilians do not move around much but several studies demonstrated that some species showed movement patterns. Detection of these movements along the individual life is still a challenge. In this study we analyzed the variation of strontium isotopic ratio (87Sr/86Sr) in the femur bones of 70 Caimanya care individuals caught in 16 sites located in five hydrological sectors of the Beni river floodplain in Bolivia. Our results demonstrated for the first time that such a methodology could yield indications about the capture sites and reconstruct individual life history. Analyses of the outer part of the femur of 70 individuals showed that capture sites could be differentiated between sectors and even between sites or groups of sites in each sector. Studies of complete 87Sr/86Sr profiles along the femur, representing the individual’s entire life, were performed on 33 yacares. We found that most of the individuals did not show any significant isotopic variation throughout their lives. This absence of variation could result from a high fidelity to the birth site, and/or from an insignificant isotopic variation between the water bodies through which the animal has potentially moved. However, 24% of the analyzed individuals presented significant variations that can be considered as movements between different habitats. Based on the observed low proportion of moving yacares, we advocated that each water body should be considered an individual management unit.
From partial to whole genome imputation of SARS-CoV-2 for epidemiological surveillance

Background the current SARS-CoV-2 pandemic has emphasized the utility of viral whole genome sequencing in the surveillance and control of the pathogen. An unprecedented ongoing global initiative is increasingly producing hundreds of thousands of sequences worldwide. However, the complex circumstances in which viruses are sequenced, along with the demand of urgent results, causes a high rate of incomplete and therefore useless, sequences. However, viral sequences evolve in the context of a complex phylogeny and therefore different positions along the genome are in linkage disequilibrium. Therefore, an imputation method would be able to predict missing positions from the available sequencing data. Results We developed impuSARS, an application that includes Minimac, the most widely used strategy for genomic data imputation and, taking advantage of the enormous amount of SARS-CoV-2 whole genome sequences available, a reference panel containing 239,301 sequences was built. The impuSARS application was tested in a wide range of conditions (continuous fragments, amplicons or sparse individual positions missing) showing great fidelity when reconstructing the original sequences. The impuSARS application is also able to impute whole genomes from commercial kits covering less than 20% of the genome or only from the Spike protein with a precision of 0.96. It also recovers the lineage with a 100% precision for almost all the lineages, even in very poorly covered genomes (< 20%) Conclusions imputation can improve the pace of SARS-CoV-2 sequencing production by recovering many incomplete or low-quality sequences that would be otherwise discarded. impuSARS can be incorporated in any primary data processing pipeline for SARS-CoV-2 whole genome sequencing.
Genetic mapping of sex and self-incompatibility determinants in the androdioecious plant Phillyrea angustifolia

The diversity of mating and sexual systems in angiosperms is spectacular, but the factors driving their evolution remain poorly understood. In plants of the Oleaceae family, an unusual self-incompatibility (SI) system has been discovered recently, whereby only two distinct homomorphic SI specificities segregate stably. To understand the role of this peculiar SI system in preventing or promoting the diversity of sexual phenotypes observed across the family, an essential first step is to characterize the genetic architecture of these two traits. Here, we developed a high-density genetic map of the androdioecious shrub P. angustifolia based on a F1 cross between a hermaphrodite and a male parent with distinct SI genotypes. Using a double restriction-site associated digestion (ddRAD) sequencing approach, we obtained reliable genotypes for 196 offspring and their two parents at 10,388 markers. The resulting map comprises 23 linkage groups totaling 1,855.13 cM on the sex-averaged map. We found strong signals of association for the sex and SI phenotypes, that were each associated with a unique set of markers on linkage group 12 and 18 respectively, demonstrating inheritance of these traits as single, independent, mendelian factors. The P. angustifolia linkage map shows robust synteny to the olive tree genome overall. Two of the six markers strictly associated with SI in P. angustifolia have strong similarity with a recently identified 741kb chromosomal region fully linked to the SI phenotype on chromosome 18 of the olive tree genome, providing strong cross-validation support. The SI locus stands out as being markedly rearranged, while the sex locus has remained relatively more collinear between the two species. This P. angustifolia linkage map will be a useful resource to investigate the various ways by which the sex and SI determination systems have co-evolved in the broader phylogenetic context of the Oleaceae family.
Latent functional diversity may accelerate microbial community responses to temperature fluctuations

How complex microbial communities respond to climatic fluctuations remains an open question. Due to their relatively short generation times and high functional diversity, microbial populations harbor great potential to respond as a community through a combination of strain-level phenotypic plasticity, adaptation, and species sorting. However, the relative importance of these mechanisms remains unclear. We conducted a laboratory experiment to investigate the degree to which bacterial communities can respond to changes in environmental temperature through a combination of phenotypic plasticity and species sorting alone. We grew replicate soil communities from a single location at six temperatures between 4°C and 50°C. We found that phylogenetically- and functionally-distinct communities emerge at each of these temperatures, with K-strategist taxa favoured under cooler conditions, and r-strategist taxa under warmer conditions. We show that this dynamic emergence of distinct communities across a wide range of temperatures (in essence, community-level adaptation), is driven by the resuscitation of latent functional diversity: the parent community harbors multiple strains pre-adapted to different temperatures that are able to “switch on” at their preferred temperature without immigration or adaptation. Our findings suggest that microbial community function in nature is likely to respond rapidly to climatic temperature fluctuations through shifts in species composition by resuscitation of latent functional diversity.