GWP-ASan: Sampling-Based Detection of Memory-Safety Bugs in Production

Despite the recent advances in pre-production bug detection, heap-use-after-free and heap-buffer-overflow bugs remain the primary problem for security, reliability, and developer productivity for applications written in C or C++, across all major software ecosystems. Memory-safe languages solve this problem when they are used, but the existing code bases consisting of billions of lines of C and C++ continue to grow, and we need additional bug detection mechanisms. This paper describes a family of tools that detect these two classes of memory-safety bugs, while running in production, at near-zero overhead. These tools combine page-granular guarded allocation and low-rate sampling. In other words, we added an "if" statement to a 36-year-old idea and made it work at scale. We describe the basic algorithm, several of its variants and implementations, and the results of multi-year deployments across mobile, desktop, and server applications

Genomic Signatures Characterize Leukocyte Infiltration in Myositis Muscles

Background: Leukocyte infiltration plays an important role in the pathogenesis and progression of myositis, and is highly associated with disease severity. Currently, there is a lack of: efficacious therapies for myositis; understanding of the molecular features important for disease pathogenesis; and potential molecular biomarkers for characterizing inflammatory myopathies to aid in clinical development. Methods: In this study, we developed a simple model and predicted that 1) leukocyte-specific transcripts (including both protein-coding transcripts and microRNAs) should be coherently overexpressed in myositis muscle and 2) the level of over-expression of these transcripts should be correlated with leukocyte infiltration. We applied this model to assess immune cell infiltration in myositis by examining mRNA and microRNA (miRNA) expression profiles in muscle biopsies from 31 myositis patients and 5 normal controls. Results: Several gene signatures, including a leukocyte index, type 1 interferon (IFN), MHC class I, and immunoglobulin signature, were developed to characterize myositis patients at the molecular level. The leukocyte index, consisting of genes predominantly associated with immune function, displayed strong concordance with pathological assessment of immune cell infiltration. This leukocyte index was subsequently utilized to differentiate transcriptional changes due to leukocyte infiltration from other alterations in myositis muscle. Results from this differentiation revealed biologically relevant differences in the relationship between the type 1 IFN pathway, miR-146a, and leukocyte infiltration within various myositis subtypes. Conclusions: Results indicate that a likely interaction between miR-146a expression and the type 1 IFN pathway is confounded by the level of leukocyte infiltration into muscle tissue. Although the role of miR-146a in myositis remains uncertain, our results highlight the potential benefit of deconvoluting the source of transcriptional changes in myositis muscle or other heterogeneous tissue samples. Taken together, the leukocyte index and other gene signatures developed in this study may be potential molecular biomarkers to help to further characterize inflammatory myopathies and aid in clinical development. These hypotheses need to be confirmed in separate and sufficiently powered clinical trials

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Objective: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. Methods: A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. Results: The IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. Conclusions: Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy

Land Settlement Alternatives for the Chugach Region: Effects on Public Values of Transferring Public Lands to Private Ownership. Volume I

Prepared for U.S. Forest Service Department of Agricultur

The jumping spider Saitis barbipes lacks a red photoreceptor to see its own sexually dimorphic red coloration

Examining the role of color in mate choice without testing what colors the study animal is capable of seeing can lead to ill-posed hypotheses and erroneous conclusions. Here, we test the seemingly reasonable assumption that the sexually dimorphic red coloration of the male jumping spider Saitis barbipes is distinguishable, by females, from adjacent black color patches. Using microspectrophotometry, we find clear evidence for photoreceptor classes with maximal sensitivity in the UV (359 nm) and green (526 nm), inconclusive evidence for a photoreceptor maximally sensitive in the blue (451 nm), and no evidence for a red photoreceptor. No colored filters within the lens or retina could be found to shift green sensitivity to red. To quantify and visualize whether females may nevertheless be capable of discriminating red from black color patches, we take multispectral images of males and calculate photoreceptor excitations and color contrasts between color patches. Red patches would be, at best, barely discriminable from black, and not discriminable from a low-luminance green. Some color patches that appear achromatic to human eyes, such as beige and white, strongly absorb UV wavelengths and would appear as brighter “spider-greens” to S. barbipes than the red color patches. Unexpectedly, we discover an iridescent UV patch that contrasts strongly with the UV-absorbing surfaces dominating the rest of the spider. We propose that red and black coloration may serve identical purposes in sexual signaling, functioning to generate strong achromatic contrast with the visual background. The potential functional significance of red coloration outside of sexual signaling is discussed

Validation of a direct-to-PCR COVID-19 detection protocol utilizing mechanical homogenization: a model for reducing resources needed for accurate testing

Efficient and effective viral detection methodologies are a critical piece in the global response to COVID-19, with PCR-based nasopharyngeal and oropharyngeal swab testing serving as the current gold standard. With over 100 million confirmed cases globally, the supply chains supporting these PCR testing efforts are under a tremendous amount of stress, driving the need for innovative and accurate diagnostic solutions. Herein, the utility of a direct-to-PCR method of SARS-CoV-2 detection grounded in mechanical homogenization is examined for reducing resources needed for testing while maintaining a comparable sensitivity to the current gold standard workflow of nasopharyngeal and oropharyngeal swab testing. In a head-to-head comparison of 30 patient samples, this initial clinical validation study of the proposed homogenization-based workflow demonstrated significant agreeability with the current extraction-based method utilized while cutting the total resources needed in half

Primary Teachers’ Recommendations for the Development of a Teacher-Oriented Movement Assessment Tool for 4–7 Years Children

To inform the development of a teacher-oriented movement assessment tool, this study aimed to explore primary school teachers’ perceptions of assessing fundamental movement skills (FMS) within Physical Education (PE) lessons. Thirty-nine primary school teachers of PE, located in the United Kingdom, participated in an individual or group in-depth interview. Findings signify that teachers perceive a need for a movement assessment tool that is simple for them to use, quick to administer and provides valuable feedback to guide future teaching and learning. This is vital as teachers indicated a lack of appropriate resources and a shortage of curriculum time restricts their use of assessment within PE. A movement assessment tool that was integrated on a digital technology platform could increase teachers’ understanding of assessing FMS and enhance children’s learning of FMS

Peripheral lymph nodes contain migratory and resident innate lymphoid cell populations

Tissue residency is considered a defining feature of the innate lymphoid cell (ILC) populations located within mucosal and adipose tissues. ILCs are also present within all lymphoid tissues, but whether ILCs migrate between lymphoid and nonlymphoid sites and in what context is poorly understood. To determine whether migratory ILCs exist within peripheral lymph nodes (LNs), we labeled all cells within the brachial LN (bLN) of transgenic mice expressing a photoconvertible fluorescent protein by direct exposure to light. Tracking of cellular changes in the labeled LN revealed the gradual migration of new ILCs into the tissue, balanced by egress of ILCs dependent on sphingosine-1-phosphate receptors. Most of the migratory ILCs were ILC1s, entering LNs directly from the circulation in a CD62L- and CCR7-dependent manner and thus behaving like conventional natural killer (cNK) cells. Upon egress, both ILC1s and cNK cells were found to recirculate through peripheral LNs. A distinct population of migratory ILC2s were detected in the LN, but most of the ILC3s were tissue resident. Functionally, both migratory and resident ILC1s within LNs were able to rapidly produce IFN-γ to support the generation of robust TH1 T cell responses after immunization. Thus, migratory and resident ILC populations exist within peripheral LNs, with ILC1s, akin to cNK cells, able to traffic into these tissues where they can contribute to the initiation of adaptive immunity

Activity of Bdellovibrio Hit Locus Proteins, Bd0108 and Bd0109, Links Type IVa Pilus Extrusion/Retraction Status to Prey-Independent Growth Signalling

Bdellovibrio bacteriovorus are facultatively predatory bacteria that grow within gram-negative prey, using pili to invade their periplasmic niche. They also grow prey-independently on organic nutrients after undergoing a reversible switch. The nature of the growth switching mechanism has been elusive, but several independent reports suggested mutations in the hit (host-interaction) locus on the Bdellovibrio genome were associated with the transition to preyindependent growth. Pili are essential for prey entry by Bdellovibrio and sequence analysis of the hit locus predicted that it was part of a cluster of Type IVb pilus-associated genes, containing bd0108 and bd0109. In this study we have deleted the whole bd0108 gene, which is unique to Bdellovibrio, and compared its phenotype to strains containing spontaneous mutations in bd0108 and the common natural 42 bp deletion variant of bd0108. We find that deletion of the whole bd0108 gene greatly reduced the extrusion of pili, whereas the 42 bp deletion caused greater pilus extrusion than wild-type. The pili isolated from these strains were comprised of the Type IVa pilin protein; PilA. Attempts to similarly delete gene bd0109, which like bd0108 encodes a periplasmic/secreted protein, were not successful, suggesting that it is likely to be essential for Bdellovibrio viability in any growth mode. Bd0109 has a sugar binding YD- repeat motif and an N-terminus with a putative pilin-like fold and was found to interact directly with Bd0108. These results lead us to propose that the Bd0109/Bd0108 interaction regulates pilus production in Bdellovibrio (possibly by interaction with the pilus fibre at the cell wall), and that the presence (and possibly retraction state) of the pilus feeds back to alter the growth state of the Bdellovibrio cell. We further identify a novel small RNA encoded by the hit locus, the transcription of which is altered in different bd0108 mutation background