PAD: Towards Principled Adversarial Malware Detection Against Evasion Attacks

Machine Learning (ML) techniques can facilitate the automation of malicious software (malware for short) detection, but suffer from evasion attacks. Many studies counter such attacks in heuristic manners, lacking theoretical guarantees and defense effectiveness. In this paper, we propose a new adversarial training framework, termed Principled Adversarial Malware Detection (PAD), which offers convergence guarantees for robust optimization methods. PAD lays on a learnable convex measurement that quantifies distribution-wise discrete perturbations to protect malware detectors from adversaries, whereby for smooth detectors, adversarial training can be performed with theoretical treatments. To promote defense effectiveness, we propose a new mixture of attacks to instantiate PAD to enhance deep neural network-based measurements and malware detectors. Experimental results on two Android malware datasets demonstrate: (i) the proposed method significantly outperforms the state-of-the-art defenses; (ii) it can harden ML-based malware detection against 27 evasion attacks with detection accuracies greater than 83.45%, at the price of suffering an accuracy decrease smaller than 2.16% in the absence of attacks; (iii) it matches or outperforms many anti-malware scanners in VirusTotal against realistic adversarial malware.Comment: Accepted by IEEE Transactions on Dependable and Secure Computing; To appea

Highly Efficient CRISPR-Mediated Base Editing in Sinorhizobium meliloti

Rhizobia are widespread gram-negative soil bacteria and indispensable symbiotic partners of leguminous plants that facilitate the most highly efficient biological nitrogen fixation in nature. Although genetic studies in Sinorhizobium meliloti have advanced our understanding of symbiotic nitrogen fixation (SNF), the current methods used for genetic manipulations in Sinorhizobium meliloti are time-consuming and labor-intensive. In this study, we report the development of a few precise gene modification tools that utilize the CRISPR/Cas9 system and various deaminases. By fusing the Cas9 nickase to an adenine deaminase, we developed an adenine base editor (ABE) system that facilitated adenine-to-guanine transitions at one-nucleotide resolution without forming double-strand breaks (DSB). We also engineered a cytidine base editor (CBE) and a guanine base editor (GBE) that catalyze cytidine-to-thymine substitutions and cytidine-to-guanine transversions, respectively, by replacing adenine deaminase with cytidine deaminase and other auxiliary enzymes. All of these base editors are amenable to the assembly of multiple synthetic guide RNA (sgRNA) cassettes using Golden Gate Assembly to simultaneously achieve multigene mutations or disruptions. These CRISPR-mediated base editing tools will accelerate the functional genomics study and genome manipulation of rhizobia

Allelic Interactions among Pto-MIR475b and Its Four Target Genes Potentially Affect Growth and Wood Properties in Populus

MicroRNAs (miRNAs) play crucial roles in plant growth and development, but few studies have illuminated the allelic interactions among miRNAs and their targets in perennial plants. Here, we combined analysis of expression patterns and single-nucleotide polymorphism (SNP)-based association studies to explore the interactions between Pto-MIR475b and its four target genes (Pto-PPR1, Pto-PPR2, Pto-PPR3, and Pto-PPR4) in 435 unrelated individuals of Populus tomentosa. Expression patterns showed a significant negative correlation (r = -0.447 to -0.411, P < 0.01) between Pto-MIR475b and its four targets in eight tissues of P. tomentosa, suggesting that Pto-miR475b may negatively regulate the four targets. Single SNP-based association studies identified 93 significant associations (P < 0.01, Q < 0.1) representing associations of 80 unique SNPs in Pto-MIR475b and its four targets with nine traits, revealing their potential roles in tree growth and wood formation. Moreover, one common SNP in the precursor region significantly altered the secondary structure of the pre-Pto-miR475b and changed the expression level of Pto-MIR475b. Analysis of epistatic interactions identified 115 significant SNP–SNP associations (P < 0.01) representing 45 unique SNPs from Pto-MIR475b and its four targets for 10 traits, revealing that genetic interactions between Pto-MIR475b and its targets influence quantitative traits of perennial plants. Our study provided a feasible strategy to study population genetics in forest trees and enhanced our understanding of miRNAs by dissecting the allelic interactions between this miRNA and its targets in P. tomentosa

Upregulated Interleukin 21 Receptor Enhances Proliferation and Epithelial-Mesenchymal Transition Process in Benign Prostatic Hyperplasia

Background: Interleukins (ILs) and related chronic inflammation have been found to contribute to the development of benign prostatic hyperplasia (BPH) in recent decades. As a late member of the ILs family, IL-21 receptor (IL-21R) can modulate cell proliferation, however, IL-21R activity in the prostate has not been examined. The current study aimed to elucidate a potential role of IL-21R in the development of BPH.Material and Methods: Human prostate tissues, cell lines and rats were used. QRT-PCR, Western blot, and immunohistochemistry, along with hematoxylin and eosin, Masson's trichrome, and immunofluorescent staining were performed. BPH-1 cells with IL-21R silenced were cultured or co-cultured with macrophages (active THP-1, AcTHP-1). Apoptosis and cell cycle phases were determined via flow cytometry. Epithelial-mesenchymal transition (EMT) processes were also examined. In vivo, rat prostatitis was induced with intraprostatic injected lipopolysaccharide (LPS).Results: IL-21R was highly expressed in human as well as rat prostate, mainly in the epithelial compartment. BPH concomitant with prostatitis significantly upregulated the expression of IL-21R. Knockdown of IL-21R induced cell apoptosis and cycle arrest at G0/G1 phase, and blocked the EMT process in BPH-1 cells. When IL-21R silenced BPH-1 cells were co-cultured with AcTHP-1 cells, these aforementioned processes and IL-21R change were completely reversed. Prostatic hyperplasia was observed with IL-21R upregulated in LPS induced prostatitis rats. More specifically, the expression of apoptosis, cyclin, and EMT proteins in this rat model are altered in a manner consistent with that seen in the cell line model.Conclusions: Our novel data demonstrates the expression and functional activities of IL-21R in the mechanism for development of BPH. IL-21R mainly localized in prostate epithelium and it was upregulated in hyperplastic prostate tissues. IL-21R enhanced proliferation of BPH-1 cells, via inhibiting cell apoptosis, and modulating cell cycles, as well as the EMT process, in response to inflammatory stimuli

CNTF Induces Regeneration of Cone Outer Segments in a Rat Model of Retinal Degeneration

Cone photoreceptors are responsible for color and central vision. In the late stage of retinitis pigmentosa and in geographic atrophy associated with age-related macular degeneration, cone degeneration eventually causes loss of central vision. In the present work, we investigated cone degeneration secondary to rod loss in the S334ter-3 transgenic rats carrying the rhodopsin mutation S334ter.Recombinant human ciliary neurotrophic factor (CNTF) was delivered by intravitreal injection to the left eye of an animal, and vehicle to the right eye. Eyes were harvested 10 days after injection. Cone outer segments (COS), and cell bodies were identified by staining with peanut agglutinin and cone arrestin antibodies in whole-mount retinas. For long-term treatment with CNTF, CNTF secreting microdevices were implanted into the left eyes at postnatal day (PD) 20 and control devices into the right eyes. Cone ERG was recorded at PD 160 from implanted animals. Our results demonstrate that an early sign of cone degeneration is the loss of COS, which concentrated in many small areas throughout the retina and is progressive with age. Treatment with CNTF induces regeneration of COS and thus reverses the degeneration process in early stages of cone degeneration. Sustained delivery of CNTF prevents cones from degeneration and helps them to maintain COS and light-sensing function.Loss of COS is an early sign of secondary cone degeneration whereas cell death occurs much later. At early stages, degenerating cones are capable of regenerating outer segments, indicating the reversal of the degenerative process. Sustained delivery of CNTF preserves cone cells and their function. Long-term treatment with CNTF starting at early stages of degeneration could be a viable strategy for preservation of central vision for patients with retinal degenerations

Natural variation in the prolyl 4-hydroxylase gene PtoP4H9 contributes to perennial stem growth in Populus

Perennial trees must maintain stem growth throughout their entire lifespan to progressively increase in size as they age. The overarching question of the molecular mechanisms that govern stem perennial growth in trees remains largely unanswered. Here we deciphered the genetic architecture that underlies perennial growth trajectories using genome-wide association studies (GWAS) for measures of growth traits across years in a natural population of Populus tomentosa. By analyzing the stem growth trajectory, we identified PtoP4H9, encoding prolyl 4-hydroxylase 9, which is responsible for the natural variation in the growth rate of diameter at breast height (DBH) across years. Quantifying the dynamic genetic contribution of PtoP4H9 loci to stem growth showed that PtoP4H9 played a pivotal role in stem growth regulation. Spatiotemporal expression analysis showed that PtoP4H9 was highly expressed in cambium tissues of poplars of various ages. Overexpression and knockdown of PtoP4H9 revealed that it altered cell expansion to regulate cell wall modification and mechanical characteristics, thereby promoting stem growth in Populus. We showed that natural variation in PtoP4H9 occurred in a BASIC PENTACYSTEINE transcription factor PtoBPC1-binding promoter element controlling PtoP4H9 expression. The geographic distribution of PtoP4H9 allelic variation was consistent with the modes of selection among populations. Altogether, our study provides important genetic insights into dynamic stem growth in Populus, and we confirmed PtoP4H9 as a potential useful marker for breeding or genetic engineering of poplars

Genome-Wide Association Studies to Improve Wood Properties: Challenges and Prospects

Wood formation is an excellent model system for quantitative trait analysis due to the strong associations between the transcriptional and metabolic traits that contribute to this complex process. Investigating the genetic architecture and regulatory mechanisms underlying wood formation will enhance our understanding of the quantitative genetics and genomics of complex phenotypic variation. Genome-wide association studies (GWASs) represent an ideal statistical strategy for dissecting the genetic basis of complex quantitative traits. However, elucidating the molecular mechanisms underlying many favorable loci that contribute to wood formation and optimizing GWAS design remain challenging in this omics era. In this review, we summarize the recent progress in GWAS-based functional genomics of wood property traits in major timber species such as Eucalyptus, Populus, and various coniferous species. We discuss several appropriate experimental designs for extensive GWAS in a given undomesticated tree population, such as omics-wide association studies and high-throughput phenotyping technologies. We also explain why more attention should be paid to rare allelic and major structural variation. Finally, we explore the potential use of GWAS for the molecular breeding of trees. Such studies will help provide an integrated understanding of complex quantitative traits and should enable the molecular design of new cultivars

High-Resolution Boundary Detection for Medical Image Segmentation with Piece-Wise Two-Sample T-Test Augmented Loss

Deep learning methods have contributed substantially to the rapid advancement of medical image segmentation, the quality of which relies on the suitable design of loss functions. Popular loss functions, including the cross-entropy and dice losses, often fall short of boundary detection, thereby limiting high-resolution downstream applications such as automated diagnoses and procedures. We developed a novel loss function that is tailored to reflect the boundary information to enhance the boundary detection. As the contrast between segmentation and background regions along the classification boundary naturally induces heterogeneity over the pixels, we propose the piece-wise two-sample t-test augmented (PTA) loss that is infused with the statistical test for such heterogeneity. We demonstrate the improved boundary detection power of the PTA loss compared to benchmark losses without a t-test component

Identification and functional analysis of serine protease inhibitor gene family of Eocanthecona furcellata (Wolff)

The predatory natural enemy Eocanthecona furcellata plays a crucial role in agricultural ecosystems due to its effective pest control measures and defensive venom. Predator venom contains serine protease inhibitors (SPIs), which are the primary regulators of serine protease activity and play key roles in digestion, development, innate immunity, and other physiological regulatory processes. However, the regulation mechanism of SPIs in the salivary glands of predatory natural enemies is still unknown. In this study, we sequenced the transcriptome of E. furcellata salivary gland and identified 38 SPIs genes named EfSPI1∼EfSPI38. Through gene structure, multiple sequence alignment and phylogenetic tree analysis, real-time quantitative PCR (RT-PCR) expression profiles of different developmental stages and different tissues were analyzed. RNAi technology was used to explore the gene function of EFSPI20. The results showed that these 38 EfSPIs genes contained 8 SPI domains, which were serpin, TIL, Kunitz, Kazal, Antistasin, Pacifastin, WAP and A2M. The expression profile results showed that the expression of different types of EfSPIs genes was different at different developmental stages and different tissues. Most of the EfSPIs genes were highly expressed in the egg stage. The EfSPI20, EfSPI21, EfSPI22, and EfSPI24 genes of the Pacifastin subfamily and the EfSPI35 gene of the A2M subfamily were highly expressed in the nymphal and adult stages, which was consistent with the RT-qPCR verification results. These five genes are positively correlated with each other and have a synergistic effect on E. furcellata, and they were highly expressed in salivary glands. After interfering with the expression of the EfSPI20 gene, the survival rate and predatory amount of male and female adults were significantly decreased. Taken together, we speculated some EfSPIs may inhibit trypsin, chymotrypsin, and elastase, and some EfSPIs may be involved in autoimmune responses. EfSPI20 was essential for the predation and digestion of E. furcellata, and the functions of other EfSPIs were discussed. Our findings provide valuable insights into the diversity of EfSPIs in E. furcellata and the potential functions of regulating their predation, digestion and innate immunity, which may be of great significance for developing new pest control strategies