Oxidative stress caused by production of reactive oxygen species (ROS) due to normal metabolism and/or external environment results in changes in follicular fluid microenvironment, oxidation of oocyte DNA (8‑hydroxy-2'deoxyguanosine levels; 8-OHdG) and poor-quality oocyte. Therefore, the present investigation was designed to evaluate the relationship between oocyte quality and intra-follicular environment (melatonin, 8-OHdG, 17β-estradiol and progesterone concentrations) in different sized follicles during summer and winter in water buffaloes. Slaughterhouse-derived ovaries were subjected for collection of follicular fluid from three (n = 42 each category in summer and winter) different categories of follicle based on diameter (Small: 8-9.9 mm; Medium: 10-11.9 mm; Large: 12-14 mm). Individual follicles were treated as independent observational units and analyzed using a factorial model including effects of season, follicular size, and their interaction. The results revealed higher (P < 0.05) melatonin and 17β-estradiol concentrations were associated with larger follicles and improved oocyte quality. Melatonin was positively associated (P < 0.05) with 17β-estradiol concentrations in different follicular categories during both seasons. Conversely, 8-OHdG followed an inverse association (P < 0.05) with melatonin in different categories of follicles during both seasons. Irrespective of follicles size, data revealed that good-quality oocytes (Grade A) were associated with higher melatonin concentrations, 102.11±3.88 pg/mL and 116.59±3.32 pg/mL in summer and winter, respectively. Ordinal logistic regression analysis identified melatonin concentration as the only significant independent predictor of oocyte quality (β=-0.226, OR=0.798; P < 0.001). Thus, it may be concluded that higher intra-follicular melatonin concentrations were associated with lower oxidative DNA damage and improved oocyte quality in water buffalo.

Arterial endothelial cells (ECs) reside in a complex biomechanical environment. ECs sense and respond to wall shear stress. Low and oscillatory wall shear stress is characteristic of disturbed flow and commonly found at arterial bifurcations and around atherosclerotic plaques. Disturbed flow is pro-inflammatory to ECs. Arteries also stiffen with aging and/or the onset of vascular disease. ECs sense and respond to stiffening in a pro-fibrotic manner. Thus, flow and stiffening disturbances elicit EC responses that promote pathologic arterial remodeling. However, the pathways elicited by ECs under pathologic stiffening and disturbed flow are not well understood. The objective of this work was to discover and test the modifiability of key pathways in ECs. To do this we used the partial carotid ligation model to impose disturbed flow onto the precociously stiffened fibulin-5 knockout (Fbln5-/-) mouse carotid arteries. Biomechanical testing demonstrated that Fbln5-/- arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these Fbln5-/- arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow Fbln5-/- arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (Ctgf/Ccn2) was upregulated in vivo in ECs with aging, with stiffening in the Fbln5-/- arteries, and increased again by disturbed flow under stiffened conditions, supporting CTGF as a key biomarker for flow and stiffening. This was validated by immunohistochemistry, which demonstrated increased CTGF deposition in areas of disturbed flow in patient carotid endarterectomy and peripheral artery disease (PAD) specimens. Finally, to test the role of CTGF in regulating and combining these processes, we created an EC-specific Ctgf knockout (Ctgfecko). We identified that carotid arteries under disturbed flow and atherogenic conditions in male Ctgfecko, but not female, mice had decreased plaque area compared to WT control mice. We then tested the Ctgf expression in the carotid endothelium exposed to disturbed or stable flow in WT and Fbln5-/- mice. Here we found that under disturbed flow male mice had greater Ctgf expression than female mice. This work demonstrates that stiffened + disturbed flow conditions drive EC reprogramming, that CTGF is increased by these conditions, and that this increase is more prominent in male carotid arteries. Future exploration of sex-based differences in these fibrotic pathways are warranted to develop targeted therapeutics to limit pathologic arterial remodeling under pathologically stiffened + disturbed flow environments.

Aortic valve (AV) disease is one of the leading causes of cardiovascular related deaths. It is a side-dependent pathology; preferentially occurring in the fibrosa of the AV. Altered shear stress induces inflammatory response in the fibrosa but not the ventricularis of AV. Studies showed that this preferential response could be in part due to differential gene expression in the fibrosa compared to the ventricularis. Based on our microarray analysis, four miRNAs (miRs-181a, 181b, 199a, and 214) were identified to be side-dependent in human AV endothelial cells. This study, using an ex vivo approach investigated if any of these microRNAs were involved in this side-dependent AV pathology. The fibrosa or ventricularis sides of freshly isolated porcine AV leaflets were exposed to either oscillatory shear stress (OS, +/-5dyne/cm2) or unidirectional pulsatile shear stress (LS, 80dyne/cm2). The leaflets were sheared in a shear stress bioreactor for 2 days in regular media and 3 & 7 days in osteogenic media. An increased thickness of the fibrosa layer, increase in miR-214 expression, and calcification was observed in the fibrosa exposed to OS compared to the ventricularis exposed to LS or OS. Using anti-miR-214, the miR-214 was silenced in fibrosa exposed to OS, to further understand its functional role in AV pathology. Silencing of miR-214 significantly increased the protein expression of TGFβ1, moderately increased collagen content but did not affect AV calcification. Thus miR-214 is a side- and shear-dependent miRNA that regulates mechanosensitive gene such as TGFβ1, a key cytokine involved in AV pathology.

Objective: The objectives of this work are to: define murine femoral artery stiffening with age and the modifiability of this process by exercise; impose peripheral arterial disease (PAD) hemodynamics on murine femoral arteries and to deliver focal atherosclerotic plaque to femoral arteries; and test piezo-type mechanosensitive ion channel component 1 (PIEZO1) expression in human and murine femoral arteries of PAD. Methods: We used a running wheel to exercise young and old S129 mice and biomechanical testing to quantify changes in arterial stiffness. We created a novel partial femoral artery ligation (PFL) model to impose PAD hemodynamics via low wall shear stress (WSS) to create a flow-mediated model of arterial aging in femoral arteries. In vivo mechanics were defined with ultrasound. Ex vivo arteries underwent biaxial tests. Atherogenic conditions were induced using PCSK9 infection and a high-fat diet. Arterial remodeling and PIEZO1 expression were quantified by histology. Results: Femoral arteries are naturally stiffer than carotid arteries; both stiffen further with aging, but exercise improved compliance in old femoral arteries. PFL imposed low WSS and stiffening, similar to that seen in aging. Under atherogenic conditions, PFL delivered focal atherosclerotic plaques in femoral arteries. Low WSS increased PIEZO1 expression in femoral arteries (∼1.8× in endothelial cells, ∼2.4× in smooth muscle cells, and ∼2.8× in macrophages). Human PAD arteries with high-grade stenosis validated increased PIEZO1 mRNA (∼1.83×). Conclusions: Femoral artery mechanics differ significantly from the carotid artery but can be modified by exercise. This PFL model confers arterial stiffness, and under atherogenic conditions, delivers focal femoral atherosclerotic plaque. PIEZO1 expression increases in both PFL-treated mouse femoral arteries and human PAD arteries with severe stenosis, supporting this as a translational target for PAD. Clinical Relevance: Peripheral artery disease (PAD) is the third most common atherosclerotic bed. PAD is associated with increased risk of limb loss and death, but the mechanisms driving site-specific arterial remodeling in PAD remain unclear. This work uniquely creates a model of PAD that incorporates arterial stiffening via aging and flow disturbances and inducing atherosclerotic plaque into the murine femoral artery. By comparing murine femoral arteries with PAD arteries, piezo-type mechanosensitive ion channel component 1 (PIEZO1) was discovered as key mediator linking PAD blood flow and stiffening to untoward changes in endothelial cells, smooth muscle cells, and macrophages within femoral arteries. Targeted modulation of PIEZO1 activity provide PAD-centric therapeutic strategies and help promote the vascular health, life, and limb outcomes in patients with PAD.

Background: Diabetes is a leading cause of mortality and disability globally, with increasing prevalence and associated disabilities over the past decade, diabetes affects 13.7% of the population, with a significant number atrisk due to prediabetic conditions. Family history is a recognized risk factor influencing diabetes susceptibilityand perceived risk, prompting the need for preventative measures.Aim: The purpose of this study was to evaluate the association between the risk of prediabetes and diabetes inurban populations in Bihar, India, and family history of the disease.Methodology: This retrospective study was conducted at the Department of Community Medicine, Netaji SubhasMedical College and Hospital, Bihta ,Bihar India for six months. 80 participants were surveyed, excludingpregnant women and known diabetes cases, to examine the impact of family history on fasting blood glucoselevels also body mass index. Participants provided informed consent, underwent fasting blood glucose tests, andcompleted questionnaires regarding their family medical history.Results: Analysis revealed that individuals with a family history of diabetes exhibited significantly lowerpercentages of normal blood glucose levels (71.4% in diabetics) compared to those without such a history (85%).Additionally, people with a positive family history of diabetes had a greater frequency of obesity (51.6%)compared to people without such a history (27.8%).Conclusion: The findings underscore the critical role of family history in influencing diabetes risk and relatedhealth behaviors. With a notable association between familial risk and both glucose metabolism and BMI, targetedlifestyle interventions are necessary for individuals with a family history of diabetes to mitigate their risk.

Redox processes can modulate vascular pathophysiology. The endoplasmic reticulum redox chaperone protein disulfide isomerase A1 (PDIA1) is overexpressed during vascular proliferative diseases, regulating thrombus formation, endoplasmic reticulum stress adaptation, and structural remodeling. However, both protective and deleterious vascular effects have been reported for PDIA1, depending on the cell type and underlying vascular condition. Further understanding of this question is hampered by the poorly studied mechanisms underlying PDIA1 expression regulation. Here, we showed that PDIA1 mRNA and protein levels were upregulated (average 5-fold) in the intima and media/adventitia following partial carotid ligation (PCL). Our search identified that miR-204-5p and miR-211-5p (miR-204/211), two broadly conserved miRNAs, share PDIA1 as a potential target. MiR-204/211 was downregulated in vascular layers following PCL. In isolated endothelial cells, gain-of-function experiments of miR-204 with miR mimic decreased PDIA1 mRNA while having negligible effects on markers of endothelial activation/stress response. Similar effects were observed in vascular smooth muscle cells (VSMCs). Furthermore, PDIA1 downregulation by miR-204 decreased levels of the VSMC contractile differentiation markers. In addition, PDIA1 overexpression prevented VSMC dedifferentiation by miR-204. Collectively, we report a new mechanism for PDIA1 regulation through miR-204 and identify its relevance in a model of vascular disease playing a role in VSMC differentiation. This mechanism may be regulated in distinct stages of atherosclerosis and provide a potential therapeutic target.

Background New drugs to tackle the next pathway or mutation fueling cancer are constantly proposed, but 97% of them are doomed to fail in clinical trials, largely because they are identified by cellular or in silico screens that cannot predict their in vivo effect. Methods We screened an Adeno-Associated Vector secretome library (> 1000 clones) directly in vivo in a mouse model of cancer and validated the therapeutic effect of the first hit, EMID2, in both orthotopic and genetic models of lung and pancreatic cancer. Results EMID2 overexpression inhibited both tumor growth and metastatic dissemination, consistent with prolonged survival of patients with high levels of EMID2 expression in the most aggressive human cancers. Mechanistically, EMID2 inhibited TGFβ maturation and activation of cancer-associated fibroblasts, resulting in more elastic ECM and reduced levels of YAP in the nuclei of cancer cells. Conclusion This is the first in vivo screening, precisely designed to identify proteins able to interfere with cancer cell invasiveness. EMID2 was selected as the most potent protein, in line with the emerging relevance of the tumor extracellular matrix in controlling cancer cell invasiveness and dissemination, which kills most of cancer patients.

Metabolic syndrome (MetS) is a constellation of abnormalities that include hypertension, central obesity, insulin resistance, and atherogenic dyslipidemia. MetS is strongly associated with an increased risk for developing diabetes and atherosclerotic and non-atherosclerotic cardiovascular diseases. At the core, the pathophysiology of MetS consists of aggravated inflammation and activation of immune cells. In the last 2 decades, microRNAs (miRNAs) have emerged as pivotal players in many physiological and pathological processes that resulted in MetS. miRNAs modulate gene expression by activating the RNA-induced silencing complex. Furthermore, miRNAs are considered as diagnostic biomarkers and envision as potential therapeutic targets in diverse diseases. Here, we summarized the functional role of miRNAs as regulators of gene expression and outlined their relationship to the pathogenesis of MetS. We further elaborated the role of these miRNAs in signaling pathways involved in cell-type or tissue-specific manner in various prevalent conditions such as inflammation, oxidative stress, altered shear stress, and vascular dysfunction. This review also addressed the contributions of miRNAs in atherosclerosis, diabetes, cardiovascular diseases in the settings of MetS.

Memory accounts for 33 - 50% of the total cost of ownership (TCO) in modern data centers. We propose a novel solution to tame memory TCO through the novel creation and judicious management of multiple software-defined compressed memory tiers. As opposed to the state-of-the-art solutions that employ a 2-Tier solution, a single compressed tier along with DRAM, we define multiple compressed tiers implemented through a combination of different compression algorithms, memory allocators for compressed objects, and backing media to store compressed objects. These compressed memory tiers represent distinct points in the access latency, data compressibility, and unit memory usage cost spectrum, allowing rich and flexible trade-offs between memory TCO savings and application performance impact. A key advantage with ntier is that it enables aggressive memory TCO saving opportunities by placing warm data in low latency compressed tiers with a reasonable performance impact while simultaneously placing cold data in the best memory TCO saving tiers. We believe our work represents an important server system configuration and optimization capability to achieve the best SLA-aware performance per dollar for applications hosted in production data center environments. We present a comprehensive and rigorous analytical cost model for performance and TCO trade-off based on continuous monitoring of the application's data access profile. Guided by this model, our placement model takes informed actions to dynamically manage the placement and migration of application data across multiple software-defined compressed tiers. On real-world benchmarks, our solution increases memory TCO savings by 22% - 40% percentage points while maintaining performance parity or improves performance by 2% - 10% percentage points while maintaining memory TCO parity compared to state-of-the-art 2-Tier solutions.

Background Peripheral arterial disease (PAD) is the 3rd leading type of atherosclerotic disease (ASD) morbidity. Arterial stiffness is intimately connected to the onset and progression of peripheral artery disease (PAD). The role of arterial stiffening on flow-mediated atherosclerotic plaque formation is not well understood. The objective of this study is to discover endothelial cell (EC) pathways under PAD conditions and test the modifiability of these pathways on ASD. Methods PAD conditions in mice were conferred by partial carotid ligation to induce disturbed Flow (D-flow) in pre-stiffened Fibulin-5 knockout (KO) mice that lack normal elastin function. EC pathways, including Connective tissue growth factor (CTGF/CCN) were quantified by gene analysis and histology. Atherogenic mice had PCSK9 infection + high fat diet. CTGF was inhibited in an EC-specific knockout (ECKOCTGF) and with a CTGF antibody (FG-3149). Human vascular tissue was used to validate PAD biomechanics and CTGF upregulation. Results Biomechanical testing demonstrated that d-flow KO arteries mimic biomechanics of PAD arteries. RNA microarray, qPCR, and immunohistochemistry identified EC plasticity in these arteries compared to WT and KO under stable flow. Under atherogenic conditions, KO arteries demonstrated vulnerable plaques not seen in WT animals. CTGF expression was increased by d-flow, in KO arteries, in aged (18 months) WT arteries, and vascular tissue under d-flow. CTGF inhibition by ECKOCTGF favorably improved plaque characteristics in male but not female animals. FG-3149 treatment of ECWTCTGF male animals delivered similar benefits to plaque characteristics and arterial compliance. Conclusion ECs in PAD arteries exist under a complex hemodynamic environment that integrates stiffness and d-flow into an atherogenic and inflammatory environment. Stiffness + d-flow stimulates precocious onset of EC plasticity and a vulnerable plaque phenotype. CTGF is a matricellular protein that can tune fibro-inflammatory pathways. CTGF is a prominent mediator of D-flow-mediated arterial remodeling and focal atherosclerotic plaque remodeling. Inhibition of CTGF improves plaque phenotype and arterial compliance. CTGF-associated pathways hold promise as therapeutic targets for PAD patients. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by awards from the National Institutes of Health to Drs. Brewster, Gleason, and Jo (HL143348). The authors' work is supported by funding from the NIH grants HL119798, HL139757, and HL151358 (to H.J.). H.J. was also supported by Wallace H. Coulter Distinguished Faculty Professorship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Emory University approved IRB protocol numbers: 51432 and 70813 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable Resource Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Lead Contact Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Luke Brewster. Materials Availability Further requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Luke Brewster. This study did not generate new unique reagents. Data availability The RNA files generated from the study (fibulin-5 KO and WT animals) will be available at the NCBI GEO repository on January 1, 2024, as GEO Submission (accession number GSE222583).

Background Cellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease. Methods Myeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. In vitro, bone marrow-derived macrophages (BMDM) were obtained from Mye-CCN3-KO and control mice and the expression of bone morphogenic protein signaling related gene were verified via quantitative real-time PCR and Western blotting. The BMDM conditioned medium was cocultured with human valvular intersititial cells which was artificially induced calcification to test the effect of the conditioned medium via Western blotting and Alizarin red staining. Results Echocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification. Conclusion Our data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3’s anti-calcification function in the development of CAVD.

Introduction: Atherosclerosis, a leading cause of death worldwide, is a chronic inflammatory disease that occurs preferentially in the arterial regions exposed to disturbed flow (d-flow), while those exposed to stable flow (s-flow) are protected. Recently, we reported d- F low I nduced R eprogramming of E ndothelial cells (ECs) ( FIRE ), including endothelial inflammation, endothelial-to-mesenchymal transition (EndMT) and endothelial-to-immune-cell transition (EndIT). Hypothesis: D-flow plus hypercholesterolemia (HighChol) exacerbates reprogramming of arterial cells leading to atherosclerosis development compared to d-flow alone and HighChol alone. Methods: To test this hypothesis, we induced atherosclerosis in C57BL/6 mice by an AAV-PCSK9 injection and high-fat diet to induce HighChol and/or partial carotid ligation (PCL) surgery to expose left carotid artery (LCA) to d-flow compared to the right CA (RCA) exposed to s-flow. Single cells prepared from collagenase digestion of the LCAs and RCAs at 2 and 4 weeks post-PCL were analyzed by scRNA-seq and integrated with our prior scRNA-seq data obtained at 2 days and 2 weeks post-PCL under normal blood cholesterol levels. Results: Overall, our data showed that d-flow was the most predominant regulator of arterial cell characteristics while HighChol alone had relatively minor effects. In the RCA, homeostatic EC, smooth muscle cell (SMC), and macrophage (MΦ) clusters were dominant regardless of cholesterol levels. Additionally, for these cell types, we found clusters that increased in response to d-flow in the LCA, which further increased with HighChol and time. Surprisingly, diffusion map trajectory analysis revealed a clear convergence of transcriptomic profiles of EndIT ECs, SMC-derived foam cell SMCs, and foamy MΦs. Conclusions: These results suggest FIRE initiated by d-flow is exacerbated by HighChol. We also found that SMCs and MΦs transition toward proatherogenic phenotypes under d-flow, which is further exacerbated by HighChol. Furthermore, differential gene expression analysis showed that proatherogenic ECs, SMCs, and MΦs show common transcriptomic profiles, suggesting common set of genes and pathways that could be targeted as effective atherosclerotic therapeutics.

Estimating the quality of a benchmark suite is a non-trivial task. A poorly selected or improperly configured bench-mark suite can present a distorted picture of the performance of the evaluated framework. With computing venturing into new domains, the total number of benchmark suites available is increasing by the day. Researchers must evaluate these suites quickly and decisively for their effectiveness. We present Perspector, a novel tool to quantify the performance of a benchmark suite. Perspector comprises novel metrics to characterize the quality of a benchmark suite. It provides a math-ematical framework for capturing some qualitative suggestions and observations made in prior work. The metrics are generic and domain-agnostic. Furthermore, our tool can be used to compare the efficacy of one suite vis-a-vis other benchmark suites, systematically and rigorously create a suite of workloads, and appropriately tune them for a target system.

Introduction Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified Kallikrein-Related Peptidase 10 (KLK10, a secreted serine protease) as a flow-sensitive gene in arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown. Methods and Results Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured endothelial cells (ECs). Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated KLK10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced inflammation and permeability dysfunction in human artery ECs (HAECs). Further, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of KLK10-expressing plasmids inhibited atherosclerosis in ApoE-/- mice. Studies using pharmacological inhibitors and siRNAs revealed that the anti-inflammatory effects of KLK10 were mediated by a Protease Activated Receptors (PAR1/2)-dependent manner. However, unexpectedly, KLK10 did not cleave the PARs. Through a proteomics study, we identified HTRA1 (High-temperature requirement A serine peptidase 1), which bound and cleaved KLK10. Further, siRNA knockdown of HTRA1 prevented KLK10’s anti-inflammatory and barrier protective function in HAECs, suggesting that HTRA1 regulates KLK10 function. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. Conclusion KLK10 is a flow-sensitive endothelial protein and, in collaboration with HTRA1, serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.

The utilization of molecular techniques to predict the phylogenetic similarity within the honey bee topologically divided these into three groups ., giant bees, dwarf bees and cavity-nesting bees.Four species of honey bee, i.e., Asian honey bee ( ), dwarf bee viz Apis cerana ( ), the rock or giant honey bee ) and European honey bee ( ) collected from North Western Himalaya Apis florea (Apis dorsata Apis mellifera region were molecularly characterized using partial mitochondrial Cytochrome oxidase I (COI).Nucleotide frequency analysis revealed that partial COI gene sequences were A+T biased (>73%), while the amino acid frequency analysis showed higher frequency of leucine (13.71%) and serine (12.27%).Among the tested species of honey bees showed exceptionally higher concentration of Cystine Amino acid.The A. florea overall variation in 72 SNPs was revealed by multiple sequence alignment of COI sequences from four species.The results reveal more transversion (56.5%) compared to transition (43.5%).Additionally, the pairwise genetic distance analysis described that and A. cerana A. dorsata had least genetic distance (0.102).The Ts/Tv value of 0.61 suggests that there is insignificant neutral selection in honeybees of north western Himalayan region of Uttarakhand.Such researches are significantly important to analyze the biodiversity of area, distinguish cryptic species and develop distinct taxonomic tools for integrative taxonomy of Honey bees.

Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE−/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE−/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.

Today, a vast amount of sensitive data worth millions of dollars is processed in untrusted data centers; hence, the confidentiality and integrity of the code and data are of paramount importance. Given the high incentive of mounting a successful attack, the complexity of attack methods has grown rapidly over the years. The attack methods rely on vulnerabilities present in the system to hijack the control flow of a process and use it to either steal sensitive information or degrade the quality of service. To thwart these attacks, the complexity of the defense methods has also increased in tandem. Researchers have explored different methods to ensure the secure execution of an application. The defense methods range from software-only to hardware-only to hybrid defense methods. In this survey, we focus on the relatively new hybrid form of defense methods where software and hardware work in tandem to protect the control flow of applications. We present a novel three-level taxonomy of these defense mechanisms based on first principles and use them to classify existing defense methods. After presenting the taxonomy, we critically analyze the proposed defense methods, study the evolution of the field and outline the challenges for future work.

Trusted execution environments (TEEs) such as facilitate the secure execution of an application on untrusted machines. Sadly, such environments suffer from serious limitations and performance overheads in terms of writing back data to the main memory, their interaction with the OS, and the ability to issue I/O instructions. There is thus a plethora of work that focuses on improving the performance of such environments – this necessitates the need for a standard, widely accepted benchmark suite (something similar to SPEC and PARSEC). To the best of our knowledge, such a suite does not exist. Our suite, SGXGauge, contains a diverse set of workloads such as blockchain codes, secure machine learning algorithms, lightweight web servers, secure key-value stores, etc. We thoroughly characterizes the behavior of the benchmark suite on a native platform and on a platform that uses a library OS-based shimming layer (GrapheneSGX). We observe that the most important metrics of interest are performance counters related to paging, memory, and TLB accesses. There is an abrupt change in performance when the memory footprint starts to exceed the size of the EPC size in Intel SGX, and the library OS does not add a significant overhead ( +- 10