External Memory Algorithms for Factoring Sparse Matrices

We consider the factorization of sparse symmetric matrices in the context of a two-layer storage system: disk/core. When the core is sufficiently large the factorization can be performed in-core. In this case we must read the input, compute, and write the output, in this sequence. On the other hand, when the core is not large enough, the factorization becomes out-of-core, which means that data movement and computation must be interleaved. We identify two major out-of-core factorization scenarios: read-once/write-once (R1/W1) and read-many/write-many (RM/WM). The former requires minimum traffic, exactly as much as the in-core factorization: reading the input and writing the output. More traffic is required for the latter. We investigate three issues: the size of the core that determines the boundary between the two out-of-core scenarios, the in-core data structure reorganizations required by the R1/W1 factorization and the traffic required by the RM/WM factorization. We use three common factorization algorithms: left-looking, right-looking and multifrontal. In the R1/W1 scenario, our results indicate that for problems with good separators, such as those coming from the discretization of partial differential equations, ordered with nested dissection, right-looking and multifrontal factorization perform slightly better than left-looking factorization. There are, however, applications for which multifrontal is a bad choice, requiring too much temporary storage. On the other hand, right-looking factorization should be avoided in the RM/WM scenario. Left-looking is a good choice, but only if data is blocked along one dimension. Multifrontal performs well for both one and two dimensional blocks as long as not too much storage is required. We also explore a framework for a software implementation. We have implemented an in-core solver that relies on some object-oriented constructs. Most of the code is written in C++, except for some kernels written in Fortran 77. We intend to add out-of-core functionality to the code and data movement is a major concern. Implicit data movement represents the easy way, but, as some of our experiments show, good performance can be achieved only with explicit data movement. This complicates the code and we expect a substantial effort in order to implement an efficient out-of-core solver

Extracellular Vesticles in Acute Respiratory Distress Syndrome: Understanding Protective and Harmful Signaling for the Development of New Therapeutics

Acute respiratory distress syndrome (ARDS) is a severe respiratory condition characterized by increased lung permeability, hyper-inflammatory state, and fluid leak into the alveolar spaces. ARDS is a heterogeneous disease, with multiple direct and indirect causes that result in a mortality of up to 40%. Due to the ongoing Covid-19 pandemic, its incidence has increased up to ten-fold. Extracellular vesicles (EVs) are small liposome-like particles that mediate intercellular communication and play a major role in ARDS pathophysiology. Indeed, they participate in endothelial barrier dysfunction and permeability, neutrophil, and macrophage activation, and also in the development of a hypercoagulable state. A more thorough understanding of the variegated and cell-specific functions of EVs may lead to the development of safe and effective therapeutics. In this review, we have collected evidence of EVs role in ARDS, revise the main mechanisms of production and internalization and summarize the current therapeutical approaches that have shown the ability to modulate EV signaling

The gamma-ray telescope Gamma-1

French and Soviet specialists have designed and built the gamma-ray telescope GAMMA-1 to detect cosmic gamma rays above 50 MeV. The sensitive area of the detector is 1400 sq cm, energy resolution is 30% at 300 MeV, and angular resolution 1.2 deg at 300 MeV (and less than 20' arc when a coded aperture mask is used). Results on calibration of the qualification model and Monte-Carlo calculations are presented

Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment

When primitive vertebrates evolved from ancestral members of the animal kingdom and acquired complex locomotive and neurological toolsets, a constant supply of energy became necessary for their continued survival. To help fulfill this need, the endocannabinoid (eCB) system transformed drastically with the addition of the cannabinoid-1 receptor (CB1R) to its gene repertoire. This established an eCB/CB1R signaling mechanism responsible for governing the whole organism's energy balance, with its activation triggering a shift toward energy intake and storage in the brain and the peripheral organs (i.e., liver and adipose). Although this function was of primal importance for humans during their pre-historic existence as hunter-gatherers, it became expendable following the successive lifestyle shifts of the Agricultural and Industrial Revolutions. Modernization of the world has further increased food availability and decreased energy expenditure, thus shifting the eCB/CB1R system into a state of hyperactive deregulated signaling that contributes to the 21st century metabolic disease pandemic. Studies from the literature supporting this perspective come from a variety of disciplines, including biochemistry, human medicine, evolutionary/comparative biology, anthropology, and developmental biology. Consideration of both biological and cultural evolution justifies the design of improved pharmacological treatments for obesity and Type 2 diabetes (T2D) that focus on peripheral CB1R antagonism. Blockade of peripheral CB1Rs, which universally promote energy conservation across the vertebrate lineage, represents an evolutionary medicine strategy for clinical management of present-day metabolic disorders

Endothelial Cell-Derived Extracellular Vesicles Impair the Angiogenic Response of Coronary Artery Endothelial Cells

Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local and distant tissue function. Systemic inflammation associated with conditions such as obesity as well as the acute inflammatory response elicited by a cardiac event can significantly increase the EV release by endothelium and alter their miRNA, protein or lipid cargo. Our laboratory has previously shown that EVs released by adipose tissue endothelial cells exposed to chronic inflammation have angiostatic effects on naïve adipose tissue EC in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro-inflammatory cues is currently unclear. The objective of this study was to investigate the angiostatic effects of EVs produced by EC from the coronary artery and adipose microvasculature exposed to pro-inflammatory cytokines (PIC) on naïve coronary artery EC. We have found that EVs from both EC sources have angiostatic effects on the coronary endothelium. EVs produced by cells in a pro-inflammatory environment reduced proliferation and barrier function of EC without impacting cellular senescence. Some of these functional effects could be attributed to the miRNA cargo of EVs. Several miRNAs such as miR-451, let-7, or miR-23a impact on multiple pathways responsible for proliferation, cellular permeability and angiogenesis. Collectively, our data suggests that EVs may compete with pro-angiogenic cues in the ischemic myocardium therefore slowing down the repair response. Acute treatments with inhibitors that prevent endogenous EV release immediately after an ischemic event may contribute to better efficacy of therapeutic approaches using functionalized exogenous EVs or other pro-angiogenic approaches

Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors

STAT4 deficiency reduces the development of atherosclerosis in mice

Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe(-/-) M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) MΦs was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses

Расчет пульсаций продуктов химического превращения при газоимпульсной регенерации фильтров скважин

The paper considers a mathematical model of pulsation of gas explosion products in the operational chamber during gas-impulse regeneration of water well filters. Second-order differential equation with constant coefficients has been derived. A special calculation program has been developed to solve the equation. The paper proposes analytical method for determination of maximum hydraulic flow rate. In order to increase efficiency of regeneration improved technological treatment schemes are given in the paper.Рассмотрена математическая модель процесса пульсаций продуктов газового взрыва в рабочей камере при газоимпульсной регенерации фильтров водозаборных скважин. Получено дифференциальное уравнение второго порядка с постоянными коэффициентами, для решения которого составлена программа расчета. Предложены аналитический метод определения максимальной скорости гидропотока, а также усовершенствованные технологические схемы обработки для повышения эффективности регенерации