T cells play a key role in cell-mediated immunity, and strategies to genetically modify T cells, including chimeric antigen receptor (CAR) T cell therapy and T cell receptor (TCR) T cell therapy, ...have achieved substantial advances in the treatment of malignant tumors. In clinical trials, CAR-T cell and TCR-T cell therapies have produced encouraging clinical outcomes, thereby demonstrating their therapeutic potential in mitigating tumor development. This article summarizes the current applications of CAR-T cell and TCR-T cell therapies in clinical trials worldwide. It is predicted that genetically engineered T cell immunotherapies will become safe, well-tolerated, and effective therapeutics and bring hope to cancer patients.
During winter 2013, extremely high concentrations (i.e., 4–20 times higher than the World Health Organization guideline) of PM2.5 (particulate matter with an aerodynamic diameter < 2.5 μm) mass ...concentrations (24 h samples) were found in four major cities in China including Xi'an, Beijing, Shanghai and Guangzhou. Statistical analysis of a combined data set from elemental carbon (EC), organic carbon (OC), 14C and biomass-burning marker measurements using Latin hypercube sampling allowed a quantitative source apportionment of carbonaceous aerosols. Based on 14C measurements of EC fractions (six samples each city), we found that fossil emissions from coal combustion and vehicle exhaust dominated EC with a mean contribution of 75 ± 8% across all sites. The remaining 25 ± 8% was exclusively attributed to biomass combustion, consistent with the measurements of biomass-burning markers such as anhydrosugars (levoglucosan and mannosan) and water-soluble potassium (K+). With a combination of the levoglucosan-to-mannosan and levoglucosan-to-K+ ratios, the major source of biomass burning in winter in China is suggested to be combustion of crop residues. The contribution of fossil sources to OC was highest in Beijing (58 ± 5%) and decreased from Shanghai (49 ± 2%) to Xi'an (38 ± 3%) and Guangzhou (35 ± 7%). Generally, a larger fraction of fossil OC was from secondary origins than primary sources for all sites. Non-fossil sources accounted on average for 55 ± 10 and 48 ± 9% of OC and total carbon (TC), respectively, which suggests that non-fossil emissions were very important contributors of urban carbonaceous aerosols in China. The primary biomass-burning emissions accounted for 40 ± 8, 48 ± 18, 53 ± 4 and 65 ± 26% of non-fossil OC for Xi'an, Beijing, Shanghai and Guangzhou, respectively. Other non-fossil sources excluding primary biomass burning were mainly attributed to formation of secondary organic carbon (SOC) from non-fossil precursors such as biomass-burning emissions. For each site, we also compared samples from moderately to heavily polluted days according to particulate matter mass. Despite a significant increase of the absolute mass concentrations of primary emissions from both fossil and non-fossil sources during the heavily polluted events, their relative contribution to TC was even decreased, whereas the portion of SOC was consistently increased at all sites. This observation indicates that SOC was an important fraction in the increment of carbonaceous aerosols during the haze episode in China.
Coronavirus disease 2019 has markedly varied clinical presentations, with most patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease, caused by severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2), is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by ACE 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury. ACE2 is identified as an essential receptor for SARS-CoV-2 to enter the cell. The binding of ACE2 and SARS-CoV-2 leads to the exhaustion and down-regulation of ACE2. The interaction and imbalance between ACE and ACE2 result in an unopposed angiotensin II. Considering that the ACE insertion (I)/deletion (D) gene polymorphism contributes to the ACE level variability in general population, in which mean ACE level in DD carriers is approximately twice that in II carriers, we propose a hypothesis of genetic predisposition to severe lung injury in patients with coronavirus disease 2019. It is plausible that the ACE inhibitors and ACE receptor blockers may have the potential to prevent and to treat the acute lung injury after SARS-CoV-2 infection, especially for those with the ACE genotype associated with high ACE level.
Deep learning predicts path-dependent plasticity Mozaffar, M.; Bostanabad, R.; Chen, W. ...
Proceedings of the National Academy of Sciences - PNAS,
12/2019, Letnik:
116, Številka:
52
Journal Article
Recenzirano
Odprti dostop
Plasticity theory aims at describing the yield loci and work hardening of a material under general deformation states. Most of its complexity arises from the nontrivial dependence of the yield loci ...on the complete strain history of a material and its microstructure. This motivated 3 ingenious simplifications that underpinned a century of developments in this field: 1) yield criteria describing yield loci location; 2) associative or nonassociative flow rules defining the direction of plastic flow; and 3) effective stress–strain laws consistent with the plastic work equivalence principle. However, 2 key complications arise from these simplifications. First, finding equations that describe these 3 assumptions for materials with complex microstructures is not trivial. Second, yield surface evolution needs to be traced iteratively, i.e., through a return mapping algorithm. Here, we show that these assumptions are not needed in the context of sequence learning when using recurrent neural networks, diverting the above-mentioned complications. This work offers an alternative to currently established plasticity formulations by providing the foundations for finding history- and microstructure-dependent constitutive models through deep learning.
Adoptive cell therapy (ACT) is a kind of immunotherapy in which T cells are genetically modified to express a chimeric antigen receptor (CAR) or T cell receptor (TCR), and ACT has made a great ...difference in treating multiple types of tumors. ACT is not perfect, and it can be followed by severe side effects, which hampers the application of ACT in clinical trials. One of the most promising methods to minimize side effects is to endow adoptive T cells with the ability to target neoantigens, which are specific to tumor cells. With the development of antigen screening technologies, more methods can be applied to discover neoantigens in cancer cells, such as whole-exome sequencing combined with mass spectrometry, neoantigen screening through an inventory-shared neoantigen peptide library, and neoantigen discovery via trogocytosis. In this review, we focus on the side effects of existing antigens and their solutions, illustrate the strategies of finding neoantigens in CAR-T and TCR-T therapies through methods reported by other researchers, and summarize the clinical behavior of these neoantigens.
A large change in albedo has a significant effect on glacier ablation. Atmospheric aerosols – e.g. black carbon (BC) and dust – can reduce the albedo of glaciers and thus contribute to their melting. ...In this study, two main themes were explored: (1) the decrease in albedo of the Zhadang glacier on Mt. Nyainqentanglha between 2001 and 2012, as observed by the Moderate Resolution Imaging Spectroradiometer (MODIS) on-board the Terra satellite, and the correlation of this albedo with mass balance; and (2) the concentrations of BC and dust in the glacier measured during 2012, and the associated impacts of these impurities on albedo and radiative forcings (RF). The average albedo of the Zhadang glacier from the MODIS increased with the altitude and fluctuated but had a decreasing trend (−0.003 a−1) during the period 2001–2012, with the highest (0.722) in 2003 and the lowest (0.597) in 2009 and 2010. The mass balance of the glacier has a positively significant correlation with its surface albedo derived from MODIS. Snow samples were collected on the Zhadang glacier to measure the BC and dust in the summer of 2012. The impacts of BC and dust on albedo reduction in different melting conditions were identified with the SNow ICe Aerosol Radiative (SNICAR) model initiated by in situ observation data. The sensitivity analysis showed that BC was a major factor in albedo reduction when the glacier was covered by newly fallen snow. Nevertheless, the contribution of dust to albedo reduction can reach as high as 56%, much exceeding that of BC (28%), when the glacier experiences strong surficial melting and its surface is almost bare ice. The average RF caused by dust could increase from 1.1 to 8.6 W m−2, exceeding the RF caused by BC after snow was deposited and surface melting occurred in the Zhadang glacier. This implies that it may be dust that primarily dominates the melting of some glaciers in the inner Tibetan Plateau during melting seasons, rather than BC.
Abstract Diabetes mellitus (DM) adversely affects the number and function of circulating endothelial progenitor cells (EPCs). Consequently, there is also a reduction in the repair mechanism of these ...cells, which is a critical and initiating factor in the development of diabetic vascular disease. The aim of the present study was to analyze miR expression profiles in EPCs from patients with DM and choose the most significantly regulated miR to study its possible role on EPC dysfunction and elucidate its mechanism of action. EPCs were collected from subjects with Type II DM and non-diabetic control subjects. Total RNA was harvested from EPCs, and a total of 5 candidate miRNAs were identified by microarray screening and were quantified by TaqMan real-time PCR. Lentiviral vectors expressing miR-126 and miR-126 inhibitor (anti-miR-126) were transfected into EPCs, and the EPC colony-forming capacity, proliferation activity, migratory activity, differentiation capacity, and apoptotic susceptibility were determined and Western Blotting and mRNA real-time PCR analyses were performed. To study the mechanisms, lentiviral vectors expressing Spred-1 and a short interfering RNA (siRNA) targeting Spred-1 were prepared. Five miRs were aberrantly downregulated in EPCs from DM patients. These miRs included miR-126, miR-21, miR-27a, miR-27b and miR-130a. Anti-miR-126 inhibited EPC proliferation, migration, and enhanced apoptosis. Restored miR-126 expression in EPCs from DM promoted EPC proliferation, migration, and inhibited EPC apoptosis ability. Despite this, miR-126 had no effect on EPC differentiation. miR-126 overexpression significantly downregulated Spred-1 in EPCs. The knockdown of Spred-1 expression in EPCs from DM promoted proliferation, migration, and inhibited apoptosis of the cells. The signal pathway of miR-126 effecting on EPCs is partially mediated through Ras/ERK/VEGF and PI3K/Akt/eNOS regulation. This study provides the first evidence that miR-126 is downregulated in EPCs from diabetic patients, and impairs EPCs-mediated function via its target, Spred-1, and through Ras/ERK/VEGF and PI3K/Akt/eNOS signal pathway.
Obesity is traditionally viewed to be beneficial to bone health because of well-established positive effect of mechanical loading conferred by body weight on bone formation, despite being a risk ...factor for many other chronic health disorders. Although body mass has a positive effect on bone formation, whether the mass derived from an obesity condition or excessive fat accumulation is beneficial to bone remains controversial. The underline pathophysiological relationship between obesity and bone is complex and continues to be an active research area. Recent data from epidemiological and animal studies strongly support that fat accumulation is detrimental to bone mass. To our knowledge, obesity possibly affects bone metabolism through several mechanisms. Because both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, obesity may increase adipocyte differentiation and fat accumulation while decrease osteoblast differentiation and bone formation. Obesity is associated with chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin pathway. Furthermore, the excessive secretion of leptin and/or decreased production of adiponectin by adipocytes in obesity may either directly affect bone formation or indirectly affect bone resorption through up-regulated proinflammatory cytokine production. Finally, high-fat intake may interfere with intestinal calcium absorption and therefore decrease calcium availability for bone formation. Unraveling the relationship between fat and bone metabolism at molecular level may help us to develop therapeutic agents to prevent or treat both obesity and osteoporosis. Obesity, defined as having a body mass index ≥ 30 kg/m2, is a condition in which excessive body fat accumulates to a degree that adversely affects health. The rates of obesity rates have doubled since 1980 and as of 2007, 33% of men and 35% of women in the US are obese. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year.Bone mass and strength decrease during adulthood, especially in women after menopause. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell and agents inhibiting adipogenesis stimulated osteoblast differentiation and vice versa, those inhibiting osteoblastogenesis increased adipogenesis. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review.
Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal ...tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.
We introduce a scheme for the quantum simulation of many-body decoherence based on the unitary evolution of a stochastic Hamiltonian. Modulating the strength of the interactions with stochastic ...processes, we show that the noise-averaged density matrix simulates an effectively open dynamics governed by k-body Lindblad operators. Markovian dynamics can be accessed with white-noise fluctuations; non-Markovian dynamics requires colored noise. The time scale governing the fidelity decay under many-body decoherence is shown to scale as N^{-2k} with the system size N. Our proposal can be readily implemented in a variety of quantum platforms including optical lattices, superconducting circuits, and trapped ions.
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