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Immune and Inflammatory Mechanisms of Atherosclerosis*

Several reports demonstrate T and B lymphocyte accumulation in the aortic adventitia in normal (9) and atherosclerotic vessels (9, 85, 86). Adoptive transfer experiments suggest that lymphocytes accumulate in the adventitia through the migration from the adventitial vasa vasorum rather than from the intimal lumen site (9). Local revascularization correlates with an increase in cellular composition within vulnerable regions of human atherosclerotic plaques (Figure 1). In contrast, the inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis (87). Recently, investigators have shown that vasa vasorum can penetrate the media, enter atherosclerotic plaques, and come close to the arterial lumen (88). This is an important direct demonstration of the existence of a vascular network connecting the adventitia with the plaque tissue. Thus, we now better understand the role of neovascularization in atherosclerosis (87), but further studies are necessary to elucidate the role of small adventitial vessels in the immune response during this disease.

The presence of antigen-presenting cells and T cells within atherosclerosis-prone artery walls is well documented, but there is little information about local antigen-dependent activation of T cells. It remains to be determined whether elevated numbers of lymphocytes, which have been seen in atherosclerotic vessels, are a consequence of the accelerated recruitment of activated cells from draining lymph nodes or of local antigen-induced proliferation that leads to the increased aortic lymphocyte numbers.

One of the possible sites of T cell activation in aorta may be vascular-associated tertiary lymphoid structures (Figure 1). The lymphoid-like structures are formed in a variety of autoimmune-mediated diseases, such as rheumatoid arthritis or Hashimoto’s thyroiditis. Conglomerates of leukocytes within the adventitia were reported in the early 1970s; however, only in 1997 did Wick et al. (44) name these conglomerates vascular-associated lymphoid tissues (VALTs). These lymphoid structures are formed within advanced atherosclerosis-prone vessels and contain T and B lymphocytes, plasma cells, CD4+/CD3 inducer (LTi) cells, and some MECA-32+ and HECA-452+ microvessels (9, 86, 89). Follicles located close to the arterial external elastic lamina contain proliferating Ki67+ leukocytes, apoptotic cells, and CD138+ plasma cells, showing local B cell maturation and possible humoral immune response in these structures (86). Whether the VALTs in atherosclerosis are beneficial or proatherogenic is still unclear.

Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication

The mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress. Meanwhile, heterotrimer complexes of a stable signal peptide (SSP) together with glycoprotein subunits GP1 and GP2, generated via co-and post-translational processing of the surface glycoprotein precursor GPC, form the spikes that decorate the virion surface and mediate virus cell entry via receptor-mediated endocytosis. The Z protein and the SSP undergo N-terminal myristoylation by host cell N-myristoyltransferases (NMT1 and NMT2), and G2A mutations that prevent myristoylation of Z or SSP have been shown to affect the Z-mediated virus budding and GP2-mediated fusion activity that is required to complete the virus cell entry process.

Mitochondrial building block balance linked to age-related inflammation

Research led by the Max Planck Institute for Biology of Aging in Cologne reports that misincorporation of ribonucleotides into mitochondrial DNA (mtDNA) initiates an inflammatory cascade.

Mitochondria support cell survival through metabolic and signaling roles. Conversely, their disruption has been associated with inflammation, and disease.

Innate immune activation through the cGAS-STING-TBK1 pathway can move a cell from short-term defense to a chronic state of alarm. cGAS-STING activity is linked to autoimmune and inflammatory diseases and contributes to senescence and aging, intertwining immune signaling with tissue decline.

A New Class of Drug Created That Fights Aging on a Cellular Level

Scientists continue to explore ways we can live longer and ensure those lives are healthier. A new discovery of note in this field comes from experiments in fission yeast (an organism often used for studies of aging).

Researchers from Queen Mary University of London have been testing a new drug called Rapalink-1, building on an existing immunosuppressant called rapamycin that has been shown to extend the life of cells and rodents. In these new tests, Rapalink-1 extended yeast lifespan to a similar degree as rapamycin.

What’s more, molecular analysis revealed that the drug increased the production of enzymes that convert a compound made by gut bacteria, called agmatine, into a variety of other chemicals.

James Wilson’s GEMMABio launches new gene therapy biotech for ‘ultra-orphan’ diseases

Clinical setbacks and controversial pricing may have put a dampener on the gene therapy sector, but one of the industry’s pioneers is looking for a way forward.

GEMMA Biotherapeutics, the biotech founded by gene therapy trailblazer James Wilson M.D., Ph.D., has launched a clinical-stage spinout focused specifically on ultra-orphan diseases.

Schizophrenia is linked to iron and myelin deficits in the brain, neuroimaging study finds

Schizophrenia is a severe and debilitating psychiatric disorder characterized by hallucinations, disorganized speech and thought patterns, false beliefs about the world or oneself, difficulties concentrating and other symptoms impacting people’s daily functioning. While schizophrenia has been the topic of numerous research studies, its biological and neural underpinnings have not yet been fully elucidated.

While some past brain imaging studies suggest that is associated with abnormal levels of and in the brain, the results collected so far are conflicting. Iron is a metal known to contribute to healthy brain function, while myelin is a fatty substance that forms a sheath around nerve fibers, protecting them and supporting their conduction of electrical signals.

Researchers at King’s College London, Hammersmith Hospital and Imperial College London recently set out to further explore the possibility that schizophrenia is linked to abnormal levels of iron and myelin in the brain. Their findings, published in Molecular Psychiatry, uncovered potential new biomarkers of schizophrenia that could improve the understanding of its underlying brain mechanisms.

Genetically encoded biosensor tracks plants’ immune hormone in real time

From willow bark remedies to aspirin tablets, salicylic acid has long been part of human health. It also lies at the heart of how plants fight disease. Now, researchers at the University of Cambridge have developed a pioneering biosensor that allows scientists to watch, for the first time, how plants deploy this critical immune hormone in their battle against pathogens.

Published in Science, Dr. Alexander Jones’s group at the Sainsbury Laboratory, Cambridge University (SLCU) presents SalicS1, a genetically encoded biosensor that can detect and track the dynamics of the plant immune hormone (SA) with exquisite precision inside living plants.

Salicylic acid is a central regulator of plant immunity, triggering defense responses against a huge diversity of invaders. Until now, however, scientists have lacked the tools to measure SA at high enough spatial and to understand how plants balance growth with immune defense.

Experimental drug findings pave way for clinical trial to target cancer’s elusive growth switch

Researchers at the Francis Crick Institute and Vividion Therapeutics have identified chemical compounds that can precisely block the interaction between the major cancer-driving gene RAS and a key pathway for tumor growth.

Now entering the first clinical trial in humans, if found to be safe and effective, these drugs could be used to treat many different types of cancers while avoiding effects on .

A gene called RAS, which kickstarts cell growth pathways, is mutated in around one in five cancers. Mutated versions of the gene lock the RAS protein in an activated state, telling the cancer cell to keep growing bigger and keep dividing.

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