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"Russell, David"
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Engineering universal cells that evade immune detection
The prospect of transplanting cells and tissues without the risk of immune rejection or the need for powerful immunosuppressive drugs is the ‘holy grail’ of transplantation medicine. Now, with the advent of pluripotent stem cells, CRISPR–Cas9 and other gene-editing technologies, the race to create ‘off-the-shelf’ donor cells that are invisible to the immune system (‘universal cells’) has started. One important approach for creating such cells involves the manipulation of genes required for immune recognition, in particular HLA class I and II proteins. Other approaches leverage knowledge of immune-cloaking strategies used by certain bacteria, viruses, parasites, the fetus and cancer cells to induce tolerance to allogeneic cell-based therapies by modifying cells to express immune-suppressive molecules such as PD-L1 and CTLA4–Ig. Various academic groups as well as biotechnology and pharmaceutical companies are on the verge of bringing these therapies into the clinic.
Journal Article
Immunometabolism at the interface between macrophages and pathogens
It is generally regarded that the progression of an infection within host macrophages is the consequence of a failed immune response. However, recent appreciation of macrophage heterogeneity, with respect to both development and metabolism, indicates that the reality is more complex. Different lineages of tissue-resident macrophages respond divergently to microbial, environmental and immunological stimuli. The emerging picture that the developmental origin of macrophages determines their responses to immune stimulation and to infection stresses the importance of in vivo infection models. Recent investigations into the metabolism of infecting microorganisms and host macrophages indicate that their metabolic interface can be a major determinant of pathogen growth or containment. This Review focuses on the integration of data from existing studies, the identification of challenges in generating and interpreting data from ongoing studies and a discussion of the technologies and tools that are required to best address future questions in the field.Different lineages of macrophages respond divergently to immune stimuli and microbial infection. This Review explores our current knowledge of how the different metabolic states of macrophage lineages impact the control or progression of intracellular bacterial infections.
Journal Article
Early U.S. Navy carrier raids, February-April 1942 : five operations that tested a new dimension of American air power
\"After the Japanese attack on Pearl Harbor, America's fast carrier task forces, with their aircraft squadrons and powerful support warships, went on the offensive. Under orders from the Fleet Admiral Ernest J. King, the newly appointed Admiral Chester W. Nimitz, as the Commander-in-Chief of the Pacific Fleet, took the fight to the Japanese, using island raids to slow their advance in the Pacific. Beginning in February 1942, a series of task force raids led by the carriers USS Enterprise, USS Yorktown, USS Lexington and USS Hornet were launched, beginning in the Marshall Islands and Gilbert Islands. An attempted raid on Rabaul was followed by successful attacks on Wake Island and Marcus Island. The Lae-Salamaua Raid countered Japanese invasions on New Guinea. The most dramatic was the unorthodox Tokyo (Doolittle) Raid, where 16 carrier-launched B-25 medium bombers demonstrated that the Japanese mainland was open to U.S. air attacks. The raids had a limited effect on halting the Japanese advance but kept the enemy away from Hawaii, the U.S. West coast and the Panama Canal, and kept open lines of communications to Australia.\"-- Provided by publisher.
Book
Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides
The nature of the first genetic polymer is the subject of major debate
1
. Although the ‘RNA world’ theory suggests that RNA was the first replicable information carrier of the prebiotic era—that is, prior to the dawn of life
2
,
3
—other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA
4
. Such a theory streamlines the eventual ‘genetic takeover’ of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life
5
.
A prebiotic synthesis of the purine DNA nucleosides (deoxyadenosine and deoxyinosine) in which the pyrimidine RNA nucleosides (cytidine and uridine) persist has implications for the coexistence of DNA and RNA at the dawn of life.
Journal Article
The Hellenistic, Roman, and Medieval Glass from Cosa
The Hellenistic, Roman, and Medieval Glass from Cosa continues the exemplary record of publication by the American Academy in Rome on important classes of materials recovered in excavation from one of the principal archaeological sites of Roman Italy. Over 15,000 fragments of glass tableware, ranging in date from the mid-second century BCE to the early fifth century CE, were found at Cosa, a small town in Etruria (modern Tuscany). Cosa's products were chiefly exported to North Africa and Europe, but its influence was felt throughout the Mediterranean world. The research and analysis presented here are the work of the late David Frederick Grose, who began this project when no other city site excavations in Italy focused on ancient glass. He confirmed that the Roman glass industry began to emerge in the Julio-Claudian era, beginning in the principate of Augustus. His study traces the evolution of manufacturing techniques from core-formed vessels to free blown glass, and it documents changes in taste and style that were characteristic of the western glass industry throughout its long history. At the time of Grose's unexpected passing, his study was complete but not yet published. Nevertheless, the reputation of his work in this area has done much to establish the value and importance of excavating and researching Cosa's glass. This volume, arranged and edited by R.T. Scott, makes Grose's essential scholarship on the subject available for the first time.
Book
Novel Inhibitors of Cholesterol Degradation in Mycobacterium tuberculosis Reveal How the Bacterium’s Metabolism Is Constrained by the Intracellular Environment
Mycobacterium tuberculosis (Mtb) relies on a specialized set of metabolic pathways to support growth in macrophages. By conducting an extensive, unbiased chemical screen to identify small molecules that inhibit Mtb metabolism within macrophages, we identified a significant number of novel compounds that limit Mtb growth in macrophages and in medium containing cholesterol as the principle carbon source. Based on this observation, we developed a chemical-rescue strategy to identify compounds that target metabolic enzymes involved in cholesterol metabolism. This approach identified two compounds that inhibit the HsaAB enzyme complex, which is required for complete degradation of the cholesterol A/B rings. The strategy also identified an inhibitor of PrpC, the 2-methylcitrate synthase, which is required for assimilation of cholesterol-derived propionyl-CoA into the TCA cycle. These chemical probes represent new classes of inhibitors with novel modes of action, and target metabolic pathways required to support growth of Mtb in its host cell. The screen also revealed a structurally-diverse set of compounds that target additional stage(s) of cholesterol utilization. Mutants resistant to this class of compounds are defective in the bacterial adenylate cyclase Rv1625/Cya. These data implicate cyclic-AMP (cAMP) in regulating cholesterol utilization in Mtb, and are consistent with published reports indicating that propionate metabolism is regulated by cAMP levels. Intriguingly, reversal of the cholesterol-dependent growth inhibition caused by this subset of compounds could be achieved by supplementing the media with acetate, but not with glucose, indicating that Mtb is subject to a unique form of metabolic constraint induced by the presence of cholesterol.
Journal Article
Who puts the tubercle in tuberculosis?
Key Points
Mycobacterium tuberculosis
probably evolved from a founder strain similar to the TB-like strains found today in central Africa, and invaded mankind prior to the spread of humans out of Africa. Contrary to popular literature, TB did not evolve from
Mycobacterium bovis
that was acquired from cows during the evolution of animal husbandry in the Fertile Crescent.
Mycobacterium tuberculosis
infections result in the formation of granulomas at the established infection site. The progression of these granulomas determines, locally, the outcome of the infection and not all granulomas in the same host progress in the same way.
Granulomas can resolve, mineralize, or progress to yield a productive infection. A productive infection is achieved when the centre of the granuloma caseates, degenerates and spills live infectious bacteria into the lung airways inducing a cough and transmission through aerosol droplets.
The peripheral cell-wall lipids from
Mycobacterium tuberculosis
are potent immunomodulating agents that, when inoculated into experimental animals, induce tissue pathology that is reminiscent of the granulomas produced in a viable infection.
Mycobacterium tuberculosis
releases peripheral cell-wall lipids inside the infected host macrophage. The macrophage sequesters these lipids into the membranes of internal vesicles in the multi-vesicular lysosomes and releases these vesicles as exosomes.
The release and trafficking of bioactive lipids might be an active mechanism whereby
Mycobacterium tuberculosis
exacerbates the pathology of the infection, driving granuloma progression, and ultimately leading to caseation and spread.
The tuberculoma or tubercle is the granuloma that is formed during tuberculosis infection. The role of the immune system in the formation of the granuloma is documented extensively, but this Review takes a different tack and examines the role of
Mycobacterium tuberculosis
in the biology of the granuloma and how this relates to disease transmission and progression.
Tuberculosis (TB), an illness that mainly affects the respiratory system, is one of the world's most pernicious diseases. TB currently infects one-third of the world's population and kills approximately 1.7 million people each year. Most infected individuals fail to progress to full-blown disease because the TB bacilli are 'walled off' by the immune system inside a tissue nodule known as a granuloma. The granuloma's primary function is one of containment and it prevents the dissemination of the mycobacteria. But what is the role of the TB bacillus in the progression of the granuloma? This Review explores how
Mycobacterium tuberculosis
influences granuloma formation and maintenance, and ensures the spread of the disease.
Journal Article