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Alzheimer's disease (AD) affects one in ten people older than 65 years. Thus far, there is no cure or even disease-modifying treatment for this disease. The immune system is a major player in the pathogenesis of AD. Bacillus Calmette-Guérin (BCG), developed as a vaccine against tuberculosis, modulates the immune system and reduces recurrence of non-muscle invasive bladder cancer. Theoretical considerations suggested that treatment with BCG may decrease the risk of AD. We tested this hypothesis on a natural population of bladder cancer patients. After removing all bladder cancer patients presenting with AD or developing AD within one-year following diagnosis of bladder cancer, we collected data on a total of 1371 patients (1134 males and 237 females) who were followed for at least one year after the diagnosis of bladder cancer. The mean age at diagnosis of bladder cancer was 68.1 years (SD 13.0). Adjuvant post-operative intra-vesical treatment with BCG was given to 878 (64%) of these patients. The median period post-operative follow-up was 8 years. During follow-up, 65 patients developed AD at a mean age of 84 years (SD 5.9), including 21 patients (2.4%) who had been treated with BCG and 44 patients (8.9%) who had not received BCG. Patients who had been treated with BCG manifested more than 4-fold less risk for AD than those not treated with BCG. The Cox proportional hazards regression model and the Kaplan-Meier analysis of AD free survival both indicated high significance: patients not treated with BCG had a significantly higher risk of developing AD compared to BCG treated patients (HR 4.778, 95%CI: 2.837-8.046, p = 4.08x10-9 and Log Rank Chi-square 42.438, df = 1, p = 7.30x10-11, respectively). Exposure to BCG did not modify the prevalence of Parkinson's disease, 1.9% in BCG treated patients and 1.6% in untreated (Fisher's Exact Test, p = 1). Bladder cancer patients treated with BCG were significantly less likely to develop AD at any age than patients who were not so treated. This finding of a retrospective study suggests that BCG treatment might also reduce the incidence of AD in the general population. Confirmation of such effects of BCG in other retrospective studies would support prospective studies of BCG in AD.

•Retrospective birth cohorts and national vaccination history show BCG effect on T1D.•Newborn BCG vaccination and boosting prevents T1D in female but not in male youth.•BCG mitigates murine and human T1D glycaemia by induction of aerobic glycolysis.•BCG prevents T1D in female NOD mice by suppression of diabetogenic immune cells.•BCG may prevent T1D in human females by a similar mechanism as in NOD mice. Type 1 diabetes (T1D), like other autoimmune diseases, is on the rise since the second half of the 20th century. Hypothetically this has been ascribed to restricted exposure to microbial diversity due to advanced hygienic practices accompanying modernization, and increasing prosperity in urban versus rural habitats. The autoimmune animal model of T1D, inhibited by Bacillus Calmette Guerine (BCG), motivated testing the impact of BCG on T1D incidence in humans. Several epidemiological analyses, short of one, failed to demonstrate a protective effect of BCG against T1D. The present retrospective analysis of two data sets reevaluates the hypothetic inhibitory effect of BCG on human T1D. Reassessment of data from a Swedish study reveals that a single BCG vaccination provided a small but significant protection against T1D. A second data set of T1D prevalence/1000 Israeli military conscripts, from a doctoral thesis presenting 17 birth cohorts at age 17 is evaluated against the national schedule of vaccination related to years of birth. To correct for the annual increasing T1D trend the mean urbanization (census) rate was set as an annual moving average and factored into the prevalence (T1D/1000) of respective birth cohorts. Three groups of cohorts corresponding to BCG vaccination are presently identified; Group A corresponds to the years in which newborns were vaccinated and boosted if necessary, at age 12. Group B corresponds to the period when boosting was discontinued. Group C corresponds to years when newborn BCG vaccination was discontinued. T1D (only in females) was slightly but significantly lower in group B (n = 5 cohorts) versus C (n = 8 cohorts, p = 0.0475, by Mann Whitney U test). T1D in group A (n = 4 cohorts) was lower than in group B (p = 0.02). This analysis supports the hypothesis that in human females postnatal BCG vaccination, reinforced by boosting, has a protective impact on T1D being superior to omitted boosting, which in its turn is still better than stopping vaccination altogether. This analysis further suggests that upon advanced modernization the BCG vaccine compensates for reduced exposure to microbial diversity early in life.

At the subduction zone interface, a combination of mechanical deformation and (fluid‐mediated) chemical mixing of oceanic crust, sediment and mantle lithologies yields heterogeneous mélange lithologies. These mélanges have compositions and metamorphic mineral assemblages dissimilar to their endmember source lithologies, resulting in a subduction zone interface with physical properties (e.g., H2O capacity, density, and viscosity) that are distinct from both the source lithologies and simple mechanical mixtures of these lithologies. Using phase equilibria modeling, we find that a large range of mélange compositions carry more H2O to sub‐arc depths and are less dense compared to equivalent mechanical mixtures. We further show that mélange is much weaker than the overlying mantle but remains stronger than quartzite deforming by dislocation creep. Lastly, we synthesize these results and find that at all subduction zones, a range of mélange compositions are likely to form diapirs at sub‐arc depths and sub‐solidus temperatures. Plain Language Summary At subduction zones, a range of different rock types from the Earth's surface are carried into its interior. During subduction, these different rock types are mixed, both physically and, eventually, chemically, producing new distinct rock types. In this study, we examine the consequences of this process. We use models to predict the stable minerals that will form in these new rock types and calculate the strength, density, and amount of water contained in these rocks. We find that the mixed rocks have significantly different properties than the initial rocks input into subduction zones. These new properties have implications for when water and other fluids are released from the subducting slab, an important driver of magma production at subduction zones, and also for the generation of buoyant diapirs of slab top material. Key Points Hybridization of slab‐top mélange produces unique compositions with distinct mineral assemblages compared to the source lithologies This hybridization modifies the H2O budget, density, and strength of slab‐top materials Diapirism is favored for ultramafic and sediment dominated mélange compositions at both hot and cold subduction zones

The origin of the wide range of sulfur isotope compositions (i.e., δ 34 S) measured in arc rocks remains debated. While the observed δ 34 S variability has been attributed to slab-related fluids that flux the sub-arc mantle, others have argued that it primarily reflects crustal-derived processes by some combination of magmatic differentiation, country rock assimilation, and/or degassing. Here, we present new whole rock sulfur isotopes for the Late Cretaceous Bear Valley Intrusive Suite (BVIS) that represents a continuous arc crustal section in the southern Sierra Nevada Batholith, exposing lower crustal mafic cumulates and cogenetic mid-upper crustal tonalites. Our data reveal a range of δ 34 S-depleted values (–1.2 to − 5.1‰) for the BVIS with overlapping δ 34 S between mafic cumulates and tonalites. Complementary δ 34 S measurements of structurally concordant metasedimentary pendants indicate δ 34 S-depleted values (–11.5 to − 5.2‰) for deep metasedimentary rocks compared to δ 34 S-enriched values (+ 1.6 to + 6.4‰) for shallower ones. Quantitative mixing models suggest that assimilation of crustal-derived sulfur from metasedimentary rocks in the lower crust can account for the δ 34 S-depleted values in the BVIS, whereas assimilation of shallower ones is unlikely. Sulfur degassing modelling indicates that the range of δ 34 S-depleted values observed within mid-upper crustal tonalites can be reproduced by degassing  ~60–80% of the initial melt sulfur at f O 2  ≤ FMQ + 1 with initial H 2 O content of 10–12 wt%. Finally, the identical ranges of δ 34 S values within the tonalites and mafic cumulates argue for limited sulfur isotope fractionation related to magmatic sulfide immiscibility. Although assimilation, magma degassing and sulfide immiscibility are not mutually exclusive during crustal magmatic processes, field, thermal and geochemical evidence favor lower crustal-derived sulfur assimilation as the primary mechanism to explain the range of δ 34 S- depleted values within the mafic cumulates, which are ultimately inherited by the derivative tonalitic melts. Overall, this study emphasizes that deep crustal magmatic processes can severely influence the early δ 34 S evolution of arc magmas.

Exposures of arc crustal sections represent rare opportunities to directly evaluate lower crustal magmatic processes and their link to arc products in the middle and upper crust. Within the southernmost Sierra Nevada batholith, the Bear Valley Intrusive Suite (BVIS) exposes a contemporaneously constructed ~ 30 km thick intrusive suite, and thus is ideal for this type of examination. Here we present detailed petrography and mineral major and trace element data for the BVIS. The deepest exposed portion of the BVIS (8–9 kbars) is composed of heterogeneous mafic igneous intrusions of olivine metagabbro, olivine-hornblende orthopyroxenite, olivine-bearing hornblende norite, hornblende norite, hornblende gabbronorite, hornblendite and hornblende gabbro. Shallower crustal intrusions (3–7 kbars) are comparatively homogeneous and dominated by hypersthene-bearing and hypersthene-free tonalites. Using amphibole-plagioclase geothermometry, we show that the mafic lower crustal intrusions crystallized over a wide temperature range from 850 to 1070 °C, highlighting mafic igneous fractionation during isobaric cooling in the lower crust of the Sierran arc, while tonalitic liquids were emplaced at temperatures < 800 °C in the middle and upper crust. Calculated trace element melt compositions in equilibrium with amphibole in lower crustal gabbros are similar to measured tonalite bulk compositions and support the generation of tonalites through fractionation of the observed gabbros. Further, petrography and mineral chemistry suggest multiple distinct crystallization sequences recorded in the different types of gabbro, requiring the presence of coexisting parental melts with contrasting compositions and H2O contents. Using available experimental data, we develop a model by which mixing of variably fractionated dry and wet magmas with similar viscosities followed by crystallization-differentiation in the deep crust to explain the formation of uniform tonalitic melts at shallower crustal levels in the BVIS. This process also explains the unusual predominance of orthopyroxene in the BVIS, and the limited aluminum enrichment compared to experimental differentiation sequences of hydrous basalts. Considering the similar geochemical characteristics of intermediate and felsic igneous rocks from the Sierra Nevada batholith and the Cascades, mixing magmas of variable H2O contents in the lower crust represents a viable petrological process to produce SiO2-rich liquids that may be more common than previously recognized.

During the differentiation of arc magmas, fractionating liquids follow a series of cotectics, where the co‐crystallization of multiple minerals control the melt compositional trajectories, commonly referred to as liquid lines of descent (LLD). These cotectics are sensitive to intensive properties, including fractionation pressure and melt H2O concentration, and changes in these variables produce systematic differences in the LLDs of arc lavas. Based on a compilation of experimental studies, we develop two major element proxies that exploit differences in LLDs to constrain the fractionation conditions of arc magmas. Near‐primary fractionating magmas evolve along the olivine‐clinopyroxene cotectic, which is pressure‐sensitive. We use this sensitivity to develop a proxy for early fractionation pressure based on the normative mineral compositions of melts with 8 ± 1 wt.% MgO. Fractionation in more evolved magmas is controlled by the clinopyroxene‐plagioclase cotectic, which is strongly sensitive to magmatic H2O contents. We use this relationship to develop an H2O proxy that is calibrated to the normative mineral components of melts with 2–4 wt.% MgO. These two proxies provide new tools for estimating the variations in pressure and temperature between magmatic systems. We applied these proxies to compiled major element data and phenocryst assemblages from modern volcanic arcs and show that in island arcs early fractionation is relatively shallow and magmas are dominantly H2O‐poor, while continental arcs are characterized by more hydrous and deeper early fractionation. These differences likely reflect variations in the relative contributions of decompression and flux melting in combination with distinct upper plate controls on arc melt generation. Plain Language Summary Within volcanic arcs, magmas evolve from silica‐poor basalts to more silica‐rich compositions. This process is dominantly controlled by the minerals that crystallize from the magmas and generates characteristic changes in magma compositions that can be measured in erupted lavas. The crystallizing minerals and evolution in magma composition are sensitive to changes in the conditions at which magmas crystalize including the amount of water dissolved in the magma and the depth of crystallization within the crust. We develop two new methods that use changes in magma composition to understand how these conditions vary between different volcanic arcs. We find that arcs built on continental crust typically erupt lavas that began to crystallize at greater depths and are more water‐rich, while arcs built on oceanic crust primarily erupt water‐poor lavas that began to crystallize at shallower depths. These differences have important implications for the processes by which new continental crust is created within volcanic arcs. Key Points The major element evolution of arc magmas is controlled by the fractionation of pressure and H2O sensitive mineral assemblages We use these relationships to develop two proxies that calculate early fractionation pressure and H2O contents from magma compositions Continental arcs are dominantly H2O‐rich and deeper fractionating, while island arcs are more H2O‐poor and shallower fractionating

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund–Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.

Cutaneous lupus erythematosus (CLE) represents a complex autoimmune disease with a broad phenotypic spectrum ranging from acute to chronic destructive cutaneous lesions. Patients with CLE exhibit high photosensitivity and ultraviolet (UV) irradiation can lead to systemic flares in systemic lupus erythematosus. However, the exact mechanisms how UV irradiation enhances cutaneous inflammation in lupus are not fully understood. Recently, new molecular mechanisms of UV-driven immune responses in CLE were identified, offering potential therapeutic approaches. Especially the induction of type I interferons, central cytokines in lupus pathogenesis which are released by various skin cells, have become the focus of current research. In this review, we describe current pathogenic concepts of photosensitivity in lupus erythematosus, including UV-driven activation of intracellular nucleic acid sensors, cellular cytokine production and immune cell activation. Furthermore, we discuss activated pathways contributing to enhanced apoptosis as well as intracellular translocation of autoantigens thereby promoting CLE upon UV light exposure.