Differential structure associated to axiomatic Sobolev spaces

The aim of this note is to explain in which sense an axiomatic Sobolev space over a general metric measure space (\ue0 la Gol'dshtein\u2013Troyanov) induces \u2013 under suitable locality assumptions \u2013 a first-order differential structure

Differential of metric valued Sobolev maps

We introduce a notion of differential of a Sobolev map between metric spaces. The differential is given in the framework of tangent and cotangent modules of metric measure spaces, developed by the first author. We prove that our notion is consistent with Kirchheim's metric differential when the source is a Euclidean space, and with the abstract differential provided by the first author when the target is R. We also show compatibility with the concept of co-local weak differential introduced by Convent and Van Schaftingen

Quasi-Continuous Vector Fields on RCD Spaces

In the existing language for tensor calculus on RCD spaces, tensor fields are only defined m-a.e. In this paper we introduce the concept of tensor field defined \u20182-capacity-a.e.\u2019 and discuss in which sense Sobolev vector fields have a 2-capacity-a.e. uniquely defined quasi-continuous representative

Glutathione limits Ero1-dependent oxidation in the endoplasmic reticulum

Many proteins of the secretory pathway contain disulfide bonds that are essential for structure and function. In the endoplasmic reticulum (ER), Ero1alpha and Ero1beta oxidize protein disulfide isomerase (PDI), which in turn transfers oxidative equivalents to newly synthesized cargo proteins. However, oxidation must be limited, as some reduced PDI is necessary for disulfide isomerization and ER-associated degradation. Here we show that in semipermeable cells, PDI is more oxidized, disulfide bonds are formed faster, and high molecular mass covalent protein aggregates accumulate in the absence of cytosol. Addition of reduced glutathione (GSH) reduces PDI and restores normal disulfide formation rates. A higher GSH concentration is needed to balance oxidative folding in semipermeable cells overexpressing Ero1alpha, indicating that cytosolic GSH and lumenal Ero1alpha play antagonistic roles in controlling the ER redox. Moreover, the overexpression of Ero1alpha significantly increases the GSH content in HeLa cells. Our data demonstrate tight connections between ER and cytosol to guarantee redox exchange across compartments: a reducing cytosol is important to ensure disulfide isomerization in secretory proteins

Molecular characterization of intergeneric hybrids between Malus and Pyrus

Apple (Malus) and pear (Pyrus) are economically important fruit crops well known for their unique textures, flavours, and nutritional qualities. Both genera are characterised by a distinct pattern of secondary metabolites, which directly affect not only resistance to certain diseases, but also have significant impacts on the flavour and nutritional value of the fruit. The identical chromosome numbers, similar genome size, and their recent divergence date, together with DNA markers have shown that apple and pear genomes are highly co-linear. This study utilized comparative genomic approaches, including simple sequence repeats, high resolution single nucleotide polymorphism melting analysis, and single nucleotide polymorphism chip analysis to identify genetic differences among hybrids of Malus and Pyrus, and F2 offspring. This research has demonstrated and validated that these three marker types, along with metabolomics analysis are very powerful tools to detect and confirm hybridity of progeny derived from crosses between apple and pear in both cross directions. Furthermore, this work analysed the genus-specific metabolite patterns and the resistance to fire blight (Erwinia amylovora) in progeny. The findings of this work will enhance and accelerate the breeding of novel tree fruit crops that benefit producers and consumers, by enabling marker assisted selection of desired traits introgressed between pear and apple

A Construção e a Evolução da CEASA-GO: A Central de Abastecimento do Cerrado Brasileiro

Resumo: ao final de 1950 e na década de 1960, surgiram as primeiras discussões para a formação de um mercado de hortigranjeiro devido a existência de atividade fragmentada e informal que vinha causando problemas urbanísticos no Brasil. Objetivou-se contextualizar a criação da Central de Abastecimento de Goiás, inaugurada em 1975, seu papel e diretrizes para implantação dos espaços físicos. Realizou-se pesquisa descritiva em manuais operacionais das CEASAS do Brasil; documentos internos da CEASA-GO, artigos da época do Sistema Nacional de Centrais de Abastecimento (SINAC) pelo Ministério da Agricultura, Pecuária e Abastecimento em conjunto com a Companhia Nacional de Abastecimento (CONAB) e a Superintendência de Programas Institucionais e Sociais de Abastecimento (SUPAD) entre os anos de 1976 a 2008. Os resultados demonstram que a CEASA-GO tem um papel fundamental no comércio atacadista de hortigranjeiros, não só no Estado de Goiás, mas em todo Cerrado Brasileiro. Palavras-chave: Ceasa. Central de Abastecimento. Hortigranjeiros. Cerrado

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10(−5) to 10(−3). Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD

T. brucei Infection Reduces B Lymphopoiesis in Bone Marrow and Truncates Compensatory Splenic Lymphopoiesis through Transitional B-Cell Apoptosis

African trypanosomes of the Trypanosoma brucei species are extracellular protozoan parasites that cause the deadly disease African trypanosomiasis in humans and contribute to the animal counterpart, Nagana. Trypanosome clearance from the bloodstream is mediated by antibodies specific for their Variant Surface Glycoprotein (VSG) coat antigens. However, T. brucei infection induces polyclonal B cell activation, B cell clonal exhaustion, sustained depletion of mature splenic Marginal Zone B (MZB) and Follicular B (FoB) cells, and destruction of the B-cell memory compartment. To determine how trypanosome infection compromises the humoral immune defense system we used a C57BL/6 T. brucei AnTat 1.1 mouse model and multicolor flow cytometry to document B cell development and maturation during infection. Our results show a more than 95% reduction in B cell precursor numbers from the CLP, pre-pro-B, pro-B, pre-B and immature B cell stages in the bone marrow. In the spleen, T. brucei induces extramedullary B lymphopoiesis as evidenced by significant increases in HSC-LMPP, CLP, pre-pro-B, pro-B and pre-B cell populations. However, final B cell maturation is abrogated by infection-induced apoptosis of transitional B cells of both the T1 and T2 populations which is not uniquely dependent on TNF-, Fas-, or prostaglandin-dependent death pathways. Results obtained from ex vivo co-cultures of living bloodstream form trypanosomes and splenocytes demonstrate that trypanosome surface coat-dependent contact with T1/2 B cells triggers their deletion. We conclude that infection-induced and possibly parasite-contact dependent deletion of transitional B cells prevents replenishment of mature B cell compartments during infection thus contributing to a loss of the host's capacity to sustain antibody responses against recurring parasitemic waves

Equivalence of two different notions of tangent bundle on rectifiable metric measure spaces

We prove that for a suitable class of metric measure spaces the abstract notion of tangent module as defined by the first author can be isometrically identified with the space of L2-sections of the ‘Gromov-Hausdorff tangent bundle’. The key assumption that we make is a form of rectifiability for which the space is ‘almost isometrically’ rectifiable (up to m-null sets) via maps that keep under control the reference measure. We point out that RCD∗(K, N) spaces fit in our framework