Alpha-1 antitrypsin deficiency in Italy: regional differences of the PIS and PIZ deficiency alleles

Background. Critical to the effective diagnosis and management of disease is information on its prevalence in a particular geographic area such as Italy. Alpha-1- antitrypsin deficiency (AAT Deficiency) is one of the most common serious hereditary diseases in the world, but its prevalence varies markedly from one country to another. AAT Deficiency affects at least 120.5 million carriers and deficient subjects worldwide for the two most prevalent deficiency alleles PIS and PIZ. This genetic disease is known to exist in Italy and is related to a high risk for development of jaundice in infants, liver disease in children and adults, and pulmonary emphysema in adults. Methods. Studies on the genetic epidemiology of AAT Deficiency has resulted in the development of a unique database that permits a unique analysis of the geographic distribution in 14 different regions located at random from Piemonte to Sicilia. Results. The use of Hardy-Weinberg statistical analysis to evaluate the distribution of these two deficiency alleles has demonstrated striking differences in the frequencies of these two deficiency alleles in these 14 different regions with 23/84 pair wise combinations significantly different (P=0.05) for PIS, and 5/84 combinations for PIZ. Conclusions. These findings demonstrate differences that impact the standards of care and diagnosis of AAT Deficiency in Italy since the prevalence of these deficiency alleles is not uniform throughout the country

Genetic strategies for improving crop yields.

The current trajectory for crop yields is insufficient to nourish the world's population by 20501. Greater and more consistent crop production must be achieved against a backdrop of climatic stress that limits yields, owing to shifts in pests and pathogens, precipitation, heat-waves and other weather extremes. Here we consider the potential of plant sciences to address post-Green Revolution challenges in agriculture and explore emerging strategies for enhancing sustainable crop production and resilience in a changing climate. Accelerated crop improvement must leverage naturally evolved traits and transformative engineering driven by mechanistic understanding, to yield the resilient production systems that are needed to ensure future harvests

Estimates of PI*S and PI*Z Alpha-1 antitrypsin deficiency alleles prevalence in the Caribbean and North, Central and South America

Background. AAT deficiency is not a rare disease, but one of the most common congenital disorders increasing susceptibility of individuals with this deficiency to both lung and liver disease as well as other several adverse health effects. Studies to develop accurate estimates of the magnitude of this genetic disorder in any given country is critical for the development of screening programs for detection, diagnosis, and treatment of those individuals and/or families at risk. In the present study, estimates of the prevalence of the two major deficiency alleles PI S and PI Z were estimated for 25 countries in the Caribbean and North, Central, and South America to supplement our previous studies on 69 countries worldwide. Method. Using data on the prevalence of the two most common deficiency alleles PI S and PIZ in the mother countries that provided the majority of immigrants to these 25 countries, as well as genetic epidemiological studies on various genetic subgroups indigenous to the Caribbean and North, Central and South America it was possible to develop new formulas to estimate the numbers in each of five phenotypic classes, namely PI MS, PI MZ, PI SS, PI SZ and PI ZZ for each country. Results. When these 25 countries were grouped into six different geographic regions, the present study demonstrated striking differences when comparisons were made in numeric tables, maps and figures. Highly significant numbers of individuals at risk for AAT Deficiency were found in both the European, Mestizo and Mulatto populations for most of the 25 countries studied in the Caribbean and North, Central and South America. Conclusions. Our studies demonstrated striking differences in the prevalence of both the PIS and PIZ alleles among these 25 countries in the Caribbean and North, Central and South America and significant numbers of individuals at risk for adverse health effects associated with AAT Deficiency in a given country. When these data are added to the results from our earlier studies on 69 countries, we now have data on AAT Deficiency in 94 of the 193 countries worldwide listed in the CIA FactBook

PI S and PI Z Alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data

Background. AAT deficiency is not a rare disease, but one of the most common congenital disorders increasing susceptibility of deficiency individuals to both lung and liver disease as well as other several adverse health effects. Therefore, information on accurate estimates of the magnitude of alpha-1 antitrypsin deficiency in any given country is critical for the development of screening programs for detection, diagnosis, and treatment of those individuals and/or families at risk. Method. Genetic epidemiological studies for alpha-1 antitrypsin deficiency made by others have been used to determine the percentages and estimates of the numbers in each of the five phenotypic classes (PI MS, PI MZ, PI SS, PI SZ, and PI ZZ) of the most common deficiency alleles: PI S and PI Z in each of 69 countries worldwide and also when grouped into 13 major geographic regions. Results. Our studies have demonstrated striking differences between these estimates when comparisons were made in numeric tables, maps and figures. Conclusions. Our studies demonstrated striking differences in the prevalences of both the PIS and PIZ alleles among these 69 countries and the numbers at risk for AAT Deficiency in a given country in specific geographic regions. Data on the prevalence of the two major deficiency alleles as well as the numbers in those phenotypic classes known to be at risk for AAT Deficiency is considered critical for the identification of individuals at risk for adverse health effects associated with AAT Deficiency as well as the treatment and management of those individuals identified in a given country

Potential of Extracellular Vesicle-Associated TSG-6 from Adipose Mesenchymal Stromal Cells in Traumatic Brain Injury

Multipotent mesenchymal stromal cells (MSC) represent a promising strategy for a variety of medical applications. Although only a limited number of MSC engraft and survive after in vivo cellular infusion, MSC have shown beneficial effects on immunomodulation and tissue repair. This indicates that the contribution of MSC exists in paracrine signaling, rather than a cell-contact effect of MSC. In this review, we focus on current knowledge about tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) and mechanisms based on extracellular vesicles (EV) that govern long-lasting immunosuppressive and regenerative activity of MSC. In this context, in particular, we discuss the very robust set of findings by Jha and colleagues, and the opportunity to potentially extend their research focus on EV isolated in concentrated conditioned media (CCM) from adipose tissue derived MSC (ASC). Particularly, the authors showed that ASC-CCM mitigated visual deficits after mild traumatic brain injury in mice. TSG-6 knockdown ASC were, then, used to generate TSG-6-depleted CCM that were not able to replicate the alleviation of abnormalities in injured animals. In light of the presented results, we envision that the infusion of much distilled ASC-CCM could enhance the alleviation of visual abnormalities. In terms of EV research, the advantages of using size-exclusion chromatography are also highlighted because of the enrichment of purer and well-defined EV preparations. Taken together, this could further delineate and boost the benefit of using MSC-based regenerative therapies in the context of forthcoming clinical research testing in diseases that disrupt immune system homeostasis

Proteomic Characterization of Urinary Extracellular Vesicles from Kidney-Transplanted Patients Treated with Calcineurin Inhibitors

Use of immunosuppressive drugs is still unavoidable in kidney-transplanted patients. Since their discovery, calcineurin inhibitors (CNI) have been considered the first-line immunosuppressive agents, in spite of their known nephrotoxicity. Chronic CNI toxicity (CNIT) may lead to kidney fibrosis, a threatening scenario for graft survival. However, there is still controversy regarding CNIT diagnosis, monitoring and therapeutic management, and their specific effects at the molecular level are not fully known. Aiming to better characterize CNIT patients, in the present study, we collected urine from kidney-transplanted patients treated with CNI who (i) had a normal kidney function, (ii) suffered CNIT, or (iii) presented interstitial fibrosis and tubular atrophy (IFTA). Urinary extracellular vesicles (uEV) were enriched and the proteome was analyzed to get insight into changes happening during CNI. Members of the uroplakin and plakin families were significantly upregulated in the CNIT group, suggesting an important role in CNIT processes. Although biomarkers cannot be asserted from this single pilot study, our results evidence the potential of uEV as a source of non-invasive protein biomarkers for a better detection and monitoring of this renal alteration in kidney-transplanted patients

Mesenchymal stromal cells induced regulatory B cells are enriched in extracellular matrix genes and IL-10 independent modulators

Regulatory B cells (Breg) are essential players in tolerance and immune homeostasis. However, lack of specific Breg markers limit their potential in clinical settings. Mesenchymal stromal cells (MSC) modulate B cell responses and are described to induce Breg in vitro. The aim of this work was to characterize MSC induced Breg (iBreg) and identify specific Breg biomarkers by RNAseq. After 7-day coculture with adipose tissue-derived MSC, B cells were enriched in transitional B cell populations, with increased expression and secretion of IL-10 and no TNFα. In addition, iBreg showed potential to modulate T cell proliferation at 2 to 1 cell ratios and their phenotype remained stable for 72h. RNAseq analysis of sorted IL-10 positive and negative iBreg populations identified over 1500 differentially expressed genes (DEG) among both populations. Analysis of biological processes of DEG highlighted an enrichment of immune regulation and extracellular matrix genes in IL-10 - iBreg populations, while IL-10 + iBreg DEG were mostly associated with cell activation. This was supported by T cells modulation assays performed in the presence of anti-IL-10 neutralizing antibodies showing the non-essential role of IL-10 in the immunomodulatory capacity of iBregs on T cells. However, based on RNAseq results we explored the role of TGF-β and found out that it plays a major role on iBreg induction and iBreg immunomodulatory properties. Therefore, we report that MSC induce B cell populations characterized by the generation of extracellular matrix and immune modulation independently of IL-10