Human amylin proteotoxicity impairs protein biosynthesis,and alters major cellular signaling pathways in the heart,brain and liver of humanized diabetic rat model in vivo

Introduction

Chronic hypersecretion of the 37 amino acid amylin is common in type 2 diabetics (T2D). Recent studies implicate human amylin aggregates cause proteotoxicity (cell death induced by misfolded proteins) in both the brain and the heart.

Objectives

Identify systemic mechanisms/markers by which human amylin associated with cardiac and brain defects might be identified.

Methods

We investigated the metabolic consequences of amyloidogenic and cytotoxic amylin oligomers in heart, brain, liver, and plasma using non-targeted metabolomics analysis in a rat model expressing pancreatic human amylin (HIP model).

Results

Four metabolites were significantly different in three or more of the four compartments (heart, brain, liver, and plasma) in HIP rats. When compared to a T2D rat model, HIP hearts uniquely had significant DECREASES in five amino acids (lysine, alanine, tyrosine, phenylalanine, serine), with phenylalanine decreased across all four tissues investigated, including plasma. In contrast, significantly INCREASED circulating phenylalanine is reported in diabetics in multiple recent studies.

Conclusion

DECREASED phenylalanine may serve as a unique marker of cardiac and brain dysfunction due to hyperamylinemia that can be differentiated from alterations in T2D in the plasma. While the deficiency in phenylalanine was seen across tissues including plasma and could be monitored, reduced tyrosine was seen only in the brain. The 50 % reduction in phenylalanine and tyrosine in HIP brains is significant given their role in supporting brain chemistry as a precursor for catecholamines (dopamine, norepinephrine, epinephrine), which may contribute to the increased morbidity and mortality in diabetics at a multi-system level beyond the effects on glucose metabolism.

     

The 11q;22q translocation: A European collaborative analysis of 43 cases

Summary Translocation between the long arms of chromosomes 11 and 22 is usually detected in offspring with an unbalanced karyotype following a 3:1 disjunction resulting in partial trisomy. Since by the end of 1976 it was suspected that this translocation might be more frequent than one would deduce from published reports, it was decided to call for a collaborative effort in Europe to collect unpublished cases. In response, 42 cases were collected in Europe, and one case from New Zealand was added. The following countries were represented with the number of cases indicated in parentheses: Czechoslovakia (2), Denmark (4), Finland (3), France (6), Germany (1), Italy (5), The Netherlands (9), Sweden (6), United Kingdom (4), Yugoslavia (2). The wide geographical distribution indicates a multifocal origin of the translocation. Among the unpublished cases, 31 were ascertained as unbalanced carriers [47,XX or XY,+der(22),t(11;22)] and 12 as balanced balanced carriers [46,XX and XY,t(11;22)]. Among the published cases, 10 were ascertained in unbalanced and 3 in balanced carriers. The breakpoints of the translocations indicated by the contributors varied, the most frequently reported being 11q23;22q11 (25 cases), followed by q25;q13 (10 cases). While the first one seems more likely, it was not possible to decide whether the breakpoints were the same in all cases.All 32 probands with unbalanced karyotypes had inherited the translocation, 31 from the mother and only 1 from the father. This ratio became 43:1 when the published cases were added. A segregation analysis revealed that in families ascertained through probands with unbalanced karyotypes there was a ratio of carriers to normal (all karyotyped) 54:55, not a significant difference. The formal maximum (minimum) recurrence risk for this unbalanced translocation was calculated to be 5.6% (2.7%). When the ascertainment was through a balanced proband, the maximum risk was 2.7%. The risk was calculated as 5.7% for female and 4.3% for male carriers. The mean family size was 1.67 for the offspring of female carriers and 0.78 for the offspring of male carriers. This significant difference suggests that heterozygosity for the translocation reduces fertility in males. Indeed, several of the probands with balanced karyotypes were ascertained because of sub- or infertility. Only 2 de novo translocations were found among the 59 probands, and both, were among the 12 cases ascertained as balanced carriers. The source, quality, and quantity of the clinical data for the subjects with unbalanced karyotypes were variable, and no definite conclusions were possible about phenotypes. The following signs were recorded in 10 or more of the 45 cases: low birth weight, delayed psychomotor development, hypotonia, microcephaly, craniofacial asymmetry, malformed ears with pits and tags, cleft palate, micro-/retrognathia, large beaked nose, strabismus, congenital heart disease, cryptorchidism, and congenital dislocation of the hip joints. Many signs were similar to those considered typical of trisomy 11q, and the phenotype coincided almost completely with the presumptive phenotype of complete trisomy 22. No cases with coloboma was recorded, while other signs of the cat-eye syndrome were found in several probands. This might indicate that individuals with the cat-eye syndrome and carriers of the unbalanced 11/22 translocation have the same segment of 22 in triplicate plus or minus another chromosome segment.     

Photosystem II Activity in Agranal Bundle Sheath Chloroplasts from Zea mays

The photochemical activities of chloroplasts isolated from bundle sheath and mesophyll cells of maize (Zea mays var. DS606A) have been measured. Bundle sheath chloroplasts are almost devoid of grana, except in very young leaves, while mesophyll chloroplasts contain grana at all stages of leaf development.     

The University of Toronto “Sioux Lookout Project”—a model of health care delivery

The University of Toronto''s Sioux Lookout Project is described in detail. The scheme is a collaborative one in which universities, governments, doctors, dentists, nurses, communities and consumers participate. After three years of operation it appears to be a feasible model for delivery of health care in a remote area under extremely adverse conditions. It is suggested that a modified version would be applicable to other underdoctored areas. The individual roles of the various participants are outlined. Universities, by giving some preference in their postgraduate training programs to doctors who have spent a year in practice, especially in remote areas, would make a major step towards correcting the maldistribution of doctors.     

Search for a substance which selectively inhibits FSH--effects of steroids and prostaglandins on serum FSH and LH levels

In an attempt to find a preferential inhibitor of serum FSH, a number of C₁₈, C₁₉ and C₂₁ steroids were evaluated for suppressive effects on LH and FSH and stimulatory effects upon ventral prostate weight in the acutely castrate adult male rat. C₂₁ steroids had no effect. The C₁₉ steroids were listed in order of potency with regard to suppressing LH, FSH and stimulating ventral prostate weight. All C₁₉ steroids that had an inhibitory effect on gonadotropins also stimulated ventral prostate weight and all demonstrated preferential inhibition of LH over FSH. Two C₁₈ steroids were tested, estradiol-17β and estrone; estradiol-17β suppressed LH and FSH in a parallel fashion. Four prostaglandins were evaluated with regard to effect on gonadotropins and ventral prostate weight; none demonstrated effect.     

Flavonoids of the Muhlenbergia montana complex

Specimens from natural populations of Muhlenbergia montana (Nutt.) Hitch. and related species were analysed for their flavonoid content. Twenty-four flavonoids from 14 species were separated and 22 of the compounds identified. Most were glycosylated derivatives of luteolin, apigenin and tricin. Two flavonols, quercetin 3-O-rutinoside and quercetin 3-O-glycoside, and two flavanones were also identified. Flavonoid patterns were distinct for all perennial species and identical for the two annual species examined. Phenetic analysis of the flavonoid characters does not support the inclusion of the annual species M. crispiseta and M. peruviana as part of the M. montana complex.     

A comparison of three methods of hydrolysis for estrogen conjugates

The efficiencies for estrogen conjugate hydrolysis were compared between enzyme hydrolysis, acid solvolysis and a new method, ammonolysis. Samples included: 1) crystalline 1,3,5(10)-estratriene-3, 17 beta-diol disulfate (estradiol 3,17-disulfate), 2) squirrel monkey urine collected following an intravenous injection of [2,4,6,7-H] 1,3,5(10)-estratriene-3,17 beta-diol (estradiol) and 3) a pool of human pregnancy urine. Ammonolysis demonstrated a significant increase over the other techniques in "free" estrogen yields, specifically, from estradiol 3,17-disulfate.     

Assessing the “Short Mental Distance” in Eco‐Industrial Networks

Like many economic exchanges, industrial symbiosis (IS) is thought to be influenced by social relationships and shared norms among actors in a network. While many implicit references to social characteristics exist throughout the literature, there have been few explicit attempts to operationalize and measure the concepts. The “short mental distance,”“trust,”“openness,” and “communication” recorded among managers in Kalundborg, Denmark, set a precedent for examining and encouraging social interactions among key personnel in the dozens of eco‐industrial networks around the world. In this article we explore the relationships among various aspects of social embeddedness, social capital, and IS. We develop a conceptual framework and an approach using quantitative and qualitative methods to identify and measure these social characteristics, including social network structure, communication, and similarities in norms and conceptions of waste, and apply them in an industrial network in Nanjangud, South India. The findings suggest that there is a fairly high level of shared norms about dealing with waste—the “short mental distance”—in this network, but by‐product transactions are only weakly correlated with the structure and content of communication among managers. Replication of this approach can increase the understanding and comparability of the role of social characteristics in eco‐industrial activities around the world.