Induced pluripotent stem cells for disease modeling,cell therapy and drug discovery in genetic autonomic disorders: a review

Clinical Autonomic Research - The autonomic nervous system (ANS) regulates all organs in the body independent of consciousness, and is thus essential for maintaining homeostasis of the entire...     

On the origin of schizophrenia: Testing evolutionary theories in the post‐genomic era

Considering the relatively high heritability of schizophrenia and the fact that it significantly reduces the reproductive fitness of affected individuals, it is not clear how the disorder is still maintained in human populations at a disproportionally high prevalence. Many theories propose that the disorder is a result of a trade‐off between costs and benefits of the evolution of exclusively human adaptations. There have also been suggestions that schizophrenia risk alleles are accompanied with increase in fitness of affected persons or their relatives in both past and current social contexts. The discoveries of novel schizophrenia‐related genes and the advancements in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids) have finally made certain evolutionary theories testable. In this paper, we review the current understanding of the genetics of schizophrenia, the basic principles of evolution that complement our understanding of the subject, and the latest genetic studies that examine long‐standing evolutionary theories of schizophrenia using novel methodologies and data. We find that the origin of schizophrenia is complex and likely governed by different evolutionary mechanisms that are not mutually exclusive. Furthermore, the most recent evidence implies that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but has been a mildly deleterious by‐product of specific patterns of the evolution of the human brain. In other words, novel findings do not support previous hypotheses stating that schizophrenia risk genes have an evolutionary advantage.     

The effect of complexation with cyclodextrins on the antioxidant and antimicrobial activity of ellagic acid

Purpose: The aim of the paper was to develop the simple procedures for preparation of inclusion complexes of ellagic acid (EA) with cyclodextrins (CDs) and to investigate their antioxidant and antimicrobial activity.

Methods: The structural characterization was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and nuclear magnetic resonance (NMR) methods. The phase solubility technique was used to investigate the interactions between ‘host’ and ‘guest’ molecules and to estimate the molar ratio between them. The antioxidant and antimicrobial activity of EA and inclusion complexes were determined.

Results: The apparent stability constants were found to be 117?dm³ mol^?1 for the complex with β-CD and 161?dm³ mol^?1 for the complex with (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD). The results of phase-solubility studies showed that EA formed the inclusion complexes with CDs in the molar ratio of 1:1. The calculated half-maximal inhibitory concentration was 41.18?μg cm^?3 for butyl hydroxy toluene, 1.96?μg cm^?3 for EA, 0.88?μg cm^?3 for inclusion complex with HP-β-CD, and 1.27?μg cm^?3 for inclusion complex with β-CD.

Conclusion: The stability constants indicated the rapid release of EA from the inclusion complexes in the aqueous medium at 25?°C. The antioxidant activity of EA was increased, while the antimicrobial activity was preserved after complexation with CDs.     

Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney

Cyclophilin D (CypD) is an important component in mitochondrial‐dependent tubular cell death in acute kidney injury. However, it is not known whether CypD contributes to tubular cell damage in chronic interstitial fibrosis. We investigated this question in the unilateral ureter obstruction (UUO) model of renal interstitial fibrosis. Groups of CypD^?/? and wild type (WT) mice were killed 7 or 12 days after UUO surgery. The significant tubular cell apoptosis seen in WT UUO was significantly reduced in CypD^?/? UUO based on TUNEL and cleaved caspase 3 staining. Other markers of tubular cell damage; loss of E‐cadherin and AQP1 expression, were also reduced in the CypD^?/? UUO kidney. This reduced tubular damage was associated with less inflammation and a partial protection against loss of peritubular capillaries. The prominent accumulation of α‐SMA+ myofibroblasts and interstitial collagen deposition seen in WT UUO was significantly reduced in CypD^?/? UUO on day 12, but not day 7. Activation of several pro‐fibrotic signalling pathways (p38 MAPK, JNK and Smad3) was unaltered in CypD^?/? UUO, arguing that CypD acts independently to promote renal fibrosis. CypD deletion in cultured tubular cells attenuated oxidative stress‐induced pro‐inflammatory, pro‐fibrotic and apoptotic responses; however, responses to angiotensin II and LPS were unaffected. In contrast, CypD deletion in cultured renal fibroblasts did not affect PDGF‐induced proliferation or TGF‐β1‐induced collagen I expression, suggesting no direct role of CypD in the fibroblast response. In conclusion, we have identified a role for CypD in chronic tubular cell damage and in the development of renal interstitial fibrosis.     

Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis

Sequential genotyping for phenotype‐driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2‐ and MPL‐mutations were described in some triple‐negative patients. Whether noncanonical and/or concomitant JAK2‐ and MPL‐mutations exist in myelofibrosis (MF) regardless of phenotype‐driver mutations is not yet elucidated. For this, next‐generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post‐ET–MF, n = 18; post‐PV–MF, n = 17). While no atypical JAK2‐ or MPL‐mutations were seen in 24 CALR‐positive samples, two JAK2‐mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple‐negative patients. Twelve of the 82 (14.6%) JAK2V617F‐positive cases had coexisting germline JAK2‐mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL‐mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL‐mutations always coexisted with JAK2V617F and/or other MPL‐mutations. None of the JAK2V617F plus a second JAK2‐mutation carried a TET2‐mutation but all patients with JAK2V617F plus an MPL‐mutation harbored a somatic TET2‐mutation. Four genomic clusters could be identified in the JAK2V617F‐positive cohort. Cluster‐I (10%) (noncanonical JAK2_{mutated (mut)} + TET2_{wildtype (wt)}) were younger and had less proliferative disease compared with cluster‐IV (5%) (TET2_mut + MPL_mut). In conclusion, recurrent concomitant classical and/or noncanonical JAK2‐ and MPL‐mutations could be detected by NGS in 15.7% of JAK2V617F‐ and MPLW515‐positive MF patients with genotype‐phenotype associations. Many of the germline and/or somatic mutations might act as “Significantly Mutated Genes” contributing to the pathogenesis and phenotypic heterogeneity. A cost‐effective NGS‐based approach might be an important step towards patient‐tailored medicine.     

Course of changes in salivary pH-values after intake of different beverages in young children

PURPOSE: The aim of the study was to determine possible differences in decrease of pH-values of whole saliva, following the intake of different beverages. MATERIALS AND METHODS: Twelve boys and 13 girls (4.9 +/- 0.9 years old) participated in this study. A dental examination was performed (dmft). Orange juice (pH = 3.67), instant fennel tea (pH = 7.38), whole milk (pH = 6.84) and mineral water (pH = 5.88) were tested. All beverages were given at the same time of day. Salivary pH and buffering capacities of the beverages were determined with a portable pH-meter. Immediately after intake of a beverage, and 5, 10, 15 and 25 minutes later, whole saliva was collected, and the pH-value was measured again. The statistical evaluation was performed using the Wilcoxon test for paired samples. RESULTS: Fifteen children had healthy dentitions. Ten subjects had a mean dmft of 1.1 +/- 2.3. The mean base salivary pH was 7.09 +/- 0.07, without differences between the children with and without dental decay. Mineral water led over the whole period of measurements to a significant rise in salivary pH (P < 0.05). Orange juice caused a significant reduction in the salivary pH during the first 10 minutes. After intake of instant tea or milk, significant reductions were found in the period of 5 to 10 minutes. After the intake of instant tea, the reduction was still significant after 15 minutes. During the period of 5 to 10 minutes, the change in pH (deltapH) in whole saliva differed significantly only between consumption of mineral water and other beverages (P < 0.01). CONCLUSION: With regard to dental health, a regular consumption of orange juice or sweetened instant teas should be discouraged.