Inherited epithelial transporter disorders—an overview

Summary: In the late 1990s, the identification of transporters and transporter-associated genes progressed substantially due to the development of new cloning approaches such as expression cloning and, subsequently, to the implementation of the human genome project. Since then, the role of many transporter genes in human diseases has been elucidated. In this overview, we focus on inherited disorders of epithelial transporters. In particular, we review genetic defects of the genes encoding glucose transporters (SLC2 and SLC5 families) and amino acid transporters (SLC1, SLC3, SLC6 and SLC7 families

Optimal receptor-cluster size determined by intrinsic and extrinsic noise

Biological cells sense external chemical stimuli in their environment using cell-surface receptors. To increase the sensitivity of sensing, receptors often cluster, most noticeably in bacterial chemotaxis, a paradigm for signaling and sensing in general. While amplification of weak stimuli is useful in absence of noise, its usefulness is less clear in presence of extrinsic input noise and intrinsic signaling noise. Here, exemplified on bacterial chemotaxis, we combine the allosteric Monod-Wyman- Changeux model for signal amplification by receptor complexes with calculations of noise to study their interconnectedness. Importantly, we calculate the signal-to-noise ratio, describing the balance of beneficial and detrimental effects of clustering for the cell. Interestingly, we find that there is no advantage for the cell to build receptor complexes for noisy input stimuli in absence of intrinsic signaling noise. However, with intrinsic noise, an optimal complex size arises in line with estimates of the sizes of chemoreceptor complexes in bacteria and protein aggregates in lipid rafts of eukaryotic cells.Comment: 15 pages, 12 figures,accepted for publication on Physical Review

Reduction of Birth Weight Among Infants Born to Adolescents: Maternal–Fetal Growth Competition

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72838/1/j.1749-6632.1997.tb48213.x.pd

Modular microsystem for epithelial cell culture and electrical characterisation

We have realised a microsystem for the culture and electrical characterisation of epithelial cell layers for cell-based diagnostic applications. The main goal of this work is to achieve both cell culture and impedimetric and potentiometric characterisation on a single device. The miniaturised cell culture system enables the uses of scarce epithelial cells, as obtained from transgenic mice or from human biopsies. The device is completely modular and offers high flexibility: a polycarbonate membrane used as cell substrate is glued in between two moulded Polydimethylsiloxane (PDMS) layers to form a sandwich, which is placed between two stacks, containing the microfluidic channels and integrated measurement electrodes. The polycarbonate membrane sandwich can be removed, replaced or analysed at any time. We have characterised the impedimetric properties of our microsystem, demonstrated epithelial cell layer growth within it, and have done the initial electrical characterisation of epithelial cell layers

The Figure Rating Scale as an Index of Weight Status of Women on Videotape

Objective: To determine whether Stunkard's Figure Rating Scale (FRS) is a valid and reliable index of weight status when an unbiased observer assigns the figure ratings of adult women viewed on videotape. Research Methods and Procedures: Seventy‐two women drawn from a community sample participated in a videotaped study in which height and weight were measured. The FRS is a rating scale displaying 9 silhouettes ranging from very thin to very obese. Women were assigned a figure rating “in‐person” by a research assistant (FRS used as a 17‐point scale) and by additional research assistants viewing women only on videotape (FRS used as both a 17‐ and 9‐point scale). Pearson's correlation coefficients were calculated for in‐person figure ratings, mean videotape figure ratings, and BMI. Results: BMI and in‐person figure ratings were highly correlated ( r = 0.91), as were BMI and both mean 17‐point videotape figure ratings and mean 9‐point videotape figure ratings ( r = 0.89 and 0.87, respectively). Inter‐rater agreement for in‐person figure ratings and mean 17‐point videotape figure ratings was 0.86, and agreement between in‐person figure ratings and mean 9‐point videotape figure ratings was 0.82. Discussion: The FRS can be used as an index of women's weight status by an unbiased observer, with subjects viewed in‐person or on videotape.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93750/1/oby.2006.249.pd

Store-Operated Calcium Entry in Breast Cancer Cells Is Insensitive to Orai1 and STIM1 N-Linked Glycosylation.

N-linked glycosylation is a post-translational modification that affects protein function, structure, and interaction with other proteins. The store-operated Ca2+ entry (SOCE) core proteins, Orai1 and STIM1, exhibit N-glycosylation consensus motifs. Abnormal SOCE has been associated to a number of disorders, including cancer, and alterations in Orai1 glycosylation have been related to cancer invasiveness and metastasis. Here we show that treatment of non-tumoral breast epithelial cells with tunicamycin attenuates SOCE. Meanwhile, tunicamycin was without effect on SOCE in luminal MCF7 and triple negative breast cancer (TNBC) MDA-MB-231 cells. Ca2+ imaging experiments revealed that expression of the glycosylation-deficient Orai1 mutant (Orai1N223A) did not alter SOCE in MCF10A, MCF7 and MDA-MB-231 cells. However, expression of the non-glycosylable STIM1 mutant (STIM1N131/171Q) significantly attenuated SOCE in MCF10A cells but was without effect in SOCE in MCF7 and MDA-MB-231 cells. In non-tumoral cells impairment of STIM1 N-linked glycosylation attenuated thapsigargin (TG)-induced caspase-3 activation while in breast cancer cells, which exhibit a smaller caspase-3 activity in response to TG, expression of the non-glycosylable STIM1 mutant (STIM1N131/171Q) was without effect on TG-evoked caspase-3 activation. Summarizing, STIM1 N-linked glycosylation is essential for full SOCE activation in non-tumoral breast epithelial cells; by contrast, SOCE in breast cancer MCF7 and MDA-MB-231 cells is insensitive to Orai1 and STIM1 N-linked glycosylation, and this event might participate in the development of apoptosis resistance

The promotion and development of One Health at Swiss TPH and its greater potential

One Health, an integrated health concept, is now an integral part of health research and development. One Health overlaps with other integrated approaches to health such as EcoHealth or Planetary Health, which not only consider the patient or population groups but include them in the social-ecological context. One Health has gained the widest foothold politically, institutionally, and in operational implementation. Increasingly, One Health is becoming part of reporting under the International Health Legislation (IHR 2005). The Swiss Tropical and Public Health Institute (Swiss TPH) has played a part in these developments with one of the first mentions of One Health in the biomedical literature. Here, we summarise the history of ideas and processes that led to the development of One Health research and development at the Swiss TPH, clarify its theoretical and methodological foundations, and explore its larger societal potential as an integrated approach to thinking. The history of ideas and processes leading to the development of One Health research at the Swiss TPH were inspired by far-sighted and open ideas of the directors and heads of departments, without exerting too much influence. They followed the progressing work and supported it with further ideas. These in turn were taken up and further developed by a growing number of individual scientists. These ideas were related to other strands of knowledge from economics, molecular biology, anthropology, sociology, theology, and linguistics. We endeavour to relate Western biomedical forms of knowledge generation with other forms, such as Mayan medicine. One Health, in its present form, has been influenced by African mobile pastoralists' integrated thinking that have been taken up into Western epistemologies. The intercultural nature of global and regional One Health approaches will inevitably undergo further scrutiny of successful ways fostering inter-epistemic interaction. Now theoretically well grounded, the One Health approach of seeking benefits for all through better and more equitable cooperation can clearly be applied to engagement in solving major societal problems such as social inequality, animal protection and welfare, environmental protection, climate change mitigation, biodiversity conservation, and conflict transformation

The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time

Peer reviewedPreprin

Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils

Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry

Store-operated calcium entry (SOCE) through STIM-gated ORAI channels governs vital cellular functions. In this context, SOCE controls cellular redox signaling and is itself regulated by redox modifications. However, the molecular mechanisms underlying this calcium-redox interplay and the functional outcomes are not fully understood. Here, we examine the role of STIM2 in SOCE redox regulation. Redox proteomics identify cysteine 313 as the main redox sensor of STIM2 in vitro and in vivo. Oxidative stress suppresses SOCE and calcium currents in cells overexpressing STIM2 and ORAI1, an effect that is abolished by mutation of cysteine 313. FLIM and FRET microscopy, together with MD simulations, indicate that oxidative modifications of cysteine 313 alter STIM2 activation dynamics and thereby hinder STIM2-mediated gating of ORAI1. In summary, this study establishes STIM2-controlled redox regulation of SOCE as a mechanism that affects several calcium-regulated physiological processes, as well as stress-induced pathologies