The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Requirements of Business Judgment Rule and Their Effect on the Practical Use of the Rule

Pravilo poslovne presoje ima v Združenih državah Amerike že dolgo tradicijo, v evropskih državah s kontinentalnimi pravnimi sistemi pa so se ga sodišča pri presoji poslovnih odločitev članov organov vodenja in nadzora začela posluževati šele v zadnjih desetletjih. Slovenija je ena izmed vse manjše skupine držav, ki pravila poslovne presoje in njihovih kriterijev še ni prenesla iz sodne prakse v zakonodajo. Pravilo poslovne presoje omogoča sodiščem, da pri presoji, ali so člani organov vodenja in nadzora odškodninsko odgovorni za družbi škodljive odločitve, s pomočjo upoštevanja kriterijev pravila prilagodijo presojo specifičnemu položaju tožencev. Magistrska naloga z namenom iskanja bistva in praktičnega pomena kriterijev pravila poslovne presoje najprej pojasni pojem korporacijskega upravljanja in dinamiko akterjev v delovanju gospodarskih družb. Po kratki naslovitvi dolžnosti članov organov vodenja in nadzora tako v našem pravu kot v pravu tujih držav sledi pregled razvoja kriterijev pravila skozi sodno prakso v njegovem domicilu, Združenih državah Amerike. Kratko so predstavljene različne variacije pravila poslovne presoje v različnih zakonodajnih in kvazizakonodajnih aktih ter pojasnjeni razlogi za njegove pojavne oblike, ki jih v največji meri zaznamujejo različna razumevanja njegovega namena. Sledi podrobna obravnava posameznih kriterijev pravila od prve omembe do sodobne interpretacije, z ozirom na način njegove razlage v slovenski teoriji in praksi. Dilema (ne)pravilnosti slovenske percepcije pravila poslovne presoje se prevesi v zaključni sklep, ki predvsem poudarja pomen prostega polja presoje, ki ga sodiščem omogoča določena mera nedoločenosti kriterijev.Although business judgment rule has a long tradition in the United States of America, the courts in European countries with continental legal systems have only started to use it in the last decades for dealing with business decisions of management. Slovenia is one of the shrinking group of countries that has not yet transferred the rule from case law to law in books. Business judgment rule enables the courts to make use of requirements of the rule in order to properly adjust the judicial decision whether board members are liable for business decisions that resulted in losses for the company. In pursuit of finding the core purpose and practical contribution of requirements of the rule, this master\u27s thesis first explains the concept of corporate governance and dynamics among the different subjects in the company\u27s framework. After a brief mention of management\u27s duties in Slovenian law as well as the law in other countries, thesis continues with an overview of development of the rule\u27s requirements in the rule\u27s cradle, the United States of America. Following is the presentation of different varieties of business judgment rule in different legislative and quasi-legislative acts and the clarification of reasons for so many variations of the rule, which are shaped mostly by different understandings of its core purpose. Detailed explanation of each individual requirement is next, from its first mentions in case law to its modern interpretation with respect to the way each requirement is interpreted in Slovenian case law. The question of suitability of the Slovenian perception of business judgment rule is followed by final conclusion which emphasizes the importance of discretion field the rule\u27s requirements create if they are, to the certain extent, undetermined

Pressure and pain In Systemic sclerosis/Scleroderma - an evaluation of a simple intervention (PISCES): randomised controlled trial protocol

Background: foot problems associated with Systemic Sclerosis (SSc)/Scleroderma have been reported to be both common and disabling. There are only limited data describing specifically, the mechanical changes occurring in the foot in SSc. A pilot project conducted in preparation for this trial confirmed the previous reports of foot related impairment and reduced foot function in people with SSc and demonstrated a link to mechanical etiologies. To-date there have been no formal studies of interventions directed at the foot problems experienced by people with Systemic Sclerosis. The primary aim of this trial is to evaluate whether foot pain and foot-related health status in people with Systemic Sclerosis can be improved through the provision of a simple pressure-relieving insole. Methods: the proposed trial is a pragmatic, multicenter, randomised controlled clinical trial following a completed pilot study. In four participating centres, 140 consenting patients with SSc and plantar foot pain will be randomised to receive either a commercially available pressure relieving and thermally insulating insole, or a sham insole with no cushioning or thermal properties. The primary end point is a reduction in pain measured using the Foot Function Index Pain subscale, 12 weeks after the start of intervention. Participants will complete the primary outcome measure (Foot Function Index pain sub-scale) prior to randomisation and at 12 weeks post randomisation. Secondary outcomes include participant reported pain and disability as derived from the Manchester Foot Pain and Disability Questionnaire and plantar pressures with and without the insoles in situ. Discussion: this trial protocol proposes a rigorous and potentially significant evaluation of a simple and readily provided therapeutic approach which, if effective, could be of a great benefit for this group of patients

TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications

TWIK-related acid-sensitive potassium channel 1 (TASK-1 encoded by KCNK3) belongs to the family of two-pore domain potassium channels. This gene subfamily is constitutively active at physiological resting membrane potentials in excitable cells, including smooth muscle cells, and has been particularly linked to the human pulmonary circulation. TASK-1 channels are sensitive to a wide array of physiological and pharmacological mediators that affect their activity such as unsaturated fatty acids, extracellular pH, hypoxia, anaesthetics and intracellular signalling pathways. Recent studies show that modulation of TASK-1 channels, either directly or indirectly by targeting their regulatory mechanisms, has the potential to control pulmonary arterial tone in humans. Furthermore, mutations in KCNK3 have been identified as a rare cause of both familial and idiopathic pulmonary arterial hypertension. This review summarises our current state of knowledge of the functional role of TASK-1 channels in the pulmonary circulation in health and disease, with special emphasis on current advancements in the field

Health Assessment Questionnaire-Disability Index (HAQ-DI) use in modelling disease progression in diffuse cutaneous systemic sclerosis: an analysis from the EUSTAR database

BACKGROUND: Patients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression. METHODS: This was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient's lifetime. RESULTS: The analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p <  0.001) and multiple advanced major organ involvement multiplied the risk of death by 2.8 (p <  0.05). Multivariable analysis showed that baseline modified Rodnan Skin Score (mRSS) and baseline HAQ-DI score were associated with HAQ-DI score progression at 1 year (p <  0.05), but there was no association between baseline organ involvement and HAQ-DI score progression at 1 year. HAQ-DI score, major advanced organ involvement, and death were successfully used to model long-term disease progression in dcSSc. CONCLUSIONS: HAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc

14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells