LETM1-Mediated K+ and Na+ Homeostasis Regulates Mitochondrial Ca2+ Efflux

HIGHLIGHTS \u2022 Monovalent cation homeostasis is dysregulated upon LETM1 depletion \u2022 K+/H+ exchange activity is decreased in LETM1 knockdown cells \u2022 LETM1 depletion results in K+ accumulation in the mitochondrial matrix \u2022 LETM1 knockdown does not affect expression of major mitochondrial Ca2+ transport modulators \u2022 LETM1-regulated mitochondrial Ca2+ fluxes are dependent on Na+ Ca2+ transport across the inner membrane of mitochondria (IMM) is of major importance for their functions in bioenergetics, cell death and signaling. It is therefore tightly regulated. It has been recently proposed that LETM1\u2014an IMM protein with a crucial role in mitochondrial K+/H+ exchange and volume homeostasis\u2014also acts as a Ca2+/H+ exchanger. Here we show for the first time that lowering LETM1 gene expression by shRNA hampers mitochondrial K+/H+ and Na+/H+ exchange. Decreased exchange activity resulted in matrix K+ accumulation in these mitochondria. Furthermore, LETM1 depletion selectively decreased Na+/Ca2+ exchange mediated by NCLX, as observed in the presence of ruthenium red, a blocker of the Mitochondrial Ca2+ Uniporter (MCU). These data confirm a key role of LETM1 in monovalent cation homeostasis, and suggest that the effects of its modulation on mitochondrial transmembrane Ca2+ fluxes may reflect those on Na+/H+ exchange activity

Click Worthy: Stories Encourage Emergency Physicians to Learn More About Opioid Prescribing Guidelines

Narrative vignettes outperform standard summaries in promoting engagement with opioid prescription guidelines among a national sample of emergency physicians

Prospectus, April 11, 1972

ACCREDITATION!: PARKLAND RECEIVES NORTH-CENTRAL APPROVAL; Deadlines set for allied Health Applications; Miss Whipple Soon to be Teacher Aide; Agricultural Mechanics Contest at Parkland; Watchmaker Assoc. Establishes Loan Fund; Parkland Sponsors Multi-Media Course; Community band and choir open; The Editor\u27s View: Quality Education Is Here At Parkland College, Speaking Out On Stereotypes; Letters to the Editor: A Rip-off?; Spring Quarter PCSG Election Information: Hours and the requirements, openings and responsibilities; Meet Your Candidates: For Vice President, For Treasurer, For Senator-Convocations, For Senator-Organizations, Senator-Student Svs.; Parkland\u27s Preparedness Program: A step towards success in higher education; The Program: An Introduction; Disadvantaged-Marginal Student is Focus of Conference-Workshop at Parkland; President presents certificates of completion to successful Preparedness Students; What\u27s Going On; Counselor\u27s Corner: Evening Counseling, Vocational Information, Sangamon State Representative; Parkland Notices: Nurse Refresher, Population Course Offered; Health Ed. Week, Public Aids, Women Scholars, Summer Information, Telephone Service; \u27Hospital\u27 Pokes Fun At Society; Ear Wax; Orpheus Reborn: Death At Sea, des sourires enfantin..., yet even so they all (hear)...; National Wildlife Week A Success; A Short History Of Parkland; National Collegiate News; Athletic Department Praisedhttps://spark.parkland.edu/prospectus_1972/1008/thumbnail.jp

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

OBJECTIVE—Proinflammatory cytokines contribute to systemic low-grade inflammation and insulin resistance. Tumor necrosis factor (TNF)-α impedes insulin signaling in insulin target tissues. We determined the role of inhibitor of nuclear factor-κB kinase (IKK)β in TNF-α–induced impairments in insulin signaling and glucose metabolism in skeletal muscle

Muskox Health Ecology Symposium 2016: Gathering to Share Knowledge on Umingmak in a Time of Rapid Change

The Muskox, Ovibos moschatus, also known as Umingmak ‘the Bearded One,’ is a taxonomically unique, cold-adapted, ice-age survivor. Originally native to Canada and Greenland, it has established a circum-Arctic distribution via introduced populations. As a key resident herbivore in northern ecosystems, the muskox has importance that should not be underestimated. Muskoxen play an important role in the cultural identity of Arctic Indigenous peoples and provide a healthy source of country food. More recently, recognition of the economic potential of the species through tourism, sport hunting, and the traditional sale of handicrafts has generated renewed interest in muskoxen and their ecology. Recent documentation of diseases, including several zoonoses, regional mortality events, and population declines have highlighted knowledge gaps in both our understanding of the drivers of muskox population fluctuations and the potential sensitivity of this species to a rapidly changing climate (Kutz et al., 2013, 2015; Handeland et al., 2014; Ytrehus et al., 2015; Tomaselli et al., 2016c; Afema et al., 2017)

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients >= 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients >= 5 years

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation

Sphingosine- 1- phosphate (S1P) lyase is a vitamin B6- dependent enzyme that degrades sphingosine- 1- phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6- dependent enzymes, a finding ascribed largely to the vitamin’s chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6- treated patient- derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162713/2/jimd12238.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162713/1/jimd12238_am.pd

Altered Intracellular Localization and Mobility of SBDS Protein upon Mutation in Shwachman-Diamond Syndrome

Shwachman-Diamond Syndrome (SDS) is a rare inherited disease caused by mutations in the SBDS gene. Hematopoietic defects, exocrine pancreas dysfunction and short stature are the most prominent clinical features. To gain understanding of the molecular properties of the ubiquitously expressed SBDS protein, we examined its intracellular localization and mobility by live cell imaging techniques. We observed that SBDS full-length protein was localized in both the nucleus and cytoplasm, whereas patient-related truncated SBDS protein isoforms localize predominantly to the nucleus. Also the nucleo-cytoplasmic trafficking of these patient-related SBDS proteins was disturbed. Further studies with a series of SBDS mutant proteins revealed that three distinct motifs determine the intracellular mobility of SBDS protein. A sumoylation motif in the C-terminal domain, that is lacking in patient SBDS proteins, was found to play a pivotal role in intracellular motility. Our structure-function analyses provide new insight into localization and motility of the SBDS protein, and show that patient-related mutant proteins are altered in their molecular properties, which may contribute to the clinical features observed in SDS patients

NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92022/1/j.1462-5822.2010.01544.x.pd

Genetic counselling and testing in pulmonary arterial hypertension:a consensus statement on behalf of the International Consortium for Genetic Studies in PAH

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.</p