Linkage of Type I Interferon Activity and TNF-Alpha Levels in Serum with Sarcoidosis Manifestations and Ancestry

BACKGROUND: Both type I interferon (IFN), also known as IFN-α and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of sarcoidosis. We investigated serum levels of these cytokines in a large multi-ancestral sarcoidosis population to determine correlations between cytokine levels and disease phenotypes. METHODS: We studied serum samples from 98 patients with sarcoidosis, including 71 patients of African-American ancestry and 27 patients of European-American ancestry. Serum type I IFN was measured using a sensitive reporter cell assay and serum TNF-α was measured using a commercial ELISA kit. Clinical data including presence or absence of neurologic, cardiac, and severe pulmonary manifestations of sarcoidosis were abstracted from medical records. Twenty age-matched non-autoimmune controls were also studied from each ancestral background. Differences in cytokine levels between groups were analyzed with Mann-Whitney U test, and correlations were assessed using Spearman's rho. Multivariate logistic regression models were used to detect associations between cytokines and clinical manifestations. RESULTS: Significant differences in cytokine levels were observed between African- and European-American patients with sarcoidosis. In African-Americans, serum TNF-α levels were significantly higher relative to matched controls (P = 0.039), and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation (P = 0.022). In European-Americans, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN subgroup (P = 0.0032). None of the associations observed were shared between the two ancestral groups. CONCLUSIONS: Our data indicate that significant associations between serum levels of TNF-α and type I IFN and clinical manifestations exist in a sarcoidosis cohort that differ significantly by self-reported ancestry. In each ancestral background, the cytokine elevated in patients with sarcoidosis was also associated with a particular disease phenotype. These findings may relate to ancestral differences in the molecular pathogenesis of this heterogeneous disease

MICU2, a Paralog of MICU1, Resides within the Mitochondrial Uniporter Complex to Regulate Calcium Handling

Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.National Institutes of Health (U.S.) (GM0077465)National Institutes of Health (U.S.) (DK080261

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

Set-shifting as a component process of goal-directed problem-solving

In two experiments, we compared secondary task interference on Tower of London performance resulting from three different secondary tasks. The secondary tasks were designed to tap three different executive functions, namely set-shifting, memory monitoring and updating, and response inhibition. Previous work using individual differences methodology suggests that, all other things being equal, the response inhibition or memory tasks should result in the greatest interference. However, this was not found to be the case. Rather, in both experiments the set-shifting task resulted in significantly more interference on Tower of London performance than either of the other secondary tasks. Subsequent analyses suggest that the degree of interference could not be attributed to differences in secondary task difficulty. Results are interpreted in the light of related work which suggests that solving problems with non-transparent goal/subgoal structure requires flexible shifting between subgoals – a process that is held to be impaired by concurrent performance of a set-shifting task

Analysis of the Lung Microbiome in the “Healthy” Smoker and in COPD

Although culture-independent techniques have shown that the lungs are not sterile, little is known about the lung microbiome in chronic obstructive pulmonary disease (COPD). We used pyrosequencing of 16S amplicons to analyze the lung microbiome in two ways: first, using bronchoalveolar lavage (BAL) to sample the distal bronchi and air-spaces; and second, by examining multiple discrete tissue sites in the lungs of six subjects removed at the time of transplantation. We performed BAL on three never-smokers (NS) with normal spirometry, seven smokers with normal spirometry (“heathy smokers”, HS), and four subjects with COPD (CS). Bacterial 16 s sequences were found in all subjects, without significant quantitative differences between groups. Both taxonomy-based and taxonomy-independent approaches disclosed heterogeneity in the bacterial communities between HS subjects that was similar to that seen in healthy NS and two mild COPD patients. The moderate and severe COPD patients had very limited community diversity, which was also noted in 28% of the healthy subjects. Both approaches revealed extensive membership overlap between the bacterial communities of the three study groups. No genera were common within a group but unique across groups. Our data suggests the existence of a core pulmonary bacterial microbiome that includes Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. Most strikingly, there were significant micro-anatomic differences in bacterial communities within the same lung of subjects with advanced COPD. These studies are further demonstration of the pulmonary microbiome and highlight global and micro-anatomic changes in these bacterial communities in severe COPD patients

A Tale of Four “Carp”: Invasion Potential and Ecological Niche Modeling

. We assessed the geographic potential of four Eurasian cyprinid fishes (common carp, tench, grass carp, black carp) as invaders in North America via ecological niche modeling (ENM). These “carp” represent four stages of invasion of the continent (a long-established invader with a wide distribution, a long-established invader with a limited distribution, a spreading invader whose distribution is expanding, and a newly introduced potential invader that is not yet established), and as such illustrate the progressive reduction of distributional disequilibrium over the history of species' invasions.We used ENM to estimate the potential distributional area for each species in North America using models based on native range distribution data. Environmental data layers for native and introduced ranges were imported from state, national, and international climate and environmental databases. Models were evaluated using independent validation data on native and invaded areas. We calculated omission error for the independent validation data for each species: all native range tests were highly successful (all omission values <7%); invaded-range predictions were predictive for common and grass carp (omission values 8.8 and 19.8%, respectively). Model omission was high for introduced tench populations (54.7%), but the model correctly identified some areas where the species has been successful; distributional predictions for black carp show that large portions of eastern North America are at risk.ENMs predicted potential ranges of carp species accurately even in regions where the species have not been present until recently. ENM can forecast species' potential geographic ranges with reasonable precision and within the short screening time required by proposed U.S. invasive species legislation