Identification of novel proteins affected by rotenone in mitochondria of dopaminergic cells

Background: Many studies have shown that mitochondrial dysfunction, complex I inhibition in particular, is involved in the pathogenesis of Parkinson's disease (PD). Rotenone, a specific inhibitor of mitochondrial complex I, has been shown to produce neurodegeneration in rats as well as in many cellular models that closely resemble PD. However, the mechanisms through which complex I dysfunction might produce neurotoxicity are as yet unknown. A comprehensive analysis of the mitochondrial protein expression profile affected by rotenone can provide important insight into the role of mitochondrial dysfunction in PD. Results: Here, we present our findings using a recently developed proteomic technology called SILAC (stable isotope labeling by amino acids in cell culture) combined with polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry to compare the mitochondrial protein profiles of MES cells (a dopaminergic cell line) exposed to rotenone versus control. We identified 1722 proteins, 950 of which are already designated as mitochondrial proteins based on database search. Among these 950 mitochondrial proteins, 110 displayed significant changes in relative abundance after rotenone treatment. Five of these selected proteins were further validated for their cellular location and/or treatment effect of rotenone. Among them, two were confirmed by confocal microscopy for mitochondrial localization and three were confirmed by Western blotting (WB) for their regulation by rotenone. Conclusion: Our findings represent the first report of these mitochondrial proteins affected by rotenone; further characterization of these proteins may shed more light on PD pathogenesis.The study is supported by NIH grants to JZ (R01AG025327 and R01ES012703)

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes

How accurately can other people infer your thoughts -- and does culture matter?

This research investigated how accurately people infer what others are thinking after observing a brief sample of their behaviour and whether culture/similarity is a relevant factor. Target participants (14 British and 14 Mediterraneans) were cued to think about either positive or negative events they had experienced. Subsequently, perceiver participants (16 British and 16 Mediterraneans) watched videos of the targets thinking about these things. Perceivers (both groups) were significantly accurate in judging when targets had been cued to think of something positive versus something negative, indicating notable inferential ability. Additionally, Mediterranean perceivers were better than British perceivers in making such inferences, irrespective of nationality of the targets, something that was statistically accounted for by corresponding group differences in levels of independently measured collectivism. The results point to the need for further research to investigate the possibility that being reared in a collectivist culture fosters ability in interpreting others’ behaviour

The Ganymede Laser Altimeter (GALA) for the Jupiter Icy Moons Explorer (JUICE): Mission, science, and instrumentation of its receiver modules

The Jupiter Icy Moons Explorer (JUICE) is a science mission led by the European Space Agency, being developed for launch in 2023. The Ganymede Laser Altimeter (GALA) is an instrument onboard JUICE, whose main scientific goals are to understand ice tectonics based on topographic data, the subsurface structure by measuring tidal response, and small-scale roughness and albedo of the surface. In addition, from the perspective of astrobiology, it is imperative to study the subsurface ocean scientifically. The development of GALA has proceeded through an international collaboration between Germany (the lead), Japan, Switzerland, and Spain. Within this framework, the Japanese team (GALA-J) is responsible for developing three receiver modules: the Backend Optics (BEO), the Focal Plane Assembly (FPA), and the Analog Electronics Module (AEM). Like the German team, GALA-J also developed software to simulate the performance of the entire GALA system (performance model). In July 2020, the Proto-Flight Models of BEO, FPA, and AEM were delivered from Japan to Germany. This paper presents an overview of JUICE/GALA and its scientific objectives and describes the instrumentation, mainly focusing on Japan’s contribution

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Uncovering the acoustic vowel space of a previously undescribed language : the vowels of Nambo

This study presents the first acoustic description of the vowel space of a Papuan language—Nambo, spoken in southern Papua New Guinea—based on duration and first and second formant measurements from 19 adult male and female speakers across three age groups (young, middle-aged, senior). Phonemically, Nambo has six full vowels /i, e, æ, ɑ, o, u/ and a reduced vowel tentatively labeled /ə/. Unlike the full vowels, the quality of /ə/ showed great variation: seniors' and young females' realizations tended to be more open and retracted than those by young males, while middle-aged speakers' productions fell between these two variants

Uncovering the acoustic vowel space of a previously undescribed language: The vowels of Nambo

This study presents the first acoustic description of the vowel space of a Papuan language-Nambo, spoken in southern Papua New Guinea-based on duration and first and second formant measurements from 19 adult male and female speakers across three age groups (young, middle-aged, senior). Phonemically, Nambo has six full vowels /i, e, æ, ɑ, o, u/ and a reduced vowel tentatively labeled /ə/. Unlike the full vowels, the quality of /ə/ showed great variation: seniors' and young females' realizations tended to be more open and retracted than those by young males, while middle-aged speakers' productions fell between these two variants.This work was supported by Australian Research Council Laureate Project TheWellsprings of Language Diversity (FL130100111) and the Australian Research Council Centre of Excellence for the Dynamics of Language (CE140100041)