Absence of dopaminergic neuronal degeneration and oxidative damage in aged DJ-1-deficient mice

Parkinson's disease is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. Loss-of-function mutations in the DJ-1 gene have been linked to autosomal recessive forms of early-onset familial Parkinson's disease. DJ-1 is thought to play roles in protection of cells against oxidative stress and in maintenance of the normal dopaminergic function in the nigrostriatal pathway. Here we investigate the consequence of both DJ-1 inactivation and aging in mice. We found that DJ-1-/- mice at the age of 24–27 months have normal numbers of dopaminergic neurons in the substantia nigra and normal levels of dopamine and its major metabolites in the striatum. The number of noradrenergic neurons in the locus coeruleus is also unchanged in DJ-1-/- mice. Moreover, there is no accumulation of oxidative damage or inclusion bodies in aged DJ-1-/- brains. Together, these results indicate that loss of DJ-1 function alone is insufficient to cause nigral degeneration and oxidative damage in the life span of mice

Photosynthetic characteristics of phytoplankton off Adelie Land, Antarctica, during the austral summer

The photosynthesis-irradiance characteristics (P-E curves) and quantum yields of natural phytoplankton were investigated in the Southern Ocean off Adelie Land, Antarctica, during the austral summer. Data were acquired at eight stations during a cruise of T/V Umitaka-Maru III. The photosynthetic P-E curves showed low light adaptation of phytoplankton. Mean value (±standard deviation) of the P-E curve parameters, α^*, and I_k, were 0.014 (±0.013) mgC (mg chl. α)^ h^1 (μmol photons m^ s^)^ and 76 (±55) μmol photons m^ s^, respectively. Although phytoplankton were adapted to low irradiance, the phytoplankton in the SCM were not fully adapted to the low irradiance prevailing at those depths. P^*_ in the studied region was low (mean of 0.66 (±0.37) mgC (mg chl. α)^ h^) and generally lower than the previously reported values in waters near the Antarctic Peninsula. The maximum quantum yield varied widely, ranging from 0.001 to 0.038mol C (mol photons absorbed)^ at the surface and from 0.007 to 0.092mol C (mol photons absorbed)^ near the bottom of the euphotic zone. These values were within the range of published data. Comparison of photosynthetic parameters with historical data indicated that primary productivity from remotely sensed data for the whole of the Southern Ocean, based on these field estimates of photosynthetic parameters, has been overestimated

Loss of DJ-1 Does Not Affect Mitochondrial Respiration but Increases ROS Production and Mitochondrial Permeability Transition Pore Opening

Background: Loss of function mutations in the DJ-1 gene have been linked to recessively inherited forms of Parkinsonism. Mitochondrial dysfunction and increased oxidative stress are thought to be key events in the pathogenesis of Parkinson’s disease. Although it has been reported that DJ-1 serves as scavenger for reactive oxidative species (ROS) by oxidation on its cysteine residues, how loss of DJ-1 affects mitochondrial function is less clear. Methodology/Principal Findings: Using primary mouse embryonic fibroblasts (MEFs) or brains from DJ-1−/− mice, we found that loss of DJ-1 does not affect mitochondrial respiration. Specifically, endogenous respiratory activity as well as basal and maximal respiration are normal in intact DJ-1−/− MEFs, and substrate-specific state 3 and state 4 mitochondrial respiration are also unaffected in permeabilized DJ-1−/− MEFs and in isolated mitochondria from the cerebral cortex of DJ-1−/− mice at 3 months or 2 years of age. Expression levels and activities of all individual complexes composing the electron transport system are unchanged, but ATP production is reduced in DJ-1−/− MEFs. Mitochondrial transmembrane potential is decreased in the absence of DJ-1. Furthermore, mitochondrial permeability transition pore opening is increased, whereas mitochondrial calcium levels are unchanged in DJ-1−/− cells. Consistent with earlier reports, production of reactive oxygen species (ROS) is increased, though levels of antioxidative enzymes are unaltered. Interestingly, the decreased mitochondrial transmembrane potential and the increased mitochondrial permeability transition pore opening in DJ-1−/− MEFs can be restored by antioxidant treatment, whereas oxidative stress inducers have the opposite effects on mitochondrial transmembrane potential and mitochondrial permeability transition pore opening. Conclusions/Significance: Our study shows that loss of DJ-1 does not affect mitochondrial respiration or mitochondrial calcium levels but increases ROS production, leading to elevated mitochondrial permeability transition pore opening and reduced mitochondrial transmembrane potential

Two Cases of Nivolumab Re-Administration after Pneumonitis as Immune-Related Adverse Events

Nivolumab is a recently approved medication for the treatment of unresectable malignant melanoma. Many immune-related adverse events (irAEs) associated with nivolumab have been reported, such as pneumonitis, hepatitis, dermatitis, and thyroiditis. Prednisolone can effectively treat irAEs. However, it is unclear how or if nivolumab should be administered to patients after they have experienced an irAE. Herein, we show 2 patients who underwent pneumonitis as irAE. Case 1 demonstrated a cryptogenic organizing pneumonia pattern in the CT scan and case 2 had a diffuse alveolar damage (DAD) pattern. Oral corticosteroids improved chest shadow of CT scan in both cases. However, when nivolumab was re-administrated, case 1 demonstrated no symptoms, but case 2 demonstrated pneumonia again. From our cases, it is difficult to re-administrate nivolumab for the patients with pneumonitis which shows a DAD pattern in CT, even if oral corticosteroids improve their symptoms

Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway

<p>Abstract</p> <p>Background</p> <p>Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice.</p> <p>Results</p> <p>Our analysis of <it>LRRK2</it>-/- kidneys at multiple ages, such as 1, 4, 7, and 20 months, revealed unique age-dependent development of a variety of molecular, cellular, and ultrastructural changes. Gross morphological abnormalities of the kidney, including altered size, weight, texture, and color, are evident in <it>LRRK2</it>-/- mice at 3-4 months of age, along with increased accumulation of autofluorescent granules in proximal renal tubules. The ratio of kidney/body weight in <it>LRRK2</it>-/- mice is increased at 1, 4, and 7 months of age (~10% at 1 month, and ~20% at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (~50%). While kidney filtration function evaluated by levels of blood urea nitrogen and serum creatinine is not significantly affected in <it>LRRK2</it>-/- mice at 12-14 months of age, expression of kidney injury molecule-1, a sensitive and specific biomarker for epithelial cell injury of proximal renal tubules, is up-regulated (~10-fold). Surprisingly, loss of LRRK2 causes age-dependent bi-phasic alterations of the autophagic activity in <it>LRRK2</it>-/- kidneys, which is unchanged at 1 month of age, enhanced at 7 months but reduced at 20 months, as evidenced by corresponding changes in the levels of LC3-I/II, a reliable autophagy marker, and p62, an autophagy substrate. Levels of α-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in <it>LRRK2</it>-/- kidneys at 7 months of age but increased at 20 months. Interestingly, the age-dependent bi-phasic alterations in autophagic activity in <it>LRRK2</it>-/- kidneys is accompanied by increased levels of lysosomal proteins and proteases at 1, 7, and 20 months of age as well as progressive accumulation of autolysosomes and lipofuscin granules at 4, 7-10, and 20 months of age.</p> <p>Conclusions</p> <p>LRRK2 is important for the dynamic regulation of autophagy function <it>in vivo</it>.</p

Simulations of Surface X-ray Diffraction from a Monolayer 4He Film Adsorbed on Graphite

We carried out simulations of crystal truncation rod (CTR) scatterings, i.e., one of the surface X-ray diffraction techniques with atomic resolution, from a monolayer He film adsorbed on graphite. Our simulations reveal that the 00L rod scatterings from the He monolayer exhibit notable intensity modifications for those from a graphite surface in the ranges of approximately L = 0.6 - 1.7 and L = 2.2 - 3.5. The height of the He monolayer from the graphite surface largely affects the CTR scattering profiles, indicating that CTR scatterings have enough sensitivities to determine the surface structure of the various phases in the He layer. In particular, in the incommensurate solid phase, our preliminary experimental data show the intensity modulations that are expected from the present simulations.Comment: 6 pages, 4 figures, to be published in JPS Conf. Pro