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

Mass measurements of neutron-deficient Y, Zr, and Nb isotopes and their impact on rp and νp nucleosynthesis processes

© 2018 The Authors. Published by Elsevier B.V. This manuscript is made available under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND 4.0). For further details please see: https://creativecommons.org/licenses/by-nc-nd/4.0/Using isochronous mass spectrometry at the experimental storage ring CSRe in Lanzhou, the masses of 82Zr and 84Nb were measured for the first time with an uncertainty of ∼10 keV, and the masses of 79Y, 81Zr, and 83Nb were re-determined with a higher precision. The latter are significantly less bound than their literature values. Our new and accurate masses remove the irregularities of the mass surface in this region of the nuclear chart. Our results do not support the predicted island of pronounced low α separation energies for neutron-deficient Mo and Tc isotopes, making the formation of Zr–Nb cycle in the rp-process unlikely. The new proton separation energy of 83Nb was determined to be 490(400) keV smaller than that in the Atomic Mass Evaluation 2012. This partly removes the overproduction of the p-nucleus 84Sr relative to the neutron-deficient molybdenum isotopes in the previous νp-process simulations.Peer reviewe

Characterization of human Sec16B: indications of specialized, non-redundant functions

The endoplasmic reticulum (ER) represents the entry point into the secretory pathway and from here newly synthesized proteins and lipids are delivered to the Golgi. The selective cargo export from the ER is mediated by COPII-assembly at specific sites of the ER, the so-called transitional ER (tER). The peripheral membrane protein Sec16, first identified in yeast, localizes to transitional ER and plays a key role in organization of these sites. Sec16 defines the tER and is thought to act as a scaffold for the COPII coat assembly. In humans two isoforms of Sec16 are present, the larger Sec16A and the smaller Sec16B. Nevertheless, the functional differences between the two isoforms are ill-defined. Here we describe characterization of the localization and dynamics of Sec16B relative to Sec16A, provide evidence that Sec16B is likely a minor or perhaps specialized form of Sec16, and that it is not functionally redundant with Sec16A

Spring migration patterns, habitat use, and stopover site protection status for two declining waterfowl species wintering in China as revealed by satellite tracking

East Asian migratory waterfowl have greatly declined since the 1950s, especially the populations that winter in China. Conservation is severely hampered by the lack of primary information about migration patterns and stopover sites. This study utilizes satellite tracking techniques and advanced spatial analyses to investigate spring migration of the greater white‐fronted goose (Anser albifrons) and tundra bean goose (Anser serrirostris) wintering along the Yangtze River Floodplain. Based on 24 tracks obtained from 21 individuals during the spring of 2015 and 2016, we found that the Northeast China Plain is far‐out the most intensively used stopover site during migration, with geese staying for over 1 month. This region has also been intensely developed for agriculture, suggesting a causal link to the decline in East Asian waterfowl wintering in China. The protection of waterbodies used as roosting area, especially those surrounded by intensive foraging land, is critical for waterfowl survival. Over 90% of the core area used during spring migration is not protected. We suggest that future ground surveys should target these areas to confirm their relevance for migratory waterfowl at the population level, and core roosting area at critical spring‐staging sites should be integrated in the network of protected areas along the flyway. Moreover, the potential bird–human conflict in core stopover area needs to be further studied. Our study illustrates how satellite tracking combined with spatial analyses can provide crucial insights necessary to improve the conservation of declining Migratory species

Speckle-scale focusing in the diffusive regime with time reversal of variance-encoded light (TROVE)

Focusing of light in the diffusive regime inside scattering media has long been considered impossible. Recently, this limitation has been overcome with time reversal of ultrasound-encoded light (TRUE), but the resolution of this approach is fundamentally limited by the large number of optical modes within the ultrasound focus. Here, we introduce a new approach, time reversal of variance-encoded light (TROVE), which demixes these spatial modes by variance encoding to break the resolution barrier imposed by the ultrasound. By encoding individual spatial modes inside the scattering sample with unique variances, we effectively uncouple the system resolution from the size of the ultrasound focus. This enables us to demonstrate optical focusing and imaging with diffuse light at an unprecedented, speckle-scale lateral resolution of ~5 µm

Effects of Sinusoidal Electromagnetic Field on Structure and Function of Different Kinds of Cell Lines

This study investigated that whether a 2 mT, 60 Hz, sinusoidal electromagnetic field (EMF) alters the structure and function of cells. This research compared the effects of EMF on four kinds of cell lines: hFOB 1.19 (fetal osteoblast), T/G HA-VSMC (aortic vascular smooth muscle cell), RPMI 7666 (B lymphoblast), and HCN-2 (cortical neuronal cell). Over 14 days, cells were exposed to EMF for 1, 3, or 6 hours per day (hrs/d). The results pointed to a cell type-specific reaction to EMF exposure. In addition, the cellular responses were dependent on duration of EMF exposure. In the present study, cell proliferation was the trait most sensitive to EMF. EMF treatment promoted growth of hFOB 1.19 and HCN-2 compared with control cells at 7 and 14 days of incubation. When the exposure time was 3 hrs/d, EMF enhanced the proliferation of RPMI 7666 but inhibited that of T/G HA-VSMC. On the other hand, the effects of EMF on cell cycle distribution, cell differentiation, and actin distribution were unclear. Furthermore, we hardly found any correlation between EMF exposure and gap junctional intercellular communication in hFOB 1.19. This study revealed that EMF might serve as a potential tool for manipulating cell proliferation

Astrophysical and Cosmological Implications of Large Volume String Compactifications

We study the spectrum, couplings and cosmological and astrophysical implications of the moduli fields for the class of Calabi-Yau IIB string compactifications for which moduli stabilisation leads to an exponentially large volume V ~ 10^{15} l_s^6 and an intermediate string scale m_s ~ 10^{11}GeV, with TeV-scale observable supersymmetry breaking. All K\"ahler moduli except for the overall volume are heavier than the susy breaking scale, with m ~ ln(M_P/m_{3/2}) m_{3/2} ~ (\ln(M_P/m_{3/2}))^2 m_{susy} ~ 500 TeV and, contrary to standard expectations, have matter couplings suppressed only by the string scale rather than the Planck scale. These decay to matter early in the history of the universe, with a reheat temperature T ~ 10^7 GeV, and are free from the cosmological moduli problem (CMP). The heavy moduli have a branching ratio to gravitino pairs of 10^{-30} and do not suffer from the gravitino overproduction problem. The overall volume modulus is a distinctive feature of these models and is an M_{planck}-coupled scalar of mass m ~ 1 MeV and subject to the CMP. A period of thermal inflation can help relax this problem. This field has a lifetime ~ 10^{24}s and can contribute to dark matter. It may be detected through its decays to 2\gamma or e^+e^-. If accessible the e^+e^- decay mode dominates, with Br(\chi \to 2 \gamma) suppressed by a factor (ln(M_P/m_{3/2}))^2. We consider the potential for detection of this field through different astrophysical sources and find that the observed gamma-ray background constrains \Omega_{\chi} <~ 10^{-4}. The decays of this field may generate the 511 keV emission line from the galactic centre observed by INTEGRAL/SPI.Comment: 31 pages, 2 figures; v2. refs adde

Electrical switching of vortex core in a magnetic disk

A magnetic vortex is a curling magnetic structure realized in a ferromagnetic disk, which is a promising candidate of a memory cell for future nonvolatile data storage devices. Thus, understanding of the stability and dynamical behaviour of the magnetic vortex is a major requirement for developing magnetic data storage technology. Since the experimental proof of the existence of a nanometre-scale core with out-of-plane magnetisation in the magnetic vortex, the dynamics of a vortex has been investigated intensively. However, the way to electrically control the core magnetisation, which is a key for constructing a vortex core memory, has been lacking. Here, we demonstrate the electrical switching of the core magnetisation by utilizing the current-driven resonant dynamics of the vortex; the core switching is triggered by a strong dynamic field which is produced locally by a rotational core motion at a high speed of several hundred m/s. Efficient switching of the vortex core without magnetic field application is achieved thanks to resonance. This opens up the potentiality of a simple magnetic disk as a building block for spintronic devices like a memory cell where the bit data is stored as the direction of the nanometre-scale core magnetisation.Comment: 20 pages, 4 figures. Supplementary discussion included. Accepted for publication in Nature Material