Dissociation of Progressive Dopaminergic Neuronal Death and Behavioral Impairments by Bax Deletion in a Mouse Model of Parkinson's Diseases

Parkinson's disease (PD) is a common, late-onset movement disorder with selective degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Although the neurotoxin 6-hydroxydopamine (6-OHDA) has been used to induce progressive degeneration of DA neurons in various animal models of PD, the precise molecular pathway and the impact of anti-apoptotic treatment on this neurodegeneration are less understood. Following a striatal injection of 6-OHDA, we observed atrophy and progressive death of DA neurons in wild-type mice. These degenerating DA neurons never exhibited signs of apoptosis (i.e., caspase-3 activation and cytoplasmic release of cytochrome C), but rather show nuclear translocation of apoptosis-inducing factor (AIF), a hallmark of regulated necrosis. However, mice with genetic deletion of the proapoptotic gene Bax (Bax-KO) exhibited a complete absence of 6-OHDA-induced DA neuron death and nuclear translocation of AIF, indicating that 6-OHDA-induced DA neuronal death is mediated by Bax-dependent AIF activation. On the other hand, DA neurons that survived in Bax-KO mice exhibited marked neuronal atrophy, without significant improvement of PD-related behavioral deficits. These findings suggest that anti-apoptotic therapy may not be sufficient for PD treatment, and the prevention of Bax-independent neuronal atrophy may be an important therapeutic target

Does the Kyphotic Change Decrease the Risk of Fall?

ObjectivesFalls are a major problem in the elderly. Age-related degeneration of the human balance system increases the risk of falls. Kyphosis is a common condition of curvature of the upper spine in the elderly and its development occurs through degenerative change. However, relatively little is known about the effect of kyphotic changes on balance in the elderly. The aim of this study is to investigate the influence of kyphosis on the balance strategy through use of the motor control test (MCT) in computerized dynamic posturography.MethodsFifty healthy subjects who were not affected by other medical disorders that could affect gait or balance were enrolled in the study. By simulation of kyphotic condition through change of the angles of the line connecting the shoulder to the hip and the ankle axis by approximately 30°, the latency and amplitude of the MCT were measured in upright and kyphotic condition.ResultsIn the kyphotic condition, latency was shortened in backward movement. In forward movement, latency was shortened only in large stimulation. The amplitude in forward movement was decreased in kyphotic condition. However, the change of amplitude was not significant in large intensity backward movement in the same condition.ConclusionKyphotic condition decreases the latency of MCT, especially in backward movement. These findings imply that kyphotic condition may serve as a protective factor against falls

Changes in the incidence of cardiopulmonary resuscitation before and after implementation of the Life-Sustaining Treatment Decisions Act

Background The Life-Sustaining Treatment (LST) Decisions Act allows withholding and withdrawal of LST, including cardiopulmonary resuscitation (CPR). In the present study, the incidence of CPR before and after implementation of the Act was compared. Methods This was a retrospective review involving hospitalized patients who underwent CPR at a single center between February 2016 and January 2020 (pre-implementation period, February 2016 to January 2018; post-implementation period, February 2018 to January 2020). The primary outcome was monthly incidence of CPR per 1,000 admissions. The secondary outcomes were duration of CPR, return of spontaneous circulation (ROSC) rate, 24-hour survival rate, and survival-to-discharge rate. The study outcomes were compared before and after implementation of the Act. Results A total of 867 patients who underwent CPR was included in the analysis. The incidence of CPR per 1,000 admissions showed no significant difference before and after implementation of the Act (3.02±0.68 vs. 2.81±0.75, P=0.255). The ROSC rate (67.20±0.11 vs. 70.99±0.12, P=0.008) and survival to discharge rate (20.24±0.09 vs. 22.40±0.12, P=0.029) were higher after implementation of the Act than before implementation. Conclusions The incidence of CPR did not significantly change for 2 years after implementation of the Act. Further studies are needed to assess the changes in trends in the decisions of CPR and other LSTs in real-world practice

Vulnerability Assessment On Water Management For Climate Change Adaptation : Case Study To Gochang County In South Korea

Currently, 1.6 billion people live in countries and regions with absolute water scarcity and the number is expected to rise to 2.8 billion people by 2025(World Bank). Climate change will make water security more difficult and costly to achieve. Smart Water Management of water resources using an integrated approach with IT (Information Technology) will play a critical role in adapting climate change and mitigate social, economic and environmental impacts. Gochang County in Jeonbuk Province (South Korea) is one of the vulnerable areas to climate change, because it is a particularly high dependency to agricultural industry, increasing proportion of elderly people, and coastal areas where vulnerable to increases in the intensity of storm surge and heavy precipitation. The study mainly utilized the vulnerability definition adopted by IPCC that is a function of exposure, sensitivity and adaptive capacity. This study seeks to investigate the current (2000-2010) risks and vulnerability to flood and drought and those in the future (2046~2055) due to climate change. This study employs proxy indicators to measure the exposure, sensitivity and adaptive capacity. The RCP(Representative Concentration Pathways) 8.5 climate change scenario from KMA (Korea Meteorological Administration) was used and a detailed climate change scenario was compiled with administrative district-level and watershed level for spatial analysis. The climate exposure for the flood vulnerability showed that East Gochang area was more vulnerable than West in the current period. However, in the future period, South Gochang area is potentially most vulnerable than others to climate exposure. The climate exposure for the drought vulnerability showed that North Gochang area was most vulnerable than others in the future period. The results of the vulnerability assessment could be used for the taking measures for climate change adaptation and determining the priority area

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient high-throughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complex-disease targets that are traditionally deemed "undruggable.

Mind Bomb 1-Expressing Intermediate Progenitors Generate Notch Signaling to Maintain Radial Glial Cells

SummaryNotch signaling is critical for the stemness of radial glial cells (RGCs) during embryonic neurogenesis. Although Notch-signal-receiving events in RGCs have been well characterized, the signal-sending mechanism by the adjacent cells is poorly understood. Here, we report that conditional inactivation of mind bomb-1 (mib1), an essential component for Notch ligand endocytosis, in mice using the nestin and hGFAP promoters resulted in complete loss of Notch activation, which leads to depletion of RGCs, and premature differentiation into intermediate progenitors (IPs) and finally neurons, which were reverted by the introduction of active Notch1. Interestingly, Mib1 expression is restricted in the migrating IPs and newborn neurons, but not in RGCs. Moreover, sorted Mib1+ IPs and neurons can send the Notch signal to neighboring cells. Our results reveal that not only newborn neurons but also IPs are essential Notch-ligand-presenting cells for maintaining RGC stemness during both symmetric and asymmetric divisions