Amyotrophic lateral sclerosis-associated mutant SOD1 inhibits anterograde axonal transport of mitochondria by reducing Miro1 levels

Defective axonal transport is an early neuropathological feature of amyotrophic lateral sclerosis (ALS). We have previously shown that ALS-associated mutations in Cu/Zn superoxide dismutase 1 (SOD1) impair axonal transport of mitochondria in motor neurons isolated from SOD1 G93A transgenic mice and in ALS mutant SOD1 transfected cortical neurons, but the underlying mechanisms remained unresolved. The outer mitochondrial membrane protein mitochondrial Rho GTPase 1 (Miro1) is a master regulator of mitochondrial axonal transport in response to cytosolic calcium (Ca2+) levels ([Ca2+]c) and mitochondrial damage. Ca2+ binding to Miro1 halts mitochondrial transport by modifying its interaction with kinesin-1 whereas mitochondrial damage induces Phosphatase and Tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin-dependent degradation of Miro1 and consequently stops transport. To identify the mechanism underlying impaired axonal transport of mitochondria in SOD1-related ALS we investigated [Ca2+]c and Miro1 levels in ALS mutant SOD1 expressing neurons. We found that expression of ALS mutant SOD1 reduced the level of endogenous Miro1 but did not affect [Ca2+]c. ALS mutant SOD1 induced reductions in Miro1 levels were Parkin dependent. Moreover, both overexpression of Miro1 and ablation of PINK1 rescued the mitochondrial axonal transport deficit in ALS mutant SOD1-expressing cortical and motor neurons. Together these results provide evidence that ALS mutant SOD1 inhibits axonal transport of mitochondria by inducing PINK1/Parkin-dependent Miro1 degradation

Low maternal vitamin B12 status is associated with lower cord blood HDL cholesterol in white Caucasians living in the UK

Background and Aims: Studies in South Asian population show that low maternal vitamin B12 associates with insulin resistance and small for gestational age in the offspring. Low vitamin B12 status is attributed to vegetarianism in these populations. It is not known whether low B12 status is associated with metabolic risk of the offspring in whites, where the childhood metabolic disorders are increasing rapidly. Here, we studied whether maternal B12 levels associate with metabolic risk of the offspring at birth. Methods: This is a cross-sectional study of 91 mother-infant pairs (n = 182), of white Caucasian origin living in the UK. Blood samples were collected from white pregnant women at delivery and their newborns (cord blood). Serum vitamin B12, folate, homocysteine as well as the relevant metabolic risk factors were measured. Results: The prevalence of low serum vitamin B12 (<191 ng/L) and folate (<4.6 μg/L) were 40% and 11%, respectively. Maternal B12 was inversely associated with offspring’s Homeostasis Model Assessment 2-Insulin Resistance (HOMA-IR), triglycerides, homocysteine and positively with HDL-cholesterol after adjusting for age and BMI. In regression analysis, after adjusting for likely confounders, maternal B12 is independently associated with neonatal HDL-cholesterol and homocysteine but not triglycerides or HOMA-IR. Conclusions: Our study shows that low B12 status is common in white women and is independently associated with adverse cord blood cholesterol

Nitrogen Retention in Headwater Streams: The Influence of Groundwater-Surface Water Exchange

Groundwater-surface water (GW-SW) interaction lengthens hydraulic residence times, increases contact between solutes and biologically active surfaces, and often creates a gradient of redox conditions conducive to an array of biogeochemical processes. As such, the interaction of hydraulic patterns and biogeochemical activity is suspected to be an important determinant of elemental spiraling in streams. Hydrologic interactions may be particularly important in headwater streams, where the extent of the GW-SW mixing environment (i.e., hyporheic zone) is proportionately greater than in larger streams. From our current understanding of stream ecosystem function, we discuss nitrogen (N) spiraling, present a conceptual model of N retention in streams, and use both of these issues to generate specific research questions and testable hypotheses regarding N dynamics in streams

Long-term trends in tropical cyclone tracks around Korea and Japan in late summer and early fall

This study investigates long-term trends in tropical cyclones (TCs) over the extratropical western North Pacific (WNP) over a period of 35 years (1982-2016). The area analyzed extended across 30-45 degrees N and 120-150 degrees E, including the regions of Korea and Japan that were seriously affected by TCs. The northward migration of TCs over the WNP to the mid-latitudes showed a sharp increase in early fall. In addition, the duration of TCs over the WNP that migrated northwards showed an increase, specifically in early to mid-September. Therefore, more recently, TC tracks have been observed to significantly extend into the mid-latitudes. The recent northward extension of TC tracks over the WNP in early fall was observed to be associated with changes in environmental conditions that were favorable for TC activities, including an increase in sea surface temperature (SST), decrease in vertical wind shear, expansion of subtropical highs, strong easterly steering winds, and an increase in relative vorticity. In contrast, northward migrations of TCs to Korea and Japan showed a decline in late August, because of the presence of unfavorable environmental conditions for TC activities. These changes in environmental conditions, such as SST and vertical wind shear, can be partially associated with the Pacific decadal oscillation

Randomised controlled trial to evaluate the effect of foot trimming before and after first calving on subsequent lameness episodes and productivity in dairy heifers

The objective of this study was to assess both independent and combined effects of routine foot trimming of heifers at 3 weeks pre-calving and 100 days post calving on the first lactation lameness and lactation productivity. A total of 419 pre-calving dairy heifers were recruited from one heifer rearing operation over a 10-month period. Heifers were randomly allocated into one of four foot trimming regimens; pre-calving foot trim and post-calving lameness score (Group TL), pre-calving lameness score and post-calving foot trim (Group LT), pre-calving foot trim and post-calving foot trim (Group TT), and pre-calving lameness score and post-calving lameness score (Group LL, control group). All heifers were scored for lameness at 24 biweekly time points for 1 year following calving, and first lactation milk production data were collected. Following calving, 172/419 (41.1%) of heifers became lame during the study (period prevalence), with lameness prevalence at each time-point following calving ranging from 48/392 (12.2%) at 29–42 days post-calving to 4/379 (1.1%) between 295 and 383 days after calving. The effects of the four treatment groups were not significantly different from each other for overall lameness period prevalence, biweekly lameness point prevalence, time to first lameness event, type of foot lesion identified at dry off claw trimming, or the 4% fat corrected 305-day milk yield. However, increased odds lameness was significantly associated with a pre-calving trim alone (P = 0.044) compared to the reference group LL. The odds of heifer lameness were highest between 0 and 6 weeks post-partum, and heifer farm destination was significantly associated with lameness (OR 2.24), suggesting that even at high standard facilities, environment and management systems have more effect on heifer foot health than trimming

Predicting management development and learning behaviour in New Zealand SMEs

Despite concern on the part of policy makers to raise managerial capability in SMEs, there is little evidence on the key drivers of owner-manager participation in management development programmes. The authors argue that such participation is poorly understood. The paper develops a predictive model of the drivers of participation in sources of learning by owner-managers. It tests a theoretical model, based on the small firm as a learning organization, which posits that participation is driven by owner-managers\u27 learning orientation and the extent of their belief in self-improvement. The implications of the results are discussed in light of the provision of management development programmes. <br /

Slater-Pauling Behavior of the Half-Ferromagnetic Full-Heusler Alloys

Using the full-potential screened Korringa-Kohn-Rostoker method we study the full-Heusler alloys based on Co, Fe, Rh and Ru. We show that many of these compounds show a half-metallic behavior, however in contrast to the half-Heusler alloys the energy gap in the minority band is extremely small. These full-Heusler compounds show a Slater-Pauling behavior and the total spin-magnetic moment per unit cell (M_t) scales with the total number of valence electrons (Z_t) following the rule: M_t=Z_t-24. We explain why the spin-down band contains exactly 12 electrons using arguments based on the group theory and show that this rule holds also for compounds with less than 24 valence electrons. Finally we discuss the deviations from this rule and the differences compared to the half-Heusler alloys.Comment: 10 pages, 8 figures, revised figure 3, new text adde

Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation

Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD

Reducing medical device alarms by an order of magnitude: A human factors approach

The intensive care unit (ICU) is one of the most technically advanced environments in healthcare, using a multitude of medical devices for drug administration, mechanical ventilation and patient monitoring. However, these technologies currently come with disadvantages, namely noise pollution, information overload and alarm fatigue—all caused by too many alarms. Individual medical devices currently generate alarms independently, without any coordination or prioritisation with other devices, leading to a cacophony where important alarms can be lost amongst trivial ones, occasionally with serious or even fatal consequences for patients. We have called this approach to the design of medical devices the single-device paradigm, and believe it is obsolete in modern hospitals where patients are typically connected to several devices simultaneously. Alarm rates of one alarm every four minutes for only the physiological monitors (as recorded in the ICUs of two hospitals contributing to this paper) degrades the quality of the patient’s healing environment and threatens patient safety by constantly distracting healthcare professionals. We outline a new approach to medical device design involving the application of human factors principles which have been successful in eliminating alarm fatigue in commercial aviation. Our approach comprises the networked-device paradigm, comprehensive alarms and humaniform information displays. Instead of each medical device alarming separately at the patient’s bedside, our proposed approach will integrate, prioritise and optimise alarms across all devices attached to each patient, display information more intuitively and hence increase alarm quality while reducing the number of alarms by an order of magnitude below current levels