Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

Author Posting. © American Society for Clinical Investigation, 2013. This article is posted here by permission of American Society for Clinical Investigation for personal use, not for redistribution. The definitive version was published in Journal of Clinical Investigation 123 (2013): 1964–1975, doi:10.1172/JCI66387.Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.This work was supported by NIH grants 1P01GM096971 (to R.D. Goldman) and R01 NS062051 (to P. Opal) and a grant from Hannah’s Hope Fund (to R.D. Goldman and P. Opal)

Global injury morbidity and mortality from 1990 to 2017 : results from the Global Burden of Disease Study 2017

Correction:Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.Peer reviewe

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Martensitic Transformation and Magnetic Properties of Ni-Mn Quinary Heusler Alloy

Ni-Mn-based quinary Heusler alloys have seldom been investigated with respect to their martensitic transformation and mechanical properties for near room temperature transformation. In the current work, we identified and investigated martensitic transformation near room temperature, and the martensitic properties of Ni-Mn-Sn-Fe-In-based quinary Heusler alloys. Alloys prepared in an argon-rich vacuum arc melting furnace. During X-ray diffraction (XRD) analysis, it was identified that the L21 cubic structure austenite phase of the alloy transforms into L10 orthorhombic martensite phase in the case of alloys with greater Fe substitution. The martensitic transformation zone of the alloy is also shifted to the near-room-temperature range of 15–28 °C by changing the stoichiometry of the alloy composition. Magnetic measurements like field heating (FH), field cooling (FC) and zero field cooling (ZFC) indicate the presence of a dual magnetic phase in the alloy, while magnetic susceptibility testing also helped to establish claims regarding the magnetic measurement results

Investigation on Magnetization, Magnetocalory, Magnetoresistance, and Electric Properties of Ni-Mn Based Heusler Alloy

The magnetic and electrical characteristics of Ni-Mn quinary Heusler alloys are studied in the current work. The results concern the materials’ magnetic and electrical behavior. The physical property measurement system (PPMS) and superconducting quantum interference device (SQUID) were used at various magnetization levels to determine the results. The addition of Fe helps to form the alloy into a smart memory alloy with magnetocrystalline anisotropy, twin border mobility, and varied magnetic and martensite transition temperature characteristics. Character changes in the superparamagnetic (SPM) and paramagnetic (PM) alloys occur between 26 and 34 °C. The curves are supported by the alloy’s martensitic transition temperature change. A large refrigeration capacity is identified in the alloy. These properties are an indication of the alloys’ application prospects. Entropy change helps to detect the inverse magnetocaloric effect in the alloy, whereas adiabatic temperature change helps identify the origin and validity of reverse magnetic properties. The transition temperature changes occur when austenite’s sigma is larger than that of martensite, and as the magnetic field increases, the temperature declines. Isothermal magnetization curves, a large (MR)/B value at low and high magnetic fields, and temperatures near the transformation point suggest that small-crystal Heusler alloys have tremendous promise for low and high magnetic field magnetoresistance applications

Crystals of a thymidylate synthase mutant offer insights into crystal packing and plasticity of protein-protein contacts

Some crystal forms of thymidylate synthase from L. casei exhibit unit sell transformation upon irradiation by X-rays, These forms, all of which occur in the space group P6(1)22, show an elongation in the c cell dimension and in some cases stabilize to a constant cell dimension upon prolonged exposure. We present here an analysis of the possible causes of this transformation based on the crystal structures for two forms of an R178F mutant of this enzyme. We compare these structures to other structures with intermediate cell parameters reported in the literature. There are no large changes in the dimeric structure of TS in these crystal forms. Although there is a large change in the unit cell volume, the molecular contacts in the crystal structures are nearly invariant. The transformation appears to result from concerted small changes in molecular structure and intermolecular contacts. These observations corroborate the general impression that protein structures can accommodate minor changes in sequence or packing wherein the intra and intermolecular interactions are not seriously altered