The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP.

The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIPA52G point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48.

Direct Determination of Fission-Barrier Heights Using Light-Ion Transfer in Inverse Kinematics.

We demonstrate a new technique for obtaining fission data for nuclei away from ß stability. These types of data are pertinent to the astrophysical r process, crucial to a complete understanding of the origin of the heavy elements, and for developing a predictive model of fission. These data are also important considerations for terrestrial applications related to power generation and safeguarding. Experimentally, such data are scarce due to the difficulties in producing the actinide targets of interest. The solenoidal-spectrometer technique, commonly used to study nucleon-transfer reactions in inverse kinematics, has been applied to the case of transfer-induced fission as a means to deduce the fission-barrier height, among other variables. The fission-barrier height of ^{239}U has been determined via the ^{238}U(d,pf) reaction in inverse kinematics, the results of which are consistent with existing neutron-induced fission data indicating the validity of the technique.

Deformation versus Sphericity in the Ground States of the Lightest Gold Isotopes.

The changes in mean-squared charge radii of neutron-deficient gold nuclei have been determined using the in-source, resonance-ionization laser spectroscopy technique, at the ISOLDE facility (CERN). From these new data, nuclear deformations are inferred, revealing a competition between deformed and spherical configurations. The isotopes ^{180,181,182}Au are observed to possess well-deformed ground states and, when moving to lighter masses, a sudden transition to near-spherical shapes is seen in the extremely neutron-deficient nuclides, ^{176,177,179}Au. A case of shape coexistence and shape staggering is identified in ^{178}Au which has a ground and isomeric state with different deformations. These new data reveal a pattern in ground-state deformation unique to the gold isotopes, whereby, when moving from the heavy to light masses, a plateau of well-deformed isotopes exists around the neutron midshell, flanked by near-spherical shapes in the heavier and lighter isotopes-a trend hitherto unseen elsewhere in the nuclear chart. The experimental charge radii are compared to those from Hartree-Fock-Bogoliubov calculations using the D1M Gogny interaction and configuration mixing between states of different deformation. The calculations are constrained by the known spins, parities, and magnetic moments of the ground states in gold nuclei and show a good agreement with the experimental results.

Next Level Health: a holistic health and wellbeing program to empower New Zealand women.

Improving equity in women's health requires gender-specific and empowering approaches. However, health programs often disempower women by adopting a 'one-size-fits-all' approach that emphasizes diet, exercise and weight loss over other important aspects like sleep and mental wellbeing. This article reports on the design of Next Level Health (NLH), a program that aims to empower women through developing a wide range of health behaviors to support their holistic wellbeing. NLH is grounded by ethics, theory and evidence to support women to make achievable, sustainable changes that are relevant to their everyday lives. Women utilized the NLH framework to develop an integrative health routine across six domains: physical activity, sleep, nutrition, eating behavior, self-care and stress management. The framework guided them to set small, incremental goals that were adaptive to their needs and built from their existing circumstances. Participants reflected on their progress with a facilitator during monthly meetings, accessed a social media support page and received monthly text messages. Health programs remain an essential approach to improving women's health alongside community- and policy-level strategies. The development of NLH exemplifies how evidence may partner with modern health promotion values to inform relevant and ethical program design for women.

In western societies, health programs often focus on weight loss through exercise and diet to promote women's health. Such approaches disempower women by undervaluing important factors affecting their health like stress and sleep and narrow their scope for 'health success'. This article reports on the development of Next Level Health (NLH) that aims to help women gain greater health-related control by broadening their approach to health. The program is designed to support women to set small, achievable goals across six domains (physical activity, sleep, nutrition, eating behavior, self-care, and stress management) toward developing positive and sustainable health behaviors. Although women work with a facilitator each month to set goals, they are ultimately in control of formulating their health plans and their progression through NLH. Women can support each other by joining a community of other NLH participants through a social media group. NLH offers a novel program that is responsive to women's individual health needs and broadens their potential for health success.

Nanosecond-Scale Proton Emission from Strongly Oblate-Deformed

Using the fusion-evaporation reaction ^{96}Ru(^{58}Ni,p4n)^{149}Lu and the MARA vacuum-mode recoil separator, a new proton-emitting isotope ^{149}Lu has been identified. The measured decay Q value of 1920(20) keV is the highest measured for a ground-state proton decay, and it naturally leads to the shortest directly measured half-life of 450_{-100}^{+170} ns for a ground-state proton emitter. The decay rate is consistent with l_{p}=5 emission, suggesting a dominant πh_{11/2} component for the wave function of the proton-emitting state. Through nonadiabatic quasiparticle calculations it was concluded that ^{149}Lu is the most oblate deformed proton emitter observed to date.

ß-Delayed One and Two Neutron Emission Probabilities Southeast of

The ß-delayed one- and two-neutron emission probabilities (P_{1n} and P_{2n}) of 20 neutron-rich nuclei with N≥82 have been measured at the RIBF facility of the RIKEN Nishina Center. P_{1n} of ^{130,131}Ag, ^{133,134}Cd, ^{135,136}In, and ^{138,139}Sn were determined for the first time, and stringent upper limits were placed on P_{2n} for nearly all cases. ß-delayed two-neutron emission (ß2n) was unambiguously identified in ^{133}Cd and ^{135,136}In, and their P_{2n} were measured. Weak ß2n was also detected from ^{137,138}Sn. Our results highlight the effect of the N=82 and Z=50 shell closures on ß-delayed neutron emission probability and provide stringent benchmarks for newly developed macroscopic-microscopic and self-consistent global models with the inclusion of a statistical treatment of neutron and γ emission. The impact of our measurements on r-process nucleosynthesis was studied in a neutron star merger scenario. Our P_{1n} and P_{2n} have a direct impact on the odd-even staggering of the final abundance, improving the agreement between calculated and observed Solar System abundances. The odd isotope fraction of Ba in r-process-enhanced (r-II) stars is also better reproduced using our new data.

Mid-flight prey switching in the fringed-lipped bat (Trachops cirrhosus).

While foraging, eavesdropping predators home in on the signals of their prey. Many prey signal from aggregations, however, and predators already en route to attack one individual often encounter the signals of other prey. Few studies have examined whether eavesdropping predators update their foraging decisions by switching to target these more recently signaling prey. Switching could result in reduced localization errors and more current estimates of prey location. Conversely, assessing new cues while already in pursuit of another target might confuse or distract a predator. We tested whether fringed-lipped bats (Trachops cirrhosus) switch prey targets when presented with new cues mid-approach and examined how switching and the distance between simulated prey influence attack accuracy, latency, and prey capture success. During nearly 80% of attack flights, bats switched between túngara frog (Engystomops pustulosus) calls spaced 1 m apart, and switching resulted in lower localization errors. The switching rate was reduced, and the localization advantage disappeared for calls separated by 3 m. Regardless of whether bats switched targets, attacks were less accurate, took longer, and were less often successful when calls were spaced at larger distances, indicating a distraction effect. These results reveal that fringed-lipped bats attend to cues from non-targeted prey during attack flights and that the distance between prey alters the effectiveness of attacks, regardless of whether a bat switches targets. Understanding how eavesdropping predators integrate new signals from neighboring prey into their foraging decisions will lead to a fuller picture of the ways unintended receivers shape the evolution of signaling behavior.

Surface degradation of laminated metal226Ra foils used in school sealed sources in the UK.

In the few years leading up to this research, CLEAPSS noticed a small but steadily increasing number of calls from UK schools regarding a red-brown discolouration on the surface of the foil of their radium source. There were no reports of this type of discolouration on foils of other radionuclides. CLEAPSS and the University of Liverpool collaborated to investigate the nature and cause of this discolouration and the likelihood that the foils were becoming unsafe. The evidence indicates that the discolouration is principally caused by some combination of silicon, sulfur and possibly lead from within the foil diffusing into the face layer. There is no indication currently that the face layers are fragmenting on these foils, but the longer-term integrity of the discoloured foils now becomes questionable. Given the age of the foils and the radiotoxicity of radium, the recommendation from this research is that discoloured foils should be taken out of service and disposed.

First Exploration of Neutron Shell Structure below Lead and beyond N=126.

The nuclei below lead but with more than 126 neutrons are crucial to an understanding of the astrophysical r process in producing nuclei heavier than A∼190. Despite their importance, the structure and properties of these nuclei remain experimentally untested as they are difficult to produce in nuclear reactions with stable beams. In a first exploration of the shell structure of this region, neutron excitations in ^{207}Hg have been probed using the neutron-adding (d,p) reaction in inverse kinematics. The radioactive beam of ^{206}Hg was delivered to the new ISOLDE Solenoidal Spectrometer at an energy above the Coulomb barrier. The spectroscopy of ^{207}Hg marks a first step in improving our understanding of the relevant structural properties of nuclei involved in a key part of the path of the r process.

Competition between Allowed and First-Forbidden ß Decay: The Case of

The ß decay of ^{208}Hg into the one-proton hole, one neutron-particle _{81}^{208}Tl_{127} nucleus was investigated at CERN-ISOLDE. Shell-model calculations describe well the level scheme deduced, validating the proton-neutron interactions used, with implications for the whole of the N>126, Z<82 quadrant of neutron-rich nuclei. While both negative and positive parity states with spin 0 and 1 are expected within the Q_{ß} window, only three negative parity states are populated directly in the ß decay. The data provide a unique test of the competition between allowed Gamow-Teller and Fermi, and first-forbidden ß decays, essential for the understanding of the nucleosynthesis of heavy nuclei in the rapid neutron capture process. Furthermore, the observation of the parity changing 0^{+}→0^{-}ß decay where the daughter state is core excited is unique, and can provide information on mesonic corrections of effective operators.

Evolution of Octupole Deformation in Radium Nuclei from Coulomb Excitation of Radioactive

There is sparse direct experimental evidence that atomic nuclei can exhibit stable "pear" shapes arising from strong octupole correlations. In order to investigate the nature of octupole collectivity in radium isotopes, electric octupole (E3) matrix elements have been determined for transitions in ^{222,228}Ra nuclei using the method of sub-barrier, multistep Coulomb excitation. Beams of the radioactive radium isotopes were provided by the HIE-ISOLDE facility at CERN. The observed pattern of E3 matrix elements for different nuclear transitions is explained by describing ^{222}Ra as pear shaped with stable octupole deformation, while ^{228}Ra behaves like an octupole vibrator.

First Accurate Normalization of the ß-delayed α Decay of

The ^{12}C(α,γ)^{16}O reaction plays a central role in astrophysics, but its cross section at energies relevant for astrophysical applications is only poorly constrained by laboratory data. The reduced α width, γ_{11}, of the bound 1^{-} level in ^{16}O is particularly important to determine the cross section. The magnitude of γ_{11} is determined via sub-Coulomb α-transfer reactions or the ß-delayed α decay of ^{16}N, but the latter approach is presently hampered by the lack of sufficiently precise data on the ß-decay branching ratios. Here we report improved branching ratios for the bound 1^{-} level [b_{ß,11}=(5.02±0.10)×10^{-2}] and for ß-delayed α emission [b_{ßα}=(1.59±0.06)×10^{-5}]. Our value for b_{ßα} is 33% larger than previously held, leading to a substantial increase in γ_{11}. Our revised value for γ_{11} is in good agreement with the value obtained in α-transfer studies and the weighted average of the two gives a robust and precise determination of γ_{11}, which provides significantly improved constraints on the ^{12}C(α,γ) cross section in the energy range relevant to hydrostatic He burning.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Prevalence of arthritis according to age, sex and socioeconomic status in six low and middle income countries: analysis of data from the World Health Organization study on global AGEing and adult health (SAGE) Wave 1.

BACKGROUND: In higher income countries, social disadvantage is associated with higher arthritis prevalence; however, less is known about arthritis prevalence or determinants in low to middle income countries (LMICs). We assessed arthritis prevalence by age and sex, and marital status and occupation, as two key parameters of socioeconomic position (SEP), using data from the World Health Organization Study on global AGEing and adult health (SAGE). METHODS: SAGE Wave 1 (2007-10) includes nationally-representative samples of older adults (≥50 yrs), plus smaller samples of adults aged 18-49 yrs., from China, Ghana, India, Mexico, Russia and South Africa (n = 44,747). Arthritis was defined by self-reported healthcare professional diagnosis, and a symptom-based algorithm. Marital status and education were self-reported. Arthritis prevalence data were extracted for each country by 10-year age strata, sex and SEP. Country-specific survey weightings were applied and weighted prevalences calculated. RESULTS: Self-reported (lifetime) diagnosed arthritis was reported by 5003 women and 2664 men (19.9% and 14.1%, respectively), whilst 1220 women and 594 men had current symptom-based arthritis (4.8% and 3.1%, respectively). For men, standardised arthritis rates were approximately two- to three-fold greater than for women. The highest rates were observed in Russia: 38% (95% CI 36%-39%) for men, and 17% (95% CI 14%-20%) for women. For both sexes and in all LMICs, arthritis was more prevalent among those with least education, and in separated/divorced/widowed women. CONCLUSIONS: High arthritis prevalence in LMICs is concerning and may worsen poverty by impacting the ability to work and fulfil community roles. These findings have implications for national efforts to prioritise arthritis prevention and management, and improve healthcare access in LMICs.

Amniotic band syndrome with pseudoarthrosis of tibia and fibula: A case report.

Constriction of the lower limb by congenital amniotic band has been proposed to explain the development of pseudoarthrosis of tibia and fibula. We report a case of amniotic band syndrome in a preterm infant with pseudoarthrosis of tibia and fibula. Simple release of constriction band with Z-plasty resulted in the growth of mature bone, replacing the pseudoarthrosis and hence did not require surgical amputation. Our case confirms the potential for bone growth in ABS, once the constricting band is released. Early limb preserving surgery with release of the constricting band with an intention to salvage the limb appears appropriate.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

Multimodal cues improve prey localization under complex environmental conditions.

Predators often eavesdrop on sexual displays of their prey. These displays can provide multimodal cues that aid predators, but the benefits in attending to them should depend on the environmental sensory conditions under which they forage. We assessed whether bats hunting for frogs use multimodal cues to locate their prey and whether their use varies with ambient conditions. We used a robotic set-up mimicking the sexual display of a male túngara frog (Physalaemus pustulosus) to test prey assessment by fringe-lipped bats (Trachops cirrhosus). These predatory bats primarily use sound of the frog's call to find their prey, but the bats also use echolocation cues returning from the frog's dynamically moving vocal sac. In the first experiment, we show that multimodal cues affect attack behaviour: bats made narrower flank attack angles on multimodal trials compared with unimodal trials during which they could only rely on the sound of the frog. In the second experiment, we explored the bat's use of prey cues in an acoustically more complex environment. Túngara frogs often form mixed-species choruses with other frogs, including the hourglass frog (Dendropsophus ebraccatus). Using a multi-speaker set-up, we tested bat approaches and attacks on the robofrog under three different levels of acoustic complexity: no calling D. ebraccatus males, two calling D. ebraccatus males and five D. ebraccatus males. We found that bats are more directional in their approach to the robofrog when more D. ebraccatus males were calling. Thus, bats seemed to benefit more from multimodal cues when confronted with increased levels of acoustic complexity in their foraging environments. Our data have important consequences for our understanding of the evolution of multimodal sexual displays as they reveal how environmental conditions can alter the natural selection pressures acting on them.

The substantial personal burden experienced by younger people with hip or knee osteoarthritis.

OBJECTIVE: To compare Health-Related Quality of Life (HRQoL) and psychological distress in younger people with hip or knee osteoarthritis (OA) to age- and sex-matched population norms, and evaluate work limitations in this group. METHOD: People aged 20-55 years with hip or knee OA were recruited from major hospitals (n = 126) and community advertisements (n = 21). HRQoL was assessed using the Assessment of Quality of Life (AQoL) instrument (minimal important difference 0.06 AQoL units) and compared to population norms. Psychological distress was assessed using the Kessler Psychological Distress Scale (K10) and the prevalence of high/very high distress (K10 score ≥22) was compared to Australian population data. Work limitations were evaluated using the Workplace Activity Limitations Scale (WALS). RESULTS: Considering most participants had a relatively recent OA diagnosis (<5 years), the extent of HRQoL impairment was unexpected. A very large reduction in HRQoL was evident for the overall sample, compared with population norms (mean difference -0.35 AQoL units, 95% CI -0.40 to -0.31). Females, people aged 40-49 years, and those with hip OA reported average HRQoL impairment of almost 40% (mean reductions -0.38 to -0.39 AQoL units). The overall prevalence of high/very high distress was 4 times higher than for the population (relative risk 4.19, 95% CI 3.53-4.98) and 67% reported moderate to considerable OA-related work disability, according to WALS scores. CONCLUSIONS: These results clearly demonstrate the substantial personal burden experienced by younger people with hip or knee OA, and support the provision of targeted services to improve HRQoL and maximise work participation in this group.

Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures.

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid ß-peptide (Aß), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APP(swe)/PS1(L166P))-green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type γ-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.