We describe the rehabilitation management during a 12-month period of a 14-year-old female with Friedreich ataxia. Interventions included task-oriented bimanual reaching activities, functional ...strengthening, and gait training using a walker featuring tension-controlled wheels and a reverse-braking system. Her physical status was assessed with the Nine-Hole Peg Test, single limb stance time, manual muscle testing, self-reported falls, isometric force control testing, and 3-dimensional gait analysis in a motion-capture laboratory. Although measures of the patient's Nine-Hole Peg Test, single limb stance time, and manual muscle testing reflected minimal changes, her gait speed decreased by 69.4%. However, the force-control targeting of her dominant knee extensors showed a 43.7% increase in force variability that was concomitant with her decline in gait performance. The decrement of her initial gait speed was reduced to 42.9% on replacing the wheeled walker with the U-Step Walking Stabilizer at the end of the intervention period. Although the patient's gait remained significantly impaired, extended use of the U-Step Walking Stabilizer modestly improved her gait performance, and her rate of falls decreased from 10 to 3 per month. Our observations suggest that use of force-control testing as proxy measures of ataxia and tension-controlled gait aids show promise in the management of Friedreich ataxia and merit further investigation.
We perform a model intercomparison of summertime high Arctic ( > 80° N) clouds observed during the 2008 Arctic Summer Cloud Ocean Study (ASCOS) campaign, when observed cloud condensation nuclei ...(CCN) concentrations fell below 1 cm.sup.-3 . Previous analyses have suggested that at these low CCN concentrations the liquid water content (LWC) and radiative properties of the clouds are determined primarily by the CCN concentrations, conditions that have previously been referred to as the tenuous cloud regime. The intercomparison includes results from three large eddy simulation models (UCLALES-SALSA, COSMO-LES, and MIMICA) and three numerical weather prediction models (COSMO-NWP, WRF, and UM-CASIM). We test the sensitivities of the model results to different treatments of cloud droplet activation, including prescribed cloud droplet number concentrations (CDNCs) and diagnostic CCN activation based on either fixed aerosol concentrations or prognostic aerosol with in-cloud processing.
Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive ...analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
We report three individuals with a cranioskeletal malformation syndrome we newly define as acrofacial dysostosis, Cincinnati type. Each individual has a heterozygous mutation in POLR1A, which encodes ...a core component of RNA polymerase 1. All three individuals exhibited varying degrees of mandibulofacial dysostosis, and two additionally had limb anomalies. Consistent with this observation, we discovered that polr1a mutant zebrafish exhibited cranioskeletal anomalies mimicking the human phenotype. Polr1a loss-of-function led to perturbed ribosome biogenesis and p53-dependent cell death, resulting in a deficiency of neural-crest derived skeletal precursor cells and consequently craniofacial anomalies. Our findings expand the genotypic and phenotypic heterogeneity of congenital acrofacial disorders caused by disruption of ribosome biogenesis.
Stratospheric ozone and water vapour are key components of the Earth system, and past and future changes to both have important impacts on global and
regional climate. Here, we evaluate long-term ...changes in these species from the pre-industrial period (1850) to the end of the 21st century
in Coupled Model Intercomparison Project phase 6 (CMIP6)
models under a range of future emissions scenarios. There is good agreement between the CMIP multi-model mean and observations for total column
ozone (TCO), although there is substantial variation between the individual CMIP6 models. For the CMIP6 multi-model mean, global mean TCO has
increased from ∼ 300 DU in 1850 to ∼ 305 DU in 1960, before rapidly declining in the 1970s and 1980s following the
use and emission of halogenated ozone-depleting substances (ODSs). TCO is projected to return to 1960s values by the middle of the 21st century
under the SSP2-4.5, SSP3-7.0, SSP4-3.4, SSP4-6.0, and SSP5-8.5 scenarios, and under the SSP3-7.0 and SSP5-8.5 scenarios TCO values are projected to
be ∼ 10 DU higher than the 1960s values by 2100. However, under the SSP1-1.9 and SSP1-1.6 scenarios, TCO is not projected to
return to the 1960s values despite reductions in halogenated ODSs due to decreases in tropospheric ozone mixing ratios. This global pattern is
similar to regional patterns, except in the tropics where TCO under most scenarios is not projected to return to 1960s values, either through
reductions in tropospheric ozone under SSP1-1.9 and SSP1-2.6, or through reductions in lower stratospheric ozone resulting from an acceleration of
the Brewer–Dobson circulation under other Shared Socioeconomic Pathways (SSPs). In contrast to TCO, there is poorer agreement between the
CMIP6 multi-model mean and observed lower
stratospheric water vapour mixing ratios, with the CMIP6 multi-model mean underestimating observed water vapour mixing ratios by
∼ 0.5 ppmv at 70 hPa. CMIP6 multi-model mean stratospheric water vapour mixing ratios in the tropical lower stratosphere have
increased by ∼ 0.5 ppmv from the pre-industrial to the present-day period and are projected to increase further by the end of the 21st
century. The largest increases (∼ 2 ppmv) are simulated under the future scenarios with the highest assumed forcing pathway
(e.g. SSP5-8.5). Tropical lower stratospheric water vapour, and to a lesser extent TCO, shows large variations following explosive volcanic eruptions.
Abstract Objective The cellular substrate of hippocampal dysfunction in schizophrenia remains unknown. We tested the hypothesis that hippocampal interneurons are abnormal in schizophrenia, but that ...the total number of hippocampal neurons in the pyramidal cell layer is normal. Methods We collected whole hippocampal specimens of 13 subjects with schizophrenia and 20 matched healthy control subjects to study the number of all neurons, the somal volume of neurons, the number of somatostatin- and parvalbumin-positive interneurons and the messenger RNA levels of somatostatin, parvalbumin and glutamic acid decarboxylase 67. Results The total number of hippocampal neurons in the pyramidal cell layer was normal in schizophrenia, but the number of somatostatin- and parvalbumin-positive interneurons, and the level of somatostatin, parvalbumin and glutamic acid decarboxylase mRNA expression were reduced. Conclusions The study provides strong evidence for a specific defect of hippocampal interneurons in schizophrenia and has implications for emerging models of hippocampal dysfunction in schizophrenia.
Sea spray aerosol (SSA) generated by bubble bursting at the ocean surface is an important component of aerosol‐cloud interactions over remote oceans, providing the atmosphere with ice‐nucleating ...particles (INPs) or particles required for heterogeneous ice nucleation. Studies have shown that organic INPs are emitted during phytoplankton blooms, but changes in INP number concentrations (nINPs) due to ocean biological activity have not been directly demonstrated in natural SSA. In this study, a clean sector sampler was used to differentiate ice nucleation and composition of pristine SSA from terrestrial aerosol at the Mace Head Research Station in August 2015. Average nINPs active at −15 °C (nINPs,−15 °C) were 0.0011 L−1, and large variability (up to a factor of 200) was observed for INPs active warmer than −22 °C. Highest nINPs in the clean sector occurred during a period of elevated marine organic aerosol from offshore biological activity (M1, nINPs,−15 °C = 0.0077 L−1). A peak in nINPs was also observed in terrestrial organic aerosol (T1, nINPs,−15 °C = 0.0076 L−1). The impacts of heating and hydrogen peroxide digestion on nINPs indicate that INPs at Mace Head Research Station were largely organic and that INPs observed during M1 and T1 were biological (i.e., protein containing). Complexities of predicting increases in nINPs due to offshore biological activity are explored. A parameterization for pristine SSA INPs over the North Atlantic Ocean was developed, illustrating that SSA is associated with a factor of 1,000 fewer ice‐nucleating sites per surface area of aerosol compared to mineral dust.
Key Points
Pristine sea spray aerosol is a dominant regional source of ice‐nucleating particles at a remote North Atlantic coastal site
Ice‐nucleating particles at a remote North Atlantic coastal site were largely composed of organic carbon and/or heat labile material
Sea spray aerosol is associated with a factor of 1,000 fewer ice‐nucleating sites per surface area of aerosol compared to mineral dust
Summary Background Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene ...initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. Methods Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations ( RB1+/+ ) with tumours carrying a mutation in both alleles ( RB1−/− ). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. Findings No RB1 mutations ( RB1+/+ ) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1+/+ tumours had high-level MYCN oncogene amplification (28–121 copies; RB1+/+ MYCNA ), whereas none of 93 RB1−/− primary tumours tested showed MYCN amplification (p<0·0001). RB1+/+ MYCNA tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1−/− tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1+/+ MYCNA retinoblastoma. One additional MYCNA tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1+/+ MYCNA tumours was 4·5 months (IQR 3·5–10), compared with 24 months (15–37) for 79 children with non-familial unilateral RB1−/− retinoblastoma. Interpretation Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1+/+ MYCNA retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. Funding National Cancer Institute–National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.
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