DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation

This work was funded by The Medical Research Council UK (MR/K000292/1), Children with Cancer UK (2013/144), Barts and The London Charity (845/1796), and Leukaemia Lymphoma Research/Bloodwise (14032)

Digital Health Data Imperfection Patterns and Their Manifestations in an Australian Digital Hospital

Whilst digital health data provides great benefits for improved and effective patient care and organisational outcomes, the quality of digital health data can sometimes be a significant issue. Healthcare providers are known to spend a significant amount of time on assessing and cleaning data. To address this situation, this paper presents six Digital Health Data Imperfection Patterns that provide insight into data quality issues of digital health data, their root causes, their impact, and how these can be detected. Using the CRISP-DM methodology, we demonstrate the utility and pervasiveness of the patterns at the emergency department of Australia's major tertiary digital hospital. The pattern collection can be used by health providers to identify and prevent key digital health data quality issues contributing to reliable insights for clinical decision making and patient care delivery. The patterns also provide a solid foundation for future research in digital health through its identification of key data quality issues, root causes, detection techniques, and terminology

Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease

Background: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. Methodology/Principal Findings: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. Conclusions/Significance: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases. © 2010 Malinowska et al

Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated <i>Ex Vivo</i> Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA

Hematopoietic stem cell gene therapy is a promising therapeutic strategy for the treatment of neurological disorders, since transplanted gene-corrected cells can traffic to the brain, bypassing the blood-brain barrier, to deliver therapeutic protein to the CNS. We have developed this approach for the treatment of Mucopolysaccharidosis type IIIA (MPSIIIA), a devastating lysosomal storage disease that causes progressive cognitive decline, leading to death in early adulthood. In a previous pre-clinical proof-of-concept study, we demonstrated neurological correction of MPSIIIA utilizing hematopoietic stem cell gene therapy via a lentiviral vector encoding the SGSH gene. Prior to moving to clinical trial, we have undertaken further studies to evaluate the efficiency of gene transfer into human cells and also safety studies of biodistribution and genotoxicity. Here, we have optimized hCD34 + cell transduction with clinical grade SGSH vector to provide improved pharmacodynamics and cell viability and validated effective scale-up and cryopreservation to generate an investigational medicinal product. Utilizing a humanized NSG mouse model, we demonstrate effective engraftment and biodistribution, with no vector shedding or transmission to germline cells. SGSH vector genotoxicity assessment demonstrated low transformation potential, comparable to other lentiviral vectors in the clinic. This data establishes pre-clinical safety and efficacy of HSCGT for MPSIIIA. </p

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events

EP 250108a/SN 2025kg:Observations of the Most Nearby Broad-line Type Ic Supernova Following an Einstein Probe Fast X-Ray Transient

With a small sample of fast X-ray transients (FXTs) with multiwavelength counterparts discovered to date, their progenitors and connections to γ-ray bursts (GRBs) and supernovae (SNe) remain ambiguous. Here, we present photometric and spectroscopic observations of SN 2025kg, the SN counterpart to the FXT EP 250108a. At z = 0.17641, this is the closest known SN discovered following an Einstein Probe (EP) FXT. We show that SN 2025kg’s optical spectra reveal the hallmark features of a broad-lined Type Ic SN. Its light-curve evolution and expansion velocities are comparable to those of GRB-SNe, including SN 1998bw, and two past FXT-SNe. We present JWST/NIRSpec spectroscopy taken around SN 2025kg’s maximum light, and find weak absorption due to He I 1.0830 μm and 2.0581 μm and a broad, unidentified emission feature at ∼4–4.5 μm. Further, we observe broadened Hα in optical data at 42.5 days that is not detected at other epochs, indicating interaction with H-rich material. From its light curve, we derive a 56Ni mass of 0.2–0.6 M⊙. Together with our companion Letter, our broadband data are consistent with a trapped or low-energy (≲1051 erg) jet-driven explosion from a collapsar with a zero-age main-sequence mass of 15–30 M⊙. Finally, we show that the sample of EP FXT-SNe supports past estimates that low-luminosity jets seen through FXTs are more common than successful (GRB) jets, and that similar FXT-like signatures are likely present in at least a few percent of the brightest Type Ic-BL SNe

The impact of work-related values and work control on the career satisfaction of female freelancers

Using the job demands-resources theory incorporating a job-crafting perspective to develop a set of hypotheses, this study contributes to the self-employment and freelancing literature by examining whether female freelancers use their agency to mobilize their personal resources (i.e. work-related values) to craft their work resources (i.e. work–control indicators: work autonomy and time-spatial flexibility) to achieve more career satisfaction. Our structural partial least squares model (N = 203) shows that the work-related value ‘intrinsically rewarding work’ prompts two motivational processes that affect career satisfaction: one running directly to ‘career satisfaction’ and one through ‘work autonomy’. Although the value ‘work–life balance’ is positively associated with greater ‘time-spatial flexibility’, this does not affect career satisfaction. Moreover, we find negative associations between the value ‘financial security’, on the one hand, and the two work resources, on the other hand. Hence, the value financial security is negatively related to work autonomy towards career satisfaction. We conclude that female freelancers’ multiple, oftentimes blended values compete with one another, implying that achieving meaningful work, work–life balance and financial independence simultaneously is difficult in female freelancers’ careers. We discuss the study’s implications for future research and advocate labour–market stakeholders (e.g. freelancers, freelancers’ networks, career coaches, temporary work agencies, unions, local and national governments, educational institutions and public and private organizations) to partner in developing value-based career strategies and policies that account for less linear career paths in increasingly flexible and individualized markets and truly support (female) workers developing portfolios that better match with their multiple work-related values on a long-term basis