Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

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A community study on burden and depressive symptoms among carers of demented relatives

Background: Most mild to moderate demented patients are cared at home. Studies have shown that carers face increased stress and are prone to depression. In order to understand their needs, a collaboration study between District Board, Community Rehabilitation Network and local hospitals was done. Objective: (1) To understand care needs of demented patients and their carers in the family. (2) To assess difficulties faced by carers and evaluate their stress. (3) To find out which factors may aggravate or relieve carer stress. Method: The study was performed by interviewing 100 carers by questionnaire. Three main themes were studied: (1) presence of depression by Center for Epidemiological Studies Depression Scale (CES-D), (2) caregiver burden by Zarit Burden Interview (ZBI), patients’ memory and behavioural problems by Revised Memory and Behaviour Problems Checklist (RMBPC), patient ADL performance, and (3) carer coping abilities by Brief COPE and perceived social support by Multidimensional Scale of Perceived Social Support (MSPSS). Results: 49% of patients are in moderate to severe stage, with moderate to high ADL dependency level (mean ADL score: 62.4, with 40% of patients scoring 60 or below). On average carers spent 13.8 hours per day on their relative. 24% of carers have rated self-perceived health status as poor or very poor. 36% have little or no knowledge about the dementia illness. Regarding carer depression, 49% had CES-D score in the moderately and severely depressed range. Caregiver burden was high with ZBI score of 38.2 (>24 being highly associated with depression). Memory and behavioural symptoms were common with mean RMBPC 38.2. Carer coping abilities as measured by Brief COPE was 24.6. Perceived social support as measured by MSPSS was 56.2. Carer depression was found to be correlated with cognitive and behaviour problems as well as carer burden; whereas it was negatively correlated with social support. After multiple linear regression analysis, caregiver burden was the most significant factor contributing to caregiver depression (β=0.55, T=5.43, p<0.001). Conclusions: This cohort of carers, having spent long hours caring for their demented relatives had limited knowledge, poor perceived health and emotional problems. They had high burden and showed signs of depression. Caregiver depression was found to be associated with a higher level of burden.published_or_final_versio

Specific downregulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-Chromosome introgression.

Hybrid incompatibility (HI) prevents gene flow between species, thus lying at the heart of speciation genetics. One of the most common HIs is male sterility. Two superficially contradictory observations exist for hybrid male sterility. First, an introgression on the X chromosome is more likely to produce male sterility than on autosome (so-called large-X theory); second, spermatogenesis genes are enriched on the autosomes but depleted on the X chromosome (demasculization of X chromosome). Analysis of gene expression in Drosophila hybrids suggests a genetic interaction between X chromosome and autosomes that is essential for male fertility. However, the prevalence of such an interaction and its underlying mechanism remain largely unknown. Here we examine the interaction in nematode species by contrasting the expression of both coding genes and transposable elements (TEs) between hybrid sterile males and its parental nematode males. We use two lines of hybrid sterile males each carrying an independent introgression fragment from C. briggsae X chromosome in an otherwise C. nigoni background, which demonstrate similar defects in spermatogenesis. We observe a similar pattern of downregulated genes that are specific for spermatogenesis between the two hybrids. Importantly, the downregulated genes caused by the X chromosome introgressions show a significant enrichment on the autosomes, supporting an epistatic interaction between the X chromosome and autosomes. We investigate the underlying mechanism of the interaction by measuring small RNAs and find a subset of 22G RNAs specifically targeting the downregulated spermatogenesis genes are significantly upregulated in hybrids, suggesting that perturbation of small RNA-mediated regulation may contribute to the X-autosome interaction

Plasma high sensitivity troponin T levels in adult survivors of childhood leukaemias: determinants and associations with cardiac function

published_or_final_versio

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

An SU(N) Mott insulator of an atomic Fermi gas realized by large-spin Pomeranchuk cooling

The Hubbard model, containing only the minimum ingredients of nearest neighbor hopping and on-site interaction for correlated electrons, has succeeded in accounting for diverse phenomena observed in solid-state materials. One of the interesting extensions is to enlarge its spin symmetry to SU(N>2), which is closely related to systems with orbital degeneracy. Here we report a successful formation of the SU(6) symmetric Mott insulator state with an atomic Fermi gas of ytterbium (173Yb) in a three-dimensional optical lattice. Besides the suppression of compressibility and the existence of charge excitation gap which characterize a Mott insulating phase, we reveal an important difference between the cases of SU(6) and SU(2) in the achievable temperature as the consequence of different entropy carried by an isolated spin. This is analogous to Pomeranchuk cooling in solid 3He and will be helpful for investigating exotic quantum phases of SU(N) Hubbard system at extremely low temperatures.Comment: 20 pages, 6 figures, to appear in Nature Physic

Contribution of discourse and morphosyntax skills to reading comprehension in Chinese dyslexic and typically developing children

This study aimed at identifying important skills for reading comprehension in Chinese dyslexic children and their typically developing counterparts matched on age (CA controls) or reading level (RL controls). The children were assessed on Chinese reading comprehension, cognitive, and reading-related skills. Results showed that the dyslexic children performed significantly less well than the CA controls but similarly to RL controls in most measures. Results of multiple regression analyses showed that word-level reading-related skills like oral vocabulary and word semantics were found to be strong predictors of reading comprehension among typically developing junior graders and dyslexic readers of senior grades, whereas morphosyntax, a text-level skill, was most predictive for typically developing senior graders. It was concluded that discourse and morphosyntax skills are particularly important for reading comprehension in the non-inflectional and topic-prominent Chinese system

Structural Model of the Rev Regulatory Protein from Equine Infectious Anemia Virus

Rev is an essential regulatory protein in the equine infectious anemia virus (EIAV) and other lentiviruses, including HIV-1. It binds incompletely spliced viral mRNAs and shuttles them from the nucleus to the cytoplasm, a critical prerequisite for the production of viral structural proteins and genomic RNA. Despite its important role in production of infectious virus, the development of antiviral therapies directed against Rev has been hampered by the lack of an experimentally-determined structure of the full length protein. We have used a combined computational and biochemical approach to generate and evaluate a structural model of the Rev protein. The modeled EIAV Rev (ERev) structure includes a total of 6 helices, four of which form an anti-parallel four-helix bundle. The first helix contains the leucine-rich nuclear export signal (NES). An arginine-rich RNA binding motif, RRDRW, is located in a solvent-exposed loop region. An ERLE motif required for Rev activity is predicted to be buried in the core of modeled structure where it plays an essential role in stabilization of the Rev fold. This structural model is supported by existing genetic and functional data as well as by targeted mutagenesis of residues predicted to be essential for overall structural integrity. Our predicted structure should increase understanding of structure-function relationships in Rev and may provide a basis for the design of new therapies for lentiviral diseases

Aged garlic extract therapy for sickle cell anemia patients

BACKGROUND: Sickle cell anemia is one of the most prevalent hereditary disorders with prominent morbidity and mortality. With this disorder oxidative, phenomena play a significant role in its pathophysiology. One of the garlic (Allium sativum L.) formulations, aged garlic extract (AGE), has been reported to exert an anti-oxidant effect in vitro, we have evaluated the anti-oxidant effect of AGE on sickle red blood cells (RBC). METHODS: Five patients (two men and three women, mean age 40 ± 15 years, range 24–58 years) with sickle cell anemia participated in the study. AGE was administered at a dose of 5 ml a day. Whole blood samples were obtained at baseline and at 4 weeks for primarily Heinz body analysis. RESULTS: The data were consistent with our hypothesis. In all patients, the number of Heinz bodies decreased over the 4 week period (58.9 ± 20.0% at baseline to 29.8 ± 15.3% at follow-up, p = 0.03). CONCLUSIONS: These data suggest that there is a significant anti-oxidant activity of AGE on sickle RBC. AGE may be further evaluated as a potential therapeutic agent to ameliorate complications of sickle cell anemia