The hydrolethalus syndrome protein HYLS-1 links core centriole structure to cilia formation

Centrioles are subcellular organelles composed of a ninefold symmetric microtubule array that perform two important functions: (1) They build centrosomes that organize the microtubule cytoskeleton, and (2) they template cilia, microtubule-based projections with sensory and motile functions. We identified HYLS-1, a widely conserved protein, based on its direct interaction with the core centriolar protein SAS-4. HYLS-1 localization to centrioles requires SAS-4 and, like SAS-4, HYLS-1 is stably incorporated into the outer centriole wall. Unlike SAS-4, HYLS-1 is dispensable for centriole assembly and centrosome function in cell division. Instead, HYLS-1 plays an essential role in cilia formation that is conserved between Caenorhabditis elegans and vertebrates. A single amino acid change in human HYLS1 leads to a perinatal lethal disorder termed hydrolethalus syndrome, and we show that this mutation impairs HYLS-1 function in ciliogenesis. HYLS-1 is required for the apical targeting/anchoring of centrioles at the plasma membrane but not for the intraflagellar transport-dependent extension of the ciliary axoneme. These findings classify hydrolethalus syndrome as a severe human ciliopathy and shed light on the dual functionality of centrioles, defining the first stably incorporated centriolar protein that is not required for centriole assembly but instead confers on centrioles the capacity to initiate ciliogenesis.     

Association of HLA class II alleles with sensitization to cow dander Bos d 2, an important occupational allergen

Allergic sensitization results from a complex interaction between genetic and environmental factors. Earlier studies have shown that highly polymorphic HLA genes are associated with a variety of allergies. Several important respiratory allergens belong to the family of lipocalin proteins. These include occupational sensitizers, such as cow Bos d 2 or rat Rat n 1, and prevalent indoor sensitizers, such as dog Can f 1 or cockroach Bla g 4. HLA associations with sensitization to lipocalin allergens are incompletely known. In the present study we have investigated an association between HLA alleles and sensitization to the major cow allergen Bos d 2. The HLA-DR/DQ genotypes of 40 Bos d 2-sensitized subjects having occupational asthma were determined by polymerase chain reaction (PCR) and the results were compared with the genotypes of 151 unrelated Finnish subjects. The frequencies of HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501 were significantly higher among Bos d 2-sensitized than among control subjects. In addition, the allergic subjects expressed significantly lower frequencies of HLA-DRB1*0301 and DQB1*0201 alleles than did the control subjects. These data suggest that the HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501, and the haplotypes that include them, are associated with sensitization to the major cow allergen Bos d 2, whereas HLA-DRB1*0301 and DQB1*0201 are dissociated with it. Amino acid analysis provides a biologically plausible explanation for the HLA associations.     

The clinical and occupational effectiveness of condition management for Incapacity Benefit recipients

OBJECTIVES.?The aim of the Condition Management Programme (CMP) is to help Incapacity Benefit recipients manage their health conditions more effectively and return to work. This paper seeks to examine the clinical and employment outcomes from a group-based and mixed-condition CMP. DESIGN.?In a prospective cohort design, measures of employment status and psychological well-being were taken at three time points; pre-CMP, post-CMP, and at 3-month follow-up. METHOD.?Participants (N= 2,064) with a variety of physical and mental health conditions voluntarily attended a seven session cognitive-behaviourally informed psychoeducational group intervention. The psychological measures used were the Clinical Outcomes in Routine Evaluation - Outcome Measure, Work and Social Adjustment Scale, Self-Efficacy Scale, and the Intrinsic Motivation Scale. The employment status of participants was also measured at the three time points of the evaluation. RESULTS.?Following CMP, 50% of participants experienced a reliable improvement in psychological well-being and 26% had either taken some steps towards work or returned to work at follow-up. Participants with a mental health condition were more likely to experience a reliable improvement in psychological well-being compared to those with physical health conditions. CONCLUSIONS.?The results suggest that participation in CMP may be helpful in facilitating more effective self-management of the health conditions contributing to unemployment. The results have implications for whether formal employment assistance should be available in mental health services.     

Memory precursor phenotype of CD8+ T cells reflects early antigenic experience rather than memory numbers in a model of localized acute influenza infection

The mechanistic basis of memory T‐cell development is poorly defined. Phenotypic markers that define precursors at effector stages have been characterized for acute systemic infections with high antigen load. We asked whether such markers can identify memory precursors from early effectors (d6) to late memory (>d500) for two immunodominant CD8⁺ responses during the course of a localized low‐load influenza infection in mice. CD8⁺ T cells stained with the D^bNP₃₆₆ and D^bPA₂₂₄ tetramers were characterized as IL‐7Rα^hi, IL‐7Rα^hiCD62L^hi or IL‐7Rα^hiKLRG1^lo. While the D^bNP₃₆₆‐ and D^bPA₂₂₄‐specific responses were comparable in size, decay kinetics and memory precursor frequency, their expansion characteristics differed. This correlated with a divergence in the IL‐7Rα^hi, IL‐7Rα^hiCD62L^hi and IL‐7Rα^hiKLRG1^lo phenotypes on effector, but not naïve, CD8⁺ populations. That effect was abrogated by priming with viruses engineered to present equivalent levels of NP₃₆₆ and PA₂₂₄ peptides, indicating that memory phenotypes reflect early antigenic experience rather than memory potential. Thus, the IL‐7Rα^hiKLRG1^lo phenotype had a poor predictive value in identifying memory precursors in the spleen and at the site of infection. Greater consistency in influenza‐specific IL‐7Rα^hiKLRG1^loCD8⁺ T‐cell numbers was found in draining lymph nodes, suggesting that this may be the preferential site for memory establishment and maintenance following localized virus infections.     

Dyslexia and attentional shifting

Dyslexia is a neurocognitive deficit primarily expressed in reading difficulties, but also affecting non-linguistic performance. Several studies report that dyslexics perform differently in the attentional blink paradigm, which indicates an impaired capacity to rapidly shift visual attention. However, attentional shifting can occur at different levels of cognitive processing, and it is unclear whether dyslexic attentional shifting is impaired at all levels, or only at the peripheral levels. We studied performance on a task-switching paradigm by dyslexics and normal readers to test whether the difficulty with attentional shifting occurs at the level of central cognitive processing. We found no specific impairments in task-switching in dyslexics. However, dyslexics performed generally much more slowly across all conditions than normal readers. We conclude that while dyslexics have a problem with attentional switching at a perceptual level, their capacity to rapidly switch between tasks is normal. Our findings add to previous studies indicating that dyslexic problems with shifting visual attention are caused by anomalies in more peripheral neural pathways, such as the magnocellular layers in the lateral geniculate nucleus.     

Serum Adenosine Deaminase and Total Immunoglobulin G Correlate with Markers of Immune Activation and Inversely with CD4 Counts in Asymptomatic, Treatment-Naive HIV Infection

Purpose

HIV-infection is characterized by aberrant immune activation and ongoing inflammation. Markers of inflammation are now recognized to have prognostic value for adverse events, independent of viral loads and CD4 counts. This study aimed to delineate a panel of affordable markers of immune activation in untreated HIV-infection that may have an impact on the management of HIV in resource-limited settings.

Methods

This was a cross-sectional study of 86 untreated newly diagnosed HIV-infected patients and 54 matched controls attending a voluntary testing clinic in Cape Town, South Africa. Serum levels of adenosine deaminase (ADA), total immunoglobulin G (IgG), soluble CD14 and lipopolysaccharide-binding protein (LBP) were measured and correlated with CD4 counts, viral loads and expression of CD38 on CD8+ T cells.

Results

ADA, IgG and LBP were all significantly increased in the HIV infected group (p?<?0.0001) compared with uninfected controls. Soluble CD14 was also significantly increased (p?=?0.0187). Furthermore, all these parameters correlated inversely with CD4 counts (r?=??0.481 p?<?0.0001; r?=??0.561; p?<?0.0001; r?=??0.387 p?=?0.0007 and r?=??0.254 p?=?0.0240, respectively). Only ADA correlated with viral load (r?=?0.260 p?=?0.0172). Importantly, ADA, IgG and LBP correlated directly with %CD38 on CD8+ T cells (r?=?0.369 p?<?0.0001; r?=?0.284 p?=?0.001; r?=?0.408 p?=?0.0006, respectively).

Conclusion

Affordable parameters such as serum ADA and IgG correlated significantly with immune activation levels and markers of disease progression in untreated HIV-infection and therefore may add value to the management of these patients in resource-limited settings.     

Ruthenium Red Colorimetric and Birefringent Staining of Amyloid-β Aggregates in Vitro and in Tg2576 Mice

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The Role of the Medical Expert in the Retrospective Assessment of Testamentary Capacity

Objectives:Physicians and other mental health experts are increasingly called on to assist the courts with the determination of testamentary capacity. We aim to improve the understanding of the retrospective assessment of testamentary capacity for medical experts in order to provide more useful reports for the court’s determinations and to provide a methodology for the retrospective assessment of testamentary capacity.Method:Medical experts with experience in the retrospective assessment of testamentary capacity collaborated with lawyers who practice estate litigation. The medical literature on the assessment of testamentary capacity was reviewed and integrated. The medical experts provided a clinical perspective, while the lawyers ensured that the case law and legal perspective were integrated into this review.Results:The focus and limitations of the medical expert are outlined including the need to be objective, nonpartisan, and fair. For the benefit of the court, the medical expert should describe the nature and severity of relevant medical, psychiatric, and cognitive disorders, and how they may impact on the specific criteria for testamentary capacity as defined by the leading case of Banks v Goodfellow. Medical experts should opine only on the issue of vulnerability to influence and defer to the court to determine the facts of the case regarding any influence that may have been exerted.Conclusions:Although the ultimate determination of testamentary capacity is a legal one, medical experts can help the court achieve the most informed legal decision by providing relevant information on clinical issues that may impact the criteria for testamentary capacity.     

Lineage tracing reveals dynamic changes in oligodendrocyte precursor cells following cuprizone‐induced demyelination

The regeneration of oligodendrocytes is a crucial step in recovery from demyelination, as surviving oligodendrocytes exhibit limited structural plasticity and rarely form additional myelin sheaths. New oligodendrocytes arise through the differentiation of platelet‐derived growth factor receptor α (PDGFRα) expressing oligodendrocyte progenitor cells (OPCs) that are widely distributed throughout the CNS. Although there has been detailed investigation of the behavior of these progenitors in white matter, recent studies suggest that disease burden in multiple sclerosis (MS) is more strongly correlated with gray matter atrophy. The timing and efficiency of remyelination in gray matter is distinct from white matter, but the dynamics of OPCs that contribute to these differences have not been defined. Here, we used in vivo genetic fate tracing to determine the behavior of OPCs in gray and white matter regions in response to cuprizone‐induced demyelination. Our studies indicate that the temporal dynamics of OPC differentiation varies significantly between white and gray matter. While OPCs rapidly repopulate the corpus callosum and mature into CC1 expressing mature oligodendrocytes, OPC differentiation in the cingulate cortex and hippocampus occurs much more slowly, resulting in a delay in remyelination relative to the corpus callosum. The protracted maturation of OPCs in gray matter may contribute to greater axonal pathology and disease burden in MS.     

Effects of stressors and immune activating agents on peripheral and central cytokines in mouse strains that differ in stressor responsivity

The impact of inflammatory immune activation on behavioral and physiological processes varies with antecedent stressor experiences. We assessed whether immune activation would differentially influence such outcomes as a function of stressor reactivity related to genetic differences. To this end, we assessed the influence of a social stressor (exposure to a dominant mouse) in combination with an acute immune challenge on behavior and on peripheral and central cytokines in stressor-reactive BALB/cByJ mice and the less reactive C57BL/6ByJ strain. As C57BL/6ByJ and BALB/cByJ mice are highly T helper type-1 (Th1) and Th2 responsive, respectively, the stressor effects were assessed in response to different challenges, namely the viral analogue poly I:C and the bacterial endotoxin lipopolysaccharide (LPS). The stressor enhanced the effects of LPS on sickness behaviors and plasma corticosterone particularly in BALB/cByJ mice, whereas the effects of poly I:C, which primarily affects Th1 processes, were not augmented by the stressor. As well, the stressor increased circulating cytokines in LPS treated C57BL/6ByJ mice, whereas the effects of poly I:C were diminished. Finally, like circulating cytokines, mRNA expression of pro-inflammatory cytokines within the prefrontal cortex and hippocampus varied with the mouse strain and with the stressor experience, and with the specific cytokine considered. Together, the experiments indicated that the impact of stressors vary with the nature of the immune challenge to which animals had been exposed. Moreover, given the diversity of the stressor effects on central and peripheral processes, it seems likely that the cytokine changes, HPA activity and sickness operate through independent mechanisms.