Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.     

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells

Background  

Glioblastoma remains one of the most devastating human malignancies, and despite therapeutic advances, there are no drugs that significantly improve the patient survival. Altered expression of the Aurora kinases was found in different malignancies, and their inhibition has been studied in cancer therapy. In this study, we analyzed the expression of Aurora A and Aurora B in glioblastoma samples and also analyzed whether the effects of Aurora kinase inhibition were associated with temozolomide or not on cell lines and primary cultures of glioblastoma.     

Surgeons blinded by enhanced navigation: the effect of augmented reality on attention

Background

Advanced image-guidance systems allowing presentation of three-dimensional navigational data in real time are being developed enthusiastically for many medical procedures. Other industries, including aviation and the military, have noted that shifting attention toward such compelling assistance has detrimental effects. Using the detection rate of unexpected findings, we assess whether inattentional blindness is significant in a surgical context and evaluate the impact of on-screen navigational cuing with augmented reality.

Methods

Surgeons and trainees performed an endoscopic navigation exercise on a cadaveric specimen. The subjects were randomized to either a standard endoscopic view (control) or an AR view consisting of an endoscopic video fused with anatomic contours. Two unexpected findings were presented in close proximity to the target point: one critical complication and one foreign body (screw). Task completion time, accuracy, and recognition of findings were recorded.

Results

Detection of the complication was 0/15 in the AR group versus 7/17 in the control group (p = 0.008). Detection of the screw was 1/15 (AR) and 7/17 (control) (p = 0.041). Recognition of either finding was 12/17 for the control group and 1/15 for the AR group (p < 0.001). Accuracy was greater for the AR group than for the control group, with the median distance from the target point measuring respectively 2.10 mm (interquartile range [IQR], 1.29–2.37) and 4.13 (IQR, 3.11–7.39) (p < 0.001).

Conclusion

Inattentional blindness was evident in both groups. Although more accurate, the AR group was less likely to identify significant unexpected findings clearly within view. Advanced navigational displays may increase precision, but strategies to mitigate attentional costs need further investigation to allow safe implementation.     

Paradox Regained: Conversion,Conversation, and Conservation

I offer the view that the source of therapeutic action in psychoanalysis is a shared minding of the dissociative gap—a process that simultaneously decreases the mind's fear of otherness and the vulnerability of the brain's neural networks to potential affect dysregulation. Through a patient's “me” and “not-me” self-states becoming more at home with each other, the automatic neurosynaptic warning signal that triggers immediate dissociation as a protection against potential hyperarousal becomes more selective at the brain level and, through a feedback loop, allows the patient's mind to support increased development of intersubjectivity. Little by little, the patient's capacity to bear internal conflict is increased by easing the mental struggle to hold it cognitively. For a classical psychoanalyst, taking this seriously does not lead to abandoning Freud, but it does lead to a different listening stance. It requires listening to clinical process not only dyadically, but listening to it as an inherently confusing affective event to be processed together, rather than as content to be “understood”; that is, organized by the analyst into something he deems cognitively conceptual and then made available for potential interpretation. Clinical examples are provided for consideration.     

I don't know what I know: Evidence of preserved semantic knowledge but impaired metalinguistic knowledge in adults with probable Alzheimer's disease

Abstract

This paper will address the current practice of speech therapists setting homework for aphasic patients.     

The semantic deficit in dementia: Connectionist approaches to what goes wrong in picture naming

Abstract

This paper addresses two main issues. First, what is the focus (or foci) of the naming deficit in patients with probable Alzheimer's disease? Secondly, how is semantic memory degraded by dementia? This paper will attempt to answer these questions by emphasizing connectionist modelling of semantic and neuropsychological processes. It will be argued that the loss of semantic microfeatures leads to the observed pattern of performance on naming and semantic memory tasks in dementia. These microfeatures may not represent linguistically simple lexical concepts or attributes, but are components of semantic representations that are relatively abstract. It is hypothesized that word meanings are equivalent to semantic attractors across these microfeatures. It is a central theme of this paper that connectionist modelling reveals how apparently disparate phenomena may in fact be related.     

Naming problems in dementia: Semantic or lexical?

Abstract

The naming behaviour was explored of patients moderately deteriorated with probable Alzheimer's disease (pAD) by analysing responses made on a picture naming and two word-picture matching tasks for the same items. Naming responses were classified into target and non-target and the relationship between non-target responses and their targets were explored. It was found that semantic relatedness influenced these non-target responses but frequency and imageability did not. The pAD participants performed significantly better on the two word-picture matching tasks than the naming task, while there was no difference on these within- and between-category tasks. These findings are explored with reference to a two-stage model of lexical access, which has separate storage of semantic, lexical and phonological information. The participants' difficulties appear to lie largely in retrieving the labels for items they comprehend.