ResearchPad - 4 Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism]]> Presenilins (PS) are the catalytic components of γ-secretase complexes that mediate intramembrane proteolysis. Mutations in the PS genes are a major cause of familial early-onset Alzheimer disease and affect the cleavage of the amyloid precursor protein, thereby altering the production of the amyloid β-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of γ-secretase. Here, we demonstrate that inhibition of γ-secretase causes dysregulation of cellular lipid homeostasis, including up-regulation of liver X receptors, and complex changes in the cellular lipid composition. Genetic and pharmacological inhibition of γsecretase leads to strong accumulation of cytoplasmic lipid droplets, associated with increased levels of acylglycerols, but lowered cholesteryl esters. Furthermore, accumulation of lipid droplets was augmented by increasing levels of amyloid precursor protein C-terminal fragments, indicating a critical involvement of this γ-secretase substrate. Together, these data provide a mechanism that functionally connects γ-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of γ-secretase in cells critical for lipid homeostasis in the brain.

<![CDATA[Prognostic impact of pre-existing interstitial lung disease in non-HIV patients with <i>Pneumocystis</i> pneumonia]]> Pre-existing interstitial lung disease (ILD) is an independent prognostic risk factor for non- HIV Pneumocystis pneumonia (PCP). Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression.

<![CDATA[Mobilising community networks for early identification of tuberculosis and treatment initiation in Cambodia: an evaluation of a seed-and-recruit model]]> A tuberculosis active case finding model that mobilises community networks using a seed-and-recruit approach is associated with early identification and treatment of TB, and is also more likely to find bacteriologically confirmed TB cases in Cambodia

<![CDATA[Letter: Emergency Response Plan During the COVID-19 Pandemic: The University of Alabama at Birmingham Experience]]> <![CDATA[In Reply: Rongeurs, Neurosurgeons, and COVID-19: How Do We Protect Health Care Personnel During Neurosurgical Operations in the Midst of Aerosol-Generation From High-Speed Drills?]]> <![CDATA[Letter: The Impact of the Coronavirus (COVID-19) Pandemic on Neurosurgeons Worldwide]]> <![CDATA[In Reply: COVID-19 Infection Affects Surgical Outcome of Chronic Subdural Hematoma]]> <![CDATA[Letter: Approaches to Mitigate Impact of COVID-19 Pandemic on Neurosurgical Residency Application Cycle]]> <![CDATA[Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD]]> Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1–driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1–driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1–dependent inflammatory disease.

<![CDATA[Letter: Considerations for Performing Emergent Neurointerventional Procedures in a COVID-19 Environment]]> <![CDATA[Letter: Neurological Implications of COVID-19 and Lessons Learned From Prior Epidemics and Pandemics]]> <![CDATA[Letter: Safety Instructions for Neurosurgeons During COVID-19 Pandemic Based on Recent Knowledge and Experience]]> <![CDATA[Letter: Neurosurgical Patients’ Management During the COVID-19 Pandemic—An Institutional Report From an African Neurosurgical Center]]> <![CDATA[Letter: COVID-19 Impact on the Medical Student Path to Neurosurgery]]> <![CDATA[Letter: The Use of Absorbable Sutures in Neurosurgical Procedures in the Time of COVID-19]]> <![CDATA[Loop-closure kinetics reveal a stable, right-handed DNA intermediate in Cre recombination]]> In Cre site-specific recombination, the synaptic intermediate is a recombinase homotetramer containing a pair of loxP DNA target sites. The enzyme system's strand-exchange mechanism proceeds via a Holliday-junction (HJ) intermediate; however, the geometry of DNA segments in the synapse has remained highly controversial. In particular, all crystallographic structures are consistent with an achiral, planar Holliday-junction (HJ) structure, whereas topological assays based on Cre-mediated knotting of plasmid DNAs are consistent with a right-handed chiral junction. We use the kinetics of loop closure involving closely spaced (131–151 bp) loxP sites to investigate the in-aqueo ensemble of conformations for the longest-lived looped DNA intermediate. Fitting the experimental site-spacing dependence of the loop-closure probability, J, to a statistical-mechanical theory of DNA looping provides evidence for substantial out-of-plane HJ distortion, which unequivocally stands in contrast to the square-planar intermediate geometry from Cre-loxP crystal structures and those of other int-superfamily recombinases. J measurements for an HJ-isomerization-deficient Cre mutant suggest that the apparent geometry of the wild-type complex is consistent with temporal averaging of right-handed and achiral structures. Our approach connects the static pictures provided by crystal structures and the natural dynamics of macromolecules in solution, thus advancing a more comprehensive dynamic analysis of large nucleoprotein structures and their mechanisms.

<![CDATA[Viral neuroimmunology/Viral neuropathogenesis I]]> ]]> <![CDATA[Quasi-Herglotz functions and convex optimization]]>

We introduce the set of quasi-Herglotz functions and demonstrate that it has properties useful in the modelling of non-passive systems. The linear space of quasi-Herglotz functions constitutes a natural extension of the convex cone of Herglotz functions. It consists of differences of Herglotz functions and we show that several of the important properties and modelling perspectives are inherited by the new set of quasi-Herglotz functions. In particular, this applies to their integral representations, the associated integral identities or sum rules (with adequate additional assumptions), their boundary values on the real axis and the associated approximation theory. Numerical examples are included to demonstrate the modelling of a non-passive gain medium formulated as a convex optimization problem, where the generating measure is modelled by using a finite expansion of B-splines and point masses.

<![CDATA[Viral infections & autoimmune disease]]> ]]> <![CDATA[Analysis of Differentially Expressed MicroRNAs and Circulating Tumor Cells as Predictive Biomarkers of Platinum Chemoresistance in Primary Ovarian Carcinomas: A Prospective Study]]>


Lesson Learned.

  • Circulating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials.


Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor‐based predictive biomarkers of platinum resistance.


Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs).


The average age of the patients was 64 years, and 82.6% had high‐grade epithelial carcinomas. The baseline median CA‐125 was 464 (range 32–2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum‐resistant/refractory versus platinum‐sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance.


Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.