A defect in early myogenesis causes Otitis media in two mouse models of 22q11.2 Deletion Syndrome

Otitis media (OM), the inflammation of the middle ear, is the most common disease and cause for surgery in infants worldwide. Chronic Otitis media with effusion (OME) often leads to conductive hearing loss and is a common feature of a number of craniofacial syndromes, such as 22q11.2 Deletion Syndrome (22q11.2DS). OM is more common in children because the more horizontal position of the Eustachian tube (ET) in infants limits or delays clearance of middle ear effusions. Some mouse models with OM have shown alterations in the morphology and angle of the ET. Here, we present a novel mechanism in which OM is caused not by a defect in the ET itself but in the muscles that control its function. Our results show that in two mouse models of 22q11.2DS (Df1/+ and Tbx1(+/-)) presenting with bi- or unilateral OME, the fourth pharyngeal arch-derived levator veli palatini muscles were hypoplastic, which was associated with an earlier altered pattern of MyoD expression. Importantly, in mice with unilateral OME, the side with the inflammation was associated with significantly smaller muscles than the contralateral unaffected ear. Functional tests examining ET patency confirmed a reduced clearing ability in the heterozygous mice. Our findings are also of clinical relevance as targeting hypoplastic muscles might present a novel preventative measure for reducing the high rates of OM in 22q11.2DS patients

Functional consequences of sphingomyelinase-induced changes in erythrocyte membrane structure.

Inflammation enhances the secretion of sphingomyelinases (SMases). SMases catalyze the hydrolysis of sphingomyelin into phosphocholine and ceramide. In erythrocytes, ceramide formation leads to exposure of the removal signal phosphatidylserine (PS), creating a potential link between SMase activity and anemia of inflammation. Therefore, we studied the effects of SMase on various pathophysiologically relevant parameters of erythrocyte homeostasis. Time-lapse confocal microscopy revealed a SMase-induced transition from the discoid to a spherical shape, followed by PS exposure, and finally loss of cytoplasmic content. Also, SMase treatment resulted in ceramide-associated alterations in membrane-cytoskeleton interactions and membrane organization, including microdomain formation. Furthermore, we observed increases in membrane fragility, vesiculation and invagination, and large protein clusters. These changes were associated with enhanced erythrocyte retention in a spleen-mimicking model. Erythrocyte storage under blood bank conditions and during physiological aging increased the sensitivity to SMase. A low SMase activity already induced morphological and structural changes, demonstrating the potential of SMase to disturb erythrocyte homeostasis. Our analyses provide a comprehensive picture in which ceramide-induced changes in membrane microdomain organization disrupt the membrane-cytoskeleton interaction and membrane integrity, leading to vesiculation, reduced deformability, and finally loss of erythrocyte content. Understanding these processes is highly relevant for understanding anemia during chronic inflammation, especially in critically ill patients receiving blood transfusions

Effects of dipole position, orientation and noise on the accuracy of EEG source localization

BACKGROUND: The electroencephalogram (EEG) reflects the electrical activity in the brain on the surface of scalp. A major challenge in this field is the localization of sources in the brain responsible for eliciting the EEG signal measured at the scalp. In order to estimate the location of these sources, one must correctly model the sources, i.e., dipoles, as well as the volume conductor in which the resulting currents flow. In this study, we investigate the effects of dipole depth and orientation on source localization with varying sets of simulated random noise in 4 realistic head models. METHODS: Dipole simulations were performed using realistic head models and using the boundary element method (BEM). In all, 92 dipole locations placed in temporal and parietal regions of the head with varying depth and orientation were investigated along with 6 different levels of simulated random noise. Localization errors due to dipole depth, orientation and noise were investigated. RESULTS: The results indicate that there are no significant differences in localization error due tangential and radial dipoles. With high levels of simulated Gaussian noise, localization errors are depth-dependant. For low levels of added noise, errors are similar for both deep and superficial sources. CONCLUSION: It was found that if the signal-to-noise ratio is above a certain threshold, localization errors in realistic head models are, on average the same for deep and superficial sources. As the noise increases, localization errors increase, particularly for deep sources

Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Gyrate atrophy of the choroid and retina with hyper-ornithinemia responsive to vitamin B6: a case report

<p>Abstract</p> <p>Background</p> <p>Gyrate atrophy of the retina and choroid is a rare autosomal recessive inherited disease, characterized by progressive chorioretinal atrophy that results in progressive deterioration of peripheral and night vision and leading to blindness.</p> <p>Case presentation</p> <p>This report presents a case of a 28-year-old man consulting for a progressive fall of visual acuity with hemeralopia. Eye fundoscopy showed regions of confluent rounded chorioretinal atrophy. The visual field and retinal angiography were altered. A high level of plasma ornithine (629 nmol/mL) was detected and a diagnosis of gyrate atrophy of the retina and choroid was made. The patient was treated with high dose Pyridoxine supplement (300 mg/d for 6 months) and the ornithine level of his serum was successfully reduced.</p> <p>Conclusion</p> <p>The exact mechanism of chorioretinal atrophy in hyper-ornithinemia is not known and a small percentage of the affected people respond to Vitamin B6 supplementation.</p

Magnetic vortex oscillator driven by dc spin-polarized current

Transfer of angular momentum from a spin-polarized current to a ferromagnet provides an efficient means to control the dynamics of nanomagnets. A peculiar consequence of this spin-torque, the ability to induce persistent oscillations of a nanomagnet by applying a dc current, has previously been reported only for spatially uniform nanomagnets. Here we demonstrate that a quintessentially nonuniform magnetic structure, a magnetic vortex, isolated within a nanoscale spin valve structure, can be excited into persistent microwave-frequency oscillations by a spin-polarized dc current. Comparison to micromagnetic simulations leads to identification of the oscillations with a precession of the vortex core. The oscillations, which can be obtained in essentially zero magnetic field, exhibit linewidths that can be narrower than 300 kHz, making these highly compact spin-torque vortex oscillator devices potential candidates for microwave signal-processing applications, and a powerful new tool for fundamental studies of vortex dynamics in magnetic nanostructures.Comment: 14 pages, 4 figure

Borrelia recurrentis employs a novel multifunctional surface protein with anti-complement, anti-opsonic and invasive potential to escape innate immunity

Borrelia recurrentis, the etiologic agent of louse-borne relapsing fever in humans, has evolved strategies, including antigenic variation, to evade immune defence, thereby causing severe diseases with high mortality rates. Here we identify for the first time a multifunctional surface lipoprotein of B. recurrentis, termed HcpA, and demonstrate that it binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. Cell surface bound factor H was found to retain its activity and to confer resistance to complement attack. Moreover, ectopic expression of HcpA in a B. burgdorferi B313 strain, deficient in Factor H binding proteins, protected the transformed spirochetes from complement-mediated killing. Furthermore, HcpA-bound plasminogen/plasmin endows B. recurrentis with the potential to resist opsonization and to degrade extracellular matrix components. Together, the present study underscores the high virulence potential of B. recurrentis. The elucidation of the molecular basis underlying the versatile strategies of B. recurrentis to escape innate immunity and to persist in human tissues, including the brain, may help to understand the pathological processes underlying louse-borne relapsing fever

Time-resolved detection of spin-transfer-driven ferromagnetic resonance and spin torque measurement in magnetic tunnel junctions

Several experimental techniques have been introduced in recent years in attempts to measure spin transfer torque in magnetic tunnel junctions (MTJs). The dependence of spin torque on bias is important for understanding fundamental spin physics in magnetic devices and for applications. However, previous techniques have provided only indirect measures of the torque and their results to date for the bias dependence are qualitatively and quantitatively inconsistent. Here we demonstrate that spin torque in MTJs can be measured directly by using time-domain techniques to detect resonant magnetic precession in response to an oscillating spin torque. The technique is accurate in the high-bias regime relevant for applications, and because it detects directly small-angle linear-response magnetic dynamics caused by spin torque it is relatively immune to artifacts affecting competing techniques. At high bias we find that the spin torque vector differs markedly from the simple lowest-order Taylor series approximations commonly assumed.Comment: 29 pages, 5 figures including supplementary materia

Ramucirumab in combination with pembrolizumab in treatment-naïve advanced gastric or gej adenocarcinoma: Safety and antitumor activity from the phase 1a/b jvdf trial

Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (≥18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score ≥ 1) in 19 and-negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%; PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months; PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months; PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-naïve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors

LRRK2 in Parkinson's disease – drawing the curtain of penetrance: a commentary

Parkinson's disease is the most common neurodegenerative movement disorder and affects about 2% of the population over the age of 60 years. In 2004, mutations in the LRRK2 gene were first described and turned out to be the most frequent genetic cause of familial and sporadic Parkinson's disease and may account for up to 40% of patients in distinct populations. Based on these findings, Latourelle and colleagues show that the penetrance of the most common LRRK2 mutation is higher in patients with familial compared with sporadic Parkinson's disease and identified a substantial number of affected relatives of mutation carriers not presenting with a LRRK2 mutation themselves. This commentary discusses the role of genetic and/or environmental susceptibility factors modulating the expressivity of the disease trait, how these factors may contribute to the phenomenon of phenocopies in genetically defined Parkinson's disease pedigrees, and how the findings of Latourelle and colleagues, published this month in BMC Medicine, relate to current concepts of genetic counselling