The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington’s disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD. We found that the HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and can also be readily detected in the sensory motor cortex, hippocampus and cerebellum of post-mortem brains from HD individuals, particularly in those with early onset disease. This finding will have important implications for strategies to lower mutant HTT levels in patients and the design of future therapeutics

Risk and sensitivity quantification of fracture failure employing cohesive zone elements

Many structures are subjected to the risk of fatigue failure. For their reliability-based design, it is thus important to calculate the probability of fatigue failure and assess the relative importance of the involved parameters. Although various studies have analyzed the fatigue failure, the stage of fracture failure has been less focused. In particular, the risk analysis of fracture failure needs to be conducted considering its importance in actual structures. This article proposes a new probabilistic framework for the risk and sensitivity analysis of structural fatigue failure employing cohesive zone elements. The proposed framework comprises three steps, namely finite element analysis using cohesive zone elements, response surface construction, and risk and sensitivity analysis of fatigue failure, which require several mathematical techniques and algorithms. The proposed framework is tested by applying it to an illustrative example, and the corresponding analysis results of fracture failure probability with different threshold values of a limit-state function are presented. In addition, the sensitivities of failure risk with respect to the statistical parameters of random variables are presented and their relative importance is discussed

5D gravitational waves from complexified black rings

In this paper we construct and briefly study the 5D time-dependent solutions of general relativity obtained via double analytic continuation of the black hole (Myers-Perry) and of the black ring solutions with a double (Pomeransky-Senkov) and a single rotation (Emparan-Reall). The new solutions take the form of a generalized Einstein-Rosen cosmology representing gravitational waves propagating in a closed universe. In this context the rotation parameters of the rings can be interpreted as the extra wave polarizations, while it is interesting to state that the waves obtained from Myers-Perry Black holes exhibit an extra boost-rotational symmetry in higher dimensions which signals their better behavior at null infinity. The analogue to the C-energy is analyzed.Comment: 18 pages, 4 figures. References added, introduction and conclusions are amended, some issues related to singularity structure and symmetries are discussed. Matches the print version to appear in JHE

Wilsonian Approach to Fluid/Gravity Duality

The problem of gravitational fluctuations confined inside a finite cutoff at radius $r=r_c$ outside the horizon in a general class of black hole geometries is considered. Consistent boundary conditions at both the cutoff surface and the horizon are found and the resulting modes analyzed. For general cutoff $r_c$ the dispersion relation is shown at long wavelengths to be that of a linearized Navier-Stokes fluid living on the cutoff surface. A cutoff-dependent line-integral formula for the diffusion constant $D(r_c)$ is derived. The dependence on $r_c$ is interpreted as renormalization group (RG) flow in the fluid. Taking the cutoff to infinity in an asymptotically AdS context, the formula for $D(\infty)$ reproduces as a special case well-known results derived using AdS/CFT. Taking the cutoff to the horizon, the effective speed of sound goes to infinity, the fluid becomes incompressible and the Navier-Stokes dispersion relation becomes exact. The resulting universal formula for the diffusion constant $D(horizon)$ reproduces old results from the membrane paradigm. Hence the old membrane paradigm results and new AdS/CFT results are related by RG flow. RG flow-invariance of the viscosity to entropy ratio $\eta /s$ is shown to follow from the first law of thermodynamics together with isentropy of radial evolution in classical gravity. The ratio is expected to run when quantum gravitational corrections are included.Comment: 34 pages, harvmac, clarified boundary conditio

A rare case of pigmented villonodular synovitis after unicompartmental knee replacement: a case report

Pigmented villonodular synovitis is a benign proliferative disease involving the synovium. Pigmented villonodular synovitis is rare after replacement arthroplasty and has not been recognised and reported as a cause of failure of unicompartmental knee replacement in the literature

Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder

OBJECTIVE: To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia. METHODS: We performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures. RESULTS: Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days–13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance. CONCLUSION: MBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management

Identification of a protein encoded in the EB-viral open reading frame BMRF2

Using monospecific rabbit sera against a peptide derived from a potential antigenic region of the Epstein-Barr viral amino acid sequence encoded in the open reading frame BMRF2 we could identify a protein-complex of 53/55 kDa in chemically induced B95-8, P3HR1 and Raji cell lines. This protein could be shown to be membrane-associated, as predicted by previous computer analysis of the secondary structure and hydrophilicity pattern, and may be a member of EBV-induced membrane proteins in lytically infected cells

Kikuchi Fujimoto disease associated with cryptogenic organizing pneumonia: case report and literature review

<p>Abstract</p> <p>Background</p> <p>The association of Kikuchi Fujimoto disease (KFD) with cryptogenic organizing pneumonia (COP) is extremely rare. We report a case of simultaneous diagnosis of KFD and COP.</p> <p>Case Presentation</p> <p>A 33-year-old male presented with a 1-month cough illness and fever lasting for 5 days. The chest radiograph revealed double lower lobe infiltrate, which was unresponsive to antibiotics. A cervical lymph node was first found in the development of this disease. Bronchoscopy, bronchoalveolar lavage and lung biopsy established the diagnosis of COP, while a lymph node biopsy was consistent with KFD. The patient improved on steroids.</p> <p>Conclusions</p> <p>KFD and COP are possible part of a disease continuum, rather than separate entities.</p