Free-energy minimization and the dark-room problem.

Recent years have seen the emergence of an important new fundamental theory of brain function. This theory brings information-theoretic, Bayesian, neuroscientific, and machine learning approaches into a single framework whose overarching principle is the minimization of surprise (or, equivalently, the maximization of expectation). The most comprehensive such treatment is the "free-energy minimization" formulation due to Karl Friston (see e.

Characteristics of Epstein-Barr virus hepatitis among patients with jaundice or acute hepatitis.

Background: Abnormal liver blood tests are common in Epstein-Barr virus (EBV) infection, but symptomatic hepatitis is rare. The demographics, clinical features and outcome of EBV hepatitis are incompletely understood, particularly in the elderly people.

Aim: To identify the demographics, presenting features and natural history of EBV hepatitis.

From dynamic combinatorial 'hit' to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy.

The myotonic dystrophies (DM) are human diseases in which the accumulation of toxic RNA (CUG or CCUG) repeats in the cell causes sequestration of splicing factors, including MBNL1, leading to clinical symptoms such as muscle wasting and myotonia. We previously used Dynamic Combinatorial Chemistry to identify the first compounds known to inhibit (CUG)-MBNL1 binding in vitro. We now report transformation of those compounds into structures with activity in vivo.

Detection of invasive pulmonary aspergillosis in haematological malignancy patients by using lateral-flow technology.

Invasive pulmonary aspergillosis (IPA) is a leading cause of morbidity and mortality in haematological malignancy patients and hematopoietic stem cell transplant recipients(1). Detection of IPA represents a formidable diagnostic challenge and, in the absence of a 'gold standard', relies on a combination of clinical data and microbiology and histopathology where feasible. Diagnosis of IPA must conform to the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycology Study Group (EORTC/MSG) consensus defining "proven", "probable", and "possible" invasive fungal diseases(2).

Molecular mechanisms of neonatal brain injury.

Fetal/neonatal brain injury is an important cause of neurological disability. Hypoxia-ischemia and excitotoxicity are considered important insults, and, in spite of their acute nature, brain injury develops over a protracted time period during the primary, secondary, and tertiary phases. The concept that most of the injury develops with a delay after the insult makes it possible to provide effective neuroprotective treatment after the insult.

Mitochondria and perinatal brain injury.

Secondary brain injury after hypoxia-ischemia is associated with delayed loss of high energy phosphates implicating bioenergetic mitochondrial failure at least partly related to deregulation of the energy sensor adenosine monophosphate-activated protein kinase. Furthermore, the toxic intracellular environment (accumulation of reactive oxygen/nitrosative species and intracellular calcium) during post-ischemic reperfusion triggers Bax-dependent mitochondrial permeabilization (MP) leading to activation of caspase-dependent and apoptosis-inducing factor dependent cell death. We still do not understand how MP is induced but some data suggest that mitochondrial fusion/fission as well as migration play a critical role.

Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA.

Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching.

Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5'CUG/3'GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, sarco(endo)plasmic reticulum Ca(2+) ATPase 1, and cardiac troponin T.

Two high-throughput screening assays for aberrant RNA-protein interactions in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1), the most prevalent form of adult muscular dystrophy, is caused by expansion of a CTG repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The pathogenic effects of the CTG expansion arise from the deleterious effects of the mutant transcript. RNA with expanded CUG tracts alters the activities of several RNA binding proteins, including muscleblind-like 1 (MBNL1).

If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD).

Introduction: Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally.

Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel.

Myotonic dystrophy type 1 and type 2 (DM1 and DM2) are genetic diseases in which mutant transcripts containing expanded CUG or CCUG repeats cause cellular dysfunction by altering the processing or metabolism of specific mRNAs and miRNAs. The toxic effects of mutant RNA are mediated partly through effects on proteins that regulate alternative splicing. Here we show that alternative splicing of exon 29 (E29) of Ca(V)1.

Stabilization of expanded (CTG)•(CAG) repeats by antisense oligonucleotides.

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the gene DMPK. The expansion is highly unstable in somatic cells, a feature that may contribute to disease progression. The RNA expressed from the mutant allele exerts a toxic gain of function, due to the presence of an expanded CUG repeat (CUG(exp)).

Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy.

The genetic basis of oculopharyngeal muscular dystrophy (OPMD) is a short expansion of a polyalanine tract (normal allele: 10 alanines, mutant allele: 11-17 alanines) in the nuclear polyadenylate binding protein PABPN1 which is essential for controlling poly(A) tail length in messenger RNA. Mutant PABPN1 forms nuclear inclusions in OPMD muscle. To investigate the pathogenic role of mutant PABPN1 in vivo, we generated a ligand-inducible transgenic mouse model by using the mifepristone-inducible gene expression system.

Urinary placental growth factor differentiates the hypertensive disorders of pregnancy.

Aims:   To evaluate the discriminating capacity of urinary placental growth factor (uPlGF) for different hypertensive diseases of pregnancy during the third trimester.

Methods:   A prospective descriptive case-control study conducted in an urban tertiary referral hospital and district general hospital, Sydney South West Area Health Service, Australia. Inpatients and outpatients with and without hypertension in the third trimester were recruited.

Saprotrophic competitiveness and biocontrol fitness of a genetically modified strain of the plant-growth-promoting fungus Trichoderma hamatum GD12.

Trichoderma species are ubiquitous soil fungi that hold enormous potential for the development of credible alternatives to agrochemicals and synthetic fertilizers in sustainable crop production. In this paper, we show that substantial improvements in plant productivity can be met by genetic modification of a plant-growth-promoting and biocontrol strain of Trichoderma hamatum, but that these improvements are obtained in the absence of disease pressure only. Using a quantitative monoclonal antibody-based ELISA, we show that an N-acetyl-β-d-glucosaminidase-deficient mutant of T.

Benchmarking and patient safety in hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy are a major cause of morbidity and mortality worldwide. Reliable, published individual patient data from units and countries are lacking. Without these data, clinicians are unable to benchmark their incidence, treatments and outcomes, and patient safety is unable to be routinely assessed.

Replacement of the myotonic dystrophy type 1 CTG repeat with 'non-CTG repeat' insertions in specific tissues.

Background: Recently, curious mutations have been reported to occur within the (CTG)n repeat tract of the myotonic dystrophy type 1 (DM1) locus. For example, the repeat, long presumed to be a pure repeat sequence, has now been revealed to often contain interruption motifs in a proportion of cases with expansions. Similarly, a few de novo somatic CTG expansions have been reported to arise from non-expanded DM1 alleles with 5-37 units, thought to be genetically stable.

Identification of restriction endonucleases sensitive to 5-cytosine methylation at non-CpG sites, including expanded (CAG)n/(CTG)n repeats.

Most epigenetic studies assess methylation of 5'-CpG-3' sites but recent evidence indicates that non-CpG cytosine methylation occurs at high levels in humans and other species. This is most prevalent at 5'-CHG-3', where H = A, C or T, and it preferentially occurs at 5'-CpA-3' and 5'-CpT-3' sites. With the goal of facilitating the detection of non-CpG methylation, the restriction endonucleases ApeKI, BbvI, EcoP15I, Fnu 4HI, MwoI and TseI were assessed for their sensitivity to 5-methylcytosine at GpCpA, GpCpT, GpCpC or GpCpG sites, where methylation is catalyzed by the DNA 5-cytosine 5'-GpC-3' methyltransferase M.

Analysis of quantum dot fluorescence stability in primary blood mononuclear cells.

A quantitative assessment of fluorescence signal generation and persistence in blood cells, measured at multiple points over a time course, is presented. Quantum dots (QDs) are inorganic fluorophores that are photostable and nonmetabolized and so can provide quantitative measures of cell biology over multiple cell generations. However, if the potential of these nanoparticles for long-term reporting is to be realized, an understanding of the stability of their fluorescence in living cells is essential.

The effect of fear of movement beliefs on pain and disability after surgery for lumbar and cervical degenerative conditions.

Study Design: Prospective cohort study.

Objective: To examine differences between preoperative and postoperative fear of movement and investigate the relationship between fear of movement and pain, disability and physical health after spinal surgery for degenerative conditions.

Summary Of Background Data: Consistent evidence supports the relationship between fear of movement and higher levels of pain and disability in various chronic pain populations.

AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure.

Hyperphosphorylation of tau is a hallmark of Alzheimer's disease and other tauopathies. Although the mechanisms underlying hyperphosphorylation are not fully understood, cellular stresses such as impaired energy metabolism are thought to influence the signalling cascade. The AMPK (AMP-activated protein kinase)-related kinases MARK (microtubule-associated protein-regulating kinase/microtubule affinity-regulating kinase) and BRSK (brain-specific kinase) have been implicated in tau phosphorylation, but are insensitive to activation by cellular stress.

Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny.

Background: Microbial products are of central interest in the modulation of allergic propensity.

Objective: We sought to explore whether allergic children show differences in microbial Toll-like receptor (TLR)-mediated responses over their first 5 years of life.

Methods: Mononuclear cells isolated from 35 allergic and 35 nonallergic children at birth and 1, 2.

Bidirectional transcription stimulates expansion and contraction of expanded (CTG)*(CAG) repeats.

More than 12 neurogenetic disorders are caused by unstable expansions of (CTG)•(CAG) repeats. The expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have shown that contractions of (CAG)(95) are more frequent when the repeat tract is transcribed.

Sarcolemmal-restricted localization of functional ClC-1 channels in mouse skeletal muscle.

Skeletal muscle fibers exhibit a high resting chloride conductance primarily determined by ClC-1 chloride channels that stabilize the resting membrane potential during repetitive stimulation. Although the importance of ClC-1 channel activity in maintaining normal muscle excitability is well appreciated, the subcellular location of this conductance remains highly controversial. Using a three-pronged multidisciplinary approach, we determined the location of functional ClC-1 channels in adult mouse skeletal muscle.