Searching for Hidden Neutrons with a Reactor Neutrino Experiment: Constraints from the STEREO Experiment.

Different extensions of the standard model of particle physics, such as braneworld or mirror matter models, predict the existence of a neutron sterile state, possibly as a dark matter candidate. This Letter reports a new experimental constraint on the probability p for neutron conversion into a hidden neutron, set by the STEREO experiment at the high flux reactor of the Institut Laue-Langevin. The limit is p<3.1×10^{-11} at 95% C.L. improving the previous limit by a factor of 13. This result demonstrates that short-baseline neutrino experiments can be used as competitive passing-through-walls neutron experiments to search for hidden neutrons.

Accurate Measurement of the Electron Antineutrino Yield of

We report a measurement of the antineutrino rate from the fission of ^{235}U with the STEREO detector using 119 days of reactor turned on. In our analysis, we perform several detailed corrections and achieve the most precise single measurement at reactors with highly enriched ^{235}U fuel. We measure an IBD cross section per fission of σ_{f}=(6.34±0.06[stat]±0.15[sys]±0.15[model])×10^{-43} cm^{2}/fission and observe a rate deficit of (5.2±0.8[stat]±2.3[sys]±2.3[model])% compared to the model, consistent with the deficit of the world average. Testing ^{235}U as the sole source of the deficit, we find a tension between the results of lowly and highly enriched ^{235}U fuel of 2.1 standard deviations.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Sterile Neutrino Constraints from the STEREO Experiment with 66 Days of Reactor-On Data.

The reactor antineutrino anomaly might be explained by the oscillation of reactor antineutrinos toward a sterile neutrino of eV mass. In order to explore this hypothesis, the STEREO experiment measures the antineutrino energy spectrum in six different detector cells covering baselines between 9 and 11 m from the compact core of the ILL research reactor. In this Letter, results from 66 days of reactor turned on and 138 days of reactor turned off are reported. A novel method to extract the antineutrino rates has been developed based on the distribution of the pulse shape discrimination parameter. The test of a new oscillation toward a sterile neutrino is performed by comparing ratios of cells, independent of absolute normalization and of the prediction of the reactor spectrum. The results are found to be compatible with the null oscillation hypothesis and the best fit of the reactor antineutrino anomaly is excluded at 97.5% C.L.

SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome.

Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is an auto-inflammatory disease for which a genetic basis has been postulated. Nevertheless, in contrast to the other periodic fever syndromes, no candidate genes have yet been identified. By cloning, following long insert size paired-end sequencing, of a de novo chromosomal translocation t(10;17)(q11.2;p13) in a patient with typical PFAPA syndrome lacking mutations in genes associated with other periodic fever syndromes we identified SPAG7 as a candidate gene for PFAPA. SPAG7 protein is expressed in tissues affected by PFAPA and has been functionally linked to antiviral and inflammatory responses. Haploinsufficiency of SPAG7 due to a microdeletion at the translocation breakpoint leading to loss of exons 2-7 from one allele was associated with PFAPA in the index. Sequence analyses of SPAG7 in additional patients with PFAPA point to genetic heterogeneity or alternative mechanisms of SPAG7 deregulation, such as somatic or epigenetic changes.

The 3' untranslated region of messenger RNA: A molecular 'hotspot' for pathology?

The role of the 3' untranslated region in posttranscriptional regulation of mRNA expression is being elucidated. Here we describe diseases arising from anomalies in this region, that affect the expression of one or more genes.

Proof testing of ceramic femoral heads for hip joint implants.

A proof test procedure for the rejection of defective ceramic hip ball heads in the production line is presented. The procedure consists of applying a load to each ceramic ball head. This load, being somewhat higher than the maximum physiological load, should not cause any damage in cases where the highly stressed areas are free of flaws. In this procedure, a polymer ring is positioned inside the ball head bore between a socket and the head of a tie bolt. Once the tie bolt is pulled downwards, the ring creates a radial pressure on the inner bore surface of the ball head. With an iterative approach based on finite element analysis, the proof test design was optimized in order to obtain a stress distribution in the ball head similar to that resulting in in vivo conditions. The calculated results were validated by strain gauge measurements performed on an assembled proof test apparatus. Several polymers were considered for the ring. Ultrahigh-molecular-weight polyethylene (UHMWPE grade RCH 1000) showed the best durability properties and lowest wear rates. The requirement to perform 1000 reruns without significant reduction of stress in the ball head was fulfilled. Although other proof test procedures for ceramic femoral heads already exist, the procedure presented in this article shows advantages concerning maintenance and operating costs.

Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase.

A new class of synthetic antifungal agents, the allylamines , has been developed by modification of naftifine , a topical antimycotic. SF 86-327, the most effective of these compounds so far, is highly active in vitro against a wide range of fungi and exceeds clinical standards in the oral and topical treatment of guinea pig dermatophytoses. SF 86-327 is a powerful specific inhibitor of fungal squalene epoxidase, a key enzyme in sterol biosynthesis.

Optimization of the stress distribution in ceramic femoral heads by means of finite element methods.

Ceramic ball heads for total hip replacement are highly loaded in vivo and must meet the sternest requirements concerning strength and safety. High stresses inside the ball head originate from the press fit between the conical stem (made of titanium alloy or steel) and the borehole of the ball. The aim of this study was the development of an optimized contour at the fillet inside the ball head by means of numerical methods, in order to reduce local stress concentrations. The computer-aided optimization method was applied on the customary engineering fillet radius to reduce local stress peaks. The local notch stress of the examined ball head design was reduced by up to 27 per cent for the relevant load cases. Verification by rupture testing of prototypes turned out to be difficult for axisymmetric load cases, since the static fracture load is governed by the hoop stresses in the contact area of the taper (global maximum), thus making it difficult to prove a local improvement. The sensitivity of the design to asymmetric loading was clearly shown (varying the load angle and bearing type). Stress relocation in the ball-stem interface at higher burst loads indicated the necessity of optimizing each ceramic femoral head design individually (i.e. for different borehole depths).

McLeod syndrome: Five new pedigrees with novel mutations.

OBJECTIVE: To present five new McLeod Syndrome (MLS) pedigrees with novel XK gene mutations, review the literature of this disorder, and discuss the typical and atypical clinical features noted with these new mutations. METHODS: This is a multi-center retrospective review of five MLS cases with novel gene mutations. Genotypic and phenotypic information has been obtained from each center. RESULTS: Five novel mutations are reported in this Case series. New clinical findings include prolonged asymptomatic elevated creatine kinase (CK) levels, vocal tics, presence of obstructive sleep apnea (OSA), and one patient of Vietnamese ethnicity. CONCLUSIONS: We expand on the clinical and genetic spectrum of MLS demonstrating the clinical variability of MLS.

Influence of contaminants in the stem-ball interface on the static fracture load of ceramic hip joint ball heads.

The probability of in-vivo failure of ceramic hip joint implants is very low (0.05-0.004 per cent). Besides material flaws and overloading, improper handling during implantation may induce fractures of the ceramic ball head in the long term. This study focuses on the influence of contaminants located in the stem-ball interface and on the use of damaged metal tapers on the strength of ceramic ball heads. Mechanical tests on alumina ball heads according to the standard ISO 7206-10 were performed to identify their effect on the static fracture load. A decrease of up to 90 per cent with respect to the reference static fracture load was found when contaminants such as bone chips, soft tissue, or blood were present. Reductions of 57 per cent and 27 per cent were observed for deformed stem cross-sections (from circular to elliptical) and for flattened stems respectively, making deformed stems another influential parameter. Since any alteration of the interface between the metal taper and the ceramic ball head yields a nonuniform load introduction and hence results in stress concentrations, its presence has to be avoided.

Translational control. Awakening dormant mRNAs.

The translational control of many maternal mRNAs in oocytes and early embryos relies on changes in poly(A) tail length; the factors controlling poly(A) tail length are being identified in a range of species.

Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.

In vivo antisense oligodeoxynucleotide mapping reveals masked regulatory elements in an mRNA dormant in mouse oocytes.

In mouse oocytes, tissue-type plasminogen activator (tPA) mRNA is under translational control. The newly transcribed mRNA undergoes deadenylation and translational silencing in growing oocytes, while readenylation and translation occur during meiotic maturation. To localize regulatory elements controlling tPA mRNA expression, we identified regions of the endogenous transcript protected from hybridization with injected antisense oligodeoxynucleotides. Most of the targeted sequences in either the 5' untranslated region (5'UTR), coding region, or 3'UTR were accessible to hybridization, as revealed by inhibition of tPA synthesis and by RNase protection. Two protected regions were identified in the 3'UTR of tPA mRNA in primary oocytes: the adenylation control element (ACE) and the AAUAAA polyadenylation signal. These sequences were previously shown to be involved in the translational control of injected reporter transcripts. During the first hour of meiotic maturation, part of the ACE and the AAUAAA hexanucleotide became accessible to hybridization, suggesting a partial unmasking of the 3'UTR of this mRNA before it becomes translationally competent. Our results demonstrate that in vivo antisense oligodeoxynucleotide mapping can reveal the dynamics of regulatory features of a native mRNA in the context of the intact cell. They suggest that specific regions in the 3'UTR of tPA mRNA function as cis-acting masking determinants involved in the silencing of tPA mRNA in primary oocytes.

Immunosuppressive macrolides of the type FK 506: a novel class of topical agents for treatment of skin diseases?

The immunosuppressive macrolide antibiotics FK 506 and rapamycin were tested for topical activity in experimental allergic contact dermatitis of farm pigs. This species was used because pig skin, in comparison to rodent skin, resembles human skin more closely. For comparison, cyclosporine A (CyA), which is orally but not topically active in patients with skin disease, dexamethasone, and clobetasol propionate were used. Treatment was performed twice, 30 min and 6 h after elicitation of challenge reaction. Topical application of 0.4 to 0.04% FK 506 caused a pronounced inhibition of inflammatory skin reactions of hypersensitivity to dinitrofluorobenzene. The treatment response was similar to the activity of 0.13% clobetasole. Dexamethasone (1.2%) was less active than clobetasol. In contrast, rapamycin and CyA were inactive at concentrations of 1.2 and 10%, respectively. Because the pig data on corticosteroids and cyclosporine A are in agreement with clinical findings, these studies indicate that immunosuppressive macrolides of the type FK 506 may be useful drugs for the topical treatment of human skin diseases that respond to local corticosteroids and oral treatment with cyclosporine A.

Clearing of psoriasis by a novel immunosuppressive macrolide.

Accumulating evidence suggests that psoriasis may be a genetically determined immunogenic, inflammatory disorder based on an ongoing autoreactive Th-1 response. Systemic immunosuppressive therapy is highly effective but fraught with longterm side effects. Our research therefore focuses on therapeutic strategies that induce local immunosuppression in the skin by topical, transepidermal delivery of immunosuppressive drugs. SDZ 281-240 is a newly developed macrolide of the ascomycin type. It is immunosuppressive by mechanism of action similar to that of FK506 but has no antiproliferative activity against keratinocytes in vitro. To evaluate whether SDZ 281-240 exhibits antipsoriatic activity when applied topically, we tested 15 patients with severe, recalcitrant psoriasis, using a microplaque assay in randomized, double-blind, placebo-controlled study, comparing the therapeutic efficacy of the macrolide with a potent halogenated corticosteroid and vehicle. All patients showed a significant improvement of psoriatic lesions treated with two concentrations of the macrolide and, as expected, with the corticosteroid but not with placebo. Both concentrations of the macrolide led to clearing of psoriasis after 10 days of treatment and biopsies confirmed a reversal of the histopathological and immunopathological phenotype of psoriasis to that of normal skin. Thus, an immunosuppressive agent that interferes with early T cell activation can be designed to penetrate into psoriatic lesions when applied topically and to be functionally active within the skin to suppress the ongoing psoriatic process.

Intestinal lactase-phlorizin hydrolase (LPH): the two catalytic sites; the role of the pancreas in pro-LPH maturation.

Brush border lactase-phlorizin hydrolase carries two catalytic sites. In the human enzyme lactase comprises Glu-1749, phlorizin hydrolase Glu-1273. The proteolytic processing of pro-lactase-phlorizin hydrolase by (rat) enterocytes stops two amino acid residues short of the N-terminus of 'mature' final, brush border lactase-phlorizin hydrolase. Only these two amino acid residues are removed by luminal pancreatic protease(s), probably trypsin.

Iminosugars and relatives as antiviral and potential anti-infective agents.

Iminosugars have emerged in the literature during mid-1960's as synthetic compounds. Around the same time, the first examples were found in Nature and their interesting enzyme inhibitory properties were recognised. Due to their powerful interference with glycohydrolases (glycosidases) as well as glycosyltransferases, quite a few representatives exhibit notable biological activities. These range from anti-diabetic, insect antifeedant, nematicidal, plant growth regulating to immunomodulating, anti-cancer as well as - in selected cases - anti-infective properties. The latter will be the focus of the following survey.

Synthesis and antifungal activity of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphtha lenemethanamine (SF 86-327) and related allylamine derivatives with enhanced oral activity.

The allylamine derivatives are a new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. A new subclass, which features an acetylene group conjugated with the allylamine double bond, is characterized by enhanced antifungal activity, especially on oral treatment of guinea pig dermatophytoses. Increased branching of the alkyl group next to the triple bond led to the tert-butylacetylene derivative SF 86-327, a compound with strikingly increased activity in vitro and in vivo, which is now under clinical evaluation. Versatile synthetic routes, comparative biological data, and structure--activity relationships are presented.