First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.

Limits on Spin-Dependent WIMP-Nucleon Cross Section Obtained from the Complete LUX Exposure.

We present experimental constraints on the spin-dependent WIMP-nucleon elastic cross sections from the total 129.5 kg yr exposure acquired by the Large Underground Xenon experiment (LUX), operating at the Sanford Underground Research Facility in Lead, South Dakota (USA). A profile likelihood ratio analysis allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=1.6×10^{-41} cm^{2} (σ_{p}=5×10^{-40} cm^{2}) at 35 GeV c^{-2}, almost a sixfold improvement over the previous LUX spin-dependent results. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.

First Searches for Axions and Axionlike Particles with the LUX Experiment.

The first searches for axions and axionlike particles with the Large Underground Xenon experiment are presented. Under the assumption of an axioelectric interaction in xenon, the coupling constant between axions and electrons g_{Ae} is tested using data collected in 2013 with an exposure totaling 95 live days ×118 kg. A double-sided, profile likelihood ratio statistic test excludes g_{Ae} larger than 3.5×10^{-12} (90% C.L.) for solar axions. Assuming the Dine-Fischler-Srednicki-Zhitnitsky theoretical description, the upper limit in coupling corresponds to an upper limit on axion mass of 0.12 eV/c^{2}, while for the Kim-Shifman-Vainshtein-Zhakharov description masses above 36.6 eV/c^{2} are excluded. For galactic axionlike particles, values of g_{Ae} larger than 4.2×10^{-13} are excluded for particle masses in the range 1-16 keV/c^{2}. These are the most stringent constraints to date for these interactions.

Results from a Search for Dark Matter in the Complete LUX Exposure.

We report constraints on spin-independent weakly interacting massive particle (WIMP)-nucleon scattering using a 3.35×10^{4} kg day exposure of the Large Underground Xenon (LUX) experiment. A dual-phase xenon time projection chamber with 250 kg of active mass is operated at the Sanford Underground Research Facility under Lead, South Dakota (USA). With roughly fourfold improvement in sensitivity for high WIMP masses relative to our previous results, this search yields no evidence of WIMP nuclear recoils. At a WIMP mass of 50 GeV c^{-2}, WIMP-nucleon spin-independent cross sections above 2.2×10^{-46} cm^{2} are excluded at the 90% confidence level. When combined with the previously reported LUX exposure, this exclusion strengthens to 1.1×10^{-46} cm^{2} at 50 GeV c^{-2}.

Improved Limits on Scattering of Weakly Interacting Massive Particles from Reanalysis of 2013 LUX Data.

We present constraints on weakly interacting massive particles (WIMP)-nucleus scattering from the 2013 data of the Large Underground Xenon dark matter experiment, including 1.4×10^{4} kg day of search exposure. This new analysis incorporates several advances: single-photon calibration at the scintillation wavelength, improved event-reconstruction algorithms, a revised background model including events originating on the detector walls in an enlarged fiducial volume, and new calibrations from decays of an injected tritium ß source and from kinematically constrained nuclear recoils down to 1.1 keV. Sensitivity, especially to low-mass WIMPs, is enhanced compared to our previous results which modeled the signal only above a 3 keV minimum energy. Under standard dark matter halo assumptions and in the mass range above 4 GeV c^{-2}, these new results give the most stringent direct limits on the spin-independent WIMP-nucleon cross section. The 90% C.L. upper limit has a minimum of 0.6 zb at 33 GeV c^{-2} WIMP mass.

Results on the Spin-Dependent Scattering of Weakly Interacting Massive Particles on Nucleons from the Run 3 Data of the LUX Experiment.

We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×10^{4} kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=9.4×10^{-41} cm^{2} (σ_{p}=2.9×10^{-39} cm^{2}) at 33 GeV/c^{2}. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.

First results from the LUX dark matter experiment at the Sanford underground research facility.

The Large Underground Xenon (LUX) experiment is a dual-phase xenon time-projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota). The LUX cryostat was filled for the first time in the underground laboratory in February 2013. We report results of the first WIMP search data set, taken during the period from April to August 2013, presenting the analysis of 85.3 live days of data with a fiducial volume of 118 kg. A profile-likelihood analysis technique shows our data to be consistent with the background-only hypothesis, allowing 90% confidence limits to be set on spin-independent WIMP-nucleon elastic scattering with a minimum upper limit on the cross section of 7.6 × 10(-46) cm(2) at a WIMP mass of 33 GeV/c(2). We find that the LUX data are in disagreement with low-mass WIMP signal interpretations of the results from several recent direct detection experiments.

High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

Obsessive-compulsive disorder in UK clozapine-treated schizophrenia and schizoaffective disorder: a cause for clinical concern.

The association between schizophrenia and obsessive-compulsive disorder (OCD) is complex. This study systematically examined a UK cohort of clozapine-treated individuals with schizophrenia/schizoaffective disorder. Fourteen of 59 cases (24%) scored positively on item H of the Mini-International Neuropsychiatric Interview (MINI) for OCD. The mean Yale- Brown Obsessive-Compulsive Scale (Y-BOCS) score in MINI-positive cases was 17.6 (SD+/-6.3). Sixty-four percent scored 16 or more on the Y-BOCS, representing clinically meaningful illness severity. Seven (50%) patients with OCD had previously received the diagnosis by their treating clinicians and were already receiving with selective serotonin re-uptake inhibitors (SSRIs) treatment. OCD cases scored significantly worse than their non-OCD counterparts on the Abnormal Involuntary Movement Scale (P=0.01) and the Simpson Angus Scale (SAS; P=0.01). There was also a non-significant trend toward higher ratings for OCD cases on the Clinical Global Impression-Schizophrenia scale (P=0.06). Comparing the OCD cases taking SSRI (n=7) with those not on SSRI (n=7), significant differences emerged on the SAS (P=0.03). Our results suggest that OCD is common among patients receiving clozapine for schizophrenic disorders and that the comorbidity is associated with greater motoric impairment. The role of medication in this condition remains unclear.

Abnormal cancellous bone collagen metabolism in osteoarthritis.

Biochemical investigations into the pathogenesis of osteoarthritis have, for the last two decades, concentrated on the mechanisms involved in the destruction of the articular cartilage. Although bone changes are known to occur, the biochemistry of the collagenous matrix within osteoarthritic bone has received scant attention. We report that bone collagen metabolism is increased within osteoarthritic femoral heads, with the greatest changes occurring within the subchondral zone. Collagen synthesis and its potential to mineralize were determined by the carboxy-terminal propeptide content and alkaline phosphatase activity, respectively. These data supported elevated new matrix formation. Our finding of a three- to fourfold increase in TGF-beta in osteoarthritic bone indicates that this might represent a stimulus for the increased collagen synthesis observed. Of additional significance is the hypomineralization of deposited collagen in the subchondral zone of osteoarthritic femoral heads, supporting a greater proportion of osteoid in the diseased tissue. The cross-linking of collagen was similar to that observed for controls. In addition, the degradative potential of osteoarthritic bone was considerably higher as demonstrated by increased matrix metalloproteinase 2 activity, and again the greater activity was associated with the subchondral bone tissue. The polarization exhibited in the metabolism of bone collagen from osteoarthritic hips might exacerbate the processes involved in joint deterioration by altering joint morphology. This in turn may alter the distribution of mechanical forces to the various tissues, to which bone is a sensitive responder. Bone collagen metabolism is clearly an important factor in the pathogenesis of osteoarthritis and certainly warrants further biochemical study.

Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.

BACKGROUND AND METHODS: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. RESULTS: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male-male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male-male and 74 male-female/female-female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male-female/female-female ASP (MLS = 2.62 v 0.00, for non-male and male-male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at approximately 112 cM, and maternal MLS = 1.83 at approximately 135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at approximately 30 cM; paternal MLS = 0.02). CONCLUSION: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.

Ultrastructural differences in cranial cruciate ligaments from dogs of two breeds with a differing predisposition to ligament degeneration and rupture.

Cranial (anterior) cruciate ligament (CCL) samples were obtained from dogs of the Labrador retriever (LR) and greyhound (GH) breeds, of which the former but not the latter is predisposed to CCL rupture. Electron microscopy revealed that the collagen fibril diameters of GHs were larger than those of LRs (P=0.03). Histological examination revealed a "fibrocartilaginous" appearance of CCLs in seven of eight GHs, and, to a lesser extent, in three of eight LRs. The formation of fibrocartilage is clearly not a disadvantage to the healthy racing GH, and cannot be regarded as a pathological degeneration in this breed. It is suggested that fibrocartilage is formed as a beneficial physiological adaptation to the compression of CCLs caused by tensile stress as a result of the tightening of two twisted bands. Fibrocartilage would appear to protect CCLs in the GH, but it may be indicative of a mild degenerative change, which may eventually lead to rupture in the LR.

Some observations on the ageing in vitro of reprecipitated collagen fibres.

The changes in solubility and amounts of reducible cross-links have been studied during "ageing" in vitro of reprecipitated rat skin collagen fibres by incubation at 37 degrees C. Fibres from pre-reduced collagen devoid of aldehyde precursors became insoluble at the same rate as that of normal fibres during "ageing". Insolubilization occurred at a much faster rate in the presence of oxygen than in air and was almost completely inhibited when oxygen was excluded. The rate of decline of the reducible cross-links was, however, unaffected by oxygen tension. The results indicate that, during "ageing" in vitro, conversion of the lysine-derived cross-links to a non-reducible form is not associated with solubility changes. The relationship of these in vitro changes to those ocurring in vivo is unknown.

Thermal stability, mechanical properties and reducible cross-links of rat tail tendon in experimental diabetes.

Thermal stability (measured as isometric contraction force), biomechanical properties and reducible cross-links were measured in tail tendons from streptozotocin diabetic rats, with and without insulin treatment. After 10 days of diabetes the maximum thermal contraction force was unchanged, but the relaxation following the maximal contraction was retarded. After 30 days the maximum contraction force was increased and the relaxation rate was decreased. The maximum strength and stiffness of the tendons were increased after 10 days of diabetes and even more after 30 days. There was no change in the density of reducible cross-links. However, diabetes increased the amount of glucose attached to the lysine and hydroxylysine residues of collagen. Insulin treatment prevented all changes in thermal stability and mechanical properties. The results indicate that stabilization of collagen fibres in diabetes does not follow the same pattern as that seen in normal ageing.

Reducible components in the proteins of human erythrocyte membrane.

In contrast to a previous report, no collagen or elastin-type cross-linked derived from lysine-aldehydes were detected in human erythrocyte membranes. The major reducible components of erythrocyte membranes were shown to be hexosyllysines. From their structure it is clear that these components cannot act as cross-links between the protein subunits of the membrane. The components were also shown to be present in varying proportions in human serum albumin and haemoglobin. Whether the hexose attachments have any physiological significance or are artefacts of the analytical procedure has not yet been demonstrated. One other major reducible component was present but, although unidentified, this compound was shown to be unrelated to any of the known lysine-aldehyde-derived cross-links of collagen and elastin. A minor acidic component was identified as glucosylvaline derived from the N-terminus of the beta chain of haemoglobin A1c and not a lysine-aldehyde precursor of the collagen cross-links.

Characterization of the collagen of human hypertrophic and normal scars.

The collagen produced in response to an injury of human skin is initially stabilized by a cross-link derived from hydroxyallysine, and characteristic of embryonic skin. In normal healing there is a change over with time to the cross-link derived from allysine, which is typical of young skin collagen. In contrast, hypertrophic scars fail to follow the time-related changes of normal skin, but retain the characteristics of embryonic collagen, indicating a continued rapid turnover of the collagen. This is further supported by the high proportion of the embryonic Type III collagen present in hypertrophic scars.

Patient-reported short-term and long-term physical and psychologic symptoms: results of the continuous hyperfractionated accelerated [correction of acclerated] radiotherapy (CHART) randomized trial in non-small-cell lung cancer. CHART Steering Committee.

PURPOSE: The randomized multicenter trial of continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy for patients with non-small-cell lung cancer (NSCLC) showed a significant survival benefit to CHART (29% v 20% at 2 years, P=.004). However, an assessment of the effect on physical and psychologic symptoms is vital to balance the costs and benefits of the two treatments. METHODS: A total of 356 patients in the United Kingdom completed the Rotterdam Symptom Checklist (RSCL) and the Hospital Anxiety and Depression Scale (HADS) at 10 time points. The principal aim of the analyses was to keep the methods simple, so as to allow the presentation and interpretation of the results to be as clear as possible. This was achieved by (1) considering individual symptoms rather than symptom subscales or domains, (2) assessing short-term effects (up to 3 months) and long-term effects (at 1 and 2 years) separately, and (3) for the short-term analyses, (a) splitting the data randomly into an exploratory data set and a confirmatory data set, and (b) using two different methods of analysis: a subject-specific approach, which used the area under the curve (AUC) as a summary measure, and a group-based method, which plotted the percent of patients with moderate or severe symptoms over time. RESULTS: The results indicate that apart from CHART causing transient pain on swallowing and heartburn, there was little difference between the regimens in the short or long-term. CONCLUSION: Combining the results of the patient-assessed symptom comparisons with the clinical results indicates that CHART confers a major benefit without serious morbidity.

The kinetics of the thermal denaturation of collagen in unrestrained rat tail tendon determined by differential scanning calorimetry.

This paper shows that the position and shape of the denaturation endothem of collagen fibrils are governed by the kinetics of an irreversible rate process. This was proved by measuring the rate of denaturation in rat tail tendons held isothermally at different temperatures, thereby determining rate constant characteristics such as the activation enthalpy and entropy and predicting endotherm position and shape therefrom. Comparison with actual scanning results showed good correspondence. Isothermal measurements of the rate of collagen denaturation, measured continuously using a calorimetric method, were used to determine rate constants for collagen denaturation in tendons immersed in water and 0.5 M acetic acid. The temperature dependence of the rate constants were fitted to the three rate process models, previously examined theoretically: the D and z formulation, the Arrhenius equation and the absolute rate theory. For example, in water the activation enthalpy was 0.518 (+/- 0.016) Mj mol-1 and the activation entropy 1.485 (+/- 0.049) kj mol-1 K-1, while in acetic acid the corresponding figures were 1.306 (+/- 0.099) Mj mol-1 and 4.142 (+/- 0.323) kj mol-1 K-1. These characteristics are discussed in terms of the thermal activation of a region of the molecule, the co-operative unit. The ratio of the activation enthalpy to the calorimetry enthalpy of denaturation indicated a co-operative unit that was 66 (+/- 5) residues long when fibrils were swollen in acetic and the collagen molecules acted essentially independently. On the other hand the intact fibrils in water gave a co-operative unit of 26 (+/- 1) residues long. The reason for the reduction in size of the co-operative unit is that it is surrounded, and therefore stabilized by other molecules in the fibre. It is interesting to note that the suggested co-operative unit lies almost entirely within the "gap" zone of the collagen fibril in its quarter-staggered arrangement of molecules. We believe that the co-operative unit would be represented by a domain that is free of stabilising hydroxyproline residues. Indeed such a domain exists near the C terminus of the triple helix from Gly877 to Pro941, i.e. 65 residues. In acetic acid, activation is similar to that of collagen molecules in solution. All the inter alpha-chain hydrogen bonds in the co-operative unit are broken and the separate chains in this short region are free to flail around under the action of thermal collisions relatively unimpeded by intermolecular interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Differences between the thermal stabilities of the three triple-helical domains of type IX collagen.

Fibre-forming collagens in dilute solution show highly co-operative helix-coil transitions at temperatures that are remarkably close to the body temperature of the animal from which the collagen was extracted. This close correlation holds across animal Phyla and the transition temperatures, which range from 5 degrees C to 40 degrees C, are adjusted to suit by changing the primary structure, especially the concentration of the water-bridge-enhancing hydroxyproline residue. Fibril-forming collagens are thermally stabilised by fibrillogenesis, which causes a loss of random coil configurational entropy by intermolecular and intramolecular cross-linking and by spacial confinement of the molecule within the lattice of the fibre. But this mechanism cannot apply to the full length of the type IX collagen molecule, since its COL3 arm, according to current models, projects out from the stabilising influence of the type II fibre. In this paper we examine the thermal stability of the type IX collagen molecule and its three triple-helical domains, thereby demonstrating that the COL3 arm is much more stable than the rest of the molecule. At a scanning rate of 60 deg. C/h COL3 exhibited an unfolding endotherm with a tmax at 49.0 degrees C, well above body temperature. Corresponding peak maxima for COL1 and COL2 were seen at 40.6 degrees C and 39.6 degrees C, respectively. The sizes of the thermally labile units of COL1, COL2 and COL3, calculated from the measured activation enthalpies, were 24, 28 and 28 residues, respectively, much smaller than type I (65 residues) because of the relatively short lengths of triple helix to be unfolded. However, unlike type I collagen, no regions of the required size were found completely devoid of hydroxyproline. Consequently, the intrinsic stabilities of these thermally labile units were higher than that of type I with DeltaH updownarrow DeltaS updownarrow for COL1, COL2 and COL3 being, respectively, 385 K, 371 K and 384 K, contrasting with the much lower 349 K of type I collagen. We therefore speculate that the increased thermal stability of the thermally labile units was caused by the presence of the water-bridge-enhancing residue, hydroxyproline. Finally the stabilisation of type IX collagen tissue is considered and an alternative structural organisation of the type IX molecule on the type II fibre is proposed.

Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy.

OBJECTIVE: Canine dilated cardiomyopathy, commonly affecting Doberman pinschers, results in extracellular matrix remodelling within the myocardium. The aim of this study was to examine the proteolytic activity in myocardium from Doberman pinschers with dilated cardiomyopathy. METHODS: Samples of myocardium, obtained rapidly post mortem from the left ventricular free wall of Dobermans with dilated cardiomyopathy, clinically normal Dobermans and control dogs (non-Dobermans), were examined for proteolytic activity using substrate gel zymography. Gels were analysed by scanning densitometry. RESULTS: Promatrix metalloproteinase-9 activity was significantly increased in all Doberman myocardium when compared to controls. A significant increase in an enzyme, identified to be neutrophil elastase by inhibition of its activity by Elastatinal and Western blotting, was also detected in all Dobermans when compared to controls. CONCLUSIONS: The results indicate that promatrix metalloproteinase-9 and neutrophil elastase, both of which are implicated in inflammatory responses, are present in significantly elevated levels in Doberman dilated cardiomyopathy and are raised in clinically normal Dobermans. Both proteolytic enzymes degrade a wide variety of connective tissue components and thus the increased levels found may play an important role in the structural remodelling seen in the myocardium and subsequent heart failure. Increased proteolytic enzyme levels in clinically normal Dobermans may be indicative of the predisposition of the breed to dilated cardiomyopathy.