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.

New interview and observation measures of the broader autism phenotype: impressions of interviewee measure.

A 20 item observational measure of social functioning, the Impression of Interviewee rating scale, is one of three measures devised to assess the broader autism phenotype. The sample studied included families containing at least two individuals with autism spectrum disorder; observations were undertaken by the researcher who interviewed the subject. An exploratory factor analysis suggested a single factor was most appropriate (Cronbach's α of 0.78). There was a modest but significant retest correlation of 0.42. Correlations between live ratings and blind consensus ratings of vignettes were high (0.93). Correlations with the interview measures were moderate but statistically significant. In conclusion, the observational scale provides a promising start but further work is required before general use can be recommended.

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.

The effects of the Maillard reaction on the physical properties and cell interactions of collagen.

The non-enzymic glycation of collagen occurs as its turnover decreases during maturation, with complex carbohydrates accumulating slowly and the end-products of these reactions being permanent. The nature of these advanced glycation end-reaction products (AGEs) can be categorised as: 1) cross-linking: intermolecular cross-linking may occur between two adjacent molecules and involve lysine to lysine or lysine to arginine residues. Several compounds have been characterised. They are believed to be located between the triple helical domains of adjacent molecules in the fibre resulting in major changes of the physical properties, primarily, fibre stiffness, thermal denaturation temperature and enzyme resistance, all of which increase slowly with age but the rate is accelerated in diabetes mellitus due to high glucose levels: 2) side-chain modifications: these changes alter the charge profile of the molecule affecting the interactions within the fibre and if they occur at specific sites can affect the cell-collagen interaction. Modification of arginine within the sites RGD and GFOGER recognised by the two specific integrins (alpha1beta2 and alpha2beta1) for collagen reduce cell interactions during turnover and for platelet interactions (alpha1beta2). These changes can ultimately affect repair of, for example, vascular damage and dermal wound healing in diabetes mellitus. Both types of modification are deleterious to the optimal properties of collagen as a supporting framework structure and as a controlling factor in cell matrix interactions. Glycation during ageing and diabetes is therefore responsible for malfunctioning of the diverse collagenous tissues throughout the body.

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.

Distal femoral intercondylar notch dimensions and their relationship to composition and metabolism of the canine anterior cruciate ligament.

OBJECTIVE: To determine the relationship between the dimensions of the distal femoral intercondylar notch (ICN) and the composition and metabolism of the anterior cruciate ligament (ACL) in three dog breeds with different relevant risks to ligament rupture and subsequent osteoarthritis (OA). DESIGN: ICN measurements were obtained from the femurs of Golden Retrievers (high risk), Labrador Retrievers (high risk) and Greyhounds (low risk). Femoral condyle width and height, ICN height and width indices, and notch shape index were measured using Vernier callipers in all dogs. Intact ACLs were obtained from the same dog breeds for a study of the impinged areas and were analysed for collagen content, collagen cross-links, and sulphated glycosaminoglycan (GAG) content, matrix metalloproteinase (MMP)-2 and the tissue inhibitors of metalloproteinases (TIMPs)-1 and -2. RESULTS: Femoral condyle width and height and ICN width indices were significantly greater in the low risk compared to the high risk breeds (P<0.01 for all parameters). In contrast, the pro (P=0.003) and active (P=0.007) forms of MMP-2 and sulphated GAGs (P=0.0002) were significantly greater in the impinged areas of the ACLs of the rupture predisposed breeds. CONCLUSIONS: Impingement by the ICN on the ACLs of the high risk breeds may result in increased collagen remodelling and increased sulphated GAG deposition, causing reduced structural integrity of the ligament. Altered ACL composition may predispose the ligament to increased laxity leading to joint degeneration and OA. This may have a comparative implication for pathogenesis of ACL rupture in humans.

Enzymic and non-enzymic cross-linking mechanisms in relation to turnover of collagen: relevance to aging and exercise.

The molecular mechanisms involved in the aging of collagen and consequent increase in mechanical strength and stiffness occur in a series of enzymic and non-enzymic intermolecular cross-links. The enzymic mechanism involves divalent aldimine intermolecular cross-links derived from the reaction of aldehydes which then mature to trivalent cross-links and further stabilize the collagen fiber and is now well known. Recent studies have demonstrated that the rate of turnover and level of telopeptide lysyl hydroxylation modifies the nature of the cross-link and hence the mechanical strength of the fiber. The slow turnover of mature collagen subsequently allows accumulation of the products of the adventitious non-enzymic reaction of glucose with the lysines in the triple helix to form glucosyl lysine and its Amadori product, that is, the Maillard reaction. These products are subsequently oxidized to a complex series of advanced glycation end-products, some of which are intermolecular cross-links between the triple helices rendering the fiber too stiff for optimal functioning of the collagen fibers, and consequently of the particular tissue involved. The glycation reactions following maturation are true aging processes, and attempts at their specific inhibition involve competitive inhibition of the Maillard reaction and chemical cleavage of the glycation cross-links. It is clear that the nature of the age-related cross-links and hence tissue strength depends on the rate of turnover of the collagen. An examination of the particular effect of strenuous exercise on the rate of turnover of collagen and hence cross-linking in different tissues could lead to a better understanding of optimal sports training regimes.

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.

Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene.

The results from several genome scans indicate that chromosome 2q21-q33 is likely to contain an autism susceptibility locus. We studied the potential contribution of nine positional and functional candidate genes: TBR-1; GAD1; DLX1; DLX2; cAMP-GEFII; CHN1; ATF2; HOXD1 and NEUROD1. Screening these genes for DNA variants and association analysis using intragenic single nucleotide polymorphisms did not provide evidence for a major role in the aetiology of autism. Four rare nonsynonymous variants were identified, however, in the cAMP-GEFII gene. These variants were present in five families, where they segregate with the autistic phenotype, and were not observed in control individuals. The significance of these variants is unclear, as their low frequency in IMGSAC families does not account for the relatively strong linkage signal at the 2q locus. Further studies are needed to clarify the contribution of cAMP-GEFII gene variants to autism susceptibility.

Analysis of reelin as a candidate gene for autism.

Genetic studies indicate that chromosome 7q is likely to contain an autism susceptibility locus (AUTS1). We have followed a positional candidate gene approach to identify relevant gene(s) and report here the analysis of reelin (RELN), a gene located under our peak of linkage. Screening RELN for DNA changes identified novel missense variants absent in a large control group; however, the low frequency of these mutations does not explain the relatively strong linkage results on 7q. Furthermore, analysis of a previously reported triplet repeat polymorphism and intragenic single nucleotide polymorphisms, using the transmission disequilibrium test, provided no evidence for association with autism in IMGSAC and German singleton families. The analysis of RELN suggests that it probably does not play a major role in autism aetiology, although further analysis of several missense mutations is warranted in additional affected individuals.

Properties of collagen in OIM mouse tissues.

The deletion of the alpha2 chain from type I collagen in the oim mouse model of osteogenesis imperfecta has been shown to result in a significant reduction in the mechanical strength of the tail tendon and bone tissue. However, the exact role of the alpha2 chain in reducing the mechanical properties is not clear. We now report that the stabilizing intermolecular cross-links in bone are significantly reduced by 27%, thereby contributing to the loss of tensile strength and the change in stress-strain profile. We also report that, in contrast to previous studies, the denaturation temperature of the triple helical molecule and the intact fibers are 2.6 degrees and 1.9 degrees C higher than the corresponding tail tendon collagen from wild-type mice. The increase in hydroxyproline content accounts, at least in part, for the increase in denaturation temperature. The alpha2 chain clearly plays an important part in stabilizing the type I collagen triple helix and fiber packing, but further studies are required to determine the precise mechanism.

Increased metabolism of bone collagen in post-menopausal female osteoporotic femoral heads.

Our previous studies demonstrated that the residual collagen in osteoporotic bone was not normal but possessed higher levels of lysine hydroxylation and modified cross-linking. However, the mechanism for these changes was not clear. In the current investigation, an assessment of bone collagen metabolism in osteoporosis (OP) revealed an increase in the overall metabolism of collagen relative to age-matched controls. The increased metabolism accounts for the observed post-translational modifications of collagen which lead to a more fragile bone matrix. The rate of bone metabolism is therefore an important aspect of the pathogenesis of osteoporosis, the greater the turnover the greater the propensity of a more fragile tissue. Clearly, the quality of bone tissue does not depend solely on adequate bone density but also on the state of the collagenous matrix.