Eighty phenomena about the self: representation, evaluation, regulation, and change

We propose a new approach for examining self-related aspects and phenomena. The approach includes (1) a taxonomy and (2) an emphasis on multiple levels of mechanisms. The taxonomy categorizes approximately eighty self-related phenomena according to three primary functions involving the self: representing, effecting, and changing. The representing self encompasses the ways in which people depict themselves, either to themselves or to others (e.g., self-concepts, self-presentation). The effecting self concerns ways in which people facilitate or limit their own traits and behaviors (e.g., self-enhancement, self-regulation). The changing self is less time-limited than the regulating self; it concerns phenomena that involve lasting alterations in how people represent and control themselves (e.g., self-expansion, self-development). Each self-related phenomenon within these three categories may be examined at four levels of interacting mechanisms (social, individual, neural, and molecular). We illustrate our approach by focusing on seven self-related phenomena

Don't Stop Thinking About Leptoquarks: Constructing New Models

We discuss the general framework for the construction of new models containing a single, fermion number zero scalar leptoquark of mass $\simeq 200-220$ GeV which can both satisfy the D0/CDF search constraints as well as low energy data, and can lead to both neutral and charged current-like final states at HERA. The class of models of this kind necessarily contain new vector-like fermions with masses at the TeV scale which mix with those of the Standard Model after symmetry breaking. In this paper we classify all models of this type and examine their phenomenological implications as well as their potential embedding into SUSY and non-SUSY GUT scenarios. The general coupling parameter space allowed by low energy as well as collider data for these models is described and requires no fine-tuning of the parameters.Comment: Modified text, added table, and updated reference

Much Ado About Leptoquarks: A Comprehensive Analysis

We examine the phenomenological implications of a 200 GeV leptoquark in light of the recent excess of events at HERA. Given the relative predictions of events rates in e^+p versus e^-p, we demonstrate that classes of leptoquarks may be excluded, including those contained in E_6 GUT models. It is shown that future studies with polarized beams at HERA could reveal the chirality of the leptoquark fermionic coupling and that given sufficient luminosity in each e^\pm_{L,R} channel the leptoquark quantum numbers could be determined. The implications of 200-220 GeV leptoquarks at the Tevatron are examined. While present Tevatron data most likely excludes vector leptoquarks and leptogluons in this mass region, it does allow for scalar leptoquarks. We find that while leptoquarks have little influence on Drell-Yan production, further studies at the Main Injector are possible in the single production channel. We investigate precision electroweak measurements as well as the process e^+e^-\to q\bar q at LEP II and find they provide no further restrictions on these leptoquark models. We then ascertain that cross section and polarization asymmetry measurements at the NLC provide the only direct mechanism to determine the leptoquark's electroweak quantum numbers. The single production of leptoquarks in \gamma e collisions by both the backscattered laser and Weisacker-Williams techniques at the NLC is also discussed. Finally, we demonstrate that we can obtain successful coupling constant unification in models with leptoquarks, both with or without supersymmetry. The supersymmetric case requires the GUT group to be larger than SU(5) such as flipped SU(5)\times U(1)_X.Comment: Corrected single production cross section at Tevatron, updated atomic parity violation constraints, 55 page

PINK1 Is Necessary for Long Term Survival and Mitochondrial Function in Human Dopaminergic Neurons

Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Spatially resolved transcriptomics deconvolutes prognostic histological subgroups in patients with colorectal cancer and synchronous liver metastases

Background: Patients demonstrating strong immune responses to primary colorectal cancer (CRC) have a survival benefit following surgery, while those with predominantly stromal microenvironments do poorly. Biomarkers to identify patients with colorectal cancer liver metastases (CRLM) who have good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary CRC and CRLM, and to interrogate the underlying functional biology that drives disease progression. Methods: Patients undergoing synchronous resection of primary CRC and CRLM underwent detailed histological assessment, panel genomic and bulk transcriptomic assessment, immunohistochemistry (IHC) and GeoMx Spatial Transcriptomics (ST) analysis. Integration with genomic features, pathway enrichment analysis and immune deconvolution were performed. Results: High-immune metastases were associated with improved cancer specific survival (HR, 0.36, P=0.01). Bulk transcriptomic analysis was confounded by stromal content but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for Type II Interferon signalling (NES=-2.05 P.Adj&lt;0.005) and MHC-Class II Antigen Presentation (NES=-2.09 P.Adj&lt;0.005). In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T-cells and neutrophils with enrichment of Notch (NES=2.2 P.Adj=0.022) and TGF-β (NES=2.2 P.Adj=0.02) signalling pathways at the metastatic tumor centre. Conclusions: Histological assessment stratifies outcome in patients undergoing synchronous resection of CRLM. ST analysis reveals significant intra-tumoral and inter-lesional heterogeneity with underlying transcriptomic programmes identified in driving each phenotype

Deletion of Genes Implicated in Protecting the Integrity of Male Germ Cells Has Differential Effects on the Incidence of DNA Breaks and Germ Cell Loss

Infertility affects approximately 20% of couples in Europe and in 50% of cases the problem lies with the male partner. The impact of damaged DNA originating in the male germ line on infertility is poorly understood but may increase miscarriage. Mouse models allow us to investigate how deficiencies in DNA repair/damage response pathways impact on formation and function of male germ cells. We have investigated mice with deletions of ERCC1 (excision repair cross-complementing gene 1), MSH2 (MutS homolog 2, involved in mismatch repair pathway), and p53 (tumour suppressor gene implicated in elimination of germ cells with DNA damage).We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells. Sertoli cell-only tubules were detected in testes from mice lacking expression of ERCC1 or MSH2 but not p53. The number of sperm recovered from epididymes was significantly reduced in mice lacking testicular ERCC1 and 40% of sperm contained DNA breaks whereas the numbers of sperm were not different to controls in adult Msh2 -/- or p53 -/- mice nor did they have significantly compromised DNA.These data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production. These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)