Comparing Adolescent Only Children with Those Who Have Siblings on Academic Related Outcomes and Psychosocial Adjustment

This study uses a large and representative sample of adolescents to test the theoretically informed hypotheses comparing adolescent singletons with those who have siblings. The results found that, for academic related outcomes (educational expectations, time spent on homework, and self-reported grades), there are no differences between singletons and firstborns who have any number of younger siblings. Singletons are also not different from laterborns from two-child families. In contrast, singletons are more advantageous compared to laterborns who have two or more siblings on educational expectations and grades. Singletons also spend more time on homework than laterborns who have three or more siblings. For psychosocial outcomes (psychological distress, susceptibility to negative peer pressure, and problem behaviors), singletons are not different from both firstborns and laterborns with any number of siblings. The findings suggest that singletons are not at any disadvantage compared to their peers who have siblings and they enjoy some advantages over laterborns from medium to large families on academic related outcomes

Form factors for semi-leptonic B decays

We report on form factors for the B->K l^+ l^- semi-leptonic decay process. We use several lattice spacings from a=0.12 fm down to 0.06 fm and a variety of dynamical quark masses with 2+1 flavors of asqtad quarks provided by the MILC Collaboration. These ensembles allow good control of the chiral and continuum extrapolations. The b-quark is treated as a clover quark with the Fermilab interpretation. We update our results for f_\parallel and f_\perp, or, equivalently, f_+ and f_0. In addition, we present new results for the tensor form factor f_T. Model independent results are obtained based upon the z-expansion.Comment: 7 pages, 4 figures, presented at The XXXth International Symposium on Lattice Field Theory - Lattice 2012, June 24-29, 2012 Cairns, Australia, to appear as PoS(Lattice 2012)12

Temperature Fluctuations and Abundances in HII Galaxies

There is evidence for temperature fluctuations in Planetary Nebulae and in Galactic HII regions. If such fluctuations occur in the low-metallicity, extragalactic HII regions used to probe the primordial helium abundance, the derived 4He mass fraction, Y_P, could be systematically different from the true primordial value. For cooler, mainly high-metallicity HII regions the derived helium abundance may be nearly unchanged but the oxygen abundance could have been seriously underestimated. For hotter, mainly low-metallicity HII regions the oxygen abundance is likely accurate but the helium abundance could be underestimated. The net effect is to tilt the Y vs. Z relation, making it flatter and resulting in a higher inferred Y_P. Although this effect could be large, there are no data which allow us to estimate the size of the temperature fluctuations for the extragalactic HII regions. Therefore, we have explored this effect via Monte Carlos in which the abundances derived from a fiducial data set are modified by \Delta-T chosen from a distribution with 0 < \Delta-T < \Delta-T_max where \Delta-T_max is varied from 500K to 4000K. It is interesting that although this effect shifts the locations of the HII regions in Y vs. O/H plane, it does not introduce any significant additional dispersion.Comment: 11 pages, 9 postscript figures; submitted to the Ap

Sleep habits and sleep disturbances in Dutch children: a population-based study

Sleep disorders can lead to significant morbidity. Information on sleep in healthy children is necessary to evaluate sleep disorders in clinical practice, but data from different societies cannot be simply generalized. The aims of this study were to (1) assess the prevalence of sleep disturbances in Dutch healthy children, (2) describe sleep habits and problems in this population, (3) collect Dutch norm data for future reference, and (4) compare sleep in children from different cultural backgrounds. A population-based descriptive study was conducted using the Children’s sleep habits questionnaire and the sleep self-report. One thousand five hundred seven proxy-reports and 262 self-reports were analyzed. Mean age was 8.5 years (95% confidence interval, 8.4–8.6), 52% were boys. Sleep problems in Dutch children were present in 25%, i.e., comparable to other populations. Sleep habits were age-related. Problem sleepers scored significantly higher on all scales. Correlations between parental and self-assessments were low to moderate. Dutch children had significantly more sleep disturbances than children from the USA and less than Chinese children. Cognitions and attitudes towards what is considered normal sleep seem to affect the appraisal of sleep, this probably accounts partly for cultural differences. For a better understanding of cultural influences on sleep, more information on these determinants and the establishment of cultural norms are mandatory

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Cosmological constraints combining H(z), CMB shift and SNIa observational data

Recently H(z) data obtained from differential ages of galaxies have been proposed as a new geometrical probe of dark energy. In this paper we use those data, combined with other background tests (CMB shift and SNIa data), to constrain a set of general relativistic dark energy models together with some other models motivated by extra dimensions. Our analysis rests mostly on Bayesian statistics, and we conclude that LCDM is at least substantially favoured, and that braneworld models are less favoured than general relativistic ones.Comment: 17 pages, 11 figures; improved discussion, new figures, updated to match published versio

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

Insulin-dependent Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction.Here we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD) mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells.These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D

Variants in GLIS3 and CRY2 Are Associated with Type 2 Diabetes and Impaired Fasting Glucose in Chinese Hans

Recent genome-wide association studies have identified a number of common variants associated with fasting glucose homeostasis and type 2 diabetes in populations of European origin. This is a replication study to examine whether such associations are also observed in Chinese Hans.We genotyped nine variants in or near MADD, ADRA2A, CRY2, GLIS3, PROX1, FADS1, C2CD4B, IGF1 and IRS1 in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai.We confirmed the associations of GLIS3-rs7034200 with fasting glucose (beta = 0.07 mmol/l, P = 0.03), beta cell function (HOMA-B) (beta = -3.03%, P = 0.009), and type 2 diabetes (OR [95%CI]  = 1.27 [1.09-1.49], P = 0.003) after adjustment for age, sex, region and BMI. The association for type 2 diabetes remained significant after adjusting for other diabetes related risk factors including family history of diabetes, lipid profile, medication information, hypertension and life style factors, while further adjustment for HOMA-B abolished the association. The A-allele of CRY2-rs11605924 was moderately associated with increased risk of combined IFG/type 2 diabetes (OR [95%CI]  = 1.15[1.01-1.30], P = 0.04). SNPs in or near MADD, ADRA2A, PROX1, FADS1, C2CD4B, IGF1, and IRS1 did not exhibit significant associations with type 2 diabetes or related glycemic traits (P≥0.10).In conclusion, our results indicate the associations of GLIS3 locus with type 2 diabetes and impaired fasting glucose in Chinese Hans, partially mediated through impaired beta-cell function. In addition, we also found modest evidence for the association of CRY2-rs11605924 with combined IFG/type 2 diabetes

The Mechanism of Ubiquitination in the Cullin-RING E3 Ligase Machinery: Conformational Control of Substrate Orientation

In cullin-RING E3 ubiquitin ligases, substrate binding proteins, such as VHL-box, SOCS-box or the F-box proteins, recruit substrates for ubiquitination, accurately positioning and orienting the substrates for ubiquitin transfer. Yet, how the E3 machinery precisely positions the substrate is unknown. Here, we simulated nine substrate binding proteins: Skp2, Fbw7, β-TrCP1, Cdc4, Fbs1, TIR1, pVHL, SOCS2, and SOCS4, in the unbound form and bound to Skp1, ASK1 or Elongin C. All nine proteins have two domains: one binds to the substrate; the other to E3 ligase modules Skp1/ASK1/Elongin C. We discovered that in all cases the flexible inter-domain linker serves as a hinge, rotating the substrate binding domain, optimally and accurately positioning it for ubiquitin transfer. We observed a conserved proline in the linker of all nine proteins. In all cases, the prolines pucker substantially and the pucker is associated with the backbone rotation toward the E2/ubiquitin. We further observed that the linker flexibility could be regulated allosterically by binding events associated with either domain. We conclude that the flexible linker in the substrate binding proteins orients the substrate for the ubiquitin transfer. Our findings provide a mechanism for ubiquitination and polyubiquitination, illustrating that these processes are under conformational control