Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related)

Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

Purpose: Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. Methods: We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. Results: There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Conclusions: Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus

Towards Quantum Repeaters with Solid-State Qubits: Spin-Photon Entanglement Generation using Self-Assembled Quantum Dots

In this chapter we review the use of spins in optically-active InAs quantum dots as the key physical building block for constructing a quantum repeater, with a particular focus on recent results demonstrating entanglement between a quantum memory (electron spin qubit) and a flying qubit (polarization- or frequency-encoded photonic qubit). This is a first step towards demonstrating entanglement between distant quantum memories (realized with quantum dots), which in turn is a milestone in the roadmap for building a functional quantum repeater. We also place this experimental work in context by providing an overview of quantum repeaters, their potential uses, and the challenges in implementing them.Comment: 51 pages. Expanded version of a chapter to appear in "Engineering the Atom-Photon Interaction" (Springer-Verlag, 2015; eds. A. Predojevic and M. W. Mitchell

Cavity Induced Interfacing of Atoms and Light

This chapter introduces cavity-based light-matter quantum interfaces, with a single atom or ion in strong coupling to a high-finesse optical cavity. We discuss the deterministic generation of indistinguishable single photons from these systems; the atom-photon entanglement intractably linked to this process; and the information encoding using spatio-temporal modes within these photons. Furthermore, we show how to establish a time-reversal of the aforementioned emission process to use a coupled atom-cavity system as a quantum memory. Along the line, we also discuss the performance and characterisation of cavity photons in elementary linear-optics arrangements with single beam splitters for quantum-homodyne measurements.Comment: to appear as a book chapter in a compilation "Engineering the Atom-Photon Interaction" published by Springer in 2015, edited by A. Predojevic and M. W. Mitchel

Effects of Screening and Brief Intervention Training on Resident and Faculty Alcohol Intervention Behaviours: A Pre- Post-Intervention Assessment

Background: Many hazardous and harmful drinkers do not receive clinician advice to reduce their drinking. Previous studies suggest under-detection and clinician reluctance to intervene despite awareness of problem drinking (PD). The Healthy Habits Project previously reported chart review data documenting increased screening and intervention with hazardous and harmful drinkers after training clinicians and implementing routine screening. This report describes the impact of the Healthy Habits training program on clinicians\u27 rates of identification of PD, level of certainty in identifying PD and the proportion of patients given advice to reduce alcohol use, based on self-report data using clinician exit questionnaires. Methods: 28 residents and 10 faculty in a family medicine residency clinic completed four cycles of clinician exit interview questionnaires before and after screening and intervention training. Rates of identifying PD, level of diagnostic certainty, and frequency of advice to reduce drinking were compared across intervention status (pre vs. post). Findings were compared with rates of PD and advice to reduce drinking documented on chart review. Results: 1,052 clinician exit questionnaires were collected. There were no significant differences in rates of PD identified before and after intervention (9.8% vs. 7.4%, p = .308). Faculty demonstrated greater certainty in PD diagnoses than residents (p = .028) and gave more advice to reduce drinking (p = .042) throughout the program. Faculty and residents reported higher levels of diagnostic certainty after training (p = .039 and .030, respectively). After training, residents showed greater increases than faculty in the percentage of patients given advice to reduce drinking (p = .038), and patients felt to be problem drinkers were significantly more likely to receive advice to reduce drinking by all clinicians (50% vs. 75%, p = .047). The number of patients receiving advice to reduce drinking after program implementation exceeded the number of patients felt to be problem drinkers. Recognition rates of PD were four to eight times higher than rates documented on chart review (p = .028). Conclusion: This program resulted in greater clinician certainty in diagnosing PD and increases in the number of patients with PD who received advice to reduce drinking. Future programs should include booster training sessions and emphasize documentation of PD and brief intervention

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin–induced cytotoxicity in human medulloblastoma cell lines

Asthma-susceptibility variants identified using probands in case-control and family-based analyses

<p>Abstract</p> <p>Background</p> <p>Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.</p> <p>Methods</p> <p>We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.</p> <p>Results</p> <p>We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.</p> <p>Conclusions</p> <p>Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.</p

The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study

While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis—MCTA) permits immediate replication of eQTLs using co-twins (93%–98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%–20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits