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Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats' role in physiology and beyond.

This paper presents a study of the production of a single W boson in association with one or more jets in proton-antiproton collisions at is root s = 1.96 TeV, using the entire data set collected in 2001-2011 by the Collider Detector at Fermilab at the Tevatron, which corresponds to an integrated luminosity of 9.0 fb(-1). The W boson is identified through its leptonic decays into electron and muon. The production cross sections are measured for each leptonic decay mode and combined after testing that the ratio of the W(-> mu v) + jets cross section to the W(-> ev) + jets cross section agrees with the hypothesis of e-mu lepton universality. The combination of measured cross sections, differential in the inclusive jet multiplicity (W + >= N jets with N = 1, 2, 3, or 4) and in the transverse energy of the leading jet, are compared with theoretical predictions.

Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the postmortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating gamma dT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.

As members of the National Academies of Sciences, Engineering, and Medicine committee that wrote the report on the return of individual research results (1), we reject the allegations in the Policy Forum “Return of results and data to study participants” (S. M. Wolf and B. J. Evans, 12 October, p. 159) that the report is paternalistic, misunderstands the law, burdens Institutional Review Boards (IRBs), and creates barriers to the return of results.

Background: The prevalence of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) was previously estimated as 23% in a paediatric hospital in Luanda, Angola and 18% in a general hospital in Sao Tome and Principe. Aim: To evaluate the prevalence of S. aureus/MRSA colonization among hospitalized children and their parents at two hospitals in Angola and Sao Tome and Principe. Methods: In 2017, 127 hospitalized children and 129 of their parents had nasal swabs for S. aureus/MRSA carriage in the two countries. The isolates were tested for the presence of the mecA and Panton-Valentine leukocidin (PVL) genes, and characterized by pulsed-field gel electrophoresis (PFGE), spa typing, multi-locus sequence typing and SCCmec typing. Findings: Twenty of 127 children (15.7%) and 13 of 129 parents (10.1%) were MRSA nasal carriers. Three lineages comprised 88% of the MRSA isolates: (i) PFGE A-ST5-SCCmec IVa (N=15; 45%), associated with spa type t105, recovered in Angola alone; (ii) PFGE N-ST8-IV/ V (N=7; 21%), associated with spa types t008/t121, recovered in Sao Tome and Principe alone; and (iii) PFGE B-ST88-IVa (N=7; 21%), associated with spa types t325/t786, present in both countries. Fifteen child/guardian pairs were colonized with identical MRSA (N=8) or meticillin-susceptible S. aureus (N=7) strains. PVL was detected in 25% of isolates, including two MRSA (ST30-V and ST8-IVa). Conclusion: Hospitalized children and their parents are important reservoirs of MRSA. Infection control measures should focus on parents in order to minimize the spread of MRSA to the community. (C) 2018 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new 'PresentER' antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen ('clonal fraction') is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines.

Objective Alternative ovarian stimulation protocols for in vitro fertilisation (IVF) have grown in popularity. Yet, patient populations best suited for these protocols have not been defined. Our objective was, therefore, to determine national IVF utilisation patterns and live birth rates of various ovarian stimulation protocols. Design Retrospective cohort study. Setting Academic-affiliated private fertility centre. Participants Aggregate data published by Society for Assisted Reproductive Technology for autologous IVF cycles performed in the USA during 2014 and 2015 were analysed. IVF cycles were stratified based on ovarian stimulation protocol: 205705 conventional stimulations, 4397 minimal stimulations, 2785 natural cycles and 514 in vitro maturation (IVM) cycles. Repeat cycles could not be determined in this analysis. Outcome measures Utilisation patterns and age-specific live birth rates for various ovarian stimulation protocols. Results With advancing female age, utilisation of conventional stimulation protocols decreased, while minimal stimulation and natural cycle IVF increased. Diminished ovarian reserve diagnoses were in all age groups less prevalent in patients undergoing conventional stimulation than with all other protocols. Live birth rates were highest with conventional stimulation at 42.4%, 33.1%, 22.1%, 11.7% and 3.9% for <35, 35-37, 38-40, 41-42 and >42female age groups, respectively. The difference in live birth rates between conventional stimulation and other protocols widened with advancing age from 1.6-fold to 3.9-fold among women <35 years of age, reaching 4.4-fold to 6.6-fold among women >42 years of age. Conclusions In comparison to conventional stimulation IVFminimal stimulation, natural cycle IVF and IVM protocols offer lower but still acceptable live birth rates among young women. These alternative protocols are frequently used in older women and those with diminished ovarian reserve, despite their lower live birth rates. The reasons for this apparent incongruity warrant further careful exploration.

Lead exposure is an unresolved pediatric health risk and disproportionately affects children in lower-income neighborhoods. Residences with children younger than age 5 years are the focus of mitigation policies; however, studies have shown that older children between the ages of 5 and 12 years also are at risk of central nervous system effects. Whether historically contaminated neighborhoods present ongoing risk to older children also is of concern. This study compared the blood lead levels (BLLs) of older children from an historically contaminated urban neighborhood to those of demographically matched children from a nearby rural locale and predicted significantly higher BLLs in the urban children. The study included 222 children aged 5-12 years, 111 from the urban neighborhood and 111 from local rural townships, matched for age, sex, race/ethnicity, and family income. Blood lead, cadmium, and mercury were measured using inductively coupled plasma mass spectrometry. General linear models tested whether geographic location (urban vs. rural) predicted child heavy metal levels, controlling for sex and age. Only location predicted only child BLL (R-2=0.36); children living in the urban setting had significantly higher BLLs as compared with matched rural township children (F=125, df(220,2), p<0.001). Neighborhoods with a history of lead contamination can present current risk of lead exposure for older children between the ages of 5 and 12 years, as well as for infants and toddlers. More studies are needed to better characterize the risk of lead exposure to older children, particularly in lower-income neighborhoods with a history of lead contamination.

Objective: To propose a practical ethical framework for how task-based functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) may be used in the intensive care unit (ICU) to identify covert consciousness in patients with acute severe traumatic brain injury (TBI). Methods: We present 2 clinical scenarios in which investigational task-based fMRI and EEG were performed in critically ill patients with acute severe TBI who appeared unconscious on the bedside behavioral assessment. From these cases, we consider the clinical and ethical challenges that emerge and suggest how to reconcile them. We also provide recommendations regarding communication with families about ICU patients with covert consciousness. Results: Covert consciousness was detected acutely in a patient who died in the ICU due to withdrawal of life-sustaining therapy, whereas covert consciousness was not detected in a patient who subsequently recovered consciousness, communication, and functional independence. These cases raise ethical challenges about how assessment of covert consciousness in the ICU might inform treatment decisions, prognostication, and perceptions about the benefits and burdens of ongoing care. Conclusions: Given that covert consciousness can be detected acutely in the ICU, we recommend that clinicians reconsider evaluative norms for ICU patients. As our clinical appreciation of covert consciousness evolves and its ethical import unfolds, we urge prognostic humility and transparency when clinicians communicate with families in the ICU about goals of care.