Minor early embryonic chick hemoglobin M. Amino acid sequences of the epsilon and alpha D chains

Erythrocytes of the early chick embryo contain four hemoglobins, two major and two minor. In this paper, we present amino acid sequences for the beta-like and alpha-like chains of HbM, the least abundant of the four early chick hemoglobins. The complete amino acid sequence of the beta-like chain of HbM is identical with that of the epsilon chain of HbE, the other minor early embryonic hemoglobin in the domestic chicken. Analysis of the alpha-like chain of HbM (92 of 141 residues) reveals a globin sequence closely related to the minor adult alpha D chain. Comparison of our sequence data with the nucleotide sequence of the alpha D globin gene suggests that a single gene encodes both the embryonic and adult alpha D globin polypeptides. We discuss the structure, possible function, and evolution of the HbM globin chains

Complete amino acid sequence of the major early embryonic beta-like globin in chickens

The rho globin is the major beta-like chain found in 5-day-old chick embryos. In association with two unique early embryonic alpha-like globins, it forms the two major hemoglobins of early chick development. This paper presents the complete amino acid sequence of the rho globin. There are no amino acid differences between the rho chain and the adult chicken beta chain at known Bohr effect or organophosphate-binding positions, and there are only 19 differences altogether. The rho globin ought to be functionally equivalent to the adult chicken beta globin. Since the adult and embryonic chains are very similar in sequence, they may be products of a relatively recent gene duplication in the chicken beta globin gene family. The possibility of a gene correction event is discussed

Amino acid sequences of the epsilon and alpha E globins of HbE, a minor early embryonic hemoglobin of the chicken

We have determined amino acid sequences for the alpha-like and beta- like globin components of HbE, one of the two minor hemoglobins in early chick embryos. The complete primary structure of the epsilon chain differs at 18 positions from the adult chicken beta globin, but there are no changes in heme-binding residues, alpha 1 beta 2 contact positions, or allosteric regulatory sites. By amino acid sequence analysis, we have identified a new alpha-like globin that we have called alpha E. The alpha E globin chain differs from the major adult alpha A chain at 22 amino acid positions. This paper discusses the structural and implied functional characteristics of these globins and presents hypotheses regarding the possible role of minor embryonic hemoglobins

Irritable bowel syndrome - An inflammatory disease involving mast cells

Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder - that is the presence of symptoms in the absence of demonstrable pathological abnormalities. In recent times, low grade inflammatory infiltrates in both the small and large bowel of some patients with IBS - often rich in mast cells, along with serological markers of low grade inflammation have focussed attention on IBS as an inflammatory disease. The observation that mast cells often lie in close association to enteric neurons, and in-vitro and in-vivo animal studies demonstrating that mast cell mediators may influence enteric motility provides a biologically plausible causal mechanism in IBS. Pilot studies on patients with IBS using the mast cell stabiliser sodium cromoglycate ('proof of concept') have been encouraging. The essential question remains why mast cells infiltrate the bowel of IBS patients. A disturbance of the 'brain-gut axis' is the current favoured hypothesis, whereby childhood stress or psychiatric comorbidity act via neuro-immune mechanisms to modulate low grade inflammation. An alternative hypothesis is that food allergy may be responsible. Serum specific IgE, and skin prick tests are not elevated in IBS patients, suggesting type 1 IgE mediated food allergy is not the cause. However questionnaire based studies indicate IBS patients have higher rates of atopic disease, and increased bronchial reactivity to methacholine has been demonstrated. In this review, we highlight the potential role of mast cells in IBS, and current and future research directions into this intriguing condition

A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen

The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized ubc-25, a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that ubc-25 acts in a linear pathway with cul-1/Cul1, in parallel to pathways employing cki-1/p27 and lin-35/pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that ubc-25 activity negatively regulates CYE-1/cyclin E protein abundance in vivo. Together, our results show that the ubc-25-mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development

Children's School Lives in Junior Infants

This report is the third in the series from Children’s School Lives, an innovative, longitudinal research study involving almost 4,000 children in 189 primary schools. One of the defining features of the study is the strong emphasis it places on listening to and learning directly from children about their experience of being in primary school in Ireland. This particular report introduces us to the youngest children in the study. The multiple perspectives gathered from the children themselves, their families, teachers and school principals, converge to provide us with a rich, detailed picture of the children’s first year in school. Uniquely, this period incorporates the months just prior to the arrival of the Coronavirus on Irish shores and the weeks immediately after the commencement of the first national lockdown in Spring 2020. Early childhood is a time of being and becoming, a time which provides important foundations for children’s learning and for life itself. We know from research that the first six years of a child’s life, their early childhood years, are particularly important for their holistic development. We also know from research that a positive transition from preschool to primary school is a predictor of children’s future success in terms of social, emotional and educational outcomes. Yet, despite this knowledge, relatively little research exists in the Irish context on children’s initial experiences in primary school. The Children’s School Lives study responds directly to this research gap by capturing, through multiple voices, comprehensive insights into the children’s initial weeks and months in their primary classrooms.National Council for Curriculum and Assessment (NCCA

Social and clinical determinants of preferences and their achievement at the end of life: Prospective cohort study of older adults receiving palliative care in three countries

© 2017 The Author(s). Background: Achieving choice is proposed as a quality marker. But little is known about what influences preferences especially among older adults. We aimed to determine and compare, across three countries, factors associated with preferences for place of death and treatment, and actual site of death. Methods: We recruited adults aged ≥65-years from hospital-based multiprofessional palliative care services in London, Dublin, New York, and followed them for >17 months. All services offered consultation on hospital wards, support for existing clinical teams, outpatient services and received funding from their National Health Service and/or relevant Insurance reimbursements. The New York service additionally had 10 inpatient beds. All worked with and referred patients to local hospices. Face-to-face interviews recorded most and least preferred place of death, treatment goal priorities, demographic and clinical information using validated questionnaires. Multivariable and multilevel analyses assessed associated factors. Results: One hundred and thirty eight older adults (64 London, 59 Dublin, 15 New York) were recruited, 110 died during follow-up. Home was the most preferred place of death (77/138, 56%) followed by inpatient palliative care/hospice units (22%). Hospital was least preferred (35/138, 25%), followed by nursing home (20%) and home (16%); hospice/palliative care unit was rarely least preferred (4%). Most respondents prioritised improving quality of life, either alone (54%), or equal with life extension (39%); few (3%) chose only life extension. There were no significant differences between countries. Main associates with home preference were: cancer diagnosis (OR 3.72, 95% CI 1.40-9.90) and living with someone (OR 2.19, 1.33-3.62). Adults with non-cancer diagnoses were more likely to prefer palliative care units (OR 2.39, 1.14-5.03). Conversely, functional independence (OR 1.05, 1.04-1.06) and valuing quality of life (OR 3.11, 2.89-3.36) were associated with dying at home. There was a mismatch between preferences and achievements - of 85 people who preferred home or a palliative care unit, 19 (25%) achieved their first preference. Conclusion: Although home is the most common first preference, it is polarising and for 16% it is the least preferred. Inpatient palliative care unit emerges as the second most preferred place, is rarely least preferred, and yet was often not achieved for those who wanted to die there. Factors affecting stated preferences and met preferences differ. Available services, notably community support and palliative care units, require expansion. Contrasting actual place of death with capacity for meeting patient and family needs may be a better quality indicator than simply 'achieved preferences'

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease

Extracranial and Intracranial Vasculopathy With “Moyamoya Phenomenon” in Association With Alagille Syndrome

Background: Alagille syndrome (AGS) is an autosomal-dominant, multisystem disorder caused by mutations in the JAG1 gene.Case Description: A 34-year-old man was referred to our service 10 years ago with focal seizures with impaired awareness and transient slurred speech. He had a 5-year history of intermittent left monocular low-flow retinopathy. He has a family history of AGS. General examination revealed mild hypertension, aortic regurgitation, and livedo reticularis. Neurological examination was normal.Investigations: He had mild hyperlipidaemia and persistently-positive lupus anticoagulant consistent with primary anti-phospholipid syndrome. Color Doppler ultrasound revealed low velocity flow in a narrowed extracranial left internal carotid artery (ICA). MR and CT angiography revealed a diffusely narrowed extracranial and intracranial left ICA. Formal cerebral angiography confirmed severe left ICA narrowing consistent with a left ICA “vasculopathy” and moyamoya phenomenon. Transthoracic echocardiogram revealed a bicuspid aortic valve and aortic incompetence. Molecular genetic analysis identified a missense mutation (A211P) in exon 4 of the JAG1 gene, consistent with AGS.Discussion: AGS should be considered in young adults with TIAs/stroke and unexplained extracranial or intracranial vascular abnormalities, and/or moyamoya phenomenon, even in the absence of other typical phenotypic features. Gene panels should include JAG1 gene testing in similar patients