The dynamics of hematopoiesis over the human lifespan.

Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear.

Biological sex affects functional variation across the human genome.

Humans display sexual dimorphism across many traits, but little is known about underlying genetic mechanisms and impacts on disease. We utilized single-cell RNA-seq of 480 lymphoblastoid cell lines to reveal that the vast majority (79%) of sex-biased genes are targets of transcription factors that display sex-biased expression. Further, we developed a two-step regression method that identified sex-biased expression quantitative trait loci (sb-eQTL) across the genome.

Examining holistically the experiences of mentors in school-based programs: A logic analysis.

The article presents a Logic Analysis of the Scottish MCR ("Motivation, Commitment and Resilience") Pathways school-based mentoring scheme. MCR Pathways provides vulnerable secondary school students with one-to-one support, helping them realize their full potential through education. The perceptions of 12 mentors were explored through interviews, thematically analyzed and mapped to derive the program's Theory of Change as regards the volunteers themselves.

Mapping Geographic Trends in Early Childhood Social, Emotional, and Behavioural Difficulties in Glasgow: 2010-2017.

Measuring variation in childhood mental health supports the development of local early intervention strategies. The methodological approach used to investigate mental health trends (often determined by the availability of individual level data) can affect decision making. We apply two approaches to identify geographic trends in childhood social, emotional, and behavioural difficulties using the Strengths and Difficulties Questionnaire (SDQ).

Inequalities in the dental health needs and access to dental services among looked after children in Scotland: a population data linkage study.

Background: There is limited evidence on the health needs and service access among children and young people who are looked after by the state. The aim of this study was to compare dental treatment needs and access to dental services (as an exemplar of wider health and well-being concerns) among children and young people who are looked after with the general child population.

Methods: Population data linkage study utilising national datasets of social work referrals for 'looked after' placements, the Scottish census of children in local authority schools, and national health service's dental health and service datasets.

Linking routinely collected social work, education and health data to enable monitoring of the health and health care of school-aged children in state care ('looked after children') in Scotland: a national demonstration project.

Background And Objectives: Children in state care ('looked after children') have poorer health than children who are not looked after. Recent developments in Scotland and elsewhere have aimed to improve services and outcomes for looked after children. Routine monitoring of the health outcomes of looked after children compared to those of their non-looked after peers is currently lacking.

Development and beyond: Strategy for long-term maintenance of an online laser diffraction particle size method in a spray drying manufacturing process.

The purpose of this manuscript is to present the intended use and long-term maintenance strategy of an online laser diffraction particle size method used for process control in a spray drying process. A Malvern Insitec was used for online particle size measurements and a Malvern Mastersizer was used for offline particle size measurements. The two methods were developed in parallel with the Mastersizer serving as the reference method.

Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses.

Recent studies have shown high usage of the IGHV1-69 germline immunoglobulin gene for influenza hemagglutinin stem-directed broadly-neutralizing antibodies (HV1-69-sBnAbs). Here we show that a major structural solution for these HV1-69-sBnAbs is achieved through a critical triad comprising two CDR-H2 loop anchor residues (a hydrophobic residue at position 53 (Ile or Met) and Phe54), and CDR-H3-Tyr at positions 98±1; together with distinctive V-segment CDR amino acid substitutions that occur in positions sparse in AID/polymerase-η recognition motifs. A semi-synthetic IGHV1-69 phage-display library screen designed to investigate AID/polη restrictions resulted in the isolation of HV1-69-sBnAbs that featured a distinctive Ile52Ser mutation in the CDR-H2 loop, a universal CDR-H3 Tyr at position 98 or 99, and required as little as two additional substitutions for heterosubtypic neutralizing activity.

The work of health visitors and school nurses with children with psychological and behavioural problems.

Aim: This paper is a report of a study to describe the workload of health visitors and school nurses in relation to children and young people with psychological, emotional or behavioural problems, and to identify perceived challenges, obstacles and sources of satisfaction associated with this aspect of their work.

Background: There is little published information on the work performed by non-specialist community nurses with children and young people who have psychological, emotional and behavioural problems.

Method: We analysed data from a survey conducted in 2002 - 2003 of 1049 Scottish professionals working with children and young people.

Early results of a comprehensive operative and perfusion strategy to attenuate the incidence of adverse neurological outcomes in on-pump coronary artery bypass grafting (CABG) patients.

Adverse neurological events, both focal (Type I) and non-focal (Type II), have been appreciated in postoperative on-pump coronary artery bypass grafting (CABG) patients for many years. Advanced age is a significant risk factor for adverse neurological events following CABG surgery. With full knowledge that our elderly population of patients was at high risk for these untoward neurological events, we adopted a comprehensive operative and perfusion strategy in an attempt to attenuate the incidence of these complications.

A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases.

We describe a novel and general way of generating high affinity peptide (HAP) binders to receptor tyrosine kinases (RTKs), using a multi-step process comprising phage-display selection, identification of peptide pairs suitable for hetero-dimerization (non-competitive and synergistic) and chemical synthesis of heterodimers. Using this strategy, we generated HAPs with K(D)s below 1 nM for VEGF receptor-2 (VEGFR-2) and c-Met. VEGFR-2 HAPs bound significantly better (6- to 500-fold) than either of the individual peptides that were used for heterodimer synthesis.

Site-specific characterization of the association of xylooligosaccharides with the CBM13 lectin-like xylan binding domain from Streptomyces lividans xylanase 10A by NMR spectroscopy.

Endo-beta-1,4-xylanase 10A (Xyn10A) from Streptomyces lividans includes an N-terminal catalytic module and a 130-residue C-terminal family 13 carbohydrate-binding module (CBM13). This latter domain adopts a beta-trefoil structure with three potential binding sites (alpha, beta, and gamma) for a variety of small sugars, xylooligosaccharides, and xylan polymers. To investigate the role of this multivalency in carbohydrate binding, we have used NMR spectroscopy to characterize the interaction of isolated CBM13 with a series of sugars.

Analysis of the dynamic properties of Bacillus circulans xylanase upon formation of a covalent glycosyl-enzyme intermediate.

NMR spectroscopy was used to search for mechanistically significant differences in the local mobility of the main-chain amides of Bacillus circulans xylanase (BCX) in its native and catalytically competent covalent glycosyl-enzyme intermediate states. 15N T1, T2, and 15N[1H] NOE values were measured for approximately 120 out of 178 peptide groups in both the apo form of the protein and in BCX covalently modified at position Glu78 with a mechanism-based 2-deoxy-2-fluoro-beta-xylobioside inactivator. Employing the model-free formalism of Lipari and Szabo, the measured relaxation parameters were used to calculate a global correlation time (tau(m)) for the protein in each form (9.

Drug target validation: lethal infection blocked by inducible peptide.

Genome projects are generating large numbers of potential new targets for drug discovery. One challenge is target validation, proving the usefulness of a specific target in an animal model. In this paper, we demonstrate a new approach to validation and assay development.

Immediate effect of aortic valve replacement for aortic stenosis on left ventricular diastolic chamber stiffness.

Diastolic dysfunction is common after coronary artery bypass surgery, and we hypothesized that left ventricular (LV) hypertrophy associated with aortic stenosis may lead to worsening LV diastolic function after aortic valve replacement for aortic stenosis. Transesophageal echocardiographic LV images and simultaneous pulmonary arterial wedge pressures were used to define the LV diastolic pressure cross-sectional area relation before and immediately after aortic valve replacement for aortic stenosis in 14 patients. In all patients, LV diastolic chamber stiffness increased, as evidenced by a leftward shift in the LV diastolic pressure cross-sectional area relation.

Characterization of a buried neutral histidine in Bacillus circulans xylanase: internal dynamics and interaction with a bound water molecule.

NMR spectroscopy was used to characterize the dynamic behavior of His149 in Bacillus circulans xylanase (BCX) and its interaction with an internal water molecule. Rate constants for the specific acid- and base-catalyzed exchange following bimolecular kinetics (EX2) of the nitrogen-bonded H epsilon 2 of this buried, neutral histidine were determined. At pDmin 7.

Characterization of a buried neutral histidine residue in Bacillus circulans xylanase: NMR assignments, pH titration, and hydrogen exchange.

Bacillus circulans xylanase contains two histidines, one of which (His 156) is solvent exposed, whereas the other (His 149) is buried within its hydrophobic core. His 149 is involved in a network of hydrogen bonds with an internal water and Ser 130, as well as a potential weak aromatic-aromatic interaction with Tyr 105. These three residues, and their network of interactions with the bound water, are conserved in four homologous xylanases.

N-acetylaspartate complexes with calcium and lanthanide ions.

N-acetylaspartate (NAA) is the one of the most prominent resonances observed in the solvent-suppressed NMR spectrum of the human brain. Although it is present in the brain at about 10 mM, its precise metabolic function is still unclear, We have examined the NAA as a potential chelator for divalent metal ions such as Ca2+. We have employed the perturbations induced by Ln3+ ions in the 1H and 13C NMR spectrum of NAA to monitor formation of NAA complexes.

Ischemic papillary muscle dysfunction in an adult with a parachute mitral valve.

A case of severe mitral regurgitation secondary to an infarct of a single papillary muscle in a 65-year-old female with a parachute mitral valve is described. To the best of our knowledge this is the oldest patient reported with this rare congenital anomaly. The clinical and echocardiographic features are discussed.

Right coronary artery stenosis: an independent predictor of atrial fibrillation after coronary artery bypass surgery.

Objectives: This study attempted to determine the importance of severe proximal right coronary artery disease as a predictor of atrial fibrillation in patients after coronary artery bypass surgery.

Background: Studies in patients undergoing noncardiac surgery have suggested that ischemia in the right coronary artery distribution is associated with a high incidence of atrial fibrillation. However, the importance of right coronary artery disease as a predictor of atrial fibrillation after bypass surgery is unknown.

Increased left ventricular diastolic chamber stiffness immediately after coronary artery bypass surgery.

Objectives: The aim of this study was to assess the incidence and severity of left ventricular diastolic dysfunction immediately after coronary artery bypass surgery by utilizing simultaneous transesophageal echocardiographic and hemodynamic monitoring.

Background: Left ventricular diastolic dysfunction has been documented after coronary bypass surgery, but its measurement has been technically difficult to acquire and limited by dependence on loading conditions.

Methods: End-diastolic pressure-area curves were constructed before and immediately after coronary bypass surgery in 20 patients.

Left ventricular dysfunction during infrarenal abdominal aortic aneurysm repair.

Background: Clinical observations suggest that pulmonary artery occlusion pressure (PAOP) underestimates the resuscitative volumes required prior to release of aortic cross-clamp.

Methods: To investigate pressure-volume relationships associated with repair of abdominal aortic aneurysm (AAA), we simultaneously monitored PAOP by pulmonary artery catheter (PAC) and estimated left ventricular (LV) diastolic volume using two-dimensional transesophageal echocardiography (TEE) in 22 patients undergoing AAA repair. Data from PAC monitoring and TEE were collected before, during, and after aortic occlusion.

Systolic anterior motion of the mitral valve after valve repair without an annular ring.

A 78-year-old woman underwent mitral reconstruction, consisting of a quadrangular posterior leaflet resection without a concomitant annular ring, for symptomatic mitral regurgitation. Postoperatively she became hypotensive while being treated with dopamine. Transesophageal echocardiography revealed systolic anterior motion of the mitral valve with significant mitral regurgitation.

Isotope effects in peptide group hydrogen exchange.

Kinetic and equilibrium isotope effects in peptide group hydrogen exchange reactions were evaluated. Unlike many other reactions, kinetic isotope effects in amide hydrogen exchange are small because exchange pathways are not limited by bond-breaking steps. Rate constants for the acid-catalyzed exchange of peptide group NH, ND, and NT in H2O are essentially identical, but a solvent isotope effect doubles the rate in D2O.