Self-Grading: A Commentary

The theoretical perspectives and the various ways for implementing the self-grading strategy have been extensively discussed in the literature. In this paper, we aim to synthesize pertinent information and resources to deepen our understanding around self-grading and demystify any uncertainties about this concept, if any

Kinetochore alignment within the metaphase plate is regulated by centromere stiffness and microtubule depolymerases

During mitosis in most eukaryotic cells, chromosomes align and form a metaphase plate halfway between the spindle poles, about which they exhibit oscillatory movement. These movements are accompanied by changes in the distance between sister kinetochores, commonly referred to as breathing. We developed a live cell imaging assay combined with computational image analysis to quantify the properties and dynamics of sister kinetochores in three dimensions. We show that baseline oscillation and breathing speeds in late prometaphase and metaphase are set by microtubule depolymerases, whereas oscillation and breathing periods depend on the stiffness of the mechanical linkage between sisters. Metaphase plates become thinner as cells progress toward anaphase as a result of reduced oscillation speed at a relatively constant oscillation period. The progressive slowdown of oscillation speed and its coupling to plate thickness depend nonlinearly on the stiffness of the mechanical linkage between sisters. We propose that metaphase plate formation and thinning require tight control of the state of the mechanical linkage between sisters mediated by centromeric chromatin and cohesion

Breadth of CD8 T-cell mediated inhibition of replication of diverse HIV-1 transmitted-founder isolates correlates with the breadth of recognition within a comprehensive HIV-1 Gag, Nef, Env and Pol potential T-cell epitope (PTE) peptide set.

Full characterisation of functional HIV-1-specific T-cell responses, including identification of recognised epitopes linked with functional antiviral responses, would aid development of effective vaccines but is hampered by HIV-1 sequence diversity. Typical approaches to identify T-cell epitopes utilising extensive peptide sets require subjects' cell numbers that exceed feasible sample volumes. To address this, CD8 T-cells were polyclonally expanded from PBMC from 13 anti-retroviral naïve subjects living with HIV using CD3/CD4 bi-specific antibody. Assessment of recognition of individual peptides within a set of 1408 HIV-1 Gag, Nef, Pol and Env potential T-cell epitope peptides was achieved by sequential IFNγ ELISpot assays using peptides pooled in 3-D matrices followed by confirmation with single peptides. A Renilla reniformis luciferase viral inhibition assay assessed CD8 T-cell-mediated inhibition of replication of a cross-clade panel of 10 HIV-1 isolates, including 9 transmitted-founder isolates. Polyclonal expansion from one frozen PBMC vial provided sufficient CD8 T-cells for both ELISpot steps in 12 of 13 subjects. A median of 33 peptides in 16 epitope regions were recognised including peptides located in previously characterised HIV-1 epitope-rich regions. There was no significant difference between ELISpot magnitudes for in vitro expanded CD8 T-cells and CD8 T-cells directly isolated from PBMCs. CD8 T-cells from all subjects inhibited a median of 7 HIV-1 isolates (range 4 to 10). The breadth of CD8 T-cell mediated HIV-1 inhibition was significantly positively correlated with CD8 T-cell breadth of peptide recognition. Polyclonal CD8 T-cell expansion allowed identification of HIV-1 isolates inhibited and peptides recognised within a large peptide set spanning the major HIV-1 proteins. This approach overcomes limitations associated with obtaining sufficient cell numbers to fully characterise HIV-1-specific CD8 T-cell responses by different functional readouts within the context of extreme HIV-1 diversity. Such an approach will have useful applications in clinical development for HIV-1 and other diseases

The role of single nucleotide polymorphisms in breast cancer metastasis

Our understanding of many aspects of cancer biology has been advanced through the use of modern genetics. These studies have already shown that germ line polymorphisms play a significant role in disease initiation and response to therapy. However, what is less well studied is the role of germ line polymorphisms in cancer progression. Studies in rodents indicate that differential susceptibility to cancer metastasis can be heritable; thus, the search for the genes that control cancer metastasis is underway. Although some provocative studies suggest potential candidates for metastasis regulating genes, the conclusive identification of a specific inherited genetic variant that alters metastatic potential awaits further studies

Nitrides as ammonia synthesis catalysts and as potential nitrogen transfer reagents

In this article, an overview of the application of selected metal nitrides as ammonia synthesis catalysts is presented. The potential development of some systems into nitrogen transfer reagents is also described

Normal limits for oscillometric bronchodilator responses and relationships with clinical factors.

Introduction: We aimed to determine normal thresholds for positive bronchodilator responses for oscillometry in an Australian general population sample aged ≥40 years, to guide clinical interpretation. We also examined relationships between bronchodilator responses and respiratory symptoms, asthma diagnosis, smoking and baseline lung function. Methods: Subjects recruited from Sydney, Melbourne and Busselton, Australia, underwent measurements of spirometry, resistance (R rs6 ) and reactance (X rs6 ) at 6 Hz, before and after inhalation of salbutamol 200 μg. Respiratory symptoms and/or medication use, asthma diagnosis, and smoking were recorded. Threshold bronchodilator responses were defined as the fifth percentile of decrease in R rs6 and 95th percentile increase in X rs6 in a healthy subgroup. Results: Of 1318 participants, 1145 (570 female) were analysed. The lower threshold for ΔR rs6 was -1.38 cmH2O·s·L-1 (-30.0% or -1.42 Z-scores) and upper threshold for ΔX rs6 was 0.57 cmH2O·s·L-1 (1.36 Z-scores). Respiratory symptoms and/or medication use, asthma diagnosis, and smoking all predicted bronchodilator response, as did baseline oscillometry and spirometry. When categorised into clinically relevant groups according to those predictors, ΔX rs6 was more sensitive than spirometry in smokers without current asthma or chronic obstructive pulmonary disease (COPD), ∼20% having a positive response. Using absolute or Z-score change provided similar prevalences of responsiveness, except in COPD, in which responsiveness measured by absolute change was twice that for Z-score. Discussion: This study describes normative thresholds for bronchodilator responses in oscillometry parameters, including intra-breath parameters, as determined by absolute, relative and Z-score changes. Positive bronchodilator response by oscillometry correlated with clinical factors and baseline function, which may inform the clinical interpretation of oscillometry

NOD × 129.H2g7 Backcross Delineates 129S1/SvImJ-Derived Genomic Regions Modulating Type 1 Diabetes Development in Mice

OBJECTIVE: Introduction of genes targeted in 129/Sv embryonic stem (ES) cells into NOD mice brings about linked genes that may modulate type 1 diabetes. Our objective was to identify 129S1/SvJ non-MHC regions contributing type 1 diabetes resistance or susceptibility in backcross to NOD/LtJ. RESEARCH DESIGN AND METHODS: After congenic transfer of the NOD H2(g7) haplotype onto 129S1/Sv, 310 females were produced by NOD x (NOD x 129.H2(g7))F1 backcross (N2). A genome scan for quantitative trait locus (QTL) affecting clinical diabetes, age of diabetes onset, and insulitis severity was performed using subphenotype characteristics to improve power and resolution for detection of diabetes susceptibility loci. RESULTS: Thirty-six of 310 (11.6%) N2 females developed type 1 diabetes between 14 and 40 weeks. Significant evidence of linkage for only a single previously reported Idd complex locus (Idd10/17/18, chromosome [Chr] 3) was indicated for clinical diabetes. The quantitative traits of insulitis either alone or combined with age at type 1 diabetes onset were significantly linked to known Idd regions on Chr 1 (Idd5 region), Chr 4 (Idd9 region), Chr 8 (Idd22), Chr 11 (Idd4.3), and proximal Chr 17 (Idd16 region). Significant 129S1/Sv resistance contributions were identified on Chr 1, 15 (two loci), and 19, with suggestive evidence for additional novel 129/Sv resistance QTL on Chr 5 and 17 and susceptibility on Chr 2. CONCLUSIONS: The 129S1/SvJ genome harbors collections of both known and potentially novel non-MHC Idd loci. Investigators targeting 129/Sv genes mapping within chromosomal regions reported herein or elsewhere in the genome need to exclude potential contributions from linked Idd loci by generating a NOD.129 control strain expressing the nontargeted allele

Factors modulating herbivory patterns in Cymodocea nodosa meadows

In coastal marine food webs, seagrass-grazer interactions play a fundamental role in ecological processes by regulating the structure and functioning of plant communities. Therefore, assessing the strength of these seagrass-grazer links and identifying the mechanisms that regulate these relationships are crucial to increasing our understanding of community and ecosystem structure and dynamics. Herbivory on the temperate seagrass Cymodocea nodosa was evaluated in four locations with contrasting abiotic and biotic factors (i.e., depth; meadow size; seagrass shoot density, productivity, and leaf traits; and herbivore presence) using cross-transplantation experiments carried out once per season to account for seasonal variation. Patterns of feeding rates on C. nodosa meadows showed high temporal variability, with peaks occurring in spring and summer. Results indicate that between 46.59% and 74.08% of the annual leaf production is lost to herbivory at the locations sampled in this study. Herbivory rates increased with higher nitrogen content and shoot density for all types of consumers (mesograzers, fishes, and sea urchins). This work highlights the need to integrate the abiotic and biotic factors modulating herbivory patterns, particularly in a foundation species like C. nodosa, for which changes in plant traits and grazer abundance may trigger trophic cascades with far-reaching consequences for associated species.This study was funded by the Spanish national project CTM2011-24482 (SEA-LIVE), by the Junta de Andalucia Excelence Project PRODESCA (P12-RNM-3020)) and by Ser-Cady project (FEDER-UCA18-107451) cofinanced by the 2014–2020 ERDF Operational Programme and by the Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia. We thank Carmen Henares for field assistance

The 21Na(p,gamma)22Mg Reaction and Oxygen-Neon Novae

The 21Na(p,gamma)22Mg reaction is expected to play an important role in the nucleosynthesis of 22Na in Oxygen-Neon novae. The decay of 22Na leads to the emission of a characteristic 1.275 MeV gamma-ray line. This report provides the first direct measurement of the rate of this reaction using a radioactive 21Na beam, and discusses its astrophysical implications. The energy of the important state was measured to be E$_{c.m.}$= 205.7 $\pm$ 0.5 keV with a resonance strength $\omega\gamma = 1.03\pm0.16_{stat}\pm0.14_{sys}$ meV.Comment: Accepted for publication in Physical Review Letter

Longitudinal Outcomes of Gender Identity in Children (LOGIC): study protocol for a retrospective analysis of the characteristics and outcomes of children referred to specialist gender services in the UK and the Netherlands

INTRODUCTION: Specialist gender services for children and young people (CYP) worldwide have experienced a significant increase in referrals in recent years. As rates of referrals increase, it is important to understand the characteristics and profile of CYP attending these services in order to inform treatment pathways and to ensure optimal outcomes. METHODS AND ANALYSIS: A retrospective observational study of clinical health records from specialist gender services for CYP in the UK and the Netherlands. The retrospective analysis will examine routinely collected clinical and outcome measures data including demographic, clinical, gender identity-related and healthcare resource use information. Data will be reported for each service and also compared between services. This study forms part of a wider programme of research investigating outcomes of gender identity in children (the Longitudinal Outcomes of Gender Identity in Children study). ETHICS AND DISSEMINATION: The proposed study has been approved by the Health Research Authority and London-Hampstead Research Ethics Committee as application 19/LO/0181. The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events