Evidence against the Detectability of a Hippocampal Place Code Using Functional Magnetic Resonance Imaging

Individual hippocampal neurons selectively increase their firing rates in specific spatial locations. As a population, these neurons provide a decodable representation of space that is robust against changes to sensory- and path-related cues. This neural code is sparse and distributed, theoretically rendering it undetectable with population recording methods such as functional magnetic resonance imaging (fMRI). Existing studies nonetheless report decoding spatial codes in the human hippocampus using such techniques. Here we present results from a virtual navigation experiment in humans in which we eliminated visual- and path-related confounds and statistical limitations present in existing studies, ensuring that any positive decoding results would represent a voxel-place code. Consistent with theoretical arguments derived from electrophysiological data and contrary to existing fMRI studies, our results show that although participants were fully oriented during the navigation task, there was no statistical evidence for a place code

Spectral Variations of Of?p Oblique Magnetic Rotator Candidates in the Magellanic Clouds

Optical spectroscopic monitoring has been conducted of two O stars in the Small and one in the Large Magellanic Cloud, the spectral characteristics of which place them in the Of?p category, which has been established in the Galaxy to consist of oblique magnetic rotators. All of these Magellanic stars show systematic spectral variations typical of the Of?p class, further strengthening their magnetic candidacy to the point of virtual certainty. The spectral variations are related to photometric variations derived from OGLE data by Naze et al. (2015) in a parallel study, which yields rotational periods for two of them. Now circular spectropolarimetry is required to measure their fields, and ultraviolet spectroscopy to further characterize their low-metallicity, magnetically confined winds, in support of hydrodynamical analyses.Comment: 18 pages, 6 figures, accepted for publication by A

Kinesin family member-18A (KIF18A) is a predictive biomarker of poor benefit from endocrine therapy in early ER+ breast cancer

PURPOSE: Identification of effective and reliable biomarkers that could be used to predict the efficacy of endocrine therapy is of crucial importance to the management of oestrogen receptor positive (ER+) breast cancer (BC). KIF18A, a key regulator of cell cycle, is overexpressed in many human cancers, including BC. In this study, we investigated the role of KIF18A as a biomarker to predict the benefit from endocrine treatment in early ER + BC patients.METHODS: KIF18A expression was assessed at the genomic level using the METABRIC dataset to explore its prognostic and predictive value in ER + BC patients (n = 1506). Predictive significance of KIF18A mRNA was validated using KM-Plot datasets (n = 2061). KIF18A protein expression was assessed using immunohistochemistry in a large annotated series of early-stage ER + BC (n = 1592) with long-term follow-up.RESULTS: High mRNA and protein expression of KIF18A were associated with short recurrence-free survival (RFS), distant-metastasis free survival (DMFS) and BC specific survival (all P  less than 0.05) in ER + BC in patients who received no adjuvant treatment or adjuvant endocrine therapy. In multivariate analysis, high KIF18A expression was an independent prognostic biomarker for poor RFS (P = 0.027) and DMFS (P = 0.028) in patients treated with adjuvant endocrine therapy.Conclusion: KIF18A appears to be a candidate biomarker of a subgroup of ER + BC characterised by poor clinical outcome. High KIF18A expression has prognostic significance to predict poor benefit from endocrine treatment for patients with ER + BC. Therefore, measurement of KIF18A on ER + BC patients prior to treatment could guide clinician decision on benefit from endocrine therapy

Evidence of Molecular Evolution Driven by Recombination Events Influencing Tropism in a Novel Human Adenovirus that Causes Epidemic Keratoconjunctivitis

In 2005, a human adenovirus strain (formerly known as HAdV-D22/H8 but renamed here HAdV-D53) was isolated from an outbreak of epidemic keratoconjunctititis (EKC), a disease that is usually caused by HAdV-D8, -D19, or -D37, not HAdV-D22. To date, a complete change of tropism compared to the prototype has never been observed, although apparent recombinant strains of other viruses from species Human adenovirus D (HAdV-D) have been described. The complete genome of HAdV-D53 was sequenced to elucidate recombination events that lead to the emergence of a viable and highly virulent virus with a modified tropism. Bioinformatic and phylogenetic analyses of this genome demonstrate that this adenovirus is a recombinant of HAdV-D8 (including the fiber gene encoding the primary cellular receptor binding site), HAdV-D22, (the ε determinant of the hexon gene), HAdV-D37 (including the penton base gene encoding the secondary cellular receptor binding site), and at least one unknown or unsequenced HAdV-D strain. Bootscanning analysis of the complete genomic sequence of this novel adenovirus, which we have re-named HAdV-D53, indicated at least five recombination events between the aforementioned adenoviruses. Intrahexon recombination sites perfectly framed the ε neutralization determinant that was almost identical to the HAdV-D22 prototype. Additional bootscan analysis of all HAdV-D hexon genes revealed recombinations in identical locations in several other adenoviruses. In addition, HAdV-D53 but not HAdV-D22 induced corneal inflammation in a mouse model. Serological analysis confirmed previous results and demonstrated that HAdV-D53 has a neutralization profile representative of the ε determinant of its hexon (HAdV-D22) and the fiber (HAdV-D8) proteins. Our recombinant hexon sequence is almost identical to the hexon sequences of the HAdV-D strain causing EKC outbreaks in Japan, suggesting that HAdV-D53 is pandemic as an emerging EKC agent. This documents the first genomic, bioinformatic, and biological descriptions of the molecular evolution events engendering an emerging pathogenic adenovirus

Technologies for the diagnosis of angle closure glaucoma (ACE): protocol of a prospective, multicentre, cross-sectional diagnostic study

INTRODUCTION: Angle-closure is responsible for half of all glaucoma blindness globally. Patients with suspected glaucoma require assessment of the drainage angle by an experienced clinician. The goal of this study is to evaluate the diagnostic performance and cost-effectiveness of two non-contact tests, anterior segment OCT (Optical Coherence Tomography) (AS-OCT) and limbal anterior chamber depth for patients referred to hospital with suspected angle closure compared with gonioscopy by ophthalmologist. METHODS AND ANALYSIS: Study design: prospective, multicentre, cross-sectional diagnostic accuracy study. INCLUSION CRITERIA: adults referred from community optometry to hospital with suspected angle closure. PRIMARY OUTCOME: Sensitivity and specificity. SECONDARY OUTCOMES: Positive/negative likelihood ratios, concordance, cost-effectiveness, proportion of patients requiring subsequent clinical assessment by ophthalmologist. SAMPLE SIZE: 600 individuals who have been referred with suspected angle closure from primary care (community optometry). We will have a 95% probability of detecting the true sensitivity of either test to within ±3.5% based on a sensitivity of 90%. The study would also have a 95% probability of detecting the true specificity of either test to within ±5%, assuming a specificity of 75%. ETHICS AND DISSEMINATION: Ethical Review Board approval was obtained. REC reference: 22/LO/0885. Our findings will be disseminated to those involved in eye care services. We will have a knowledge exchange event at the end of the study, published via the Health Technology Assessment web page and in specialist journals. The results will be presented at professional conferences and directly to patients via patient group meetings and the Glaucoma UK charity. TRIAL REGISTRATION NUMBER: ISRCTN15115867

The Onfp Class in the Magellanic Clouds

The Onfp class of rotationally broadened, hot spectra was defined some time ago in the Galaxy, where its membership to date numbers only eight. The principal defining characteristic is a broad, centrally reversed He II $\lambda$4686 emission profile; other emission and absorption lines are also rotationally broadened. Recent surveys in the Magellanic Clouds (MCs) have brought the class membership there, including some related spectra, to 28. We present a survey of the spectral morphology and rotational velocities, as a first step toward elucidating the nature of this class. Evolved, rapidly rotating hot stars are not expected theoretically, because the stellar winds should brake the rotation. Luminosity classification of these spectra is not possible, because the principal criterion (He II $\lambda$4686) is peculiar; however, the MCs provide reliable absolute magnitudes, which show that they span the entire range from dwarfs to supergiants. The Onfp line-broadening distribution is distinct and shifted toward larger values from those of normal O dwarfs and supergiants with >99.99% confidence. All cases with multiple observations show line-profile variations, which even remove some objects from the class temporarily. Some of them are spectroscopic binaries; it is possible that the peculiar profiles may have multiple causes among different objects. The origin and future of these stars are intriguing; for instance, they could be stellar mergers and/or gamma-ray-burst progenitors.Comment: 27 pages, 8 figures, 2 tables; AJ accepte

DNA damage response markers are differentially expressed in BRCA-mutated breast cancers

Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA-associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non-cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC