Biology subjects

Smith, E.

Publications and source records attributed to Smith, E..

7 recordsLinked to original sources

bioRxiv2018

Metabolic deregulation in prostate cancer

IntroductionThe prostate exhibits a unique metabolism that changes during initial neoplasia to aggressive prostate cancer (PCa) and metastasis. The study of PCa metabolism thus represents a new avenue for diagnostics, particularly early diagnosis of aggressive PCa cases.\n\nResultsHere, using transcriptomics data from The Cancer Genome Atlas (498 PCa patients), we identified six metabolic subgroups (C1-C6) of PCa that showed distinct disease-free survival outcomes (p<0.0001). In particular, we identified at least two PCa subgroups (C5 and C3) that exhibited significant poor prognosis (~70% and 30-40% relapse by the first 72 months; hazards ratios 9.4 and 4.4, respectively, relative to the best prognosis cluster C4 that showed <20% relapse even by 120 months). The subgroups were reproducible in an independent dataset from Taylors et al. 2010 (215 patients; p=0.00088). The subgroups displayed distinct metabolic profiles vis-a-vis normal tissues; measured as deregulation of metabolic pathways (using Pathifier, Drier & Domany, 2013). In particular, the poor-prognosis subgroups C5 and C3 showed considerable deregulation for pathways involved in synthesis and catabolism of complex forms of lipids and carbohydrates, amino acids, and TCA cycle, and these were exhibited in parallel or in the face of glycolysis, a common form of energy production in cancer cells. Furthermore, the subgroups were significantly over-enriched for different sets of genetic alterations [particularly, deletions/mutations in BRCA1 and TP53 (C5), RB1 and STK11(C3); and AR amplifications (C1); p[≤]8.6E-04], suggesting that distinct alterations may be underpinning the subgroups and pushing the subgroups towards their unique metabolic profiles. Finally, applying the classifier to blood expression profiles from 42 active surveillance (AS) and 65 advanced castrate resistant PCa (ACRPC) patients determined based on prostate-specific antigen (PSA) levels (Olmos et al., 2012) assigned 70.77% ACPRC, and interestingly reassigned 59.52% AS patients to at least one of the poor prognosis subgroups (C5, C3) with 35.71% to the poor and metabolically deregulated subgroup C3.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC=\"FIGDIR/small/371567_fig5.gif\" ALT=\"Figure 5\">\nView larger version (18K):\norg.highwire.dtl.DTLVardef@1418863org.highwire.dtl.DTLVardef@1614d77org.highwire.dtl.DTLVardef@124ca98org.highwire.dtl.DTLVardef@70d53b_HPS_FORMAT_FIGEXP M_FIG C_FIG ConclusionThe identification of PCa subgroups displaying distinct clinical outcomes solely from metabolic expression profiles of PCa tumours reiterates the significant link between deregulated metabolism and PCa outcomes (Eidelman et al., 2017). On the other hand, the time to biochemical relapse (rise in PSA levels) was not indicative of the early relapse seen for the metabolically deregulated subgroups C3 and C5 (these show considerably late BCR compared to C4). Our study thus highlights specific processes (elevated lipid and carbohydrate metabolism pathways) that could be better indicators than PSA for early diagnosis of aggressive PCa.

bioinformatics↗

bioRxiv2018

Inflammation induced by influenza virus impairs innate control of human pneumococcal carriage

Secondary bacterial pneumonia following influenza infection is a significant cause of mortality worldwide. Upper respiratory tract pneumococcal carriage is important as both determinants of disease and population transmission. The immunological mechanisms that contain pneumococcal carriage are well-studied in mice but remain unclear in humans. Loss of this control of carriage following influenza infection is associated with secondary bacterial pneumonia during seasonal and pandemic outbreaks. We used a human type 6B pneumococcal challenge model to show that carriage acquisition induces early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function associated with clearance of pneumococcal carriage. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate function and altered genome-wide nasal gene responses to pneumococcal carriage. Levels of the cytokine IP-10 promoted by viral infection at the time of pneumococcal encounter was positively associated with bacterial density. These findings provide novel insights in nasal immunity to pneumococcus and viral-bacterial interactions during co-infection.

immunology↗

bioRxiv2018

Effect of Live Attenuated Influenza Vaccine on Pneumococcal Carriage

The widely used nasally-administered Live Attenuated Influenza Vaccine (LAIV) alters the dynamics of naturally occurring nasopharyngeal carriage of Streptococcus pneumoniae in animal models. Using a human experimental model (serotype 6B) we tested two hypotheses: 1) LAIV increased the density of S. pneumoniae in those already colonised; 2) LAIV administration promoted colonisation. Randomised, blinded administration of LAIV or nasal placebo either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density of S. pneumoniae was determined from nasal washes by bacterial culture and PCR. Overall acquisition for bacterial carriage were not altered by prior LAIV administration vs. controls (25/55 [45.5%] vs 24/62 [38.7%] respectively, p=0.46). Transient increase in acquisition was detected in LAIV recipients at day 2 (33/55 [60.0%] vs 25/62 [40.3%] in controls, p=0.03). Bacterial carriage densities were increased approximately 10-fold by day 9 in the LAIV recipients (2.82 vs 1.81 log10 titers, p=0.03). When immunisation followed bacterial acquisition (n=163), LAIV did not change area under the bacterial density-time curve (AUC) at day 14 by conventional microbiology (primary endpoint), but significantly reduced AUC to day 27 by PCR (p=0.03). These studies suggest that LAIV may transiently increase nasopharyngeal density of S. pneumoniae. Transmission effects should therefore be considered in the timing design of vaccine schedules.\n\nTrial registrationThe study was registered on EudraCT (2014-004634-26)\n\nFundingThe study was funded by the Bill and Melinda Gates Foundation and the UK Medical Research Council.

immunology↗

bioRxiv2018

Electrophysiological characterization and MCH/orexin neuronal distribution in the lateral hypothalamus of naked mole-rats (Heterocephalus glaber)

The lateral hypothalamus (LH) controls various homeostatic processes, including sleep-wake cycles, energy balance and thermoregulation in many mammalian species. In the LH, melanin-concentrating hormone (MCH) and hypocretin/orexin (HO) containing neurons differentially regulate these processes. Naked mole-rats (NMR) (Heterocephalus glaber) are eusocial mammals with remarkable physiological peculiarities including extreme longevity without significant weight gain and absence of thermoregulation. Altered hypothalamic function could potentially underlie the unusual NMR phenotypes, but to date electrophysiological characterization of LH NMR neurons and expression of MCH and HO is missing. Here, we performed whole-cell recordings from LH neurons in acute NMR and mouse brain slices and found that NMR and mouse neuronal basic properties and activities were comparable. Additionally, we showed that both MCH-positive and HO-positive neuronal populations exist in the NMR hypothalamus and although the majority of MCH- and HO-positive neurons are located in the LH, as previously described in rodents, significant differences exist in MCH/HO distribution in other NMR hypothalamic areas. These results indicate that NMR LH neurons are comparable to mouse neurons with respect to their electrophysiological properties, but differences in the neuronal MCH and HO populations in hypothalamic regions exist and may contribute to the adaptive changes seen in NMR homeostatic processes.

neuroscience↗

bioRxiv2017

Paleophenotype Reconstruction Of Carbon Fixation Proteins As A Window Into Historic Biological States

Two datasets, the geologic record and the genetic content of extant organisms, provide complementary insights into the history of how key molecular components have shaped or driven global environmental and macroevolutionary trends. Changes in global physicochemical modes over time are thought to be a consistent feature of this relationship between Earth and life, as life is thought to have been optimizing protein functions for the entirety of its [~]3.8 billion years of history on Earth. Organismal survival depends on how well critical genetic and metabolic components can adapt to their environments, reflecting an ability to optimize efficiently to changing conditions. The geologic record provides an array of biologically independent indicators of macroscale atmospheric and oceanic composition, but provides little in the way of the exact behavior of the molecular components that influenced the compositions of these reservoirs. By reconstructing sequences of proteins that might have been present in ancient organisms, we can identify a subset of possible sequences that may have been optimized to these ancient environmental conditions. How can extant life be used to reconstruct ancestral phenotypes? Configurations of ancient sequences can be inferred from the diversity of extant sequences, and then resurrected in the lab to ascertain their biochemical attributes. One way to augment sequence-based, single-gene methods to obtain a richer and more reliable picture of the deep past, is to resurrect inferred ancestral protein sequences in living organisms, where their phenotypes can be exposed in a complex molecular-systems context, and to then link consequences of those phenotypes to biosignatures that were preserved in the independent historical repository of the geological record. As a first-step beyond single molecule reconstruction to the study of functional molecular systems, we present here the ancestral sequence reconstruction of the beta-carbonic anhydrase protein. We assess how carbonic anhydrase proteins meet our selection criteria for reconstructing ancient biosignatures in the lab, which we term paleophenotype reconstruction.

evolutionary biology↗

bioRxiv2017

Role of inhibitory control in modulating spread of focal ictal activity

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3 mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

neuroscience↗

bioRxiv2017

The Rise of the Middle Author: Investigating Collaboration and Division of Labor in Biomedical Research using Partial Alphabetical Authorship

Contemporary biomedical research is performed by increasingly large teams. As a consequence, an increasingly large number of individuals are being listed as authors in the byline of biomedical articles, which complicates the proper attribution of credit and responsibility to individual authors for their work. Typically, more importance is given to the first and last authors of biomedical papers, and the others (the middle authors) are considered to have made smaller contributions. However, we argue that this distinction between first, middle and last authors does not properly reflect the actual division of labor and does not allow a fair allocation of credit among the members of the research teams. In this paper, we use partial alphabetical authorship to divide the authors of all biomedical articles in the Web of Science published over the 1980-2015 period in three groups: primary authors, middle authors, and supervisory authors. We show that alphabetical ordering of middle authors is frequent in biomedical research, and that the prevalence of this practice is positively correlated with the number of authors in the bylines. We also find that, for articles with 7 or more authors, the average proportion of team members in each group is independent of the team size, more than half of the authors being middle authors. This suggests that growth in authors lists are not due to an increase in secondary contributions but, rather, in equivalent increases of all types of roles and contributions. Nevertheless, we show that the relative contribution of middle authors to the overall production of knowledge in the biomedical field as increased dramatically over the last 35 years.

scientific communication and education↗