Anorexia nervosa in males: similarities and differences to anorexia nervosa in females

INTRODUCTION Previous single case reports of males with anorexia nervosa from our database focused on the roles of gender and general personal identity conflicts and panic/guilt over the consequences of impulsivity in precipitating out the illness (Davis & Crisp, 1993; Fry & Crisp, 1989; Toms & Crisp, 1972), the growth stunting but reversible effects of early onset (Toms & Crisp, 1972), and a 35-year long follow-up of a case first seen in 1959 (Crisp, 1995). Our first reported series of 13 male patients (Crisp & Toms, 1972) drew attention to the many similarities to a female population but emphasised, descriptively, the high prevalence of psychiatric morbidity in the parents, often bound in with phobic avoidance behaviours and commonly coupled with over-protectiveness of the patient during childhood

Seasonal increases in fish trophic niche plasticity within a flood-pulse river ecosystem (Tonle Sap Lake, Cambodia)

Species' responses to seasonal environmental variation can influence trophic interactions and food web structure within an ecosystem. However, our ability to predict how species' interactions will vary spatially and temporally in response to seasonal variation unfortunately remains inadequate within most ecosystems. Fish assemblages in the Tonle Sap Lake (TSL) of Cambodia-a dynamic flood-pulse ecosystem-were studied for five years (2010-2014) using stable isotope and Bayesian statistical approaches to explore both within-and among-species isotopic niche variation associated with seasonal flooding. Roughly 600 individual fish specimens were collected during 19 sampling events within the lake. We found that fishes within the same species tended to have a broader isotopic niche during the wet season, likely reflecting assimilation of resources from either a wider range of isotopically distinct prey items or a variety of habitats, or both. Furthermore, among-species isotopic niches tended to overlap and range more broadly during the wet season, suggesting that floodplain inundation promotes exploitation of more diverse and similar resources by different species in the fish community. Our study highlights that the flood-pulse dynamic that is typical of tropical aquatic ecosystems may be an essential element supporting freshwater fish community structure and the fish diversity that underpins the TSL food web. This flow regime is currently threatened by regional dam development, which may in turn impact the natural function and structure of the fishery food web

Large magnetoelectric coupling in multiferroic oxide heterostructures assembled via epitaxial lift-off.

Epitaxial films may be released from growth substrates and transferred to structurally and chemically incompatible substrates, but epitaxial films of transition metal perovskite oxides have not been transferred to electroactive substrates for voltage control of their myriad functional properties. Here we demonstrate good strain transmission at the incoherent interface between a strain-released film of epitaxially grown ferromagnetic La0.7Sr0.3MnO3 and an electroactive substrate of ferroelectric 0.68Pb(Mg1/3Nb2/3)O3-0.32PbTiO3 in a different crystallographic orientation. Our strain mediated magnetoelectric coupling compares well with respect to epitaxial heterostructures, where the epitaxy responsible for strong coupling can degrade film magnetization via strain and dislocations. Moreover, the electrical switching of magnetic anisotropy is repeatable and non volatile. High resolution magnetic vector maps reveal that micromagnetic behaviour is governed by electrically controlled strain and film microstructure. Our demonstration should permit the physical/chemical properties in strain-released epitaxial oxide films to be controlled using electroactive substrates to impart strain via non epitaxial interfaces.Beatriu de Pinós postdoctoral fellowship (2014 BP-A 00079) from the Catalan government via the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR); Ministry of Science and Higher Education of Russian Federation, goszadanie no. 2019-1246; the Royal Society; EPSRC (Grant EP/P009050/1, EP/M010619/1 and the NoWNano DTC); European Research Council (ERC) (ERC-2016-STG-EvoluTEM-715502 and ERC Synergy HETERO2D); “la Caixa” Foundation (ID 100010434)

Use of genome sequencing to investigate the molecular basis of bacteriaphage interaction of the Escherichia coli O157 typing phages and the elucidation of the biological and public health significance of phage type

Background Shiga toxin producing Escherichia coli (STEC) O157 causes severe gastrointestinal disease and haemolytic uremic syndrome, and has a major impact on public health worldwide with regular outbreaks and sporadic infection. Phage typing, i.e. the susceptibility of STEC O157 strains to a bank of 16 bacteriophages, has been used in the UK to differentiate STEC O157 for the past 25 years and the phage type (PT) can be an epidemiological marker of strains associated with severe disease or associated with cases that occur from foreign travel. However, little is known about the molecular interactions between the typing phages (TP) and STEC O157. The aims of this thesis were to use whole genome sequencing to elucidate the genetic basis for phage typing of STEC O157 and through this understand genetic differences between strains relevant to disease severity and epidemiology. Results Sequencing the STEC O157 TPs revealed that they were clustered into 4 groups based on sequence similarity that corresponded with their infectivity. Long read sequencing revealed microevolutionary events occuring in STEC O157 genomes over a short time period (approximately 1 year), evidenced by the loss and gain of prophage regions and plasmids. An IncHI2 plasmid was found responsible for a change in Phage Type (PT) from PT8 to PT54 during two related outbreaks at the same restaurant. These changes resulted in a strain (PT54) that was fitter under certain growth conditions and associated with a much larger outbreak (140 as opposed to 4 cases). TraDIS (Transposon directed Insertion site sequencing) was used to identify 114 genes associated with phage sensitivity and 44 genes involved in phage resistance, emphasising the complex nature of identifying specific genetic markers of phage susceptibility or resistance. Further work is required to prove their phage-related functions but several are likely to encode novel phage receptors. Deletion of a Stx2a prophage from a PT21/28 strain led to a strain that typed as PT32, supporting the concept that the highly pathogenic PT21/28 lineage I strains emerged from Stx2c+ PT32 strains in the last two decades by acquisition of Stx2a-encoding prophages. Conclusions This body of work has highlighted the complexity of bacteriophage interaction and investigated the genetic basis for susceptibility and resistance in E. coli. The grouping of the TPs showed that resistance or susceptibility to all members of a typing group was likely to be caused by one mechanism. IncHI2 was identified as one of the markers for the PT54 phenotype. The Stx2a prophage region was associated with the switch from PT32 to PT21/28, although PT32 strains containing both Stx2a and Stx2c-encoding prophages have been isolated and can provide insights into phage variation underpinning the susceptibility to the relevant typing phages. The TraDIS results indicated that susceptibility or resistance was governed by multiple genetic factors and not controlled by a single gene. The significance of LPS for initial protection from phage adsorption was evident and a number of novel genes controlling phage susceptibility and resistance identified including the Sap operon and stringent starvation protein A respectively. While SNP-based typing provides an excellent indication of the evolution and relatedness of strains, phage typing can provide real insights into short term evolution of the bacteria as PTs can be altered by mobile elements such as prophages and plasmids. This study has shown that, although complex, genetic determinants for PT can be mined from the genome and allow us to understand the evolution of this zoonotic pathogen between host species and during outbreaks

Parallel ecological networks in ecosystems

In ecosystems, species interact with other species directly and through abiotic factors in multiple ways, often forming complex networks of various types of ecological interaction. Out of this suite of interactions, predator–prey interactions have received most attention. The resulting food webs, however, will always operate simultaneously with networks based on other types of ecological interaction, such as through the activities of ecosystem engineers or mutualistic interactions. Little is known about how to classify, organize and quantify these other ecological networks and their mutual interplay. The aim of this paper is to provide new and testable ideas on how to understand and model ecosystems in which many different types of ecological interaction operate simultaneously. We approach this problem by first identifying six main types of interaction that operate within ecosystems, of which food web interactions are one. Then, we propose that food webs are structured among two main axes of organization: a vertical (classic) axis representing trophic position and a new horizontal ‘ecological stoichiometry’ axis representing decreasing palatability of plant parts and detritus for herbivores and detrivores and slower turnover times. The usefulness of these new ideas is then explored with three very different ecosystems as test cases: temperate intertidal mudflats; temperate short grass prairie; and tropical savannah

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 + T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade

Panmicrobial Oligonucleotide Array for Diagnosis of Infectious Diseases

To facilitate rapid, unbiased, differential diagnosis of infectious diseases, we designed GreeneChipPm, a panmicrobial microarray comprising 29,455 sixty-mer oligonucleotide probes for vertebrate viruses, bacteria, fungi, and parasites. Methods for nucleic acid preparation, random primed PCR amplification, and labeling were optimized to allow the sensitivity required for application with nucleic acid extracted from clinical materials and cultured isolates. Analysis of nasopharyngeal aspirates, blood, urine, and tissue from persons with various infectious diseases confirmed the presence of viruses and bacteria identified by other methods, and implicated Plasmodium falciparum in an unexplained fatal case of hemorrhagic feverlike disease during the Marburg hemorrhagic fever outbreak in Angola in 2004–2005

The multistep hypothesis of ALS revisited: The role of genetic mutations.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins. METHODS: We generated incidence data from an ALS population register in Italy (2007-2015) for which genetic analysis for C9orf72, SOD1, TARDBP, and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006-2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene. RESULTS: Of the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age (r2 = 0.98) with a slope estimate of 4.65 (4.37-4.95), consistent with a 6-step process. The analysis for C9orf72-mutated patients confirmed a linear relationship (r2 = 0.94) with a slope estimate of 2.22 (1.74-2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for SOD1 and with a 4-step process for TARDBP. CONCLUSION: The identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes