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Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Gastroenteropancreatic neuroendocrine tumours (GEP‐NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non‐secreting (also known as non‐functioning NETs) are associated with severe morbidity and have a median overall survival of 75–124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP‐NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled‐receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP‐NET subtypes. Using RNA‐Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non‐functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP‐NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC‐seq analyses in the pancreatic NET cell line QGP‐1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP‐1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP‐NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type. [ABSTRACT FROM AUTHOR]

Feedforward multilayer perceptron models (MLPs) have been applied to power distribution system state estimation (DSSE) in the past. Existing methods usually employ an ad-hoc or trial and error approach to MLP hyperparameter selection, and thus a systematic way of selecting the optimal hyperparameters including the number of neurons per hidden layer, learning rate, number of training epochs and training batch size is desirable and needed. This paper presents an approach based on Bayesian Optimization with Gaussian Processes for selecting MLP model hyperparameters for state estimation purposes. Results of the optimized MLP models are presented alongside the unoptimized models to compare performance of training, testing, and validation in terms of root-mean-squared-error (RMSE). Additionally, machine learning pipelines were employed and total execution time (seconds) for each trial is presented. The study shows that the MLP models obtained through the proposed optimization method outperform unoptimized models in terms of generalization capability for unseen, new cases. [ABSTRACT FROM AUTHOR]

Background: Altered neuronal timing and synchrony are biomarkers for Alzheimer's disease (AD) and correlate with memory impairments. Electrical stimulation of the fornix, the main fibre bundle connecting the hippocampus to the septum, has emerged as a potential intervention to restore network synchrony and memory performance in human AD and mouse models. However, electrical stimulation is non‐specific and may partially explain why fornix stimulation in AD patients has yielded mixed results. We hypothesize that driving the specific circuits underlying rhythmicity within the fornix via optogenetics at the biologically relevant theta rhythm (5Hz) will stabilize septo‐hippocampal network timing in an AD mouse model (hAPP‐j20) to alleviate hypersynchronous interictal spikes (IS) and restore memory performance. Methods: GABAergic neurons in the septum were transfected with the excitatory opsin ChETA (or eYFP controls) in J20+/+ or J20± littermate controls. An optical fibre was placed above the fornix to limit excitation to the projection fibres and recording electrodes were placed in CA1 to measure network oscillations. 5Hz stimulation was applied continuously for 4 hours following the encoding phase of either novel‐object‐location or passive contextual avoidance memory tasks. We also combined in vivo calcium imaging with electrical recordings in CA1 to monitor network activity to determine how IS shape hippocampal cell assemblies in J20+/+ mice without fornix stimulation. Results: Interictal spikes were present in sleep in J20+/+ mice, and at a higher rate during REM (4.78/min) compared to slow‐wave (1.76/min; n = 11, p<0.001, one‐way ANOVA). J20+eYFP controls displayed a strong negative correlation between the rate of IS and memory recall score (n = 9, r = ‐0.62, p = 0.015). 5Hz optical fornix stimulation reduced the occurrence of IS in REM both during stimulation and 4hrs post‐stimulation (n = 11, p = 0.024, repeated measures ANOVA). Continuous 4‐hour theta stimulation between the encoding and recall phases of both memory tasks rescued J20+ChETA performance to levels comparable with healthy controls while J20+eYFP mice performed at the chance level (n = 9‐10 per group, p = 0.017, two‐way mixed ANOVA). Conclusion: These data validate theta band optical stimulation as a viable method to pace the septo‐hippocampal network effectively reducing IS events and recovering memory performance in an APP mouse model. [ABSTRACT FROM AUTHOR]

The immunomodulatory drugs lenalidomide and pomalidomide promote recruitment and ubiquitination of substrate proteins to the [CRL4.sup.CRBN] (CUL4-DDB1-RBX1-CRBN) E3 ubiquitin ligase, leading to their subsequent degradation by the 26S proteasome (1,15,16). [...], Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the [CRL4.sup.CRBN] E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Grid cells in the medial entorhinal cortex (MEC) are unique in their spatial code (1,2). Unlike other place-modulated neurons, their population firing pattern not only repeats periodically within a given [...], Grid cells in the medial entorhinal cortex have spatial firing fields that repeat periodically in a hexagonal pattern. When animals move, activity is translated between grid cells in accordance with the animal&apos;s displacement in the environment. For this translation to occur, grid cells must have continuous access to information about instantaneous running speed. However, a powerful entorhinal speed signal has not been identified. Here we show that running speed is represented in the firing rate of a ubiquitous but functionally dedicated population of entorhinal neurons distinct from other cell populations of the local circuit, such as grid, head-direction and border cells. These &apos;speed cells&apos; are characterized by a context-invariant positive, linear response to running speed, and share with grid cells a prospective bias of ~50-80 ms. Our observations point to speed cells as a key component of the dynamic representation of self-location in the medial entorhinal cortex.

Discusses the history of library education and library educators. Highlights include Melvil Dewey's proposal for formal library education, the earlier apprentice system, obstacles to formal education, changes in attitudes toward patrons, accreditation, standards, and technological changes. (LRW)

Describes a survey of graduates from master's in library and information studies programs concerning social responsibility and gender issues and the treatment that these subjects received in their classes. Results are discussed that indicate that librarians and library education are less progressive than commonly depicted, and a copy of the survey is appended. (Author/LRW)

Reviews the literature on gender issues in librarianship and reports results of a survey of male librarians that examined reasons for entering the profession, family support for this decision, awareness of and attitude toward male librarian stereotypes, career goals, effects of gender on advancement, and other gender-related issues. (67 references) (MES)

Discussion of the value of knowledge about the history of library science in the formation of professional identity focuses on a survey that was designed to provide data about the patterns of research that characterize a group of library historians concerned with biography. Barriers to biographical research are examined. (32 references) (LRW)

A study was conducted to determine the efficacy of olaparib (AZD2281) in the treatment of cancer caused due to mutations of BRCA1 or BRCA2. Results revealed that olaparib had fewer side effects of conventional chemotherapy and manifested antitumor activity linked to mutations of BRCA1 and BRCA2.

What do searchers find when they look for literature on homosexuality? This question has profound implications for older as well as younger gays in their coming out, as well as in their subsequent identity development. Library records provide credible data to answer the question, since they represent relatively free sources of information, unlike data from bookstores, publishers, and some World Wide Web sites. The records of WorldCat, the world's largest union database of library records, comprise over 30 million records listed in the Online Computer Library Center. For the purposes of the study, 18,757 records listed under 'Homosexuality,' 'Gay Men,' and 'Gays' were downloaded; records for 'Lesbian' and 'Lesbians' were not examined. Findings of the study suggest that while there has indeed been considerable growth in terms of the quantity of gay literature produced since 1969, such gains may be offset by the deteriorating quality of cataloging copy, which makes the experience of browsing records a discouraging and confusing one. KEYWORDS. Gay literature, gay publishing, libraries, gay subject headings, search terms, databases, gay nomenclature, OCLC