‘It’s a-me, Mario!’ Exploring dynamic changes and similarities in the composition of early Nintendo video game music

As with films, a thoughtfully composed video game soundtrack has the ability to dramatically enhance and elevate the experience for the audience or player. This article explores the potential issues and difficulties of composing for video game systems by studying the sound-producing hardware and music for two popular systems from one manufacturer. By comparing two of Nintendo’s Super Mario titles, which appeared on both 8-bit and 16-bit systems, through an analysis of the technology, audio, visual (audiovisual), music, and gameplay elements, it is shown that the musical composition was affected by the limitations of processing power. The discussion shows how the composer, Koji Kondo, overcame the issues of limited computing power by using layers of repetition while applying various functions of music for film to enhance player immersion. Kondo composed theme music that has become engrained in popular culture and is synonymous with one of Nintendo’s flagship franchises (Greening, 2014). By attempting to understand the method or approach behind the composition for earlier systems, it is possible to investigate and discuss the evolution of video game music while acknowledging and contributing to the study of music for games. A musical analysis of the Castle and Underwater themes on each system allows for a direct comparison of the compositional approach, while an audiovisual analysis reveals the presence of existing cinematic tropes and identifies potential influences on the creation of effective musical soundtracks for video games. Applying audiovisual theory to games will require the use of existing literature from Lissa (1965), Gorbman (1987), Chion (1994) and Tagg (2004), along with the work of Collins (2005; 2007a; 2007b; 2008a; 2008b), which adapts and applies audiovisual analysis to video games

Draft Genome Sequences of Five Novel Polyketide Synthetase-Containing Mouse

We report herein the draft genomes of five novel Escherichia coli strains isolated from surveillance and experimental mice housed at MIT and the Whitehead Institute and describe their genomic characteristics in context with the polyketide synthetase (PKS)-containing pathogenic E. coli strains NC101, IHE3034, and A192PP.National Institutes of Health (U.S.) (P30-ES002109)National Institutes of Health (U.S.) (T32OD010978)National Institutes of Health (U.S.) (R010D0111141

Systematically Searching for New Resonances at the Energy Frontier using Topological Models

We propose a new strategy to systematically search for new physics processes in particle collisions at the energy frontier. An examination of all possible topologies which give identifiable resonant features in a specific final state leads to a tractable number of `topological models' per final state and gives specific guidance for their discovery. Using one specific final state, $\ell\ell jj$, as an example, we find that the number of possibilities is reasonable and reveals simple, but as-yet-unexplored, topologies which contain significant discovery potential. We propose analysis techniques and estimate the sensitivity for $pp$ collisions with $\sqrt{s}=14$ TeV and $\mathcal{L}=300$ fb$^{-1}$

Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response

Objective: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. Results: H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Conclusions: Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.National Institutes of Health (U.S.) (grant 5R01CA093405-11)Columbia University Medical Center (Naomi Berrie Diabetes Center, grant P30DK063608

Helicobacter pylori Infection Promotes Methylation and Silencing of Trefoil Factor 2, Leading to Gastric Tumor Development in Mice and Humans

Background & Aims Trefoil factors (TFFs) regulate mucosal repair and suppress tumor formation in the stomach. Tff1 deficiency results in gastric cancer, whereas Tff2 deficiency increases gastric inflammation. TFF2 expression is frequently lost in gastric neoplasms, but the nature of the silencing mechanism and associated impact on tumorigenesis have not been determined. Methods We investigated the epigenetic silencing of TFF2 in gastric biopsy specimens from individuals with Helicobacter pylori-positive gastritis, intestinal metaplasia, gastric cancer, and disease-free controls. TFF2 function and methylation were manipulated in gastric cancer cell lines. The effects of Tff2 deficiency on tumor growth were investigated in the gp130[superscript F/F] mouse model of gastric cancer. Results In human tissue samples, DNA methylation at the TFF2 promoter began at the time of H pylori infection and increased throughout gastric tumor progression. TFF2 methylation levels were inversely correlated with TFF2 messenger RNA levels and could be used to discriminate between disease-free controls, H pylori-infected, and tumor tissues. Genome demethylation restored TFF2 expression in gastric cancer cell lines, so TFF2 silencing requires methylation. In Tff2-deficient gp130[superscript F/F]/Tff2[superscript −/−] mice, proliferation of mucosal cells and release of T helper cell type-1 (Th-1) 1 cytokines increased, whereas expression of gastric tumor suppressor genes and Th-2 cytokines were reduced, compared with gp130[superscript F/F]controls. The fundus of gp130[superscript F/F]/Tff2[superscript −/−] mice displayed glandular atrophy and metaplasia, indicating accelerated preneoplasia. Experimental H pylori infection in wild-type mice reduced antral expression of Tff2 by increased promoter methylation. Conclusions TFF2 negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H pylori infection.National Health and Medical Research Council (Australia

A 12-Week, Randomized, Controlled Trial with a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome with Constipation

Objectives: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). Methods: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration's (FDA's) primary end point for IBS-C (responder: improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored. Results: The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients. Conclusions: Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period

The mechanisms and processes of connection: developing a causal chain model capturing impacts of receiving recorded mental health recovery narratives.

BACKGROUND: Mental health recovery narratives are a core component of recovery-oriented interventions such as peer support and anti-stigma campaigns. A substantial number of recorded recovery narratives are now publicly available online in different modalities and in published books. Whilst the benefits of telling one's story have been investigated, much less is known about how recorded narratives of differing modalities impact on recipients. A previous qualitative study identified connection to the narrator and/or to events in the narrative to be a core mechanism of change. The factors that influence how individuals connect with a recorded narrative are unknown. The aim of the current study was to characterise the immediate effects of receiving recovery narratives presented in a range of modalities (text, video and audio), by establishing the mechanisms of connection and the processes by which connection leads to outcomes. METHOD: A study involving 40 mental health service users in England was conducted. Participants were presented with up to 10 randomly-selected recovery narratives and were interviewed on the immediate impact of each narrative. Thematic analysis was used to identify the mechanisms of connection and how connection leads to outcome. RESULTS: Receiving a recovery narrative led participants to reflect upon their own experiences or those of others, which then led to connection through three mechanisms: comparing oneself with the narrative and narrator; learning about other's experiences; and experiencing empathy. These mechanisms led to outcomes through three processes: the identification of change (through attending to narrative structure); the interpretation of change (through attending to narrative content); and the internalisation of interpretations. CONCLUSIONS: This is the first study to identify mechanisms and processes of connection with recorded recovery narratives. The empirically-based causal chain model developed in this study describes the immediate effects on recipients. This model can inform selection of narratives for use in interventions, and be used to support peer support workers in recounting their own recovery narratives in ways which are maximally beneficial to others

An analysis of baseline data from the PROUD study: an open-label randomised trial of pre-exposure prophylaxis

Background: Pre-exposure prophylaxis (PrEP) has proven biological efficacy to reduce the sexual acquisition of the human immunodeficiency virus (HIV). The PROUD study found that PrEP conferred higher protection than in placebo-controlled trials, reducing HIV incidence by 86 % in a population with seven-fold higher HIV incidence than expected. We present the baseline characteristics of the PROUD study population and place the findings in the context of national sexual health clinic data. Methods: The PROUD study was designed to explore the real-world effectiveness of PrEP (tenofovir-emtricitabine) by randomising HIV-negative gay and other men who have sex with men (GMSM) to receive open-label PrEP immediately or after a deferral period of 12 months. At enrolment, participants self-completed two baseline questionnaires collecting information on demographics, sexual behaviour and lifestyle in the last 30 and 90 days. These data were compared to data from HIV-negative GMSM attending sexual health clinics in 2013, collated by Public Health England using the genitourinary medicine clinic activity database (GUMCAD). Results: The median age of participants was 35 (IQR: 29–43). Typically participants were white (81 %), educated at a university level (61 %) and in full-time employment (72 %). Of all participants, 217 (40 %) were born outside the UK. A sexually transmitted infection (STI) was reported to have been diagnosed in the previous 12 months in 330/515 (64 %) and 473/544 (87 %) participants reported ever having being diagnosed with an STI. At enrolment, 47/280 (17 %) participants were diagnosed with an STI. Participants reported a median (IQR) of 10 (5–20) partners in the last 90 days, a median (IQR) of 2 (1–5) were condomless sex acts where the participant was receptive and 2 (1–6) were condomless where the participant was insertive. Post-exposure prophylaxis had been prescribed to 184 (34 %) participants in the past 12 months. The number of STI diagnoses was high compared to those reported in GUMCAD attendees. Conclusions: The PROUD study population are at substantially higher risk of acquiring HIV infection sexually than the overall population of GMSM attending sexual health clinics in England. These findings contribute to explaining the extraordinary HIV incidence rate during follow-up and demonstrate that, despite broad eligibility criteria, the population interested in PrEP was highly selective. Trial registration: Current Controlled TrialsISRCTN94465371. Date of registration: 28 February 2013