Audio producers often use musical underlays to emphasize key moments in spoken content and give listeners time to reflect on what was said. Yet, creating such underlays is time-consuming as producers must carefully (1) mark an emphasis point in the speech (2) select music with the appropriate style, (3) align the music with the emphasis point, and (4) adjust dynamics to produce a harmonious composition. We present UnderScore, a set of semi-automated tools designed to facilitate the creation of such underlays. The producer simply marks an emphasis point in the speech and selects a music track. UnderScore automatically refines, aligns and adjusts the speech and music to generate a high-quality underlay. UnderScore allows producers to focus on the high-level design of the underlay; they can quickly try out a variety of music and test different points of emphasis in the story. Amateur producers, who may lack the time or skills necessary to author underlays, can quickly add music to their stories. An informal evaluation of UnderScore suggests that it can produce high-quality underlays for a variety of examples while significantly reducing the time and effort required of radio producers.
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Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.
BACKGROUND: Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea/Trichoderma. RESULTS: Here we report an analysis of the genome sequences of the two biocontrol species Trichoderma atroviride (teleomorph Hypocrea atroviridis) and Trichoderma virens (formerly Gliocladium virens, teleomorph Hypocrea virens), and a comparison with Trichoderma reesei (teleomorph Hypocrea jecorina). These three Trichoderma species display a remarkable conservation of gene order (78 to 96%), and a lack of active mobile elements probably due to repeat-induced point mutation. Several gene families are expanded in the two mycoparasitic species relative to T. reesei or other ascomycetes, and are overrepresented in non-syntenic genome regions. A phylogenetic analysis shows that T. reesei and T. virens are derived relative to T. atroviride. The mycoparasitism-specific genes thus arose in a common Trichoderma ancestor but were subsequently lost in T. reesei. CONCLUSIONS: The data offer a better understanding of mycoparasitism, and thus enforce the development of improved biocontrol strains for efficient and environmentally friendly protection of plants.
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UNLABELLED: Crohn's disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR (P = 0.003) samples and positively correlated with levels of anti-Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli, suggesting that these organisms interact in the gut. The mass and thickness of triple-species (C. tropicalis plus S. marcescens plus E. coli) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis/E. coli, while E. coli was closely apposed with C. tropicalis Specific interkingdom microbial interactions may be key determinants in CD. IMPORTANCE: Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal (Candida tropicalis) and bacterial (Serratia marcescens and Escherichia coli) species that are associated with CD dysbiosis. Additionally, we found that the level of anti-Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis We also identified positive interkingdom correlations between C. tropicalis, E. coli, and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.
Over the past few months, COVID-19 has ravaged health systems and economies in countries across the world. While many would argue that a pandemic of respiratory disease was predictable, the systematic failures of the response came as a surprise. From the shortage of hospital beds and medical equipment to the gross insufficiencies in national surveillance systems, supply chains and laboratory capacity, COVID-19 has laid bare the health care limitations that ‘global north’ and ‘global south’ share. A stark set of differences, however, run across the parallels in our collective predicament: indeed, what has become ever-more apparent is the radically uneven distribution of the health, social and economic risks associated with the pandemic—and the public health measures implemented in response—both within and between societies. As concerns grow over a prolonged period of COVID-19 waves, further insights are needed into who bears the largest share of COVID-19 burden and why. The pursuit of health equity is widely held to be global health’s raison d’être; and yet, the deep inequities laid bare by the current pandemic underscore that the field must do more and we must do better. This article identifies five key domains for equity research and action going forward. These ‘equity frontiers’ are not meant to be exhaustive. Rather our emphasis here is on drawing lessons from the COVID-19 pandemic as a prompt for a revived—if not rethought—equity agenda for an evolving global health field.
Horizontal gene transfer shapes the genomes of prokaryotes by allowing rapid acquisition of novel adaptive functions. Conjugation allows the broadest range and the highest gene transfer input per transfer event. While conjugative plasmids have been studied for decades, the number and diversity of integrative conjugative elements (ICE) in prokaryotes remained unknown. We defined a large set of protein profiles of the conjugation machinery to scan over 1,000 genomes of prokaryotes. We found 682 putative conjugative systems among all major phylogenetic clades and showed that ICEs are the most abundant conjugative elements in prokaryotes. Nearly half of the genomes contain a type IV secretion system (T4SS), with larger genomes encoding more conjugative systems. Surprisingly, almost half of the chromosomal T4SS lack co-localized relaxases and, consequently, might be devoted to protein transport instead of conjugation. This class of elements is preponderant among small genomes, is less commonly associated with integrases, and is rarer in plasmids. ICEs and conjugative plasmids in proteobacteria have different preferences for each type of T4SS, but all types exist in both chromosomes and plasmids. Mobilizable elements outnumber self-conjugative elements in both ICEs and plasmids, which suggests an extensive use of T4SS in trans. Our evolutionary analysis indicates that switch of plasmids to and from ICEs were frequent and that extant elements began to differentiate only relatively recently. According to the present results, ICEs are the most abundant conjugative elements in practically all prokaryotic clades and might be far more frequently domesticated into non-conjugative protein transport systems than previously thought. While conjugative plasmids and ICEs have different means of genomic stabilization, their mechanisms of mobility by conjugation show strikingly conserved patterns, arguing for a unitary view of conjugation in shaping the genomes of prokaryotes by horizontal gene transfer.
Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.
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Rotaviruses (RVs) are responsible for more than 600,000 child deaths each year. The worldwide introduction of two life oral vaccines RotaTeq and Rotarix is believed to reduce this number significantly. Before the licensing of both vaccines, two new genotypes, G9 and G12, emerged in the human population and were able to spread across the entire globe in a very short time span. To quantify the VP7 mutation rates of these G9 and G12 genotypes and to estimate their most recent common ancestors, we used a Bayesian Markov chain Monte Carlo framework. Based on 356 sequences for G9 and 140 sequences for G12, we estimated mutation rates (nt substitutions/site/year) of 1.87 × 10(-3) (1.45-2.27 × 10(-3)) for G9 and 1.66 × 10(-3) (1.13-2.32 × 10(-3)) for G12. For both the G9 and G12 strains, one particular (sub) lineage was able to disseminate and cause disease across the world. The most recent common ancestors of these particular lineages were dated back to 1989 (1986-1992) and 1995 (1992-1998) for the G9 and G12 genotypes, respectively. These estimates suggest that a single novel RV (e.g., a vaccine escape mutant) can spread worldwide in little more than a decade. These results re-emphasize the need for thorough and continued RV surveillance in order to detect such potential spreading events at an early stage.
BACKGROUND: Public intimate partner violence (IPV) discourse emphasizes physical violence. In May 2016, the Twitter hashtag #MaybeHeDoesntHitYou generated a public conversation about abuse beyond physical IPV. Because of the often-disconnect between IPV research and what survivors struggle to name as abuse in their daily lives, we sought to understand how IPV discourse was unfolding as a result of the #MaybeHeDoesntHitYou hashtag. MATERIALS AND METHODS: NCapture was used to collect publically available Twitter data containing the hashtag "#MaybeHeDoesntHitYou" from May 10, 2016 to May 17, 2016. Using the Duluth Power and Control Wheel (a range of tactics used by abusers to control and harm their partners) and the Women's Experience with Battering (WEB) framework (emotional and behavioral responses to being abused), we analyzed 1,229 original content tweets using qualitative content analysis. RESULTS: All dimensions of the Power and Control Wheel and five of six dimensions of the WEB framework were expressed via #MaybeHeDoesntHitYou; users did not express yearning for intimacy with their abusive partners. Users described one form of IPV not currently represented within the Power and Control Wheel-reproductive coercion (e.g., "#MaybeHeDoesntHitYou but he refuses to use condoms and forces you not to use contraception so you try to do it behind his back"). Two additional themes emerged; users challenged the gender pronoun of the hashtag, highlighting that abuse may happen with partners of all genders, and users provided social support for others (e.g., "#MaybeHeDoesntHitYou is real. Bruises and scars aren't the only measure of abuse! If this is you, help is there…"). CONCLUSIONS: Results from our study underscore the potential for social media platforms to be powerful agents for engaging public dialogue about the realities of IPV, as well as a space for seeking and providing social support about this critical women's health issue.
The intervertebral disc is a specialized connective tissue critical for absorption of mechanical loads and providing flexibility to the spinal column. The disc ECM is complex and plays a vital role in imparting tissue its biomechanical function. The central NP is primarily composed of large aggregating proteoglycans (PGs) while surrounding AF is composed of fibrillar collagens, I and II. Aggrecan and versican in particular, due to their high concentration of sulfated GAG chains form large aggregates with hyaluronic acid (HA) and provide water binding capacity to the disc. Degradation of aggrecan core protein due to aggrecanase and MMP activity, SNPs that affect number of chondroitin sulfate (CS) substitutions and alteration in enzymes critical in synthesis of CS chains can impair the aggrecan functionality. Similarly, levels of many matrix and matrix-related molecules e.g. Col2, Col9, HAS2, ccn2 are dysregulated during disc degeneration and genetic animal models have helped establish causative link between their expression and disc health. In the degenerating and herniated discs, increased levels of inflammatory cytokines such as TNF-α, IL-1β and IL-6 are shown to promote matrix degradation through regulating expression and activity of critical proteases and stimulate immune cell activation. Recent studies of different mouse strains have better elucidated the broader impact of spontaneous degeneration on disc matrix homeostasis. SM/J mice showed an increased cell apoptosis, loss of cell phenotype, and cleavage of aggrecan during early stages followed by tissue fibrosis evident by enrichment of several collagens, SLRPs and fibronectin. In summary, while disc degeneration encompasses wide spectrum of degenerative phenotypes extensive matrix degradation and remodeling underscores all of them.
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Coral bleaching events have been predicted to occur more frequently in the coming decades with global warming. The susceptibility of corals to bleaching during thermal stress episodes is dependent on many factors and an understanding of these underlying drivers is crucial for conservation management. In 2013, a mild bleaching episode ensued in response to elevated sea temperature on the sediment-burdened reefs in Singapore. Surveys of seven sites highlighted variable bleaching susceptibility among coral genera-Pachyseris and Podabacia were the most impacted (31% of colonies of both genera bleached). The most susceptible genera such as Acropora and Pocillopora, which were expected to bleach, did not. Susceptibility varied between less than 6% and more than 11% of the corals bleached, at four and three sites respectively. Analysis of four of the most bleached genera revealed that a statistical model that included a combination of the factors (genus, colony size and site) provided a better explanation of the observed bleaching patterns than any single factor alone. This underscored the complexity in predicting the coral susceptibility to future thermal stress events and the importance of monitoring coral bleaching episodes to facilitate more effective management of coral reefs under climate change.
The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here, we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Because this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition, suggesting that this is a key feature of YAP signaling in mammalian cells.
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BACKGROUND: The ischemic heart is dependent on glycolysis for ATP generation, and therapies that increase glucose utilization during ischemia improve survival. Myocardial ischemia results in the translocation of the glucose transporter proteins GLUT1 and GLUT4 to the sarcolemma. The increased glucose entry via these transporters contributes to enhanced glycolysis during ischemia. METHODS AND RESULTS: To determine the role of GLUT4 in mediating increased glycolytic flux during ischemia, hearts from mice with cardiac-selective GLUT4 deficiency (G4H-/-) were subjected to global low-flow ischemia. During normal perfusion, hearts from fed G4H-/- mice showed increased GLUT1-mediated glucose uptake, higher concentrations of glycogen and phosphocreatine, but delayed recovery after ischemia. When these compensatory changes were eliminated by a 20-hour fast, G4H-/- hearts exhibited depressed glucose utilization during ischemia and developed profound and irreversible systolic and diastolic dysfunction associated with accelerated ATP depletion during ischemia and diminished regeneration of high-energy phosphate compounds on reperfusion. CONCLUSIONS: GLUT4 is an important mediator of enhanced glycolysis during ischemia and represents an important protective mechanism against ischemic injury.
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