Abstract
Summary
Fully exploiting the wealth of data in current bacterial population genomics datasets requires synthesizing and integrating different types of analysis across millions of base pairs ...in hundreds or thousands of isolates. Current approaches often use static representations of phylogenetic, epidemiological, statistical and evolutionary analysis results that are difficult to relate to one another. Phandango is an interactive application running in a web browser allowing fast exploration of large-scale population genomics datasets combining the output from multiple genomic analysis methods in an intuitive and interactive manner.
Availability and implementation
Phandango is a web application freely available for use at www.phandango.net and includes a diverse collection of datasets as examples. Source code together with a detailed wiki page is available on GitHub at https://github.com/jameshadfield/phandango.
Broadband access in the home is a necessity, especially since the COVID-19 pandemic. Increasingly, connectivity is of vital importance for school, work, family, and friends. Existing international ...research on the implementation of broadband has studied its adoption patterns with a focus on the rural/urban digital divide. This paper explores the digital divide in a case study of the seventh largest city, by population, in the United States; San Antonio is a majority-minority city where over half of the people are Hispanic. This paper focuses on the five key affordability factors that drive broadband adoption. Researchers test social exclusion theory, the structural facets of poverty and social marginality to ascertain its potential impact on broadband access. The authors conducted a survey in both English and Spanish to learn more about the affordability factors that influence the broadband digital divide. Through our analysis, we found evidence that four of the factors (geographical disparities, profit-based discrimination, technology deployment cost, and socio-economic factors) played a role in the digital divide in this case study. The results of this study demonstrate that the digital divide is not exclusively a rural/urban digital divide, but can also occur in an intra-city context. This is especially evident in low-income areas within the city because they have substantially lower broadband adoption rates. The results of this study demonstrate the importance of looking closely at issues of social exclusion of marginalized groups and the affordability of broadband access intra-city.
•Paper explored the digital divide in a case study a large U.S. city.•Examined five key affordability factors that drive broadband adoption.•Tested social exclusion theory and its potential impact on broadband access.•Surveyed affordability factors that influence the broadband digital divide.•Evidence for geographical disparities, profit-based discrimination, technology deployment cost, and socio-economic factors.
Many ecosystems are rapidly being transformed into new, non-historical configurations owing to a variety of local and global changes. We discuss how new systems can arise in the face of primarily ...biotic change (extinction and/or invasion), primarily abiotic change (e.g. land use or climate change) and a combination of both. Some changes will result in hybrid systems retaining some original characteristics as well as novel elements, whereas larger changes will result in novel systems, which comprise different species, interactions and functions. We suggest that these novel systems will require significant revision of conservation and restoration norms and practices away from the traditional place-based focus on existing or historical assemblages.
Fishes represent the most diverse group of vertebrates, having inhabited the Earth for approximately 480 million years during which they evolved many specialised adaptations. One such adaptation is ...the evolution of a venom system, which has convergently arisen on at least 19 separate occasions across their evolutionary history. Venom evolution across fishes has taken two forms: chemical weaponisation of previously evolved defensive spines and the development of an oral venom system. Fish venoms have been shown to contain a myriad of toxin types, some of which may have pharmacological potential. However, due to the labile nature of many toxins, fish venom has not been extensively investigated compared to other venomous groups such as reptiles and arachnids. This review provides an updated scope of our current knowledge regarding the biology, biochemistry, and evolution of fish venom systems. It also attempts to provide a coherent assessment of the dated literature while seeking to address particular issues in order to drive fish venom research further.
Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the ...Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.
Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease.
In this phase II study, we investigated the efficacy and safety of liposomal ...amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex MAC or Mycobacterium abscessus) disease.
During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events.
The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 32% of 44 vs. 4 9% of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. -25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation.
Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).
Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by
complex (MAC).
To evaluate the efficacy and safety of daily amikacin ...liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease.
Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6.
Enrolled patients (ALIS + GBT,
= 224; GBT-alone,
= 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57;
< 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively.
Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).
Massive galaxies in the early Universe have been shown to be forming stars at surprisingly high rates. Prominent examples are dust-obscured galaxies which are luminous when observed at sub-millimetre ...wavelengths and which may be forming stars at a rate of 1,000 solar masses (M ) per year. These intense bursts of star formation are believed to be driven by mergers between gas-rich galaxies. Probing the properties of individual star-forming regions within these galaxies, however, is beyond the spatial resolution and sensitivity of even the largest telescopes at present. Here we report observations of the sub-millimetre galaxy SMMJ2135-0102 at redshift z = 2.3259, which has been gravitationally magnified by a factor of 32 by a massive foreground galaxy cluster lens. This magnification, when combined with high-resolution sub-millimetre imaging, resolves the star-forming regions at a linear scale of only 100 parsecs. We find that the luminosity densities of these star-forming regions are comparable to the dense cores of giant molecular clouds in the local Universe, but they are about a hundred times larger and 107 times more luminous. Although vigorously star-forming, the underlying physics of the star-formation processes at z 2 appears to be similar to that seen in local galaxies, although the energetics are unlike anything found in the present-day Universe.
The role of airway microbiome in corticosteroid response in asthma is unknown.
To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with ...patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.
16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.
Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids.
A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.
The morphology and molecular composition of synapses provide the structural basis for synaptic function. This article reviews the electron microscopy of excitatory synapses on dendritic spines, using ...data from rodent hippocampus, cerebral cortex, and cerebellar cortex. Excitatory synapses have a prominent postsynaptic density, in contrast with inhibitory synapses, which have less dense presynaptic or postsynaptic specializations and are usually found on the cell body or proximal dendritic shaft. Immunogold labeling shows that the presynaptic active zone provides a scaffold for key molecules involved in the release of neurotransmitter, whereas the postsynaptic density contains ligand-gated ionic channels, other receptors, and a complex network of signaling molecules. Delineating the structure and molecular organization of these axospinous synapses represents a crucial step toward understanding the mechanisms that underlie synaptic transmission and the dynamic modulation of neurotransmission associated with short- and long-term synaptic plasticity.
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