The COVID-19 pandemic brought about an urgent need to monitor the community prevalence of infection and detect the presence of SARS-CoV-2. Testing individual people is the most reliable method to ...measure the spread of the virus in any given community, but it is also the most expensive and time-consuming. Wastewater-based epidemiology (WBE) has been used since the 1960s when scientists implemented monitoring to measure the effectiveness of the Polio vaccine. Since then, WBE has been used to monitor populations for various pathogens, drugs, and pollutants. In August 2020, the University of Tennessee-Knoxville implemented a SARS-CoV-2 surveillance program that began with raw wastewater surveillance of the student residence buildings on campus, the results of which were shared with another lab group on campus that oversaw the pooled saliva testing of students. Sample collection began at 8 am, and the final RT-qPCR results were obtained by midnight. The previous day's results were presented to the campus administrators and the Student Health Center at 8 am the following morning. The buildings surveyed included all campus dormitories, fraternities, and sororities, 46 buildings in all representing an on-campus community of over 8,000 students. The WBE surveillance relied upon early morning "grab" samples and 24-h composite sampling. Because we only had three Hach AS950 Portable Peristaltic Sampler units, we reserved 24-h composite sampling for the dormitories with the highest population of students. Samples were pasteurized, and heavy sediment was centrifuged and filtered out, followed by a virus concentration step before RNA extraction. Each sample was tested by RT-qPCR for the presence of SARS-CoV-2, using the CDC primers for N Capsid targets N1 and N3. The subsequent pooled saliva tests from sections of each building allowed lower costs and minimized the total number of individual verification tests that needed to be analyzed by the Student Health Center. Our WBE results matched the trend of the on-campus cases reported by the student health center. The highest concentration of genomic copies detected in one sample was 5.06 × 10
copies/L. Raw wastewater-based epidemiology is an efficient, economical, fast, and non-invasive method to monitor a large community for a single pathogen or multiple pathogen targets.
Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found ...that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, Fip200, Atg5, and Atg7 in myeloid cells also led to elevated basal lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases.
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•Epg5 deficiency causes innate immune lung inflammation and influenza resistance•Atg genes are required for homeostatic control of innate immune lung inflammation•The role of macrophages in limiting lung inflammation is Atg gene dependent•Disrupting Atg gene function increases lung inflammation and influenza resistance
Lu et al. report that Epg5, the mouse homolog of a human disease gene, and other autophagy (Atg) genes function in macrophages to maintain lung homeostasis by blunting innate immune inflammation. Disruption of this normal homeostatic mechanism results in lung inflammation and resistance to influenza infection.
Adenosine diphosphate (ADP)‐ribosylation is a post‐translational protein modification implicated in the regulation of a range of cellular processes. A family of proteins that catalyse ...ADP‐ribosylation reactions are the poly(ADP‐ribose) (PAR) polymerases (PARPs). PARPs covalently attach an ADP‐ribose nucleotide to target proteins and some PARP family members can subsequently add additional ADP‐ribose units to generate a PAR chain. The hydrolysis of PAR chains is catalysed by PAR glycohydrolase (PARG). PARG is unable to cleave the mono(ADP‐ribose) unit directly linked to the protein and although the enzymatic activity that catalyses this reaction has been detected in mammalian cell extracts, the protein(s) responsible remain unknown. Here, we report the homozygous mutation of the c6orf130 gene in patients with severe neurodegeneration, and identify C6orf130 as a PARP‐interacting protein that removes mono(ADP‐ribosyl)ation on glutamate amino acid residues in PARP‐modified proteins. X‐ray structures and biochemical analysis of C6orf130 suggest a mechanism of catalytic reversal involving a transient C6orf130 lysyl‐(ADP‐ribose) intermediate. Furthermore, depletion of C6orf130 protein in cells leads to proliferation and DNA repair defects. Collectively, our data suggest that C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP‐ribosylation, and we have implicated the importance of this protein in supporting normal cellular function in humans.
Crystal structure and biochemical data reveal a gene mutated in patients with severe neurodegeneration to encode an elusive enzyme for removing ADP‐ribose from proteins.
We present a comprehensive global catalog of the geomorphological features with clear or potential relevance to subsurface ice identified during the Dawn spacecraft's primary and first extended ...missions at Ceres. We define eight broad feature classes and describe analyses supporting their genetic links to subsurface ice. These classes include relaxed craters; central pit craters; large domes; small mounds; lobate landslides and ejecta; pitted materials; depressions and scarps; and fractures, grooves, and channels. Features in all classes are widely distributed on the dwarf planet, consistent with multiple lines of observational evidence that ice is a key component of Ceres' crust. Independent analyses of multiple feature types suggest rheological and compositional layering may be common in the upper ~10 km of the crust. Clustering of features indicates that ice concentration is heterogeneous on nearly all length scales, from ~1 km to hundreds of kilometers. Impacts are likely the key driver of heterogeneity, causing progressive devolatilization of the low latitude and midlatitude crust on billion‐year timescales but also producing localized enhancements in near surface ice content via excavation of deep ice‐rich material and possible facilitation of cryomagmatic and cryovolcanic activity. Impacts and landslides may be the dominant mechanism for ice loss on modern Ceres. Our analysis suggests specific locations where future high‐resolution imaging can be used to probe (1) current volatile loss rates and (2) the history of putative cryomagmatic and cryovolcanic features. The Cerean cryosphere and its unique morphology promise to be a rich subject of ongoing research for years to come.
Plain language summary
Planetary scientists are interested in understanding where ice is located in the solar system for two reasons. First, water is necessary to sustain life as we know it, so extraterrestrial ice may provide habitats for past or present life. Second, water ice can be used to produce rocket fuel; in the future, ice may be mined from asteroids, moons, and planets to fuel spacecraft carrying humans. Ceres has been predicted to contain large amounts of ice for decades. When the Dawn spacecraft arrived at Ceres, a major goal for the science team was confirming the presence of ice and understanding how it is distributed beneath the surface. One aspect of that investigation was identifying landforms (features like mountains or craters on the surface) whose appearance indicates the presence of ice. In this study, we compiled a catalog and global maps of all of the “icy” landforms identified during Dawn's primary mission at Ceres. We used these maps, together with detailed analysis of each type of landform, to develop a global picture of how ice is distributed in Ceres' crust. We found that the concentration of ice was spatially variable and that layering of icy and less icy materials may be common. We also identified specific areas of Ceres that may be particularly ice‐rich, so that future missions can target these areas for more analysis.
Key Points
We present a global catalog and maps of the morphological features relevant to subsurface ice identified during the Dawn mission at Ceres
Morphology suggests ice concentration is heterogeneous in the upper kilometers of Ceres' crust; impacts likely contribute to heterogeneity
We highlight locations where future analysis may provide insights into putative cryovolcanic features and current H2O loss mechanisms
We present a comprehensive report on the experimental details of the Antarctic Impulsive Transient Antenna (ANITA) long-duration balloon payload, including the design philosophy and realization, ...physics simulations, performance of the instrument during its first Antarctic flight completed in January of 2007, and expectations for the limiting neutrino detection sensitivity.
Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable ...expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.
Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main ...driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incorporating both domain expert knowledge and numerical data.
We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of a particularly high degree of uncertainty around data or domain expert knowledge.
Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an area under the receiver operating characteristic curve of 0.8 in predicting clinically-confirmed bacterial pneumonia with sensitivity 88% and specificity 66% given certain input scenarios (i.e., information that is available and entered into the model) and trade-off preferences (i.e., relative weightings of the consequences of false positive versus false negative predictions). We specifically highlight that a desirable model output threshold for practical use is very dependent upon different input scenarios and trade-off preferences. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures.
To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. We have shown how the method works and how it would help decision making on the use of antibiotics, providing insight into how computational model predictions may be translated to actionable decisions in practice. We discussed key next steps including external validation, adaptation and implementation. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.
ABSTRACT
It is still poorly constrained how the densest phase of the interstellar medium varies across galactic environment. A large observing time is required to recover significant emission from ...dense molecular gas at high spatial resolution, and to cover a large dynamic range of extragalactic disc environments. We present new NOrthern Extended Millimeter Array (NOEMA) observations of a range of high critical density molecular tracers (HCN, HNC, HCO+) and CO isotopologues (13CO, C18O) towards the nearby (11.3 Mpc) strongly barred galaxy NGC 3627. These observations represent the current highest angular resolution (1.85 arcsec; 100 pc) map of dense gas tracers across a disc of a nearby spiral galaxy, which we use here to assess the properties of the dense molecular gas, and their variation as a function of galactocentric radius, molecular gas, and star formation. We find that the HCN(1–0)/CO(2–1) integrated intensity ratio does not correlate with the amount of recent star formation. Instead, the HCN(1–0)/CO(2–1) ratio depends on the galactic environment, with differences between the galaxy centre, bar, and bar-end regions. The dense gas in the central 600 pc appears to produce stars less efficiently despite containing a higher fraction of dense molecular gas than the bar ends where the star formation is enhanced. In assessing the dynamics of the dense gas, we find the HCN(1–0) and HCO+(1–0) emission lines showing multiple components towards regions in the bar ends that correspond to previously identified features in CO emission. These features are cospatial with peaks of Hα emission, which highlights that the complex dynamics of this bar-end region could be linked to local enhancements in the star formation.
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