Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders.

Introduction: Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods: The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3- CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results: This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass progenitors of cTfh or Tfh cells as well as early effector memory T cells that have not yet lost CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies of either isotype. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions: This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are often unknown.

Hatching plasticity is associated with a more advanced stage at hatching in an Ambystoma with terrestrial eggs.

Hatching plasticity allows animals to initiate hatching in response to environmental cues including predation, flooding, and hypoxia. In species with terrestrial eggs but aquatic larvae, hatching plasticity often manifests as extended development of embryos when water is not available. Although these effects are taxonomically widespread, little attention has focused on differences in plasticity across closely related species with terrestrial and aquatic embryos. We propose that the terrestrial embryonic environment favors slower and prolonged development and, consequently, that we should see differences in development between closely related species that differ in where they lay their eggs. We test this hypothesis by comparing embryonic development between two mole salamanders, Ambystoma opacum and A. annulatum. Most Ambystoma lay eggs submerged in ponds but A. opacum lays its eggs on land, where hatching is triggered when eggs are submerged by rising pond levels. Embryos of both species were reared under common laboratory conditions simulating both aquatic and terrestrial nest sites. Consistent with our hypothesis, we found that A. opacum embryos exhibited slower development and took longer to hatch than A. annulatum embryos in both rearing environments. Furthermore, we observed in A. opacum a plasticity in hatching stage that was absent in A. annulatum. Our results indicate that the terrestrial-laying A. opacum has evolved slower and prolonged development relative to its aquatic-laying congener and suggest that embryonic survival in the unpredictable terrestrial environment may be facilitated by developmental plasticity.

The role of glycosylation in clinical allergy and immunology.

While glycans are among the most abundant macromolecules on the cell with widespread functions, their role in immunity has historically been challenging to study. This is in part due to difficulties assimilating glycan analysis into routine approaches used to interrogate immune cell function. Despite this, recent developments have illuminated fundamental roles for glycans in host immunity. The growing field of glycoimmunology continues to leverage new tools and approaches to uncover the function of glycans and glycan-binding proteins in immunity. Here we utilize clinical vignettes to examine key roles of glycosylation in allergy, inborn errors of immunity, and autoimmunity. We will discuss the diverse functions of glycans as epitopes, as modulators of antibody function, and as regulators of immune cell function. Finally, we will highlight immune modulatory therapies that harness the critical role of glycans in the immune system.

A case of neonatal sweet syndrome associated with mevalonate kinase deficiency.

BACKGROUND: Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an immunologic syndrome characterized by widespread neutrophilic infiltration. Histiocytoid Sweet syndrome (H-SS) is a histopathologic variant of SS. While SS most commonly occurs in adults, this case report discusses an infant patient who presented with H-SS. CASE PRESENTATION: Through a multidisciplinary approach, this patient was also found to have very early onset inflammatory bowel disease (VEO-IBD) and Mevalonate kinase-associated disease (MKAD). While prior case studies have characterized an association between VEO-IBD and MKAD, there is no literature describing the association of all three diagnoses this case: H-SS, VEO-IBD and MKAD. Initiation of canakinumab in this patient resulted in successful control of the disease. CONCLUSIONS: This case highlights the importance of a multidisciplinary approach to rare diagnoses, and collaboration during cases with significant diagnostic uncertainty.

Looking beyond leaves: variation in nutrient leaching potential of seasonal litterfall among different species within an urban forest.

Urban litterfall that is deposited on impervious surface leaches nutrients into stormwater, contributing to downstream eutrophication. Previous studies have focused on the leaching potential of deciduous leaf litter, while other smaller-volume litterfall types-such as blossoms and fruit-may leach significant amounts of nitrogen, phosphorus, and carbon. These additional litterfall types represent an unaccounted-for source of nutrients to urban stormwater. We explored variation in leaching potential of dissolved nutrients and organic carbon across litter types and species by collecting litterfall (blossoms, fruit, leaves) from ten common urban tree species. After 24 h of leaching, we measured total phosphorus (TP), total dissolved nitrogen (TDN), and dissolved organic carbon (DOC) contributions and compared differences across litter types and species. Litter basket estimates then allowed us to quantify annual litterfall inputs. We found that blossoms leached 3-20 times more TDN and 1.5-7 times more TP than leaves of the same species. Furthermore, considering litterfall mass, several species had greater springtime nutrient-leaching potential compared to fall due to high leaching potential in blossoms and lower potential in leaves. We found mixed effects of leaf crushing and leachate solution (stormwater, salinity) on leaching rates. This study highlights the need to consider all litterfall types as well as variation in urban forest communities and conditions when seeking to budget, control, and maintain for potential nutrient sources from the urban forest. Supplementary information: The online version contains supplementary material available at 10.1007/s11252-022-01217-8.

COVID-19 Reveals Vulnerabilities of the Food-Energy-Water Nexus to Viral Pandemics.

Food, energy, and water (FEW) sectors are inextricably linked, making one sector vulnerable to disruptions in another. Interactions between FEW systems, viral pandemics, and human health have not been widely studied. We mined scientific and news/media articles for causal relations among FEW and COVID-19 variables and qualitatively characterized system dynamics. Food systems promoted the emergence and spread of COVID-19, leading to illness and death. Major supply-side breakdowns were avoided (likely due to low morbidity/mortality among working-age people). However, COVID-19 and physical distancing disrupted labor and capital inputs and stressed supply chains, while creating economic insecurity among the already vulnerable poor. This led to demand-side FEW insecurities, in turn increasing susceptibility to COVID-19 among people with many comorbidities. COVID-19 revealed trade-offs such as allocation of water to hygiene versus to food production and disease burden avoided by physical distancing versus disease burden from increased FEW insecurities. News/media articles suggest great public interest in FEW insecurities triggered by COVID-19 interventions among individuals with low COVID-19 case-fatality rates. There is virtually no quantitative analysis of any of these trade-offs or feedbacks. Enhanced quantitative FEW and health models are urgently needed as future pandemics are likely and may have greater morbidity and mortality than COVID-19.

Analysis of a COVID-19 Clinical Trial to Emphasize Experimental Design and Quantitative Reasoning in an Introductory Biology Course.

Increasing student exposure to primary literature in early biology coursework can enhance scientific literacy and quantitative reasoning skills. The efficacy of primary literature discussion is heavily impacted by article selection, as student engagement is optimal with material that is topical and has clear relevance to real world issues. During the COVID-19 pandemic, the prevalence of COVID-19-related scientific research in the mainstream media makes it an ideal topic for current discussion in entry-level biology courses. Here, we present an activity developed to facilitate a remote, synchronous discussion of an open access clinical trial publication on the experimental drug remdesivir in the treatment of COVID-19 (Beigel et al., 2020, N Engl J Med https://doi.org/10.1056/nejmoa2007764). The activity, which is amenable to adaptation for other research articles, emphasizes concepts in experimental design, statistical analysis, graphical interpretation, and the structure, content, and organization of typical sections of a primary research article. Importantly, the activity highlights the utility of the classroom response tool Pear Deck, a Google Slides add-on, for creating engaging literature discussions that can be readily adapted to a wide variety of teaching modalities.

Zero or not? Causes and consequences of zero-flow stream gage readings.

Streamflow observations can be used to understand, predict, and contextualize hydrologic, ecological, and biogeochemical processes and conditions in streams. Stream gages are point measurements along rivers where streamflow is measured, and are often used to infer upstream watershed-scale processes. When stream gages read zero, this may indicate that the stream has fully dried; however, zero-flow readings can also be caused by a wide range of other factors. Our ability to identify whether or not a zero-flow gage reading indicates a dry fluvial system has far reaching environmental implications. Incorrect identification and interpretation by the data user can lead to hydrologic, ecological, and/or biogeochemical predictions from models and analyses. Here, we describe several causes of zero-flow gage readings: frozen surface water, flow reversals, instrument error, and natural or human-driven upstream source losses or bypass flow. For these examples, we discuss the implications of zero-flow interpretations. We also highlight additional methodss for determining flow presence, including direct observations, statistical methods, and hydrologic models, which can be applied to interpret causes of zero-flow gage readings and implications for reach- and watershed-scale dynamics. Such efforts are necessary to improve our ability to understand and predict surface flow activation, cessation, and connectivity across river networks. Developing this integrated understanding of the wide range of possible meanings of zero-flows will only attain greater importance in a more variable and changing hydrologic climate.

Effects of arthropod inquilines on growth and reproductive effort among metacommunities of the purple pitcher plant (Sarracenia purpurea var. montana).

Many plant species harbor communities of symbionts that release nutrients used by their host plants. However, the importance of these nutrients to plant growth and reproductive effort is not well understood. Here, we evaluate the relationship between the communities that colonize pitcher plant phytotelmata and the pitcher plants' vegetative growth and flower production to better understand the symbiotic role played by phytotelma communities. We focus on the mountain variety purple pitcher plant (Sarracenia purpurea var. montana), which occurs in small and isolated populations in Western North Carolina. We found that greater symbiont community diversity is associated with higher flower production the following season. We then examined geographic variation in communities and found that smaller plant populations supported less diverse symbiont communities. We relate our observations to patterns of community diversity predicted by community ecology theory.

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.

Dry Wetlands: Nutrient Dynamics in Ephemeral Constructed Stormwater Wetlands.

Constructed stormwater wetlands (CSWs) are used to address contaminants in urban stormwater such as nitrogen (N) and phosphorus (P), but their performance is variable. Ephemeral CSWs tend to be less effective than perennial CSWs at removing N and P. We asked: How does wetland vegetation and sediment affect nutrient cycling/release from sediment and vegetation in ephemeral CSWs? We focused on two ephemeral urban CSWs in Pocatello, ID, USA, one densely vegetated and the other nearly bare. We rewetted intact cores of dry wetland sediments and, separately, senesced vegetation for 1 week at the end of the summer dry period to assess whether wetland sediments and vegetation acted as sources or sinks of N and P. For both CSWs, there was a pulse of nutrients immediately following rewetting, but the magnitude of that pulse and subsequent changes in nutrient concentrations suggest different processes dominate at each wetland, driven by differences in wetland vegetation and associated sediment characteristics. There was evidence of denitrification between and during events at the vegetated wetland, but larger fluxes of P at this site suggests a tradeoff between denitrification and P release. While the experimental results suggested specific biogeochemical controls, CSW nutrient concentrations during three events were more dynamic and suggested more biogeochemical complexity than that represented in our experiment, both within events and seasonally. Ephemeral CSWs may create unique biogeochemical conditions and require careful design to ensure N and P retention. Managers will also need to consider whether perennial water sources would improve CSW function.

Distributing regionally, distinguishing locally: examining the underlying effects of local land use on airborne bacterial biodiversity.

Airborne bacteria are abundant and can vary with land use. Urban expansion is increasing rapidly at a global scale, altering natural sources of airborne bacterial biodiversity, as soils and native plants are replaced by pavement and managed yards. Urbanization homogenizes the biodiversity of larger organisms, but its effects are understudied with respect to microbes. This study uses categorical and gradient approaches to examine airborne bacterial communities in southwest Michigan (USA). Airborne communities carried a gut-microbial signature and were equally homogenous above urban and rural sites, despite greater homogeneity of soil communities at urban sites. Ruminococcaceae were abundant, the source of which is likely wildlife. Beyond the gut-microbial signature, there were underlying effects of land use, which were evident in the shared airborne taxa across urban and rural sites. Bacillales, Burkholderiales, Alteromonadales and Pseudomonadales were shared more across urban sites, while Xanthomonadales, which contains crop-plant pathogens, were shared across rural agricultural sites. These results suggest that taxa which may distribute globally, coupled with localized sources, contribute to urban communities, while regional rural activities drive rural composition. We determined that soils were unlikely to contribute to broad distribution of some plant-associated taxa, but may be a source for distribution of others.

Socio-environmental consideration of phosphorus flows in the urban sanitation chain of contrasting cities.

Understanding how cities can transform organic waste into a valuable resource is critical to urban sustainability. The capture and recycling of phosphorus (P), and other essential nutrients, from human excreta is particularly important as an alternative organic fertilizer source for agriculture. However, the complex set of socio-environmental factors influencing urban human excreta management is not yet sufficiently integrated into sustainable P research. Here, we synthesize information about the pathways P can take through urban sanitation systems along with barriers and facilitators to P recycling across cities. We examine five case study cities by using a sanitation chains approach: Accra, Ghana; Buenos Aires, Argentina; Beijing, China; Baltimore, USA; and London, England. Our cross-city comparison shows that London and Baltimore recycle a larger percentage of P from human excreta back to agricultural lands than other cities, and that there is a large diversity in socio-environmental factors that affect the patterns of recycling observed across cities. Our research highlights conditions that may be "necessary but not sufficient" for P recycling, including access to capital resources. Path dependencies of large sanitation infrastructure investments in the Global North contrast with rapidly urbanizing cities in the Global South, which present opportunities for alternative sanitation development pathways. Understanding such city-specific social and environmental barriers to P recycling options could help address multiple interacting societal objectives related to sanitation and provide options for satisfying global agricultural nutrient demand.

"As a Parent You Become a Tiger": Parents Talking about Bullying at School.

Bullying at school can be a distressing experience for children. It is also likely to be distressing for their parents. In spite of this, research in the field of school bullying and peer victimisation has tended to overlook the experience of parents when their child is bullied. This study explored school bullying from the parent's perspective. Twenty-one parents took part in semi-structured focus groups and interviews to share their experiences. Thematic analysis of the interview transcripts identified two main themes: 'perceived institutional factors' and 'being a good parent'. It was found that parents viewed their principal role as protecting their child; they referred to this as an instinct and fundamental to them being a good parent. However, during their attempts to help their child, many parents talked about difficulties working with schools and this triggered frustration and distrust towards teachers. The findings highlight the importance of communication between parents and teachers and ensuring that parents are kept informed of progress when teachers are trying to address the problem. Additionally, the findings indicate that parents may hold different views to teachers about their role in school bullying situations. This would suggest that parents looking at the situation from the teacher's perspective, and vice versa, could help to build better parent-teacher relationships when tackling school bullying.

Sources and transport of nitrogen in arid urban watersheds.

Urban watersheds are often sources of nitrogen (N) to downstream systems, contributing to poor water quality. However, it is unknown which components (e.g., land cover and stormwater infrastructure type) of urban watersheds contribute to N export and which may be sites of retention. In this study we investigated which watershed characteristics control N sourcing, biogeochemical processing of nitrate (NO3-) during storms, and the amount of rainfall N that is retained within urban watersheds. We used triple isotopes of NO3- (δ15N, δ18O, and Δ17O) to identify sources and transformations of NO3- during storms from 10 nested arid urban watersheds that varied in stormwater infrastructure type and drainage area. Stormwater infrastructure and land cover--retention basins, pipes, and grass cover--dictated the sourcing of NO3- in runoff. Urban watersheds were strong sinks or sources of N to stormwater depending on runoff, which in turn was inversely related to retention basin density and positively related to imperviousness and precipitation. Our results suggest that watershed characteristics control the sources and transport of inorganic N in urban stormwater but that retention of inorganic N at the time scale of individual runoff events is controlled by hydrologic, rather than biogeochemical, mechanisms.

The possible use of combined electrical impedance and ultrasound velocity measurements for the non-invasive measurement of temperature during mild hyperthermia.

This paper explores the possibility of using combined measurements of electrical impedance and changes in ultrasound time of flight for determining deep body temperature during mild hyperthermia. Simultaneous electrical impedance spectra (1 kHz-1024 kHz) and ultrasound time-of-flight measurements were made on layered sheep liver and fat tissue samples as the temperature was increased from 30-50 °C. The change in propagation velocity for 100% fat and 100% liver samples was found to vary linearly with temperature and the temperature coefficient of the time-of-flight was shown to vary linearly with the % fat in the sample (0.009% °C-1%-1). Tetrapolar impedance measurements normalized to 8 kHz were shown to have a small sensitivity to temperature for both liver (0.001% °C-1 ≤ 45 °C) and fat (0.002% °C-1 ≤ 512 kHz) and the best linear correlation between the normalized impedance and the % fat in the sample was found at 256 kHz (gradient 0.026%-1, r2 = 0.65). A bootstrap analysis on 15 layered tissue samples evaluated using the normalized impedance at 256 kHz to determine the % fat in the sample and the temperature coefficient of the time of flight to determine the temperature. The results showed differences (including some large differences) between the predicted and measured temperatures and an error evaluation identified the possible origins of these.

The contribution of prescription chart design and familiarity to prescribing error: a prospective, randomised, cross-over study.

PURPOSE OF STUDY: Initiatives to standardise hospital paper-based prescription charts are underway in various countries in an effort to reduce prescribing errors. The aim of this study was to investigate the extent to which prescribing error rates are influenced by prescription chart design and familiarity. STUDY DESIGN: In this prospective, randomised, cross-over study, Foundation Year 1 doctors working in five Scottish National Health Service (NHS) Boards participated in study sessions during which they were asked to prescribe lists of medications for five fictional patients using a different design of paper prescription chart for each patient. Each doctor was timed completing each set of prescriptions, and each chart was subsequently assessed against a predefined list of possible errors. A mixed modelling approach using three levels of variables (design of and familiarity with a chart, prescribing speed and individual prescriber) was employed. RESULTS: A total of 72 Foundation Year 1 doctors participated in 10 data-collection sessions. Differences in prescription chart design were associated with significant variations in the rates of prescribing error. The charts from NHS Highland and NHS Grampian produced significantly higher error rates than the other three charts. Participants who took longer to complete their prescriptions made significantly fewer errors, but familiarity with a chart did not predict error rate. CONCLUSIONS: This study has important implications for prescription chart design and prescribing education. The inverse relationship between the time taken to complete a prescribing task and the rate of error emphasises the importance of attention to detail and workload as factors in error causation. Further work is required to identify the characteristics of prescription charts that are protective against errors.

Phosphorus in Phoenix: a budget and spatial representation of phosphorus in an urban ecosystem.

As urban environments dominate the landscape, we need to examine how limiting nutrients such as phosphorus (P) cycle in these novel ecosystems. Sustainable management of P resources is necessary to ensure global food security and to minimize freshwater pollution. We used a spatially explicit budget to quantify the pools and fluxes of P in the Greater Phoenix Area in Arizona, USA, using the boundaries of the Central Arizona-Phoenix Long-Term Ecological Research site. Inputs were dominated by direct imports of food and fertilizer for local agriculture, while most outputs were small, including water, crops, and material destined for recycling. Internally, fluxes were dominated by transfers of food and feed from local agriculture and the recycling of human and animal excretion. Spatial correction of P dynamics across the city showed that human density and associated infrastructure, especially asphalt, dominated the distribution of P pools across the landscape. Phosphorus fluxes were dominated by agricultural production, with agricultural soils accumulating P. Human features (infrastructure, technology, and waste management decisions) and biophysical characteristics (soil properties, water fluxes, and storage) mediated P dynamics in Phoenix. P cycling was most notably affected by water management practices that conserve and recycle water, preventing the loss of waterborne P from the ecosystem. P is not intentionally managed, and as a result, changes in land use and demographics, particularly increased urbanization and declining agriculture, may lead to increased losses of P from this system. We suggest that city managers should minimize cross-boundary fluxes of P to the city. Reduced P fluxes may be accomplished through more efficient recycling of waste, therefore decreasing dependence on external nonrenewable P resources and minimizing aquatic pollution. Our spatial approach and consideration of both pools and fluxes across a heterogeneous urban ecosystem increases the utility of nutrient budgets for city managers. Our budget explicitly links processes that affect P cycling across space with the management of other resources (e.g., water). A holistic management strategy that deliberately couples the management of P and other resources should be a priority for cities in achieving urban sustainability.

Global urban growth and the geography of water availability, quality, and delivery.

Globally, urban growth will add 1.5 billion people to cities by 2030, making the difficult task of urban water provisions even more challenging. In this article, we develop a conceptual framework of urban water provision as composed of three axes: water availability, water quality, and water delivery. For each axis, we calculate quantitative proxy measures for all cities with more than 50,000 residents, and then briefly discuss the strategies cities are using in response if they are deficient on one of the axes. We show that 523 million people are in cities where water availability may be an issue, 890 million people are in cities where water quality may be an issue, and 1.3 billion people are in cities where water delivery may be an issue. Tapping into groundwater is a widespread response, regardless of the management challenge, with many cities unsustainably using this resource. The strategies used by cities deficient on the water delivery axis are different than for cities deficient on the water quantity or water quality axis, as lack of financial resources pushes cities toward a different and potentially less effective set of strategies.