SH2 domain protein E and ABL signaling regulate blood vessel size.

Blood vessels in different vascular beds vary in size, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow, eventually leading to the DA collapse. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA size in she mutants correlated with an increased endothelial expression of claudin 5a (cldn5a), which encodes a protein enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.

High Juvenile Mortality Overwhelms Benefits of Mating Potential for Reproductive Fitness.

AbstractAn individual's access to mates (i.e., its "mating potential") can constrain its reproduction but may also influence its fitness through effects on offspring survival. For instance, mate proximity may correspond with relatedness and lead to inbreeding depression in offspring. While offspring production and survival might respond differently to mating potential, previous studies have not considered the simultaneous effects of mating potential on these fitness components. We investigated the relationship of mating potential with both production and survival of offspring in populations of a long-lived herbaceous perennial, Echinacea angustifolia. Across 7 years and 14 sites, we quantified the mating potential of maternal plants in 1,278 mating bouts and followed the offspring from these bouts over 8 years. We used aster models to evaluate the relationship of mating potential with the number of offspring that emerged and that were alive after 8 years. Seedling emergence increased with mating potential. Despite this, the number of offspring surviving after 8 years showed no relationship to mating potential. Our results support the broader conclusion that the effect of mating potential on fitness erodes over time because of demographic stochasticity at the maternal level.

Racial and Ethnic Differences in Heroin, Methamphetamine, and Cocaine Use, Treatment, and Mortality Trends in 3 National Data Sources-United States, 2010-2019.

BACKGROUND: As overdose deaths continue to rise, public health officials need comprehensive surveillance data to design effective prevention, harm reduction, and treatment strategies. Disparities across race and ethnicity groups, as well as trends in substance use, treatment, or overdose deaths, have been examined individually, but reports rarely compare findings across multiple substances or data sources. OBJECTIVE: To provide a broad assessment of the overdose crisis, we describe trends in substance use, treatment, and overdose mortality across racial and ethnic groups for multiple substances. RESEARCH DESIGN: We conducted a longitudinal, cross-sectional analysis comparing trends. SUBJECTS: We identified self-reported use from the National Survey on Drug Use and Health, substance use treatment admissions from the Treatment Episode Data Set-Admissions, and overdose deaths from the CDC's Multiple Cause of Death files. MEASURES: We measured rates of substance use, treatment, and deaths involving heroin, methamphetamine, and cocaine among United States adults from 2010 to 2019. RESULTS: Heroin, methamphetamine, and cocaine use increased, though not all changes were statistically significant. Treatment admissions indicating heroin and methamphetamine increased while admissions indicating cocaine decreased. Overdose deaths increased among all groups: methamphetamine (257%-1,115%), heroin (211%-577%), and cocaine (88%-259%). Changes in rates of use, treatment, and death for specific substances varied by racial and ethnic group. CONCLUSIONS: Substance use, treatment, and overdose mortality changed considerably, though not always equivalently. Identifying diverging trends in substance-related measures for specific substances and racial and ethnic groups can inform targeted investment in treatment to reduce disparities and respond to emerging changes in the overdose crisis.

Hospital Addiction Medicine Consultation Service Orders and Outcomes by Patient Race and Ethnicity in an Urban, Safety-Net Hospital.

BACKGROUND: Hospital admissions involving substance use disorders are increasing and represent an opportunity to engage patients in substance use treatment. Addiction medicine consultation services improve access to medications for opioid use disorder (MOUD) and patient outcomes. However, as hospitals continue to adopt addiction medicine consultation services it is important to identify where disparities may emerge in the process of care. OBJECTIVE: To describe addiction medicine consultation service use by race and ethnicity as well as substance to identify opportunities to reduce substance use treatment disparities. DESIGN: Retrospective cohort study using 2016-2021 Electronic Health Record data from a large Midwest safety-net hospital. PARTICIPANTS: Hospitalized adults aged 18 or older, with one or more substance use disorders. MAIN MEASURES: Consultation orders placed, patient seen by consult provider, and receipt of MOUD by self-reported race. KEY RESULTS: Between 2016 and 2021, we identified 16,895 hospitalized patients with a substance use disorder. Consultation orders were placed for 6344 patients and 2789 were seen by the consult provider. Black patients were less likely (aOR = 0.58; 95% CI: 0.53-0.63) to have an addiction medicine consultation order placed and, among patients with a consultation order, were less likely (aOR = 0.74; 95% CI: 0.65-0.85) to be seen by the consult provider than White patients. Overall, Black patients with OUD were also less likely to receive MOUD in the hospital (aOR = 0.63; 95% CI: 0.50-0.79) compared to White patients. However, there were no differences in MOUD receipt among Black and White patients seen by the consult provider. CONCLUSIONS: Using Electronic Health Record data, we identified racial and ethnic disparities at multiple points in the inpatient addiction medicine consultation process. Addressing these disparities may support more equitable access to MOUD and other substance use treatment in the hospital setting.

Spatial and Temporal Resolution of Cyanobacterial Bloom Chemistry Reveals an Open-Ocean Trichodesmium thiebautii as a Talented Producer of Specialized Metabolites.

While the ecological role that Trichodesmium sp. play in nitrogen fixation has been widely studied, little information is available on potential specialized metabolites that are associated with blooms and standing stock Trichodesmium colonies. While a collection of biological material from a T. thiebautii bloom event from North Padre Island, Texas, in 2014 indicated that this species was a prolific producer of chlorinated specialized metabolites, additional spatial and temporal resolution was needed. We have completed these metabolite comparison studies, detailed in the current report, utilizing LC-MS/MS-based molecular networking to visualize and annotate the specialized metabolite composition of these Trichodesmium blooms and colonies in the Gulf of Mexico (GoM) and other waters. Our results showed that T. thiebautii blooms and colonies found in the GoM have a remarkably consistent specialized metabolome. Additionally, we isolated and characterized one new macrocyclic compound from T. thiebautii, trichothilone A (1), which was also detected in three independent cultures of T. erythraeum. Genome mining identified genes predicted to synthesize certain functional groups in the T. thiebautii metabolites. These results provoke intriguing questions of how these specialized metabolites affect Trichodesmium ecophysiology, symbioses with marine invertebrates, and niche development in the global oligotrophic ocean.

Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) ß5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.

Understanding Regional Patterns of Overdose Deaths Related to Opioids and Psychostimulants.

BACKGROUND: As overdose rates increase for multiple substances, policymakers need to identify geographic patterns of substance-specific deaths. In this study, we describe county-level opioid and psychostimulant overdose patterns and how they correlate with county-level social vulnerability measures. METHODS: A cross-sectional observational study, we used nationwide 2016-2018 restricted access Centers for Disease Prevention and Control county-level mortality files for 1,024 counties. We estimated quartiles of opioid and psychostimulant overdose mortality and provided estimates of their association with county-level Social Vulnerability Index (SVI) percentile. RESULTS: There was high opioid and psychostimulant overdose mortality in the Middle Atlantic, South Atlantic, East North Central, and Mountain regions. The Central US had the lowest opioid and psychostimulant overdose mortality rates. Counties with higher SVI scores (i.e. higher social vulnerability) were significantly more likely to experience high opioid and high psychostimulant overdose (high-high) mortality. A 10-percentile increase in SVI score was associated with a 3.1 percentage point increase in the likelihood of being a high-high county (p < 0.001) in unadjusted models and a 1.5 percentage point increase (p < 0.05) in models adjusting for region. CONCLUSION: Our results illustrated the heterogenous geographic distribution of the growing concurrent opioid and psychostimulant overdose crisis. The substantial regional variation we identified highlights the need for local data to guide policymaking and treatment planning. The association of opioid-psychostimulant overdose mortality with social vulnerability demonstrates the critical need in impacted counties for tailored treatment that addresses the complex medical and social needs of people who use both opioids and psychostimulants.

Molecular Basis of Functional Effects of Phosphorylation of the C-Terminal Domain of the Rabies Virus P Protein.

The rabies virus (RABV) phosphoprotein (P protein) is expressed as several isoforms, which differ in nucleocytoplasmic localization and microtubule (MT) association, mediated by several sequences, including nuclear localization (NLS) and export (NES) sequences. This appears to underpin a functional diversity enabling multiple functions in viral replication and modulation of host biology. Mechanisms regulating trafficking are poorly defined, but phosphorylation by protein kinase C (PKC) in the P protein C-terminal domain (PCTD) regulates nuclear trafficking, mediated by PCTD-localized NLS/NES sequences, indicating that phosphorylation contributes to functional diversity. The molecular mechanism underlying the effects of PKC, and potential roles in regulating other host-cell interactions are unresolved. Here, we assess effects of phosphorylation on the P3 isoform, which differs from longer isoforms through an ability to localize to the nucleus and associate with MTs, which are associated with antagonism of interferon (IFN) signaling. We find that phosphomimetic mutation of the PKC site S210 inhibits nuclear accumulation and MT association/bundling. Structural analysis indicated that phosphomimetic mutation induces no significant structural change to the NLS/NES but results in the side chain of N226 switching its interactions from E228, within the NES, to E210. Intriguingly, N226 is the sole substituted residue between the PCTD of the pathogenic IFN-resistant RABV strain Nishigahara and a derivative attenuated IFN-sensitive strain Ni-CE, inhibiting P3 nuclear localization and MT association. Thus, S210 phosphorylation appears to impact on N226/E228 to regulate P protein localization, with N226 mutation in Ni-CE mimicking a constitutively phosphorylated state resulting in IFN sensitivity and attenuation. IMPORTANCE Rabies virus P protein is a multifunctional protein with critical roles in replication and manipulation of host-cell processes, including subversion of immunity. This functional diversity involves interactions of several P protein isoforms with the cell nucleus and microtubules. Previous studies showed that phosphorylation of the P protein C-terminal domain (PCTD) at S210, near nuclear trafficking sequences, regulates nucleocytoplasmic localization, indicating key roles in functional diversity. The molecular mechanisms of this regulation have remained unknown. Here, we show that phosphomimetic mutation of S210 regulates nuclear localization and MT association. This regulation does not appear to result from disrupted PCTD structure, but rather from a switch of specific side chain interactions of N226. Intriguingly, N226 was previously implicated in P protein nuclear localization/MT association, immune evasion, and RABV pathogenesis, through undefined mechanisms. Our data indicate that the S210-N226 interface is a key regulator of virus-host interactions, which is significant for pathogenesis.

Taste loss as a distinct symptom of COVID-19: a systematic review and meta-analysis.

Chemosensory scientists have been skeptical that reports of COVID-19 taste loss are genuine, in part because before COVID-19 taste loss was rare and often confused with smell loss. Therefore, to establish the predicted prevalence rate of taste loss in COVID-19 patients, we conducted a systematic review and meta-analysis of 376 papers published in 2020-2021, with 235 meeting all inclusion criteria. Drawing on previous studies and guided by early meta-analyses, we explored how methodological differences (direct vs. self-report measures) may affect these estimates. We hypothesized that direct measures of taste are at least as sensitive as those obtained by self-report and that the preponderance of evidence confirms taste loss is a symptom of COVID-19. The meta-analysis showed that, among 138,015 COVID-19-positive patients, 36.62% reported taste dysfunction (95% confidence interval: 33.02%-40.39%), and the prevalence estimates were slightly but not significantly higher from studies using direct (n = 15) versus self-report (n = 220) methodologies (Q = 1.73, df = 1, P = 0.1889). Generally, males reported lower rates of taste loss than did females, and taste loss was highest among middle-aged adults. Thus, taste loss is likely a bona fide symptom of COVID-19, meriting further research into the most appropriate direct methods to measure it and its underlying mechanisms.

Performance of the Emergency Surgery Score in Nonelective Lower-Extremity Endovascular Procedures.

INTRODUCTION: Multiple studies have validated the Emergency Surgery Score (ESS) as a tool which reliably predicts outcomes after emergency general surgery. The purpose of this study was to assess the performance of the ESS for lower-extremity endovascular procedures in nonelective setting (neLEE). METHODS: The American College of Surgeons' National Surgical Quality Improvement Program database was retrospectively analyzed for patients undergoing neLEE between 2015 and 2019. The performance of the ESS in predicting mortality in each procedure was assessed using receiver operating characteristic analyses. RESULTS: Four thousand five hundred and eighty three patients underwent neLEE with median age 68 (±12.3 SD), with 1802 females (39.3%). The ESS correlated with 30-day mortality (area under the curve [AUC] was 0.729), discharge to rehab (AUC 0.638), renal failure (AUC 0.667), postintervention ventilation requirement (AUC 0.680), and stroke (AUC 0.656). The predictive ability of the ESS decreased with increasing age, with the ESS performing best for patients between 60 and 69 y in age (AUC 0.735) and worst for patients above 80 y (AUC 0.650). A Cochran-Armitage test showed linear trend towards increased 30-day mortality among the quartiles with increasing ESS (P < 0.001), with patients with ESS ≥10 having 10 times odds of increased 30-day mortality compared to reference quartile of patients with ESS ≤4 on multivariate analysis. CONCLUSIONS: The ESS score is associated with 30-day mortality and other complications after neLEE procedures. It can potentially be used as a predictive tool for preoperative risk stratification and can also be used for equitably evaluating standards and outcomes after lower extremity endovascular procedures.

Using Metal Cation to Control the Microstructure of Cobalt Oxide in Energy Conversion and Storage Applications.

Herein, a facile and efficient synthesis of microstructured Co3 O4 for both supercapacitor and water-splitting applications is reported. Metal cations (Fe3+ , Cu2+ ) serve as structure-directing agents regulating the structure of Co compounds, which are subsequently annealed to yield Co3 O4 . Detailed characterizations and density functional theory (DFT) calculations reveal that the in situ Cl-doping introduces oxygen defects and provides abundant electroactive sites, and narrows the bandgap, which enhances the electron excitation of the as-formed Co3 O4 . The as-prepared Cl-doped Co3 O4 hierarchical nanospheres (Cl-Co3 O4 -h) display a high specific capacitance of 1629 F g-1 at 1 A g-1 as an electrode for supercapacitors, with excellent rate capability and cyclability. The Cl-Co3 O4 -h//activated carbon (AC) asymmetric supercapacitor (ASC) electrode achieves a specific capacitance of 237 F g-1 at 1 A g-1 , with an energy density of 74 Wh kg-1 at a power density of 807 W kg-1 and even maintains 47 Wh kg-1 at the higher-power density of 24.2 kW kg-1 . An integrated electrolyzer for water-splitting with Cl-Co3 O4 -h as both cathode and anode can be driven by Cl-Co3 O4 -h//AC ASC. The electrolyzer provides a high current density of 35 mA cm-2 at a cell voltage of 1.6 V, with good current density retention over 50 h.

Emerging roles for IL-11 in inflammatory diseases.

Interleukin-11 (IL-11) is a cytokine that has been strongly implicated in the pathogenesis of fibrotic diseases and solid malignancies. Elevated IL-11 expression is also associated with several non-malignant inflammatory diseases where its function remains less well-characterized. Here, we summarize current literature surrounding the contribution of IL-11 to the pathogenesis of autoimmune inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory conditions such as periodontitis, asthma, chronic obstructive pulmonary disease, psoriasis and colitis.

Taste loss as a distinct symptom of COVID-19: a systematic review and meta-analysis.

Chemosensory scientists have been skeptical that reports of COVID-19 taste loss are genuine, in part because before COVID-19 taste loss was rare and often confused with smell loss. Therefore, to establish the predicted prevalence rate of taste loss in COVID-19 patients, we conducted a systematic review and meta-analysis of 376 papers published in 2020-2021, with 241 meeting all inclusion criteria. Drawing on previous studies and guided by early meta-analyses, we explored how methodological differences (direct vs. self-report measures) may affect these estimates. We hypothesized that direct measures of taste are at least as sensitive as those obtained by self-report and that the preponderance of evidence confirms taste loss is a symptom of COVID-19. The meta-analysis showed that, among 138,897 COVID-19-positive patients, 39.2% reported taste dysfunction (95% confidence interval: 35.34%-43.12%), and the prevalence estimates were slightly but not significantly higher from studies using direct (n = 18) versus self-report (n = 223) methodologies (Q = 0.57, df = 1, P = 0.45). Generally, males reported lower rates of taste loss than did females, and taste loss was highest among middle-aged adults. Thus, taste loss is likely a bona fide symptom of COVID-19, meriting further research into the most appropriate direct methods to measure it and its underlying mechanisms.

Predicting mortality in nonsurgical patients before cannulation for veno-arterial extracorporeal life support: Development and validation of the LACT-8 score.

OBJECTIVES: We sought to derive and validate a model to predict inpatient mortality after veno-arterial extracorporeal life support (VA-ECLS) based on readily available, precannulation clinical data. BACKGROUND: Refractory cardiogenic shock supported by VA-ECLS is associated with high morbidity and mortality. METHODS: VA-ECLS cases at our institution from January 2014 through July 2019 were retrospectively reviewed. Exclusion criteria were cannulation: (1) at another institution; (2) for primary surgical indication; or (3) for extracorporeal cardiopulmonary resuscitation. Multivariable logistic regression compared those with and without inpatient mortality. Multiple imputation was performed and optimism-adjusted area under the curve (oAUC) values were computed. RESULTS: VA-ECLS cases from August 2019 through November 2020 were identified as a validation cohort. In the derivation cohort (n = 135), the final model included Lactate (mmol/L), hemoglobin (g/dl; Anemia), Coma (Glasgow Coma Scale [GCS] < 8) and resusciTATEd cardiac arrest (LACTATE score; oAUC = 0.760). In the validation cohort (n = 30, LACTATE showed similar predictability [AUC = 0.710]). A simplified (LACT-8) score was derived by dichotomizing lactate (>8) and hemoglobin (<8) and summing together the number of components for each patient. LACT-8 performed similarly (derivation, oAUC = 0.724; validation, AUC = 0.725). In the derivation cohort, both scores outperformed SAVE (oAUC = 0.568) and SOFA (oAUC = 0.699) scores. A LACT-8 ≥ 3 had a specificity for mortality of 97.9% and 92.9%, in the derivation and validation cohorts, respectively. CONCLUSIONS: The LACT-8 score can predict inpatient mortality prior to before cannulation for VA-ECLS. LACT-8 can be implemented utilizing clinical data without the need for an online calculator.

Emerging harmful algal blooms caused by distinct seasonal assemblages of a toxic diatom.

Diatoms in the Pseudo-nitzschia genus produce the neurotoxin domoic acid. Domoic acid bioaccumulates in shellfish, causing illness in humans and marine animals upon ingestion. In 2017, high domoic acid levels in shellfish meat closed shellfish harvest in Narragansett Bay, Rhode Island for the first and only time in history, although abundant Pseudo-nitzschia have been observed for over 60 years. To investigate whether an environmental factor altered endemic Pseudo-nitzschia physiology or new domoic acid-producing strain(s) were introduced to Narragansett Bay, we conducted weekly sampling from 2017 to 2019 and compared closure samples. Plankton-associated domoic acid was quantified by LC-MS/MS and Pseudo-nitzschia spp. were identified using a taxonomically improved high-throughput rDNA sequencing approach. Comparison with environmental data revealed a detailed understanding of domoic acid dynamics and seasonal multi-species assemblages. Plankton-associated domoic acid was low throughout 2017-2019, but recurred in fall and early summer maxima. Fall domoic acid maxima contained known toxic species as well as a novel Pseudo-nitzschia genotype. Summer domoic acid maxima included fewer species but also known toxin producers. Most 2017 closure samples contained the particularly concerning toxic species, P. australis, which also appeared infrequently during 2017-2019. Recurring Pseudo-nitzschia assemblages were driven by seasonal temperature changes, and plankton-associated domoic acid correlated with low dissolved inorganic nitrogen. Thus, the Narragansett Bay closures were likely caused by both resident assemblages that become toxic depending on nutrient status as well as the episodic introductions of toxic species from oceanographic and climatic shifts.

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome.

BACKGROUND: Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. OBJECTIVE: Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. METHODS: We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. RESULTS: We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. CONCLUSION: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

The structure of the extracellular domains of human interleukin 11α receptor reveals mechanisms of cytokine engagement.

Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface α-receptor, IL-11Rα, and the ß-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Rα that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Rα and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Rα are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations destabilize IL-11Rα and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11Rα form a 1:1 complex with nanomolar affinity and present a model of the complex. Our results suggest that the thermodynamic and structural mechanisms of complex formation between IL-11 and IL-11Rα differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Rα that may be exploited in the development of strategies to modulate formation of the IL-11-IL-11Rα complex.

Optical transmittance of 3D printing materials.

The increasing prevalence of three-dimensional (3D) printing of optical housings and mounts necessitates a better understanding of the optical properties of printing materials. This paper describes a method for using multithickness samples of 3D printing materials to measure transmittance spectra at wavelengths from 400 to 2400 nm [visible to short-wave infrared (IR)]. In this method, 3D samples with material thicknesses of 1, 2, 3, and 4 mm were positioned in front of a uniform light source with a spectrometer probe on the opposing side to measure the light transmittance. Transmission depended primarily on the thickness and color of the sample, and multiple scattering prevented the use of a simple exponential model to relate transmittance, extinction, and thickness. A Solidworks file and a 3D printer file are included with the paper to enable measurements of additional materials with the same method.

Contrasting Patterns of Functional Diversity in Coffee Root Fungal Communities Associated with Organic and Conventionally Managed Fields.

The structure and function of fungal communities in the coffee rhizosphere are influenced by crop environment. Because coffee can be grown along a management continuum from conventional application of pesticides and fertilizers in full sun to organic management in a shaded understory, we used coffee fields to hold host constant while comparing rhizosphere fungal communities under markedly different environmental conditions with regard to shade and inputs. We characterized the shade and soil environment in 25 fields under conventional, organic, or transitional management in two regions of Costa Rica. We amplified the internal transcribed spacer 2 (ITS2) region of fungal DNA from coffee roots in these fields and characterized the rhizosphere fungal community via high-throughput sequencing. Sequences were assigned to guilds to determine differences in functional diversity and trophic structure among coffee field environments. Organic fields had more shade, a greater richness of shade tree species, and more leaf litter and were less acidic, with lower soil nitrate availability and higher soil copper, calcium, and magnesium availability than conventionally managed fields, although differences between organic and conventionally managed fields in shade and calcium and magnesium availability depended on region. Differences in richness and community composition of rhizosphere fungi between organic and conventionally managed fields were also correlated with shade, soil acidity, and nitrate and copper availability. Trophic structure differed with coffee field management. Saprotrophs, plant pathogens, and mycoparasites were more diverse, and plant pathogens were more abundant, in organic than in conventionally managed fields, while saprotroph-plant pathogens were more abundant in conventionally managed fields. These differences reflected environmental differences and depended on region.IMPORTANCE Rhizosphere fungi play key roles in ecosystems as nutrient cyclers, pathogens, and mutualists, yet little is currently known about which environmental factors and how agricultural management may influence rhizosphere fungal communities and their functional diversity. This field study of the coffee agroecosystem suggests that organic management not only fosters a greater overall diversity of fungi, but it also maintains a greater richness of saprotrophic, plant-pathogenic, and mycoparasitic fungi that has implications for the efficiency of nutrient cycling and regulation of plant pathogen populations in agricultural systems. As well as influencing community composition and richness of rhizosphere fungi, shade management and use of fungicides and synthetic fertilizers altered the trophic structure of the coffee agroecosystem.

Objective Sensory Testing Methods Reveal a Higher Prevalence of Olfactory Loss in COVID-19-Positive Patients Compared to Subjective Methods: A Systematic Review and Meta-Analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has currently infected over 6.5 million people worldwide. In response to the pandemic, numerous studies have tried to identify the causes and symptoms of the disease. Emerging evidence supports recently acquired anosmia (complete loss of smell) and hyposmia (partial loss of smell) as symptoms of COVID-19, but studies of olfactory dysfunction show a wide range of prevalence from 5% to 98%. We undertook a search of Pubmed/Medline and Google Scholar with the keywords "COVID-19," "smell," and/or "olfaction." We included any study that quantified smell loss (anosmia and hyposmia) as a symptom of COVID-19. Studies were grouped and compared based on the type of method used to measure smell loss-subjective measures, such as self-reported smell loss, versus objective measures using rated stimuli-to determine if prevalence differed by method type. For each study, 95% confidence intervals (CIs) were calculated from point estimates of olfactory disturbances. We identified 34 articles quantifying anosmia as a symptom of COVID-19 (6 objective and 28 subjective), collected from cases identified from January 16 to April 30, 2020. The pooled prevalence estimate of smell loss was 77% when assessed through objective measurements (95% CI of 61.4-89.2%) and 44% with subjective measurements (95% CI of 32.2-57.0%). Objective measures are a more sensitive method to identify smell loss as a result of infection with SARS-CoV-2; the use of subjective measures, while expedient during the early stages of the pandemic, underestimates the true prevalence of smell loss.