Background Activation of mast cells through IgE results in secretion and shedding of mast cell proteins and in vivo models suggest that these processes are governed by IgE antibody affinity. Methods We passively sensitized cultured primary human mast cells with recombinant human IgE clones with either high or low affinity for Der p 2, with a 200-fold affinity difference, and activated them with recombinant allergen. Activation was assessed by CD63 upregulation and PGD 2 secretion. Supernatants collected from mast cells activated for 0, 3, 6 and 24 hours were assessed for PGD 2 and inflammatory mediators on the OLINK platform at repeated time points. Results CD63 upregulation and PGD 2 synthesis scaled with affinity, as did secretion of cytokines like IL-8 and IL-13. Secretion of chemokines like CCL3 and CCL4 appeared to depend less on affinity, whereas shedding of surface markers CD40, SLAMF4 and CD5, and secretion of intracellular markers SIRT2 and CASP-8, were elevated by stimulation through low affinity IgE compared with high affinity IgE, illustrating differential responses dependent on the affinity of IgE. Conclusion Cytokine secretion and shedding of surface receptors of sensitized, cultured primary human mast cells is differentially regulated depending on the affinity of IgE for the Der p 2 allergen and may shape the chronic response to repeated allergic activation.

Shigella flexneri type III effector OspC3 was recently found to evade host pyroptosis by targeting caspase-11 for ADP-riboxanation. The ADP-riboxanase activity was shared by its paralogues, OspC1 and OspC2, whereas the host substrates of them are still unknown. To solve this problem, we employed eAf1521 enrichment coupled with mass spectrometry (MS)-based proteomics to profile the host substrates of OspC1. In this study, we identified HERC5 as a host target of OspC1. As described previously, HERC5 functions as an E3 ISG15 ligase and catalyzes the ISGylation of a huge subset of host and pathogen proteins upon bacterial infection. Here, we show that S. flexneri hijacks host ISGylation pathway by OspC1-catalyzed ADP-riboxanation of HERC5 to promote its own survival and proliferation in host cells.

This paper handles the identification of nonlinear systems through linear time-varying (LTV) approximation. The mathematical form of the nonlinear system is unknown and regenerated through an experiment followed by LTV and linear parameter-varying (LPV) estimation and integration. By employing a well-designed experiment the linearized model of the nonlinear system around a time-varying trajectory is obtained. The result is an LTV approximation of the nonlinear system around that trajectory. Having estimated the LTV model, an LPV model is identified. It is shown that the parameter-varying (PV) coefficients of this LPV model are partial derivatives of the nonlinear system evaluated at the trajectory. In this paper, we will show that there exists a relation between the LPV coefficients. This structural relation in the LPV model ensures the integrability of PV coefficients for nonlinear reconstruction. Indeed, the vector of the LPV coefficients is the gradient of the nonlinear system evaluated at the trajectory. Then, the nonlinear system is reconstructed through symbolic integration of the coefficients. The proposed method is a data-driven scheme that can reconstruct an estimate of the nonlinear system and its mathematical form using input-output measurements. Finally, the use of the proposed method is illustrated via a simulation example.

Bio-logging has revealed much about high-latitude seabird migratory strategies, but tropical species are comparatively understudied. Here we use geolocators to study the year-round movement behaviour of adult red-footed boobies (Sula sula rubripes) from the Chagos Archipelago, tropical Indian Ocean. Light levels suggest that red-footed boobies are resident in the archipelago year-round, although there are large latitudinal errors this close to the equator. However, immersion data revealed tracked birds returned to land year-round, with no extended at-sea periods, further indicating this population is non-migratory. Our findings have important implications for seabird conservation and phylogenetics, as well as for assessing the impact of seabird nutrients on coral reef ecosystems.

Rabies is a lethal infectious disease caused by rabies virus (RABV). The mortality rate is very high after the appearance of clinical symptoms, with a survival rate of almost 0%. There is presently no cure for rabies. In the present study, we investigated whether the extract of Shougong powder-a calcium powder prepared from gecko that has demonstrated immunomodulatory properties in mice-is an effective treatment for rabies. The antiviral effects of the extract were evaluated both in vitro and in vivo with the cytotoxicity and antiviral assays and by immunofluorescence analysis, quantitative real-time (qRT)-PCR, and western blotting. The results showed that Shougong powder and its extract increased survival rate in RABV-infected mice is up to 60% and 50% respectively, even in 20 times of LD50. Whereas the control groups treated with Isoprinosine (IPS) or saline are only 20% and 0% survival (P=0.011). qRT-PCR and western blot analyses showed that the extract strongly inhibited viral mRNA expression and protein synthesis in vitro: expression of the N, P, M, G, and L genes of RABV was decreased by 28.8%–45.0% in the IPS group (P<0.05) and by 50.1%–59.0% in the extract group (P<0.05) relative to the control group. These results demonstrate that Shougong powder has antiviral effects against RABV and can potentially be used for the treatment for rabies.

This paper presents two novel mixed-uncertainty state estimators for discrete-time descriptor linear systems, namely linear time-varying mixed-uncertainty filter (LTVMF) and linear time-invariant mixed-uncertainty filter (LTIMF). The former estimator is based on the minimum-variance approach, from which quadratic and explicit formulations are derived and addressed to LTI and LTV systems. Both formulations incorporate the knowledge of state linear constraints, such as equality (in the descriptor form) and inequality, to mitigate precision and accuracy issues related to initialization and evolution of the state estimates. The explicit version is developed to reduce the computational burden of quadratic solvers, which is based on a particularity of the state inequality constraints. The LTIMF algorithm is based on the mixed H 2 / H ∞ criterion motivated by performing low-cost computations. This speed benefit is originated from a reachability analysis involving constant design matrices. Both LTVMF and LTIMF algorithms solve state-estimation problems in which the uncertainties are combined to yield the so-called mixed-uncertainty vector, which is composed by set-bounded uncertainties, characterized by constrained zonotopes, and stochastic uncertainties, characterized by Gaussian random vectors. As mixed-uncertainty vectors imply biobjective optimization problems, we innovatively present multiobjective arguments to justify the choice of the solution on the Pareto-optimal front. According to these arguments, LTVMF is introduced with a cost normalization, which enables the combination of beyond minimum-variance approaches. Likewise, the mixed H 2 / H ∞ criterion of LTIMF is introduced with slack variables to improve the quality of the state estimates. In order to discuss the advantages and drawbacks, the state estimators are tested in two numerical examples.

Successful management of severe generalized tetanus in a 23-year man with Phenobarbital adjuvant: a case reportArezoo Ahmadi1, Elahe Karimpour-Razkenari2, Ramin Ansari2, Mahforouzalsadat Marashi3, Hamidreza Sharifnia1, Atabak Najafi1, Mojtaba Mojtahedzadeh2*1 Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran2 Department of Anesthesiology and Critical Care, School of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.3 Department of Infectious Disease and Tropical Medicine, School of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.Corresponding author: Mojtaba Mojtahedzadeh; Pharmacist; Board Certified of Pharmacotherapy Specialty; Fellowship of Critical Care Pharmacotherapy; Department of Clinical Pharmacy, Tehran University of Medical [email protected] Hospital, Imam Khomeini St, Hasanabad Square, Tehran, IranTel: +982164120Postal code: 1136746911Fax number: 00982166348587Abstract With a mortality rate of up to 50%, generalized tetanus is still a global concern, especially in low and middle-income countries. A 23-year-old man from Afghanistan was admitted to Sina Hospital, affiliated with Tehran University of Medical Sciences, with the chief complaint of generalized severe spasms and lockjaw. The patient had a history of skin lesions and had never been vaccinated against tetanus. He admitted to the intensive care unit after intubation in emergency room, with diagnose of severe generalized tetanus. After receiving tetanus immunoglobulin and intravenous metronidazole, a combination therapy of midazolam, propofol, atracurium and morphine was administered. Due to the refractory muscular spasms intravenous phenobarbital started and little by little recovery was achieved. With no symptom recurrence, after receiving the first 2 doses of the Td vaccine, the patient was discharged on day 42.Keywords: Tetanus, phenobarbital, Intensive care

The selective separation of CO2 from CH4-containing gases is crucial to produce clean energy gases. In this study, triazole anion-functionalized ionic liquids (TAFILs) were designed by combining low molecular weight cations with triazole anions containing N electronegative site, and further mixed with physical solvents to form physicochemical absorbents. The results indicated that [Cho][Triz]/TMS (80 wt%/20 wt%) not only absorb 0.125 g CO2/g absorbent equal to that of 30 wt% MEA solution at 40 °C and 1 bar, but also have low enthalpy of -35.76 kJ/mol less than half of 30 wt% MEA solution. Simultaneously, superhigh CO2/CH4 selectivity of 191.0 higher than most of reported absorbents is obtained for [Cho][Triz]/TMS solvents. Such great performance of CO2 separation was attributed to relatively weak chemical and physical interaction between CO2 and TAFIL binary absorbents. This study may provide novel promising IL absorbents for CO2 capture applications from clean energy gases.

Background: Lisinopril, an angiotensin-converting enzyme inhibitor (ACEi), is a frequently prescribed antihypertensive drug in the pediatric population, while being used off-label under the age of 6 years in the US and for all pediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive pediatric patients corresponding with the day-to-day clinical population. Methods: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05mg.kg-1 to 0.2 mg.kg-1. Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2kg (median 53.2kg). All data were analyzed using Monolix version 2020R1 (Lixoft®, France) and R version 3.6.2. Results: A one-compartment model with 1st order absorption and 1st order elimination optimally describes the data. Parameter estimates of ka (0.077h-1 [9.6%], typical value [relative standard error]), V/F (32.9L 70.g-1 [37%]) and CL/F (23.1L h-1 .70kg-1[8.5%]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a power law parameterization centered around 105 mL.min.1.73m2. The effects of body weight were implemented using fixed allometric exponents centered around an adult weight of 70kg. Conclusion: Lisinopril dose and regimen adjustments for pediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Phylogenetic generalized least squares (PGLS) regression is widely used to detect evolutionary correlations. In contrast to the equal treatment of analyzed traits in conventional correlation methods such as Pearson and Spearman’s rank tests, we must designate one trait as the independent variable and the other as the dependent variable. However, in our PGLS regression analyses (using Pagel’s λ model) of both empirical and simulated datasets, switching independent and dependent variables yielded many conflicting results. A serious problem with PGLS regression that has not been noticed before is that selecting an inappropriate trait as the dependent variable will often result in an error. To assess correlations in simulated data, we established a gold standard by analyzing changes in traits along phylogenetic branches. Next, we tested seven potential criteria for dependent variable selection: log-likelihood, Akaike information criterion, R2, p-value, Pagel’s λ, Blomberg et al.’s K, and the estimated λ in Pagel’s λ model. We determined that the last three criteria performed equally well in selecting the dependent variable and were superior to the other four. For practicality, we suggest using the trait with a higher λ or K value as the dependent variable in future PGLS regressions. In analyzing the evolutionary relationship between two traits, we should designate the trait with a stronger phylogenetic signal as the dependent variable even if it could logically assume the cause in the relationship.

Ravines represent an extreme form of land degradation. Soil and moisture saving techniques (SMSTs) have been identified as effective strategies for improving the fertility of degraded lands. Three SMSTs viz., intercrop of cow pea and castor on bench terrace (SCCBT) ii) bench terrace (SBT) iii) staggered trenches on natural slope (SSTS) and iv) sapota on natural slope (Control) were imposed to observe their impact on Sapota yield and quality, runoff, soil loss, and soil properties under rain-fed conditions during 2018-20. SMSTs have significantly affected plant growth, yield and quality and soil loss-runoff in degraded ravines. The highest tree height was observed in SBT on par with SCCBT and SSTS, and lowest in SS. Similar trend was observed in case canopy spread, canopy volume and collar diameter. Among the treatments, SCCBT recorded highest yield (38.3 kg tree -1) followed by SBT, SST and lowest in SS (16.8 kg tree -1). Pulp weight (55.55 g) and vitamin C (14.69 mg) was recorded higher in SCCBT and lowest in SS. SCCBT treatment reduced runoff by 44% and it was highest in SS. Despite this SCCBT exhibited significant higher soil loss. Terracing and trenches exhibited remarkable effect on EC, SOC, available major nutrients (NPK) compared to control. SCCBT and SBT treatments significantly had higher soil moisture (%) compare to control. Hence, the cultivation of sapota after implementing terracing and staggered trenches on natural slopes proves to be a viable approach for effectively utilizing degraded ravines while promoting productivity.

Arid and semi-arid vegetation is characterized by plant patches of different sizes, and plant cover is determined by patch size (PS) and number of patches (NP). However, it is still unclear how PS and NP contribute to the restoration of degraded grasslands through grazing exclusion (GE). Transect lines were sampled in six alpine steppe communities in Tibet in 2017 and 2018. Both PS and NP were assessed and compared between inside and outside grazing exclosures. Our results showed that grazing exclosures increased the mean size but decreased the total number of plant patches. This pattern of change was common to other species and could not be attributed to a shift in community composition. The results suggest that the recovery of the degraded alpine steppe is being driven by PS at the expense of NP. By promoting the expansion of the larger patches while excluding the smaller ones, GE led to an aggregating pattern with a higher proportion of bare ground, potentially reducing primary productivity.

A document by Kamaldeep Sadh. Click on the document to view its contents.

Introduction: A hybrid convergent approach (endocardial and epicardial ablation) demonstrated superior effectiveness in a recent randomized study for long-standing persistent atrial fibrillation (LSPAF). Yet, there is a lack of real-world, long-term evidence as to which patients are best candidates for a hybrid convergent approach compared to standard endocardial cryoballoon pulmonary vein isolation (CB PVI). Methods and Results: This single-center, retrospective analysis spanning from 2010 to 2015 compared two distinctly different atrial fibrillation (AF) cohorts; one treated with stand-alone cryoablation and one treated with a hybrid convergent approach. Baseline characteristics described candidates for each approach. The following criteria were utilized to determine CB PVI candidacy: 1) paroxysmal AF (PAF) with failed class I/III antiarrhythmic drug (AAD) or 2) persistent/LSPAF with failed class I/III AAD unwilling to undergo hybrid procedure. Selection criteria for the hybrid procedure included: 1) PAF refractory to both class I/III AAD and prior CB PVI or 2) persistent/LSPAF with failed class I/III AAD agreeable to hybrid procedure. Prior sternotomy was excluded. Serial electrocardiograms and continuous monitoring evaluated primary efficacy outcome of time-to-first recurrence of atrial arrhythmia after a 90-day blanking period. Secondary outcomes were procedure-related complications and AAD use (at discharge, 12, and 36 months). Kaplan-Meier methods evaluated arrhythmia recurrence. Of 276 patients, 197 (64.2 ± 10.6 years old; 66.5% male; 74.1% PAF; 18.3% persistent AF; 1.0% LSPAF; 6.6% undetermined) underwent CB PVI and 79 (61.4 ± 8.1 years old; 83.5% male; 41.8% PAF; 45.5% persistent AF; 12.7% LSPAF) underwent hybrid procedure. Arrhythmia freedom through 36 months was 55.2% for CB PVI and 50.4% for hybrid (p =0.32). Class I AAD utilization at discharge occurred in 38 (19.3%) patients in the CB PVI group and 5 (6.3%) patients in the hybrid group (p=0.01). CB PVI class I AAD utilization at 12 months occurred in 14 (9.0) patients versus 0 patients for hybrid convergent (p=0.004). Patients with one or more adverse event were as follows: two (1.0%) in the CB PVI group (both transient phrenic nerve palsy) and three (3.7%) in the hybrid group (two with significant bleeding and one with wound infection) (p=0.14). Conclusion: This study demonstrated that patients with more complex forms of AF (PAF refractory to both AAD and index endocardial ablation or persistent/LSPAF) could be well managed with a convergent approach. Moreover, outcomes match safety and efficacy thresholds achieved by patients with an early, less complex AF etiology treated by CB PVI alone.

Landscape structure plays a key role in mediating a variety of ecological processes affecting biodiversity patterns, however its precise effects and the mechanisms underpinning them remain unclear. While the effects of landscape structure have been extensively investigated both empirically, and theoretically from a metapopulation perspective, the effects of spatial structure at the landscape scale remain poorly explored from a metacommunity perspective. Here, we attempt to address this gap using a spatially explicit, individual-based metacommunity model to explore the effects of landscape compositional heterogeneity and per se spatial configuration on diversity at the landscape and patch level via their influence on long term community assembly processes. Our model simulates communities composed of lineages of annual, asexual organisms living, reproducing, dispersing, and competing within grid-based, fractal landscapes which vary in their magnitude of spatial environmental heterogeneity and in their degree of spatial environmental autocorrelation. Communities are additionally subject to temporal environmental fluctuation and external immigration, allowing for turnover in community composition. We found that compositional heterogeneity and spatial autocorrelation had differing effects on richness and diversity and the landscape and patch scales. We also note a slight negative effect of compositional heterogeneity on median total landscape population size. Landscape level diversity was driven by community dissimilarity at the patch level and increased with greater heterogeneity, while landscape richness was largely the result of short-term accumulation of immigrants and decreased with greater compositional heterogeneity. Both richness and diversity decreased in variance with greater compositional heterogeneity, indicating a reduction in community turnover over time. Patch-level richness and diversity patterns appeared to be driven by overall landscape richness and local mass effects, resulting in maximum patch level richness and diversity at moderate levels of compositional heterogeneity and high spatial autocorrelation.

Gene loci of highly expressed genes provide ideal sites for transgene expression. Casein genes are highly expressed in mammals leading to the synthesis of substantial amounts of casein proteins in milk. We have assessed the α-casein (CSN1S1) gene as a site of transgene expression in transgenic mice and a mammary gland cell line. A transgene encoding an antibody light chain gene (A1L) was inserted into the α-casein gene using sequential homologous and site-specific recombination. Expression of the inserted transgene is directed by the α-casein promoter, is responsive to lactogenic hormone activation, leads to the synthesis of a chimeric α-casein/A1L transgene mRNA and secretion of the recombinant A1L protein into milk. Transgene expression is highly consistent in all transgenic lines, but much lower than that of the α-casein gene (4%). Recombinant A1L protein accounted for 0.5% and 1.6% of total milk protein in heterozygous and homozygous transgenic mice, respectively. The absence of the α-casein protein in homozygous A1L transgenic mice leads to a reduction of total milk protein and delayed growth of the pups nursed by these mice. Overall, the data demonstrate that the insertion of a transgene into a highly expressed endogenous gene is insufficient to guarantee its abundant expression.

This study provides a new perspective on understanding the intricacies of water-mediated connectivity in ecosystems, bridging landscape ecology and geomorphology through network science. We highlight dryland and river floodplain ecosystems as distinct examples of contrasting water-controlled systems. We (1) discuss central considerations in developing Structural Connectivity (SC) and Functional Connectivity (FC) networks of water-mediated connectivity; (2) quantify the emergent patterns in these networks; and (3) evaluate the capacity of network science tools for investigating connectivity characteristics. Connectivity is quantified using seven parameters at both network and node levels. We find that Link Density, Betweenness Centrality, and Page Rank Centrality are highly sensitive to directionality; Global Efficiency and Degree Centrality are particularly sensitive to weights; while Relative Node Efficiency remains unaffected by weights and directions. Our study underscores the potential to transform how we quantify and understand water-mediated connectivity, especially in consideration of the role(s) of weights and directionality. This interdisciplinary review has implications for both theoretical insights and practical applications in environmental management and conservation efforts.

CASE REPORT