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Abstract Background Keratinocyte carcinomas such as basal cell carcinomas and squamous cell carcinomas are a major burden affecting morbidity and mortality in solid organ transplant recipients (SOTRs). Best treatment includes frequent skin checks for early detection and surgery for high incidence of skin cancers. Sirolimus is an immunosuppressive drug which may reduce the burden of skin cancer but may be poorly tolerated when given orally. Topical sirolimus has been proven effective at reducing the burden of skin cancers in animal models, and its safety has long been established in children with tuberous sclerosis. A recent 12-week phase II trial of topical sirolimus suggested it was safe and effective at reducing the early signs of skin cancer in the absence of major side effects. The aim of the SiroSkin trial is to determine whether topical sirolimus can fill a major gap in current therapies by reducing the onset and number of new skin cancers thus reducing burden of disease and cost-effectiveness. Methods Protocol for a multi-centred phase III, participant- and clinician assessor-blinded, placebo-controlled randomised trial in SOTRs. A minimum 146 participants randomised 1:1 will be treated with 1% topical sirolimus versus placebo applied to the face on a regular basis for 24 weeks. Participation is 24 months in total—24 weeks of treatment and 18 months of follow-up. Outcomes include the number of keratinocyte carcinomas at 24 weeks of treatment compared to placebo and then at 12 and 24 months after initiation of treatment. Analysis will be as per protocol and intention to treat. Discussion The results of this trial will inform management strategies for skin cancers in SOTRs and provide evidence for cost-effectiveness. Trial registration Clinicaltrials.gov NCT05860881. Registered on June 15, 2023, and on anzctr.org.au (registration number NCT05860881).

This empirical study assessed the potential of developing a machine-learning model to identify children and adolescents with poor oral health using only self-reported survey data. Such a model could enable scalable and cost-effective screening and targeted interventions, optimizing limited resources to improve oral health outcomes. To train and test the model, we used data from 2,133 students attending schools in a Portuguese municipality. Poor oral health (the dependent variable) was defined as having a Decayed, Missing, and Filled Teeth index for deciduous teeth (dmft) or permanent teeth (DMFT) above expert-defined thresholds (dmft/DMFT ≥ 3 or 4). The survey provided information about the students' oral health habits, knowledge, beliefs, and food and physical activity habits, which served as independent variables. Logistic regression models with variables selected through low-variance filtering and recursive feature elimination outperformed various others trained with complex machine learning algorithms based on precision@k metric, outperforming also random selection and expert rule-based models in identifying students with poor oral health. The proposed models are inherently explainable, broadly applicable, which given the context, could compensate their lower performance (Area Under the Curve = 0.64-0.70) compared to similar approaches and models. This study is one of the few in oral health care that includes bias auditing of classification models. The audit surfaced potential biases related to demographic factors such as age and social assistance status. Addressing these biases without significantly compromising model performance remains a challenge. The results confirm the feasibility of survey-based machine learning models for identifying individuals with poor oral health, but further validation of this approach and pilot testing in field trials are necessary.

Objectives: This study aims to explore the identification of older people in need of dental consultation, with a Simplified Oral Indicator (SOI) used by home care nurses (HCNs) and with the Geriatric Oral Health Assessment Index (GOHAI-NL) completed by older people themselves, compared with the Oral Health Assessment Tool (OHAT-NL), performed by dental hygienists. Methods: The HCNs completed SOI based on their professional view, knowledge and experience; scores red/orange/green were given to older people for oral health and oral hygiene. Older people completed the GOHAI-NL and dental hygienists completed the OHAT-NL. Results: Data from 141 older people were analysed. Sensitivity and specificity of SOI –OHAT-NL were low (0.45 and 0.64, respectively); SOI scored only few older people as ‘red’, while only 11 older people did not need a dental referral according to the OHAT-NL. OHAT-NL and GOHAI-NL correlation was significant, but low (r = -0.226, p = 0.012). Conclusion: Simplified Oral Indicator is currently not sensitive enough to identify older people in need of dental consultation. Additional education to HCNs and/or adjusting SOI may be needed. The GOHAI-NL seems not useful in dental triage.

OCT imaging is an important technique to study fouling in spacer-filled channels of reverse osmosis systems for seawater desalination. However, OCT imaging of membrane filtration channels with feed spacers is challenging because the spacer material can be (partly) transparent, making it difficult to detect and possibly mistaken for fouling, and the longer optical pathway through the spacer material distorts the image below the spacer. This study presents an automated 3D OCT image processing method in MATLAB for visualization and quantification of biofouling in spacer-filled channels. First, a spacer template of arbitrary size and rotation was generated from a CT scan of the feed spacer. Second, background noise and file size were reduced by representing the OCT image with a list of discrete reflectors. Finally, the spacer template was overlayed with the feed spacer in the 3D OCT image, enabling automated visualization of the feed spacer and correction of the distortions. Moreover, the method allows the selection of datasets with the same location relative to the position of the spacer, enabling systematic comparison between datasets and quantitative analysis. • A spacer template of arbitrary size and rotation was generated from a CT scan. • The background noise was removed, and the file size was reduced by representing the OCT dataset with a list of discrete reflectors. • The spacer template was overlayed with the feed spacer in the 3D OCT image.

Broadly neutralizing antibodies (bnAbs) targeting the human immunodeficiency virus-1 (HIV-1) have played a crucial role in elucidating and characterizing neutralization-sensitive sites on the HIV-1 envelope spike and in informing vaccine development. Continual advancements in identifying more potent bnAbs, along with their capacity to trigger antibody-mediated effector functions, coupled with modifications to extend their half-life, position them as promising candidates for both HIV-1 treatment and prevention. While current pharmacological interventions have made significant progress in managing HIV-1 infection and enhancing quality of life, no definitive cure or vaccines have been developed thus far. Standard treatments involve daily oral anti-retroviral therapy, which, despite its efficacy, can lead to notable long-term side effects. Recent clinical trial data have demonstrated encouraging therapeutic and preventive potential for bnAb therapies in both HIV-1-infected individuals and those without the infection. This review provides an overview of the advancements in HIV-1-specific bnAbs and discusses the insights gathered from recent clinical trials regarding their application in treating and preventing HIV-1 infection.

Abstract Solar-driven atmospheric water extraction (SAWE) is a sustainable technology for decentralized freshwater supply. However, most SAWE systems produce water intermittently due to the cyclic nature, with adoption hindered by complex design requirements or periodic manual operations. Herein, a fully passive SAWE system that can continuously produce freshwater under sunlight is presented. By optimizing the three-dimensional architecture to facilitate spontaneous mass transport and efficient energy utilization, this system can consistently produce 0.65 L m−2 h−1 of freshwater under 1-sun illumination at 90% relative humidity (RH) and functions in arid environments with an RH as low as 40%. We test the practical performance of a scaled-up system in Thuwal, Saudi Arabia over 35 days across two seasons. The system produces 2.0–3.0 L m−2 per day of freshwater during the summer and 1.0–2.8 L m−2 per day of freshwater during the fall, without requiring additional maintenance. Intriguingly, we demonstrate the system’s potential for off-grid irrigation by successfully growing cabbage plants using atmospheric water. This passive SAWE system, harnessing solar energy to continuously extract moisture from air for drinking and irrigation, offers a promising solution to address the intertwined challenges of energy, water, and food supply, particularly for remote and water-scarce regions.

Despite the unique advantages of IgG3 over other IgG subclasses, such as mediating enhanced effector functions and increased flexibility in antigen binding due to a long hinge region, the therapeutic potential of IgG3 remains largely unexplored. This may be attributed to difficulties in recombinant expression and the reduced plasma half-life of most IgG3 allotypes. Here, we report plant expression of two SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) that exhibit high (P5C3) and low (H4) antigen binding. P5C3 and H4-IgG1 mAbs were subclass-switched to IgG3 formats, designed for efficient production and increased PK values, carrying three allotypic variations, referred to as -WT, -H, and -KVH. A total of eight mAbs were produced in glycoengineered plants that synthesize fucose-free complex N-glycans with great homogeneity. Antigen, IgG-FcγR immune complex and complement binding studies demonstrated similar activities of all mAbs. In accordance, P5C3 Abs showed minor alterations in SARS-CoV-2 neutralization (NT) and antibody-dependent cell-mediated virus inhibition (ADCVI). Clear functional differences were observed between H4 variants with superior ADCVI and NT potencies of H4 IgG3 H. Our comparative study demonstrates the production of an IgG3 variant carrying an Fc domain with equivalent or enhanced functions compared to IgG3-WT, but with the stability and PK values ​​of IgG1. Our data also demonstrate that both allotypic variability and antibody specificity are important for fine-tuning of activities, an important information for the development of future therapeutics.

The bottled drinking water market has seen significant growth and diversification, yet the selection criteria lack scientific basis, as all must adhere to stringent health standards. Prior studies predominantly focused on chemical quality, with limited assessments of microbial quality using methods prone to underestimation. Moreover, insufficient research explores the impact of packaging materials and temperatures optimal for mesophilic growth on microbial quality. To understand the unique characteristics and justify the distinction among different types of bottled waters, a comprehensive analysis encompassing both chemical and microbiological aspects is imperative. Addressing these gaps, our study examines 19 diverse bottled water brands comprising purified, mineral, artesian, and sparkling water types from Saudi Arabia and abroad. Our findings reveal distinct chemical compositions among bottled waters, with notable variations across types. Flow cytometry analysis reveals significant differences in bacterial content among water types, with natural mineral waters having the highest concentrations and treated purified waters the lowest. Bacterial content in plastic-bottled mineral water suggests it may be higher than in glass-bottled water. Flow cytometry fingerprints highlight separate microbial communities for purified and mineral waters. Additionally, temperatures favorable for mesophilic growth reveal varying microbial responses among different types of bottled waters. Some variation is also observed in mineral water bottled in plastic versus glass, suggesting potential differences that warrant further investigation. 16S rRNA gene sequencing identifies unique microbial taxa among different mineral waters. Overall, our study underscores that all bottled waters meet health regulations. Furthermore, the combined chemical and microbial profiles may serve as authenticity indicators for distinct bottled water types. This study can serve as a basis for future research on the environmental impact of bottled water transportation, suggesting that locally produced water may offer a more sustainable option.

Abstract Background Long-term survival after premature birth is significantly determined by development of morbidities, primarily affecting the cardio-respiratory or central nervous system. Existing studies are limited to pairwise morbidity associations, thereby lacking a holistic understanding of morbidity co-occurrence and respective risk profiles. Methods Our study, for the first time, aimed at delineating and characterizing morbidity profiles at near-term age and investigated the most prevalent morbidities in preterm infants: bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), mild cardiac defects, perinatal brain pathology and retinopathy of prematurity (ROP). For analysis, we employed two independent, prospective cohorts, comprising a total of 530 very preterm infants: AIRR (“Attention to Infants at Respiratory Risks”) and NEuroSIS (“Neonatal European Study of Inhaled Steroids”). Using a data-driven strategy, we successfully characterized morbidity profiles of preterm infants in a stepwise approach and (1) quantified pairwise morbidity correlations, (2) assessed the discriminatory power of BPD (complemented by imaging-based structural and functional lung phenotyping) in relation to these morbidities, (3) investigated collective co-occurrence patterns, and (4) identified infant subgroups who share similar morbidity profiles using machine learning techniques. Results First, we showed that, in line with pathophysiologic understanding, BPD and ROP have the highest pairwise correlation, followed by BPD and PH as well as BPD and mild cardiac defects. Second, we revealed that BPD exhibits only limited capacity in discriminating morbidity occurrence, despite its prevalence and clinical indication as a driver of comorbidities. Further, we demonstrated that structural and functional lung phenotyping did not exhibit higher association with morbidity severity than BPD. Lastly, we identified patient clusters that share similar morbidity patterns using machine learning in AIRR (n=6 clusters) and NEuroSIS (n=8 clusters). Conclusions By capturing correlations as well as more complex morbidity relations, we provided a comprehensive characterization of morbidity profiles at discharge, linked to shared disease pathophysiology. Future studies could benefit from identifying risk profiles to thereby develop personalized monitoring strategies. Trial registration AIRR: DRKS.de, DRKS00004600, 28/01/2013. NEuroSIS: ClinicalTrials.gov, NCT01035190, 18/12/2009.

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR. Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites. Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%). Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality. Trial registration: ANZCTR ACTRN12619000241134. Registered 19 February 2019.

Abstract In northern Switzerland, Middle Muschelkalk evaporites (Zeglingen Formation) were deposited under arid conditions in the southernmost part of the epicontinental Central European Basin during times of reduced inflow of sea water from the Tethyan realm. Because of their marginal position in the basin, direct and detailed correlation of Muschelkalk sediments of northern Switzerland with equivalent strata in interior parts of the basin is not straightforward. Based on detailed sedimentological logging of 640 m of drill cores from ten wells in northern Switzerland, 22 lithofacies and 10 lithofacies associations were distinguished for the Middle Muschelkalk evaporites. High-resolution regional correlations of gamma-ray logs record substantial thickness variation of the evaporites. Locally, dissolution was recognized by visual core examination that could be dated to Middle Triassic times and that was likely related to subsurface fluid flow along deeper seated faults. In combination with the regional thickness variation, the dissolution phenomena suggest a tectonically active depositional setting in the Middle Triassic. Middle Muschelkalk evaporites consist of nine types of mainly auto-cyclic shallowing- or brining-upward mini-cycles which form a correlatable succession of five distinct 4th order cycle-sets. Despite the tectonically active depositional environment, most lithofacies encountered appear to have nearly flat bounding surfaces. Thus, marine transgressions flooded wide areas nearly simultaneously. The corresponding deposits serve as reference levels to tie the peripheral facies of northern Switzerland into the supra-regional context.

Abstract Membrane distillation (MD) is an emerging process with a proven ability to recover freshwater from streams with a wide range of salinities. However, MD is susceptible to biofouling. This study explores the efficiency of different cleaning strategies in biofilm removal during seawater MD. Hydraulic cleaning and chemical cleanings with 0.3%w w−1 ethylenediaminetetraacetic acid (EDTA), 0.3%w w−1 NaOCl, and 3%w w−1 citric acid were tested. The results showed that permeate flux recovery increased in the order of hydraulic cleaning

Infections caused by vector-borne pathogens impose a significant burden of morbidity and mortality in a global scale. In their quest for blood, hematophagous arthropods penetrate the host skin and may transmit pathogens by the bite. These pathogens are deposited along with saliva and a complex mixture of vector derived factors. Hematophagous arthopod vectors have evolved a complex array of adaptations to modulate the host immune response at the bite site with the primary goal to improve blood feeding, which have been exploited throughout evolution by these pathogens to enhance infection establishment in the host. While this paradigm has been firmly established in mouse models, comparable data from human studies are scarce. Here we review how the host skin immune response to vector bites in animal models is hijacked by microbes to promote their pathogenesis. We mainly explored four distinct vector-pathogen pairs of global health importance: sand flies and Leishmania parasites, Ixodes scapularis ticks and Borrelia burgdorferi, Aedes aegypti mosquitoes and arboviruses, and Anopheles gambiae mosquitos and Plasmodium parasites. Finally, we outline how critical it is for the field of vector biology to shift from rodent models to clinical studies focused on the interface of vector-pathogen-host immune system to push further the frontiers of knowledge of the field.

DNA extraction yield from drinking water distribution systems and premise plumbing is a key metric for any downstream analysis such as 16S amplicon or metagenomics sequencing. This research aimed to optimize DNA yield from low-biomass (chlorinated) reverse osmosis-produced tap water by evaluating the impact of different factors during the DNA extraction procedure. The factors examined are (1) the impact of membrane materials and their pore sizes; (2) the impact of different cell densities; and (3) an alternative method for enhancing DNA yield via incubation (no nutrient spiking). DNA from a one-liter sampling volume of RO tap water with varying bacterial cell densities was extracted with five different filter membranes (mixed ester cellulose 0.2 μm, polycarbonate 0.2 μm, polyethersulfone 0.2 and 0.1 μm, polyvinylidene fluoride 0.1 μm) for biomass filtration. Our results show that (i) smaller membrane pore size solely did not increase the DNA yield of low-biomass RO tap water; (ii) the DNA yield was proportional to the cell density and substantially dependent on the filter membrane properties (i.e., the membrane materials and their pore sizes); (iii) by using our optimized DNA extraction protocol, we found that polycarbonate filter membrane with 0.2 μm pore size markedly outperformed in terms of quantity (DNA yield) and quality (background level of 16S gene copy number) of recovered microbial DNA; and finally, (iv) for one-liter sampling volume, incubation strategy enhanced the DNA yield and enabled accurate identification of the core members (i.e., Porphyrobacter and Blastomonas as the most abundant indicator taxa) of the bacterial community in low-biomass RO tap water. Importantly, incorporating multiple controls is crucial to distinguish between contaminant/artefactual and true taxa in amplicon sequencing studies of low-biomass RO tap water.

Summary: The pursuit of cost-effective, high-voltage electricity generators activated by droplets represents a new frontier in hydropower technology. This study presents an economical method for crafting droplet generators using common materials such as solid polytetrafluoroethylene (PTFE) films and readily available tapes, eliminating the need for specialized cleanroom facilities. A thorough investigation into voltage-limiting factors, encompassing device capacitance and induced electrode charges, reveals specific areas with potential for optimization. A substantial enhancement in the open-circuit voltage (Voc) was achieved, reaching approximately 282.2 ± 27.9 V—an impressive increase of around 60 V compared to earlier benchmarks. One device showcased its capability to power 100 LEDs concurrently, underscoring its efficacy. Ten such devices created diverse luminous patterns with uniform light intensity for each LED, showcasing the practical potential of the approach. The methodology’s cost-effectiveness results in a remarkable cost reduction compared to solution-based materials, paving the way for the widespread adoption of large-scale water droplet energy harvesting.

Abstract While certain inorganic main‐group polymers such as silicones (polysiloxanes) are ubiquitous in our everyday life, poly(iminoborane)s have been elusive for a long time. Incorporation of heterocyclic building blocks into their backbone has recently enabled access to the first derivatives of this inorganic‐polymer class, as this approach effectively prevents undesired side‐reactions to borazines. Information about the microstructure of these cyclolinear macromolecules, however, has been scarce. Herein, we present the synthesis of a series of monodisperse oligomers with up to 7 boron and 8 nitrogen atoms, representing the longest well‐defined molecular [>B=N

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia.MethodsThe vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed.ResultsThe VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy.DiscussionOur findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics.

Abstract Optimal spacer design enhances the filtration performance in spiral-wound modules by controlling the local hydrodynamics inside the filtration channel. A novel airfoil feed spacer design fabricated using 3D-printing technology is proposed in this study. The design is a ladder-shaped configuration with primary airfoil-shaped filaments facing the incoming feed flow. The airfoil filaments are reinforced by cylindrical pillars supporting the membrane surface. Laterally, all the airfoil filaments are connected by thin cylindrical filaments. The performances of the novel airfoil spacers are evaluated at Angle of Attack (AOA) of 10° (A-10 spacer) and 30° (A-30 spacer) and compared with commercial (COM) spacer. At fixed operating conditions, simulations indicate steady-state hydrodynamics inside the channel for A-10 spacer, while an unsteady state is found for A-30 spacer. Numerical wall shear stress for airfoil spacers is uniformly distributed and has a higher magnitude than the COM spacer. A-30 spacer design is the most efficient in ultrafiltration process with enhanced permeate flux (228%) and reduced specific energy consumption (23%) and biofouling development (74%) as characterized by Optical Coherence Tomography. Results systematically demonstrate the influential role of airfoil-shaped filaments for feed spacer design. Modifying AOA allows localized hydrodynamics to be effectively controlled according to the filtration type and operating conditions.

Abstract Maximizing the scattering of visible light within disordered nano-structured materials is essential for commercial applications such as brighteners, while also testing our fundamental understanding of light-matter interactions. The progress in the research field has been hindered by the lack of understanding how different structural features contribute to the scattering properties. Here we undertake a systematic investigation of light scattering in correlated disordered structures. We demonstrate that the scattering efficiency of disordered systems is mainly determined by topologically invariant features, such as the filling fraction and correlation length, and residual variations are largely accounted by the surface-averaged mean curvature of the systems. Optimal scattering efficiency can thus be obtained from a broad range of disordered structures, especially when structural anisotropy is included as a parameter. These results suggest that any disordered system can be optimised for whiteness and give comparable performance, which has far-reaching consequences for the industrial use of low-index materials for optical scattering.

Biofouling poses a significant challenge to reverse osmosis (RO) membrane systems, necessitating timely detection for effective control. This study evaluated the efficacy of flow cytometry (FCM) for early biofilm detection in comparison to conventional system performance indicators. Feed channel pressure drop and total cell concentration in the Membrane Fouling Simulator (MFS) flowcell cross-flow outlet water were monitored over time as early biofouling indicators. The results demonstrated the potential of increased bacterial cell concentration in cross-flow outlet water as a reliable indicator of biofouling development on the membrane. Water outlet monitoring enabled faster biofouling detection compared to feed channel pressure drop. Membrane autopsy confirmed biofilm presence prior to the pressure drop increase, highlighting the advantage of early detection in implementing corrective measures. Timely intervention reduces operational costs and energy consumption in membrane-based processes.

Background: Despite the increased use of mechanical thrombectomy (MT) in recent years, there remains a lack of research on in-hospital mortality rates following the procedure, the primary factors influencing these rates, and the potential for predicting them. This study aimed to utilize interpretable machine learning (ML) to help clarify these uncertainties. Methods: This retrospective study involved patients with anterior circulation large vessel occlusion (LVO)-related ischemic stroke who underwent MT. The patient division was made into two groups: (I) the in-hospital death group, referred to as miserable outcome, and (II) the in-hospital survival group, or favorable outcome. Python 3.10.9 was utilized to develop the machine learning models, which consisted of two types based on input features: (I) the Pre-MT model, incorporating baseline features, and (II) the Post-MT model, which included both baseline and MT-related features. After a feature selection process, the models were trained, internally evaluated, and tested, after which interpretation frameworks were employed to clarify the decision-making processes. Results: This study included 602 patients with a median age of 76 years (interquartile range (IQR) 65–83), out of which 54% (n = 328) were female, and 22% (n = 133) had miserable outcomes. Selected baseline features were age, baseline National Institutes of Health Stroke Scale (NIHSS) value, neutrophil-to-lymphocyte ratio (NLR), international normalized ratio (INR), the type of the affected vessel (‘Vessel type’), peripheral arterial disease (PAD), baseline glycemia, and premorbid modified Rankin scale (pre-mRS). The highest odds ratio of 4.504 was observed with the presence of peripheral arterial disease (95% confidence interval (CI), 2.120–9.569). The Pre-MT model achieved an area under the curve (AUC) value of around 79% utilizing these features, and the interpretable framework discovered the baseline NIHSS value as the most influential factor. In the second data set, selected features were the same, excluding pre-mRS and including puncture-to-procedure-end time (PET) and onset-to-puncture time (OPT). The AUC value of the Post-MT model was around 84% with age being the highest-ranked feature. Conclusions: This study demonstrates the moderate to strong effectiveness of interpretable machine learning models in predicting in-hospital mortality following mechanical thrombectomy for ischemic stroke, with AUCs of 0.792 for the Pre-MT model and 0.837 for the Post-MT model. Key predictors included patient age, baseline NIHSS, NLR, INR, occluded vessel type, PAD, baseline glycemia, pre-mRS, PET, and OPT. These findings provide valuable insights into risk factors and could improve post-procedural patient management.

IntroductionEndovascular thrombectomy (EVT) and concomitant usage of intravenous alteplase (alteplase) in large vessel occlusion stroke may produce unwanted excess intracerebral hemorrhage (ICH). Whether this applies specifically to isolated occlusion of the M1 segment of the middle cerebral artery (MCA) is unknown.MethodsA retrospective study from two tertiary thrombectomy centers. ICH was determined according to Heidelberg Bleeding Classification (HBC). Factors associated with the occurrence of ICH in EVT alone vs. EVT with alteplase were evaluated using logistic regression analysis. Factors related to the clinical outcome as determined with a modified Rankin scale (mRS) were investigated with univariate and adjusted multivariate logistic regression analysis. The interaction between clinical variables and the usage of alteplase on the occurrence of ICH was evaluated.ResultsAny ICH occurred in 156/457 (34.1%) patients Class 1a bleeding in 37 (8.1%), type 2 in 45 (9.8%) Class 1c in 22 (4.8%), Class 2 in 25 (5.5%), and Class 3 (extraparenchymal) in 27 (5.9%). ICH occurred in similar frequency between alteplase-treated patients vs. EVT alone (85/262 [32%] vs. 71/195 [36%]; OR 1.19 (95% CI 0.81–1.76). After adjustment, odds for clinical outcome were lower in ICH patients (OR 0.44 [95% CI 0.25–0.74]), p = 0.002). Higher ICH rate was associated with more EVT steps (p for interaction −0.005), and usage of only stent-retriever (p for interaction =0.005).ConclusionUtilization of alteplase alongside EVT for MCA M1 occlusion did not result in excessive ICH occurrences or clinical deterioration.

N-Glycosylation of immunoglobulin G1 (IgG1) at the heavy chain Fc domain (Asn297) plays an important role for antibody structure and effector functions. While numerous recombinant IgG1 antibodies have been successfully expressed in plants, they frequently display a considerable amount (up to 50%) of unglycosylated Fc domain. To overcome this limitation, we tested a single-subunit oligosaccharyltransferase from the protozoan Leishmania donovani (LdOST) for its ability to improve IgG1 Fc glycosylation. LdOST fused to a fluorescent protein was transiently expressed in Nicotiana benthamiana and confocal microscopy confirmed the subcellular location at the endoplasmic reticulum. Transient co-expression of LdOST with two different IgG1 antibodies resulted in a significant increase (up to 97%) of Fc glycosylation while leaving the overall N-glycan composition unmodified, as determined by different mass spectrometry approaches. While biochemical and functional features of “glycosylation improved” antibodies remained unchanged, a slight increase in FcγRIIIa binding and thermal stability was observed. Collectively, our results reveal that LdOST expression is suitable to reduce the heterogeneity of plant-produced antibodies and can contribute to improving their stability and effector functions.

Abstract What limits the value of the superconducting transition temperature (T c) is a question of great fundamental and practical importance. Various heuristic upper bounds on T c have been proposed, expressed as fractions of the Fermi temperature, T F, the zero-temperature superfluid stiffness, ρ s(0), or a characteristic Debye frequency, ω 0. We show that while these bounds are physically motivated and are certainly useful in many relevant situations, none of them serve as a fundamental bound on T c. To demonstrate this, we provide explicit models where T c/T F (with an appropriately defined T F), T c/ρ s(0), and T c/ω 0 are unbounded.

Chirality transfer across length-scales is an intriguing phenomenon but connecting the properties of individual building blocks to the emergent features of their resulting large-scale structure remains challenging. Here, the authors investigate the origins of mesophase chirality in cellulose nanocrystal suspensions, whose self-assembly into chiral photonic films has attracted significant interest.

Abstract Mortality in type 2 diabetes, is determined not only by classical complications, but also by comorbidities, and is linked to hyperglycaemia and apparent even in prediabetes. We aimed to comprehensively investigate, in a population-based cohort, health burden defined as the presence of comorbidities in addition to classical complications and cardiometabolic risk factors, in not only type 2 diabetes but also prediabetes. Such population-based study has not been performed previously. Extensive phenotyping was performed in 3,410 participants of the population-based Maastricht Study (15.0% prediabetes and 28.6% type 2 diabetes) to assess presence of 17 comorbidities, six classical complications, and ten cardiometabolic risk factors. These were added up into individual and combined sum scores and categorized. Group differences were studied with multinomial regression analyses adjusted for age and sex. Individuals with type 2 diabetes and prediabetes, as compared to normal glucose metabolism (NGM), had greater comorbidities, classical complications, cardiometabolic risk factors and combined sum scores (comorbidities sum score ≥ 3: frequencies (95% CI) 61.5% (57.6;65.4) and 41.2% (36.5;45.9) vs. 25.4% (23.5;27.4), p-trend

Abstract For many arctic species, the spatial (re‐)colonization patterns after the last Pleistocene glaciation have been described. However, the temporal aspects of their colonization are largely missing. Did one route prevail early, while another was more important later? The high Arctic archipelago Svalbard represents a good model system to address timeframe of postglacial plant colonization. Svalbard was almost fully glaciated during last glacial maximum and (re‐)colonization of vascular plants began in early Holocene. Early Holocene climatic optimum (HCO) supported an expanded establishment of a partly thermophilic vegetation. Today, we find remnants of this vegetation in sheltered regions referred to as “Arctic biodiversity hotspots”. The oldest record of postglacial plant colonization to Svalbard is found in Ringhorndalen‐Flatøyrdalen. Even though thermophilic species could establish also later in Holocene, only HCO was favorable for vast colonization, and only hotspots offered stable conditions for thermophilic populations throughout Holocene. Thus, these relic populations may reflect colonization patterns of HCO. We investigate whether the colonization direction of thermophilic plants (Arnica angustifolia, Campanula uniflora, Pinguicula alpina, Tofieldia pusilla, and Vaccinium uliginosum ssp. microphyllum) in Ringhorndalen‐Flatøyrdalen was uniform and different from later colonization events in other localities and non‐thermophilic plants (Arenaria humifusa, Bistorta vivipara, Juncus biglumis, Oxyria digyna, and Silene acaulis). We analyzed plastid haplotypes of the 10 taxa from Ringhorndalen‐Flatøyrdalen, from later‐colonized localities in Svalbard, and from putative source regions outside Svalbard. Only rare and thermophilic taxa Campanula uniflora and Vaccinium uliginosum ssp. microphyllum provided results suggesting at least two colonization events from different source regions. Tofieldia pusilla and all the non‐thermophilic plants showed no clear phylogeographically differentiation within Svalbard. Two of the thermophilic species showed no sequence variation. Based on the results, a uniform colonization direction to Svalbard in early Holocene is not probable; several source areas and dispersal directions were contemporarily involved.

Placozoa is an ancient phylum of extraordinarily unusual animals: miniscule, ameboid creatures that lack most fundamental animal features. Despite high genetic diversity, only recently have the second and third species been named. While prior genomic studies suffer from incomplete placozoan taxon sampling, we more than double the count with protein sequences from seven key genomes and produce the first nuclear phylogenomic reconstruction of all major placozoan lineages. This leads us to the first complete Linnaean taxonomic classification of Placozoa, over a century after its discovery: This may be the only time in the 21st century when an entire higher taxonomy for a whole animal phylum is formalized. Our classification establishes 2 new classes, 4 new orders, 3 new families, 1 new genus, and 1 new species, namely classes Polyplacotomia and Uniplacotomia; orders Polyplacotomea, Trichoplacea, Cladhexea, and Hoilungea; families Polyplacotomidae, Cladtertiidae, and Hoilungidae; and genus Cladtertia with species Cladtertia collaboinventa, nov. Our likelihood and gene content tree topologies refine the relationships determined in previous studies. Adding morphological data into our phylogenomic matrices suggests sponges (Porifera) as the sister to other animals, indicating that modest data addition shifts this node away from comb jellies (Ctenophora). Furthermore, by adding the first genomic protein data of the exceptionally distinct and branching Polyplacotoma mediterranea, we solidify its position as sister to all other placozoans; a divergence we estimate to be over 400 million years old. Yet even this deep split sits on a long branch to other animals, suggesting a bottleneck event followed by diversification. Ancestral state reconstructions indicate large shifts in gene content within Placozoa, with Hoilungia hongkongensis and its closest relatives having the most unique genetics.

Abstract Feed spacers are the critical components of any spiral-wound filtration module, dictating the filtration performance. Three spacer designs, namely a non-woven commercial spacer (varying filament cross-section), a symmetric pillar spacer, and a novel hole-pillar spacer (constant filament diameter) were studied using Direct Numerical Simulations (DNS), 3-D printed and subsequently experimentally tested in a lab-scale ultrafiltration set-up with high biofouling potential feed water at various feed pressures. Independent of the applied pressure, the novel hole-pillar spacer showed initially the lowest feed channel pressure drop, the lowest shear stress, and the highest permeate flux compared to the commercial and pillar spacers. Furthermore, less biofilm thickness development on membrane surface was visualized by Optical Coherent Tomography (OCT) imaging for the proposed hole-pillar spacer. At higher feed pressure, a thicker biofilm developed on membrane surface for all spacer designs explaining the stronger decrease in permeate flux at high pressure. The findings systematically demonstrated the role of various spacer designs and applied pressure on the performance of pre-treatment process, while identifying specific shear stress distribution guidelines for engineering a new spacer design in different filtration techniques.

Background: The success of clinical trials in Epidermolysis Bullosa (EB) is dependent upon the availability of a valid and reliable scoring tool that can accurately assess and monitor disease severity. The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) and Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (iscorEB) were independently developed and validated against the Birmingham Epidermolysis Bullosa Severity Score but have never been directly compared. Objective: To compare the reliability, convergent validity, and discriminant validity of the EBDASI and iscorEB scoring tools. Methods: An observational cohort study was conducted in 15 patients with EB. Each patient was evaluated using the EBDASI and iscorEB-clinician scoring tools by 6 dermatologists with expertise in EB. Quality of life was assessed using the iscorEB-patient and Quality of Life in EB measures. Results: The intraclass correlation coefficients for interrater reliability were 0.942 for the EBDASI and 0.852 for the iscorEB-clinician. The intraclass correlation coefficients for intrarater reliability was 0.99 for both scores. The two tools demonstrated strong convergent validity with each other. Conclusion: Both scoring tools demonstrate excellent reliability. The EBDASI appears to better discriminate between EB types and disease severities.

Introduction Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand.Methods and analysis Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data.Ethics and dissemination This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences.Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).

Abstract Background Proving that specific genes are essential for the intracellular viability of Leishmania parasites within macrophages remains a challenge for the identification of suitable targets for drug development. This is especially evident in the absence of a robust inducible expression system or functioning RNAi machinery that works in all Leishmania species. Currently, if a target gene of interest in extracellular parasites can only be deleted from its genomic locus in the presence of ectopic expression from a wild type copy, it is assumed that this gene will also be essential for viability in disease-promoting intracellular parasites. However, functional essentiality must be proven independently in both life-cycle stages for robust validation of the gene of interest as a putative target for chemical intervention. Methods Here, we have used plasmid shuffle methods in vivo to provide supportive genetic evidence that N-myristoyltransferase (NMT) is essential for Leishmania viability throughout the parasite life-cycle. Following confirmation of NMT essentiality in vector-transmitted promastigotes, a range of mutant parasites were used to infect mice prior to negative selection pressure to test the hypothesis that NMT is also essential for parasite viability in an established infection. Results Ectopically-expressed NMT was only dispensable under negative selection in the presence of another copy. Total parasite burdens in animals subjected to negative selection were comparable to control groups only if an additional NMT copy, not affected by the negative selection, was expressed. Conclusions NMT is an essential gene in all parasite life-cycle stages, confirming its role as a genetically-validated target for drug development.

Can we rely on computational methods to accurately analyze complex texts? To answer this question, we compared different dictionary and scaling methods used in predicting the sentiment of German literature reviews to the “gold standard” of human-coded sentiments. Literature reviews constitute a challenging text corpus for computational analysis as they not only contain different text levels—for example, a summary of the work and the reviewer's appraisal—but are also characterized by subtle and ambiguous language elements. To take the nuanced sentiments of literature reviews into account, we worked with a metric rather than a dichotomous scale for sentiment analysis. The results of our analyses show that the predicted sentiments of prefabricated dictionaries, which are computationally efficient and require minimal adaption, have a low to medium correlation with the human-coded sentiments (r between 0.32 and 0.39). The accuracy of self-created dictionaries using word embeddings (both pre-trained and self-trained) was considerably lower (r between 0.10 and 0.28). Given the high coding intensity and contingency on seed selection as well as the degree of data pre-processing of word embeddings that we found with our data, we would not recommend them for complex texts without further adaptation. While fully automated approaches appear not to work in accurately predicting text sentiments with complex texts such as ours, we found relatively high correlations with a semiautomated approach (r of around 0.6)—which, however, requires intensive human coding efforts for the training dataset. In addition to illustrating the benefits and limits of computational approaches in analyzing complex text corpora and the potential of metric rather than binary scales of text sentiment, we also provide a practical guide for researchers to select an appropriate method and degree of pre-processing when working with complex texts.

BackgroundDecline of hand function, especially reduced hand strength, is a common problem that can be caused by many disorders and results in difficulties performing activities of daily living. A wearable soft robotic glove may be a solution, enabling use of the affected arm and hand repeatedly during functional daily activities and providing intensive and task-specific training simultaneously with assistance of hand function. ObjectiveWe aim to investigate the therapeutic effect of an assistive soft robotic glove (Carbonhand). MethodsThis multicenter uncontrolled intervention study consists of 3 preassessments (T0, T1, and T2), a postassessment (T3), and a follow-up assessment (T4). Participants are patients who experience hand function limitations. For the intervention, participants will use the glove during activities of daily living at home for 6 weeks, with a recommended use of at least 180 minutes per week. The primary outcome measure is handgrip strength, and secondary outcome measures are related to functional arm and hand abilities, amount of glove use, and quality of life. ResultsThe first participant was included on June 25, 2019. Currently, the study has been extended due to the COVID-19 pandemic; data collection and analysis are expected to be completed in 2022. ConclusionsThe Carbonhand system is a wearable assistive device, allowing performance of functional activities to be enhanced directly during functional daily activities. At the same time, active movement of the user is encouraged as much as possible, which has potential to provide highly intensive and task-specific training. As such, it is one of the first assistive devices to incorporate assist-as-needed principles. This is the first powered clinical trial that investigates the unique application of an assistive grip-supporting soft robotic glove outside of clinical settings with the aim to have a therapeutic effect. Trial RegistrationNetherlands Trial Register NTR NL7561; https://www.trialregister.nl/trial/7561 International Registered Report Identifier (IRRID)DERR1-10.2196/34200

The 3D Ising transition, the most celebrated and unsolved critical phenomenon in nature, has long been conjectured to have emergent conformal symmetry, similar to the case of the 2D Ising transition. Yet, the emergence of conformal invariance in the 3D Ising transition has rarely been explored directly, mainly due to unavoidable mathematical or conceptual obstructions. Here, we design an innovative way to study the quantum version of the 3D Ising phase transition on spherical geometry, using the “fuzzy (noncommutative) sphere” regularization. We accurately calculate and analyze the energy spectra at the transition, and explicitly demonstrate the state-operator correspondence (i.e., radial quantization), a fingerprint of conformal field theory. In particular, we identify13 parity-even primary operators within a high accuracy and two parity-odd operators that were not known before. Our result directly elucidates the emergent conformal symmetry of the 3D Ising transition, a conjecture made by Polyakov half a century ago. More importantly, our approach opens a new avenue for studying 3D conformal field theories by making use of the state-operator correspondence and spherical geometry.

Correlated electron states are at the root of many important phenomena including unconventional superconductivity (USC), where electron pairing arises from repulsive interactions. Computing the properties of correlated electrons, such as the critical temperature T_{c} for the onset of USC, efficiently and reliably from the microscopic physics with quantitative methods remains a major challenge for almost all models and materials. In this theoretical work, we combine matrix product states (MPS) with static mean field (MF) to provide a solution to this challenge for quasi-one-dimensional (Q1D) systems: two- and three-dimensional materials comprised of weakly coupled correlated 1D fermions. This MPS+MF framework for the ground state and thermal equilibrium properties of Q1D fermions is developed and validated for attractive Hubbard systems first, and further enhanced via analytical field theory. We then deploy it to compute T_{c} for superconductivity in 3D arrays of weakly coupled, doped, and repulsive Hubbard ladders. The MPS+MF framework thus enables the quantitative study of USC and high-T_{c} superconductivity—and potentially many more correlated phases—in fermionic Q1D systems based directly on their microscopic parameters, in ways inaccessible to previous methods. This approach further allows one to treat competing macroscopic orders, such as superconducting and insulating ones, on an equal footing. Benchmarks of the framework using auxiliary-field quantum Monte Carlo techniques show that the overestimation of, e.g., T_{c} due to its mean-field component, is near constant in microscopic parameters. These features of the MPS+MF approach to correlated fermions open up the possibility of designing deliberately optimized Q1D superconductors, from experiments in ultracold gases to synthesizing new materials.

Platelets enhance coagulation by exposing phosphatidylserine (PS) on their cell surface in response to strong agonist activation. Transient receptor potential channels, including TRPC6, have been implicated in the calcium influx central to this process. Here, we characterize the effect of a Trpc6 gain-of-function (GOF) disease-associated, and a dominant negative (DN), mutation on murine platelet activation. Platelets from mice harboring Trpc6E896K/E896K (GOF) and Trpc6DN/DN mutations were subject to in vitro analysis. Trpc6E896K/E896K and Trpc6DN/DN mutant platelets show enhanced and absent calcium influx, respectively, upon addition of the TRPC3/6 agonist GSK1702934A (GSK). GSK was sufficient to induce integrin αIIbβ3 activation, P-selection and PS exposure, talin cleavage, and MLC2 phosphorylation in Trpc6E896K/E896K, but not in wild-type, platelets. Thrombin-induced calcium influx and PS exposure were enhanced, and clot retraction delayed, by GOF TRPC6, while no differences were noted between wild-type and Trpc6DN/DN platelets. In contrast, Erk activation upon GSK treatment was absent in Trpc6DN/DN, and enhanced in Trpc6E896K/E896K, platelets, compared to wild-type. The positive allosteric modulator, TRPC6-PAM-C20, and fluoxetine maintained their ability to enhance and inhibit, respectively, GSK-mediated calcium influx in Trpc6E896K/E896K platelets. The data demonstrate that gain-of-function mutant TRPC6 channel can enhance platelet activation, including PS exposure, while confirming that TRPC6 is not necessary for this process. Furthermore, the results suggest that Trpc6 GOF disease mutants do not simply increase wild-type TRPC6 responses, but can affect pathways not usually modulated by TRPC6 channel activity, displaying a true gain-of-function phenotype.

Mutations in TRPC6 are a cause of autosomal dominant focal segmental glomerulosclerosis in humans. Many of these mutations are known to have a gain-of-function effect on the non-specific cation channel function of TRPC6. In vitro studies have suggested these mutations affect several signaling pathways, but in vivo studies have largely compared wild-type and Trpc6-deficient rodents. We developed mice carrying a gain-of-function Trpc6 mutation encoding an E896K amino acid change, corresponding to a known FSGS mutation in TRPC6. Homozygous mutant Trpc6 animals have no appreciable renal pathology, and do not develop albuminuria until very advanced age. The Trpc6E896K mutation does not impart susceptibility to PAN nephrosis. The animals show a slight delay in recovery from the albumin overload model. In response to chronic angiotensin II infusion, Trpc6E896K/E896K mice have slightly greater albuminuria initially compared to wild-type animals, an effect that is lost at later time points, and a statistically non-significant trend toward more glomerular injury. This phenotype is nearly opposite to that of Trpc6-deficient animals previously described. The Trpc6 mutation does not appreciably impact renal interstitial fibrosis in response to either angiotensin II infusion, or folate-induced kidney injury. TRPC6 protein and TRPC6-agonist induced calcium influx could not be detected in glomeruli. In sum, these findings suggest that a gain-of-function Trpc6 mutation confers only a mild susceptibility to glomerular injury in the mouse.

Increasing evidence suggests that in hosts infected with parasites of the Leishmania donovani complex, transmission of infection to the sand fly vector is linked to parasite repositories in the host skin. However, a detailed understanding of the dispersal (the mechanism of spread) and dispersion (the observed state of spread) of these obligatory-intracellular parasites and their host phagocytes in the skin is lacking. Using endogenously fluorescent parasites as a proxy, we apply image analysis combined with spatial point pattern models borrowed from ecology to characterize dispersion of parasitized myeloid cells (including ManR+ and CD11c+ cells) and predict dispersal mechanisms in a previously described immunodeficient model of L. donovani infection. Our results suggest that after initial seeding of infection in the skin, heavily parasite-infected myeloid cells are found in patches that resemble innate granulomas. Spread of parasites from these initial patches subsequently occurs through infection of recruited myeloid cells, ultimately leading to self-propagating networks of patch clusters. This combination of imaging and ecological pattern analysis to identify mechanisms driving the skin parasite landscape offers new perspectives on myeloid cell behavior following parasitism by L. donovani and may also be applicable to elucidating the behavior of other intracellular tissue-resident pathogens and their host cells.

Ly6Chi inflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6Chi monocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6Chi monocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected with Leishmania donovani, the number of bone marrow Ly6Chi monocytes increased over time. Ly6Chi monocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2-/- mice

Abstract Southern Mongolia is part of the Central Asian Orogenic Belt, the origin and evolution of which is not fully known and is often debated. It is composed of several east–west trending lithostratigraphic domains that are attributed to an assemblage of accreted terranes or tectonic zones. This is in contrast to Central Mongolia, which is dominated by a cratonic block in the Hangai region. Terranes are typically bounded by suture zones that are expected to be deep-reaching, but may be difficult to identify based on observable surface fault traces alone. Thus, attempts to match lithostratigraphic domains to surface faulting have revealed some disagreements in the positions of suspected terranes. Furthermore, the subsurface structure of this region remains relatively unknown. Therefore, high-resolution geophysical data are required to determine the locations of terrane boundaries. Magnetotelluric data and telluric-only data were acquired across Southern Mongolia on a profile along a longitude of approximately 100.5° E. The profile extends ~ 350 km from the Hangai Mountains, across the Gobi–Altai Mountains, to the China–Mongolia border. The data were used to generate an electrical resistivity model of the crust and upper mantle, presented here, that can contribute to the understanding of the structure of this region, and of the evolution of the Central Asian Orogenic Belt. The resistivity model shows a generally resistive upper crust (0–20 km) with several anomalously conductive features that are believed to indicate suture zones and the boundaries of tectonic zones. Moreover, their spatial distribution is coincident with known surface fault segments and active seismicity. The lower crust (30–45 km) becomes generally less resistive, but contains an anomalously conductive feature below the Gobi–Altai zone. This potentially agrees with studies that have argued for an allochthonous lower crust below this region that has been relaminated and metamorphosed. Furthermore, there is a large contrast in the electrical properties between identified tectonic zones, due to their unique tectonic histories. Although penetration to greater depths is limited, the magnetotelluric data indicate a thick lithosphere below Southern Mongolia, in contrast to the previously reported thin lithosphere below Central Mongolia.

Contemporary governance is marked by increased attention for participation of non-governmental actors (NGAs) in traditionally governmental activities, such as policy-making. This trend has been prevalent across food policy processes and reflects a key feature of food democracy. However, the role of governmental actors in facilitating and responding to this participation remains a gap in the literature. In this article, we ask how civil servants frame the participation of NGAs in policy processes. Drawing on ethnographic research, we introduce the case of civil servants working on an urban food policy for the municipality of Ede (the Netherlands). Our analysis uncovers two competing frames: 1) highlighting the responsibility of the municipality to take a leading role in food policy making, and 2) responding reflexively to NGAs. The analysis provides insights into how the framing of participation by civil servants serves to shape the conditions for participation of NGAs. It further sheds light on related practices and uncovers existing tensions and contradictions, with important implications for food democracy. We conclude by showing how, in the short term, a strong leadership role for civil servants, informed by the responsibility frame, may be effective for advancing policy objectives of the municipality. However, the reactive frame illustrates that civil servants worry this approach is not effective for maintaining meaningful participation of NGAs. This remains a key tension of participatory municipal-led urban food policy making, but balancing both municipal responsibility and an open and reactive attitude towards the participation of NGAs is useful for enhancing food democracy.

Abstract Background Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016–002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. Methods EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm2) present for > 21 days and

This work describes the chemical composition of extracellular polymeric substances (EPS) produced by three bacteria (RO1, RO2, and RO3) isolated from a biofouled reverse osmosis (RO) membrane. We isolated pure cultures of three bacterial strains from a 7-year-old biofouled RO module that was used in a full-scale seawater treatment plant. All the bacterial strains showed similar growth rates, biofilm formation, and produced similar quantities of proteins and polysaccharides. The gel permeation chromatography showed that the EPS produced by all the strains has a high molecular weight; however, the EPS produced by strains RO1 and RO3 showed the highest molecular weight. Fourier Transform Infrared Spectroscopy (FTIR), Proton Nuclear Magnetic Resonance (1H NMR), and Carbon NMR (13C NMR) were used for a detailed characterization of the EPS. These physicochemical analyses allowed us to identify features of EPS that are important for biofilm formation. FTIR analysis indicated the presence of α-1,4 glycosidic linkages (920 cm–1) and amide II (1,550 cm–1) in the EPS, the presence of which has been correlated with the fouling potential of bacteria. The presence of α-glycoside linkages was further confirmed by 13C NMR analysis. The 13C NMR analysis also showed that the EPS produced by these bacteria is chemically similar to foulants obtained from biofouled RO membranes in previous studies. Therefore, our results support the hypothesis that the majority of substances that cause fouling on RO membranes originate from bacteria. Investigation using 1H NMR showed that the EPS contained a high abundance of hydrophobic compounds, and these compounds can lead to flux decline in the membrane processes. Genome sequencing of the isolates showed that they represent novel species of bacteria belonging to the genus Bacillus. Examination of genomes showed that these bacteria carry carbohydrates-active enzymes that play a role in the production of polysaccharides. Further genomic studies allowed us to identify proteins involved in the biosynthesis of EPS and flagella involved in biofilm formation. These analyses provide a glimpse into the physicochemical properties of EPS found on the RO membrane. This knowledge can be useful in the rational design of biofilm control treatments for the RO membrane.

Heterozygous missense mutations in the human COL7A1 gene – coding for collagen VII – lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and – together with a relatively mild phenotype – represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.

The use of algal biotechnologies in the production of biofuels, food, and valuable products has gained momentum in recent years, owing to its distinctive rapid growth and compatibility to be coupled to wastewater treatment in membrane photobioreactors. However, membrane fouling is considered a main drawback that offsets the benefits of algal applications by heavily impacting the operation cost. Several fouling control strategies have been proposed, addressing aspects related to characteristics in the feed water and membranes, operational conditions, and biomass properties. However, the lack of understanding of the mechanisms behind algal biofouling and control challenges the development of cost-effective strategies needed for the long-term operation of membrane photobioreactors. This paper reviews the progress on algal membrane fouling and control strategies. Herein, we summarize information in the composition and characteristics of algal foulants, namely algal organic matter, cells, and transparent exopolymer particles; and review their dynamic responses to modifications in the feedwater, membrane surface, hydrodynamics, and cleaning methods. This review comparatively analyzes (i) efficiency in fouling control or mitigation, (ii) advantages and drawbacks, (iii) technological performance, and (iv) challenges and knowledge gaps. Ultimately, the article provides a primary reference of algal biofouling in membrane-based applications.

The desalination of seawater using reverse osmosis membranes is an attractive solution to global freshwater scarcity. However, membrane performance is reduced by (bio)fouling. Membrane autopsies are essential for identifying the type of fouling material, and applying corrective measures to minimize membrane fouling. Information from full-scale membrane autopsies guiding improved plant operations is scant in the formal literature. In this case-study, a reverse osmosis membrane from a full-scale seawater desalination plant with a feed channel pressure drop increase of about 218% over the pressure vessel was autopsied. The simultaneous determination of microbial cells, ATP, and total organic carbon (TOC) abundances per membrane area allowed estimating the contributions of biofouling and organic fouling. The abundance of microbial cells determined by flow cytometry (up to 7 × 108 cells/cm2), and ATP (up to 21,000 pg/cm2) as well as TOC (up to 98 μg/cm2) were homogeneously distributed on the membrane. Inorganic fouling was also measured, and followed a similar coverage distribution to that of biofouling. Iron (∼150 μg/cm2, estimated by ICP-MS) was the main inorganic foulant. ATR-FTIR spectra supported that membrane fouling was both organic/biological and inorganic. High-resolution SEM-EDS imaging of cross-sectioned membranes allowed assessing the thickness of the fouling layer (up to 20 μm) and its elemental composition. Imaging results further supported the results of homogeneous fouling coverage. Moreover, imaging revealed both zones with and without compression of the polysulfone membrane layer, suggesting that the stress due to operating pressure was heterogeneous. The procedure for this membrane autopsy provided a reasonable overview of the diverse contributors of fouling and might be a starting point to building a consensus autopsy protocol. Next, it would be valuable to build a RO membrane autopsy database, which can be used as a guidance and diagnostic tool to improve the management and operation of RO desalination plants.

Quantity of water is a major concern, but the quality is of more urgent concern due to heavy metal pollution. In this study, the focus was to develop adsorbents (tannin resin (TR) and iron-doped tannin resin (Fe-TR)) from invasive Acacia mearnsii for Pb2+ and Ni2+ in solution. The developed TR and Fe-TR were prepared directly by crosslinking and iron-grafting; respectively with thermal stable at ≤ 350 °C. Surface functionality analysis revealed the presence of chelating groups at ≈ 1688 and 3661 cm−1. The crystallite sizes of the adsorbents were smaller compared to tannin; however, the % carbon and nitrogen were significantly higher. Also, the Brunauer–Emmet–Teller study revealed that iron-grafting of tannin after crosslinking increases the surface area, pore volume and pore size. Furthermore, the surface morphology of adsorbents indicated a well-defined structure with the formation of a whitish deposit and rough lump-like after ion uptake. Both adsorbents showed a type II isotherm with adsorption capacities of 40.650 mg/g and 13.763 mg/g for Pb2+and 120.63 mg/g and 110.74 for Ni2+ ion by TR and Fe-TR; respectively. The absorbate-adsorbent interactions were observed to be endothermic with negative and positive Gibb's free energy values for the adsorption of Pb2+ and Ni2+; respectively. The adsorption kinetics of Ni2+ is governed by several models; however, Pb2+ interaction is regulated by Pseudo-second-order model. Furthermore, the data generated offered the possibility of both chemisorption and physisorption processes; highlighting the flexibility and multifunctionality of tannin traps for the erasure of ion impurities in wastewater.

The shortage of fresh water resources has made the desalination of seawater a widely adopted technology. Seawater reverse osmosis (SWRO) is the most commonly used method for desalination. The SWRO process is energy-intensive, and most of the energy in SWRO is spent on pressurizing the seawater to overcome the osmotic barrier for producing fresh water. The pressure needed depends on the salinity of the seawater, its temperature, and the membrane surface properties. Membrane compaction occurs in SWRO due to hydraulic pressure application for long-term operations and operating temperature fluctuations due to seasonal seawater changes. This study investigates the effects of short-term feed water temperature increase on the SWRO process in a full-scale pilot with pretreatment and a SWRO installation consisting of a pressure vessel which contains seven industrial-scale 8” diameter spiral wound membrane elements. A SWRO feed water temperature of 40 °C, even for a short period of 7 days, caused a permanent performance decline illustrated by a strong specific energy consumption increase of 7.5%. This study highlights the need for membrane manufacturer data that account for the water temperature effect on membrane performance over a broad temperature range. There is a need to develop new membranes that are more tolerant to temperature fluctuations.