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The prospect of solving ‘grand challenges’ through technological innovation justifies the interest shown in deep-tech start-ups. These companies develop technological solutions, which they then seek to implement on a massive scale during their scale-up phase. They nevertheless encounter difficulties at this stage, which starts with the validation of their business model. This research supplements the results reported in the literature on business models in the scale-up phase, with a design-oriented approach, which is better suited to the case of technology companies. Based on intervention research carried out in an urban agriculture deep-tech start-up, an axiomatic design tool is used to highlight the importance of distinguishing between the validation of elements of the business model and their preservation. This ensures that the deep-tech start-up’s subsequent developments are aligned with the goals of resolving major challenges.

Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3 splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.

In semi-arid areas, groundwater (GW) represents the most reliable resource for water supply. In the semi-arid region of Ceará (Northeastern Brazil), GW of the crystalline fractured aquifers has a salinity higher than expected in this type of environment. This study implemented a multidisciplinary approach based on hydrodynamic (piezometric) and hydrogeochemical (18O, 2H, 3H, 14C, CFC, SF6, Electrical Conductivity, major ions) data to understand the salinization processes. Results demonstrate that GW is generally recent and recharged by meteoric waters mainly through indirect infiltration from evaporated surface water. The study suggests that GW, originally bicarbonated, becomes progressively enriched in chloride due to the dissolution and leaching of salts, during the wet season, which come from meteoric inputs and have precipitated in the unsaturated zone and pond sediments during dryer periods.

The study of stable isotopes in the precipitation of Ceará was conducted on monthly rainfall samples between 2011 and 2019 and on daily rainfall samples between 2018 and 2019 in order to support the global knowledge of hydrological processes in semi-arid regions given the scarcity of such data in the Northeast of Brazil. Results showed that the frequency of rainfall sampling in semi-arid regions may induce an isotopic bias, due to the partial evaporation from the water collectors during monthly storage causing isotopic fractionation. In the absence of adequate data processing, this bias may lead to a wrong definition of the Local Meteoric Water Line (LMWL), which can have major consequences on the understanding of groundwater recharge processes. The processing of the monthly isotopic data (elimination of the evaporated data) and the analysis of daily data highlighted that the LMWL of Quixeramobim is characterized by a y-intercept value greater than +12 ‰, indicating that rainwater is composed of vapours from marine origin, but also from continental recycling. Analysis of δ18O monthly variations in relation to climatic factors suggested the importance of convective systems and relative humidity in the control of the isotopic composition of precipitation in a semi-arid tropical region.

Mesa de Los Santos is an elevated plateau located in the Eastern Cordillera of Colombia (Andean region) in the Department of Santander (altimetric variation 300 to 1800 m a.s.l.). The region is marked by a shortage of potable surface water. The isotopic study of the rain and its relation to Los Santos Formation phreatic and fractured aquifer was carried out. Four rain stations were installed on top of the plateau (1275 to 1684 m a.s.l.) to collect monthly rainwater samples for stable isotopes. The rainwater stations recorded 1469 to 764 mm from North to South, and the seasonal patterns of stable isotopes were similar in all stations. The preliminary Local Meteoric Water Line is δ2H = 8.22×δ18O + 13.9, slightly above the GMWL with an intercept of +13.9 ‰, possibly indicating continental vapor recycling. The rain-weighted annual isotope means showed more depleted values in the southmost rain station (δ18O = −8.99 ‰, 1275 m a.s.l.). From the phreatic and fractured aquifer, 35 groundwater points were monitored bimonthly for stable isotopes (n=134) and three trends were differentiated in the isotopic content value of δ18O. Large temporal variability characterized 10 groundwater points (amplitudes greater than 1 ‰ in δ18O for each point) consistently with the seasonal behaviour of the rain, indicating flows with rapid transit on a monthly scale. 21 groundwater points showed a low temporal variability with year-round differences under 1 ‰ and presenting a spatial distribution of δ18O with enriched values towards the north (between −6.71 ‰ and −6.00 ‰) and depleted values towards the south (−8.97 ‰ to −8.14 ‰), which tends to be also consistent with the rainwater isotope distribution observed. The stability of year-round groundwater isotopic values is a sign of efficient mixing of groundwater and a slower transit. Finally, 4 groundwater points presented signs of evaporation, showing d-excess values between −6.4 ‰ and +4.3 ‰, in connection with surface water bodies that undergo evaporation before infiltration.

The determination of the origin of salinity in the superficial aquifer of Mornag (NE Tunisia), and the understanding of its hydrological and geochemical behaviours related to severe natural and anthropogenic constraints, were approached by the combined study of chemical elements and stable isotopes (2H and 18O). This study indicates that: (1) the high salinities of the superficial aquifer of Mornag are mainly explained by the dissolution/precipitation processes of evaporite minerals in the aquifer formation, (2) the present-day recharge during rainwater infiltration brings downward a high content of nitrates and other dissolved salts, (3) infiltration of untreated sewage from the main urban areas contaminates the aquifer, (4) two other sources of dissolved salts in groundwater exist, favoured by the intensive exploitation of the phreatic aquifer. The first one is due to mineralised water infiltration from Meliane Wadi where activities, mainly a cement factory, discharge their wastewater. Intrusion of marine saltwater is the second source of salinity caused by aquifer over-exploitation. This hypothesis is supported by the high chloride concentration (>122 m e.q. L−1), Br/Cl ratios (>1.8 ‰) and the piezometric level lower than sea level. On the other hand, the artificial recharge with low mineralization waters by the Mejerda-Cap Bon Canal and the natural recharge in the valley of wadi El Hma, contribute to a dilution of groundwater. The freshwater/saltwater mixing causes geochemical interactions modifying the water chemistry: cationic exchange, precipitation phenomena. Isotopic tools (2H and 18O) show that the water of this aquifer system has been recently recharged by direct infiltration from the boundary and in the valley of wadis.

Population growth and agricultural intensification are ever more demanding in water resources, and threaten their quality and quantity, especially in semi-arid and arid areas. The Sahara desert is typical of these multiple constraints and rapid changes making sustainable management of water resources a major issue. The wide regional aquifers have nearly fossil water. In contrast, alluvial aquifers associated with small wadis are recharged nearly each year by the rare floods. In the case of Wadi Tamanrasset, in southern Algeria, the alluvial aquifer is exploited intensively because of its accessibility and its good chemical quality. The physical conditions commanding flow and recharge of groundwater, and especially the transfer from surface to groundwater, were studied by combining hydrodynamics and isotopic tracers (18O, 2H). Monthly monitoring of groundwater level in around thirty wells was complemented by automatic recorders with hourly time steps since March 2016 in three wells, along a 600 m transect perpendicular to the wadi bed. The slow response of the water table is visible only two months after the first flood; its maximum rise was 1 m in 2016. Isotopic analyses of rainwater on a daily time scale, of the wadi water on a 1 h time scale during runoff and of groundwater (two complete campaigns in the dry and wet seasons and a specific monitoring of the transect every month) have provided additional information on surface-groundwater transfer.

Recently, interest in transcriptomic assessment of kidney biopsies has been growing. This study investigates the use of NGS to identify gene expression changes and analyse the pathways involved in rejection. An Illumina bulk RNA sequencing on the polyadenylated RNA of 770 kidney biopsies was conducted. Differentially-expressed genes (DEGs) were determined for AMR and TCMR using DESeq2. Genes were segregated according to their previous descriptions in known panels (microarray or the Banff Human Organ Transplant (B-HOT) panel) to obtain NGS-specific genes. Pathway enrichment analysis was performed using the Reactome and Kyoto Encyclopaedia of Genes and Genomes (KEGG) public repositories. The differential gene expression using NGS analysis identified 6,141 and 8,478 transcripts associated with AMR and TCMR. While most of the genes identified were included in the microarray and the B-HOT panels, NGS analysis identified 603 (9.8%) and 1,186 (14%) new specific genes. Pathways analysis showed that the B-HOT panel was associated with the main immunological processes involved during AMR and TCMR. The microarrays specifically integrated metabolic functions and cell cycle progression processes. Novel NGS-specific based transcripts associated with AMR and TCMR were discovered, which might represent a novel source of targets for drug designing and repurposing.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Abstract Antibodies reactive to human leukocyte antigens (HLA) represent a barrier for patients awaiting transplantation. Based on reactivity patterns in single-antigen bead (SAB) assays, various epitope matching algorithms have been proposed to improve transplant outcomes. However, some antibody reactivities cannot be explained by amino acid motifs, leading to uncertainty about their clinical relevance. Antibodies against the HLA class II molecule, DQβ0603:DQα0103, present in some candidates, represent one such example. Here, we show that peptides derived from amino acids 119-148 of the HLA class I heavy chain are bound to DQβ0603:DQα0103 proteins and contribute to antibody reactivity through an HLA-DM-dependent process. Moreover, antibody reactivity is impacted by the specific amino acid sequence presented. In summary, we demonstrate that polymorphic HLA class I peptides, bound to HLA class II proteins, can directly or indirectly be part of the antibody binding epitope. Our findings have potential important implications for the field of transplant immunology and for our understanding of adaptive immunity.

Abstract Phthalates constitute a family of anthropogenic chemicals developed to be used in the manufacture of plastics, solvents, and personal care products. Their dispersion and accumulation in many environments can occur at all stages of their use (from synthesis to recycling). However, many phthalates together with other accumulated engineered chemicals have been shown to interfere with hormone activities. These compounds are also in close contact with microorganisms that are free-living, in biofilms or in microbiota, within multicellular organisms. Herein, the activity of several phthalates and their substitutes were investigated on the opportunistic pathogen Legionella pneumophila, an aquatic microbe that can infect humans. Beside showing the toxicity of some phthalates, data suggested that Acetyl tributyl citrate (ATBC) and DBP (Di-n-butyl phthalate) at environmental doses (i.e. 10–6 M and 10–8 M) can modulate Legionella behavior in terms of motility, biofilm formation and response to antibiotics. A dose of 10–6 M mostly induced adverse effects for the bacteria, in contrast to a dose of 10–8 M. No perturbation of virulence towards Acanthamoeba castellanii was recorded. These behavioral alterations suggest that L. pneumophila is able to sense ATBC and DBP, in a cross-talk that either mimics the response to a native ligand, or dysregulates its physiology.

Abstract Shear stress generated by urinary fluid flow is an important regulator of renal function. Its dysregulation is observed in various chronic and acute kidney diseases. Previously, we demonstrated that primary cilium-dependent autophagy allows kidney epithelial cells to adapt their metabolism in response to fluid flow. Here, we show that nuclear YAP/TAZ negatively regulates autophagy flux in kidney epithelial cells subjected to fluid flow. This crosstalk is supported by a primary cilium-dependent activation of AMPK and SIRT1, independently of the Hippo pathway. We confirm the relevance of the YAP/TAZ-autophagy molecular dialog in vivo using a zebrafish model of kidney development and a unilateral ureteral obstruction mouse model. In addition, an in vitro assay simulating pathological accelerated flow observed at early stages of chronic kidney disease (CKD) activates YAP, leading to a primary cilium-dependent inhibition of autophagic flux. We confirm this YAP/autophagy relationship in renal biopsies from patients suffering from diabetic kidney disease (DKD), the leading cause of CKD. Our findings demonstrate the importance of YAP/TAZ and autophagy in the translation of fluid flow into cellular and physiological responses. Dysregulation of this pathway is associated with the early onset of CKD.

Background:. Dermal scaffolds have created a paradigm shift for burn and wound management by providing improved healing and less scarring, while improving cosmesis and functionality. Dermal regeneration template (DRT) is a bilayer membrane for dermal regeneration developed by Yannas and Burke in the 1980s. The aim of this review is to summarize clinical evidence for dermal scaffolds focusing on DRT for the management and reconstruction of burn injuries and complex wounds. Methods:. A comprehensive search of PubMed was performed from the start of indexing through November 2022. Articles reporting on DRT use in patients with burns, limb salvage, and wound reconstruction were included with focus on high-level clinical evidence. Results:. DRT has become an established alternative option for the treatment of full-thickness and deep partial-thickness burns, with improved outcomes in areas where cosmesis and functionality are important. In the management of diabetic foot ulcers, use of DRT is associated with high rates of complete wound healing with a low risk of adverse outcomes. DRT has been successfully used in traumatic and surgical wounds, showing particular benefit in deep wounds and in the reconstruction of numerous anatomical sites. Conclusions:. Considerable clinical experience has accrued with the use of DRT beyond its original application for thermal injury. A growing body of evidence from clinical studies reports the successful use of DRT to improve clinical outcomes and quality of life across clinical indications at a number of anatomical sites.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic may have affected the preventability of 30-day hospital revisits, including readmissions and emergency department (ED) visits without admission. This study was conducted to examine the preventability of 30-day revisits for patients admitted with COVID-19 in order to inform the design of interventions that may decrease preventable revisits in the future. METHODS: The study team retrospectively reviewed a cohort of adults admitted to an academic medical center with COVID-19 between March 21 and June 29, 2020, and discharged alive. Patients with a 30-day revisit following hospital discharge were identified. Two-physician review was used to determine revisit preventability, identify factors contributing to preventable revisits, assess potential preventive interventions, and establish the influence of pandemic-related conditions on the revisit. RESULTS: Seventy-six of 576 COVID-19 hospitalizations resulted in a 30-day revisit (13.2%), including 21 ED visits without admission (3.6%) and 55 readmissions (9.5%). Of these 76 revisits, 20 (26.3%) were potentially preventable. The most frequently identified factors contributing to preventable revisits were related to the choice of postdischarge location and to patient/caregiver understanding of the discharge medication regimen, each occurring in 25.0% of cases. The most frequently cited potentially preventive intervention was improved self-management plan at discharge, occurring in 65.0% of cases. Five of the 20 preventable revisits (25.0%) had contributing factors that were thought to be directly related to the COVID-19 pandemic. CONCLUSION: Although only approximately one quarter of 30-day hospital revisits following admission with COVID-19 were potentially preventable, these results highlight opportunities for improvement to reduce revisits going forward.

The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins.

The integral membrane protein ATG9A plays a key role in autophagy. It displays a broad intracellular distribution and is present in numerous compartments, including the plasma membrane (PM). The reasons for the distribution of ATG9A to the PM and its role at the PM are not understood. Here, we show that ATG9A organizes, in concert with IQGAP1, components of the ESCRT system and uncover cooperation between ATG9A, IQGAP1 and ESCRTs in protection from PM damage. ESCRTs and ATG9A phenocopied each other in protection against PM injury. ATG9A knockouts sensitized the PM to permeabilization by a broad spectrum of microbial and endogenous agents, including gasdermin, MLKL and the MLKL-like action of coronavirus ORF3a. Thus, ATG9A engages IQGAP1 and the ESCRT system to maintain PM integrity.

We report a comprehensive data set characterizing and quantifying the geometrically necessary dislocation (GND) density in the crystallographic frame (ραc) and disclination density (ρθ) in fine-grained polycrystalline olivine deformed in uniaxial compression or torsion, at 1000 and 1200 ∘C, under a confining pressure of 300 MPa. Finite strains range from 0.11 up to 8.6 %, and stresses reach up to 1073 MPa. The data set is a selection of 19 electron backscatter diffraction maps acquired with conventional angular resolution (0.5∘) but at high spatial resolution (step size ranging between 0.05 and 0.1 µm). Thanks to analytical improvement for data acquisition and treatment, notably with the use of ATEX (Analysis Tools for Electron and X-ray diffraction) software, we report the spatial distribution of both GND and disclination densities. Areas with the highest GND densities define sub-grain boundaries. The type of GND densities involved also indicates that most olivine sub-grain boundaries have a mixed character. Moreover, the strategy for visualization also permits identifying minor GND that is not well organized as sub-grain boundaries yet. A low-temperature and high-stress sample displays a higher but less organized GND density than in a sample deformed at high temperature for a similar finite strain, grain size, and identical strain rate, confirming the action of dislocation creep in these samples, even for micrometric grains (2 µm). Furthermore, disclination dipoles along grain boundaries are identified in every undeformed and deformed electron backscatter diffraction (EBSD) map, mostly at the junction of a grain boundary with a sub-grain but also along sub-grain boundaries and at sub-grain boundary tips. Nevertheless, for the range of experimental parameters investigated, there is no notable correlation of the disclination density with stress, strain, or temperature. However, a broad positive correlation between average disclination density and average GND density per grain is found, confirming their similar role as defects producing intragranular misorientation. Furthermore, a broad negative correlation between the disclination density and the grain size or perimeter is found, providing a first rule of thumb on the distribution of disclinations. Field dislocation and disclination mechanics (FDDM) of the elastic fields due to experimentally measured dislocations and disclinations (e.g., strains/rotations and stresses) provides further evidence of the interplay between both types of defects. At last, our results also support that disclinations act as a plastic deformation mechanism, by allowing rotation of a very small crystal volume.

IntroductionSeveral studies have investigated the impact of circulating complement-activating anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) on organ transplant outcomes. However, a critical appraisal of these studies and a demonstration of the prognostic value of complement-activating status over anti-HLA DSA mean fluorescence intensity (MFI) level are lacking.MethodsWe conducted a systematic review, meta-analysis and critical appraisal evaluating the role of complement-activating anti-HLA DSAs on allograft outcomes in different solid organ transplants. We included studies through Medline, Cochrane, Scopus, and Embase since inception of databases till May 05, 2023. We evaluated allograft loss as the primary outcome, and allograft rejection as the secondary outcome. We used the Newcastle-Ottawa Scale and funnel plots to assess risk of bias and used bias adjustment methods when appropriate. We performed multiple subgroup analyses to account for sources of heterogeneity and studied the added value of complement assays over anti-HLA DSA MFI level.ResultsIn total, 52 studies were included in the final meta-analysis (11,035 patients). Complement-activating anti-HLA DSAs were associated with an increased risk of allograft loss (HR 2.77; 95% CI 2.33-3.29, p

Membrane integrity is essential for cellular survival and function. The spectrum of mechanisms protecting cellular and intracellular membranes is not fully known. Our recent work has uncovered a cellular system termed MERIT for lysosomal membrane repair, removal and replacement. Specifically, lysosomal membrane damage induces, in succession, ESCRT-dependent membrane repair, macroautophagy/autophagy-dominant removal of damaged lysosomes, and initiation of lysosomal biogenesis via transcriptional programs. The MERIT system is governed by galectins, a family of cytosolically synthesized lectins recognizing β-galactoside glycans. We found in this study that LGALS3 (galectin 3) detects membrane damage by detecting exposed lumenal glycosyl groups, recruits and organizes ESCRT components PDCD6IP/ALIX, CHMP4A, and CHMPB at damaged sites on the lysosomes, and facilitates ESCRT-driven repair of lysosomal membrane. At later stages, LGALS3 cooperates with TRIM16, an autophagy receptor-regulator, to engage autophagy machinery in removal of excessively damaged lysosomes. In the absence of LGALS3, repair and autophagy are less efficient, whereas TFEB nuclear translocation increases to compensate lysosomal deficiency via de novo lysosomal biogenesis. The MERIT system protects endomembrane integrity against a broad spectrum of agents damaging the endolysosomal network including lysosomotropic drugs, Mycobacterium tuberculosis, or neurotoxic MAPT/tau.AbbreviationsAMPK: AMP-activated protein kinase; APEX2: engineered ascorbate peroxidase 2; ATG13: autophagy related 13; ATG16L1: autophagy related 16 like 1; BMMs: bone marrow-derived macrophages; ESCRT: endosomal sorting complexes required for transport; GPN: glycyl-L-phenylalanine 2-naphthylamide; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MERIT: membrane repair, removal and replacement; MTOR: mechanistic target of rapamycin kinase; TFEB: transcription factor EB; TFRC: transferrin receptor; TRIM16: tripartite motif-containing 16.

Although many animals have evolved intrinsic transparency for the purpose of concealment, the development of dynamic, that is, controllable and reversible, transparency for living human cells and tissues has remained elusive to date. Here, by drawing inspiration from the structures and functionalities of adaptive cephalopod skin cells, we design and engineer human cells that contain reconfigurable protein-based photonic architectures and, as a result, possess tunable transparency-changing and light-scattering capabilities. Our findings may lead to the development of unique biophotonic tools for applications in materials science and bioengineering and may also facilitate an improved understanding of a wide range of biological systems.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

Endomembrane damage elicits homeostatic responses including ESCRT-dependent membrane repair and autophagic removal of damaged organelles. Previous studies have suggested that these systems may act separately. Here, we show that galectin-3 (Gal3), a β-galactoside-binding cytosolic lectin, unifies and coordinates ESCRT and autophagy responses to lysosomal damage. Gal3 and its capacity to recognize damage-exposed glycans were required for efficient recruitment of the ESCRT component ALIX during lysosomal damage. Both Gal3 and ALIX were required for restoration of lysosomal function. Gal3 promoted interactions between ALIX and the downstream ESCRT-III effector CHMP4 during lysosomal repair. At later time points following lysosomal injury, Gal3 controlled autophagic responses. When this failed, as in Gal3 knockout cells, lysosomal replacement program took over through TFEB. Manifestations of this staged response, which includes membrane repair, removal, and replacement, were detected in model systems of lysosomal damage inflicted by proteopathic tau and during phagosome parasitism by Mycobacterium tuberculosis.

Mathematical and numerical models are increasingly used in microbial ecology to model the fate of microbial communities in their ecosystem. These models allow to connect in a mechanistic framework species-level informations, such as the microbial genomes, with macro-scale features, such as species spatial distributions or metabolite gradients. Numerous models are built upon species-level metabolic models that predict the metabolic behaviour of a microbe by solving an optimization problem knowing its genome and its nutritional environment. However, screening the community dynamics with these metabolic models implies to solve such an optimization problem by species at each time step, leading to a significant computational load further increased by several orders of magnitude when spatial dimensions are added. In this paper, we propose a statistical framework based on Reproducing Kernel Hilbert Space (RKHS) metamodels that are used to provide fast approximations of the original metabolic model. The metamodel can replace the optimization step in the system dynamics, providing comparable outputs at a much lower computational cost. We will first build a system dynamics model of a simplified gut microbiota composed of a unique commensal bacterial strain in interaction with the host and challenged by a Salmonella infection. Then, the machine learning method will be introduced, and particularly the ANOVA-RKHS that will be exploited to achieve variable selection and model parsimony. A training dataset will be constructed with the original system dynamics model and hyper-parameters will be carefully chosen to provide fast and accurate approximations of the original model. Finally, the accuracy of the trained metamodels will be assessed, in particular by comparing the system dynamics outputs when the original model is replaced by its metamodel. The metamodel allows an overall relative error of 4.71% but reducing the computational load by a speed-up factor higher than 45, while correctly reproducing the complex behaviour occurring during Salmonella infection. These results provide a proof-of-concept of the potentiality of machine learning methods to give fast approximations of metabolic model outputs and pave the way towards PDE-based spatio-temporal models of microbial communities including microbial metabolism and host-microbiota-pathogen interactions.

Seaweed surface provides a suitable substratum for the settlement of microorganisms (bacteria, viruses, and plankton). These microbial partners may have either beneficial or detrimental effects on the host since surface microbiota can act either as a protective layer to the macroalgae (symbiotic beneficial relations) or, under changing environmental conditions, the microbial equilibrium may shift to a detrimental, pathogenic state thus inducing diseases in the host. In commercial aquaculture, seaweed diseases feature a growing concern. Pathogenicity of microorganisms that infect algal hosts is closely related to the release of virulence factors and the formation of biofilms, both of which are regulated by Quorum Sensing (QS). The main focus of this study is to determine the pathogenicity of the surface-associated bacteria of Halymenia floresii, a carrageenophyte that originated from distinct habitats. Twenty-five bacterial species isolated from the surface of H. floresii were individually tested for tip bleaching assay to evaluate their potential pathogenicity. Ten isolates significantly reduced the risk of tip bleaching in H. floresii and were designated as “significantly non-pathogenic”. Vibrio owensii was identified as a “significant pathogen” inducing bleaching disease in H. floresii. By using LC-MS, we here identified its HomoSerine Lactones (HSL) QS signal, as a C4-HSL (short-chain). This study thus suggests a possible involvement of QS signal (short-chain) in the disease-inducing bacterium from the aquaculture ponds (an integrated multitrophic aquaculture system). This study firstly reports on the surface-associated bacteria of a lambda-carrageenophyte. This study must contribute to the development of dedicated strategies for disease control based on HSL disruption in aquaculture.

Manipulation of topology of the electronic structure is highly desirable for practical applications of topological materials. Here the authors demonstrate tuning and annihilation of Weyl nodes in momentum space by means of the Zeeman effect in a strongly correlated topological semimetal Ce3Bi4Pd3.

IntroductionRecent evidence has started to demonstrate that 360°VR, a type of VR that immerses a user within a 360° video, has advantages over two-dimensional (2D) video displays in the context of perceptual-cognitive evaluation and training. However, there is currently a lack of empirical evidence to explain how perceptual-cognitive strategies differ between these two paradigms when performing sports-related tasks. Thus, the objective of this study was to examine and compare the impact of different viewing conditions (e.g., 3D-360°VR and 2D video displays), on gaze behavior and head excursions in a boxing-specific anticipatory task. A secondary objective was to assess the workload associated with each viewing mode, including the level of presence experienced. Thirdly, an exploratory analysis was conducted to evaluate any potential sex differences.MethodsThirty-two novice participants (16 females) were recruited for this study. A total of 24 single-punch sequences were randomly presented using a standalone VR headset (Pico Neo 3 Pro Eye), with two different viewing modes: 3D-360°VR and 2D. Participants were instructed to respond to the punches with appropriate motor actions, aiming to avoid punches. Gaze behavior was recorded using a Tobii eyetracker embedded in the VR headset. Workload and presence were measured with the SIM-TLX questionnaire. Fixation duration, number of fixations, saccades, search rate and head excursions (roll, pitch, yaw) were analyzed using linear mixed models.ResultsThe results revealed significant shorter fixation durations and more head excursions (roll, pitch) in 3D-360°VR, compared to the 2D viewing mode (ps

First described in the United States, outpatient parenteral antibiotic therapy (OPAT) has become an indispensable part of treating serious infections. The proportion of infectious disease (ID) physicians utilizing a formal OPAT program has increased in recent years, but remains a minority. In addition, many ID physicians have indicated that OPAT programs have inadequate financial and administrative support. Given the medical complexity of patients receiving OPAT, as well as the challenges of communicating with OPAT providers across health care facilities and systems, OPAT programs ideally should involve a multidisciplinary team. The majority of patients in the United States receive OPAT either at home with assistance from home infusion companies and visiting nurses or at a skilled nursing facility (SNF), though the latter has been associated with lower rates of patient satisfaction. Current and future opportunities and challenges for OPAT programs include providing OPAT services for people who inject drugs (PWID) and incorporating the increasing use of oral antibiotics for infections historically treated with parenteral therapy. In this review, we will discuss the current practice patterns and patient experiences with OPAT in the United States, as well as identify future challenges and opportunities for OPAT programs.

Summary: Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+ monocytes to induce inflammasomal cytokine/chemokine responses including IL1β, IL8, and CCL2. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment strategy for severe COVID-19.