Miracle-dz/UniFAR-FTUs huggingface dataset:
Persistent antigen exposure via the eryptotic pathway drives terminal T cell dysfunction

Targeting antigen to erythrocytes in vivo leads to a state of dysfunction and exhaustion in antigen-specific T cells. Co-opting erythrocyte clearance While T cell dysfunction contributes to immune evasion in cancer and chronic viral infection, strategies that induce dysfunction in autoreactive T cells may facilitate self-tolerance. Watkins et al. used phage display to identify a human antibody fragment (Fab) that selectively binds erythrocytes, enabling efficient antigen targeting to splenic antigen-presenting cells that rapidly clear apoptotic erythrocytes. Fab-tethered antigen induced antigen-specific T cell dysfunction in mice that was sustained in response to antigen rechallenge for at least 3 months and required Batf3-dependent dendritic cells. In a murine model of experimental autoimmune encephalomyelitis, erythrocyte-targeted antigen prevented encephalogenic T cells from contributing to autoimmune pathology, demonstrating the therapeutic potential of leveraging erythrocyte clearance pathways to disarm overactive T cells. Although most current treatments for autoimmunity involve broad immunosuppression, recent efforts have aimed to suppress T cells in an antigen-specific manner to minimize risk of infection. One such effort is through targeting antigen to the apoptotic pathway to increase presentation of the antigen of interest in a tolerogenic context. Erythrocytes present a rational candidate to target because of their high rate of eryptosis, which facilitates continual uptake by antigen-presenting cells in the spleen. Here, we develop an approach that binds antigens to erythrocytes to induce sustained T cell dysfunction. Transcriptomic and phenotypic analyses revealed signatures of self-tolerance and exhaustion, including up-regulation of PD-1, CTLA4, Lag3, and TOX. Antigen-specific T cells were incapable of responding to an adjuvanted antigenic challenge even months after antigen clearance. With this strategy, we prevented pathology in a mouse experimental autoimmune encephalomyelitis model. CD8+ T cell education occurred in the spleen and was dependent on cross-presenting Batf3+ dendritic cells. These results demonstrate that antigens associated with eryptotic erythrocytes induce lasting T cell dysfunction that could be protective in deactivating pathogenic T cells.
A future so close: Mapping 10 years of promises and futures across the augmented reality development cycle

When the augmented reality (AR) industry was first forming, many hyperbolic futures were imagined. These futures served important functions, whether it was growing the community, motivating investors, or setting priorities for AR companies. Over time, however, futures and collective expectations for the technology can change dramatically. This study analyzes two futures data sets to understand 10 years of futures surrounding AR—one from years of participant observation at AR conferences, the other from a digital archive of media about wearable technologies called FABRIC. By comparing a 10-year period of futures as AR moved across stages of the development cycle, this study identifies specific ways in which flows of discourses worked to shape the conferences, which in turn shaped the collective futures and expectations about AR. This study builds on our empirical and theoretical understanding of futures by comparing futures across multiple levels (macro/micro) and longitudinally mapping the interrelationships between streams of futures.
Barriers and Facilitators to Professional Mental Health Help-Seeking Behavior: Perspective of Malaysian LGBT Individuals

Abstract This qualitative study explored the facilitators and barriers influencing professional mental health help-seeking among Malaysian LGBT young adults (n = 28). The main barriers identified were internal resistance, lack of resources and information about mental health, limited availability and accessibility to services, negative perception of mental health services, and stigma against LGBT communities. The facilitators were self-awareness, having resources and information, accessibility or availability of mental health services, and positive attitudes and beliefs about these services. Perspectives from our participants strongly highlight the requirement of culturally competent practices and LGBT-affirmative policies for better provision of mental health services among the LGBT communities.
Central composite rotatable design in the development of a new method for optimization, voltammetric determination and electrochemical behavior of betaxolol in the presence of acetaminophen based on a gold nanoparticle modified electrode

In the present study, the oxidation peak current of the betaxolol in a 0.20 M Britton–Robinson buffer solution was optimized by experimental design for its determination in the presence of acetaminophen. A central composite rotatable design was used to evaluate the effects of the variables by the differential pulse voltammetry method. These variables include scan rate, step potential, modulation amplitude, gold nanoparticles content and pH. Then, under the optimized conditions the dynamic range for betaxolol in the presence of acetaminophen was from 0.50 μM to 125.00 μM and the detection limit was found to be 46.00 nM. The characterization of the gold nanoparticle modified carbon paste electrode was investigated by cyclic voltammetry and electrochemical impedance spectroscopy. Other voltammetric methods such as double-potential step chronoamperometry and linear sweep voltammetry were also applied. Using these methods, the diffusion coefficient (D = 7.43 × 10−5 cm2 s−1) and the kinetic parameters such as the electron transfer coefficient (α = 0.60) and exchanging current density (j0 = 4.6 × 10−4 μA cm−2) for BET were determined. The results indicated that the gold nanoparticle modified carbon paste electrode could be employed for the determination of betaxolol in real samples such as pharmaceutical formulations and plasma samples.
Space-time in the study of learning trajectories

ABSTRACT Space-time plays a central role in the scientific study of learning trajectories. From a sociocultural perspective, the definition of a set of space-time coordinates enables researchers to identify and examine both the learning activities in which subjects participate and those life events relevant to understanding their learning processes. The present article reports on a systematic literature review that explored the way in which different researchers define space-time coordinates in their work. We identified 24 empirical studies on the subject, analysis of which led us to conclude that the study of learning trajectories requires not only the specific space-time coordinates of those contexts in which a given learning activity takes place, but also the coordinates that people re/co-construct on an experiential or subjective level based on those activities.
A Pre-Operative Prognostic Score for Patients With Advanced Hepatocellular Carcinoma Who Underwent Resection

Background Previous studies demonstrated a promising prognosis in advanced hepatocellular carcinoma (HCC) patients who underwent surgery, yet a consensus of which population would benefit most from surgery is still unreached. Method A total of 496 advanced HCC patients who initially underwent liver resection were consecutively collected. Least absolute shrinkage and selection operator (LASSO) regression was performed to select significant pre-operative factors for recurrence-free survival (RFS). A prognostic score constructed from these factors was used to divide patients into different risk groups. Survivals were compared between groups with log-rank test. The area under curves (AUC) of the time-dependent receiver operating characteristics was used to evaluate the predictive accuracy of prognostic score. Result For the entire cohort, the median overall survival (OS) was 23.0 months and the median RFS was 12.1 months. Patients were divided into two risk groups according to the prognostic score constructed with ALBI score, tumor size, tumor-invaded liver segments, gamma-glutamyl transpeptidase, alpha fetoprotein, and portal vein tumor thrombus stage. The median RFS of the low-risk group was significantly longer than that of the high-risk group in both the training (10.1 vs 2.9 months, P<0.001) and the validation groups (13.7 vs 4.6 months, P=0.002). The AUCs of the prognostic score in predicting survival were 0.70 to 0.71 in the training group and 0.71 to 0.72 in the validation group. Conclusion Surgery could provide promising survival for HCC patients at an advanced stage. Our developed pre-operative prognostic score is effective in identifying advanced-stage HCC patients with better survival benefit for surgery.
Mitophagy in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive solid malignancies, is characterized by the presence of oncogenic KRAS mutations, poor response to current therapies, prone to metastasis, and a low 5-year overall survival rate. Macroautophagy (herein referred to as autophagy) is a lysosome-dependent degradation system that forms a series of dynamic membrane structures to engulf, degrade, and recycle various cargoes, such as unused proteins, damaged organelles, and invading pathogens. Autophagy is usually upregulated in established cancers, but it plays a dual role in the regulation of the initiation and progression of PDAC. As a type of selective autophagy, mitophagy is a mitochondrial quality control mechanism that uses ubiquitin-dependent (e.g., the PINK1-PRKN pathway) and -independent (e.g., BNIP3L/NIX, FUNDC1, and BNIP3) pathways to regulate mitochondrial turnover and participate in the modulation of metabolism and cell death. Genetically engineered mouse models indicate that the loss of PINK1 or PRKN promotes, whereas the depletion of BNIP3L inhibits oncogenic KRAS-driven pancreatic tumorigenesis. Mitophagy also play a dual role in the regulation of the anticancer activity of certain cytotoxic agents (e.g., rocaglamide A, dichloroacetate, fisetin, and P. suffruticosa extracts) in PDAC cells or xenograft models. In this min-review, we summarize the latest advances in understanding the complex role of mitophagy in the occurrence and treatment of PDAC.
Initialization of WRF Model Simulations With Sentinel-1 Wind Speed for Severe Weather Events

The model initialization with high-resolution SAR wind data provided by the Sentinel-1 mission and its impact on the meteorological model WRF-ARW simulations is discussed. The activity is performed within the Horizon 2020 CEASELESS project, focusing on one of the target areas, the northern Adriatic Sea (northern-central Mediterranean). The Sentinel-1 SAR wind is ingested into LAPS, a numerical system developed at NOAA, specifically designed for data analysis and nowcasting issues, since it has the advantage of being faster and less computational demanding than advanced data assimilation methods. Here, LAPS analyses are used to perform a smarter initialization of the WRF-ARW model simulations than using simply global model fields. The impact of the Sentinel-1 SAR wind on the model simulations is evaluated for twenty cases, ranging through several atmospheric conditions occurring in different seasons of the years 2014–2018. For each case study, a reference WRF-ARW simulation is forced with GFS analysis and forecasts used as initial and boundary conditions, respectively. Additional model runs are initialized with the LAPS analyses, which include the information of Sentinel-1 SAR wind, METAR data and the SEVIRI/MSG (Eumetsat) brightness temperature. A statistical evaluation of the WRF-ARW simulations is performed versus an independent set of surface records, provided by the Friuli Venezia Giulia regional station network (northeastern Italy), and METAR data. The comparison is performed for 10 m wind, 2 m air and dew point temperature. The results show a positive, albeit modest, impact on the WRF model simulations initialized with the LAPS analyses. The initialization with the Sentinel-1 SAR wind show benefits for all surface variables. Finally, a Mediterranean tropical-like cyclone (Medicane), occurred in the Ionian Sea in November 2017, is considered in order to show how the use of Sentinel wind data can contribute to a better analysis and simulation of severe weather episodes in the Mediterranean. The improvement in the simulation of the pressure minimum location is remarkable.
High temperature thermoelectric properties of optimized InGaN

The effects of carrier concentration, composition, and temperature on the thermoelectric properties of high quality n-type InGaN grown by metal organic chemical vapor deposition (MOCVD) were systematically investigated. The Seebeck coefficient was found to decrease and electrical conductivity increase with increasing carrier concentration, while both were found to decrease with increasing indium composition. Additionally, thermal conductivity was found to decrease by over an order of magnitude as indium composition was increased from 0 to 19%. These trends resulted in optimum carrier concentration and indium composition of 1.1×1019 cm−3 and 17%, respectively, with a room temperature ZT of 0.04. Increasing temperature resulted in a rapidly increasing ZT, reaching a maximum value of 0.34 at 875 K. This significantly improved ZT demonstrates the potential of InGaN and other III-Nitride materials for high temperature thermoelectric applications.
Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies : Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations

In this study, we used an integrative computational approach focused on comparative perturbation-based modeling to examine molecular mechanisms and determine functional signatures underlying role of functional residues in the SARS-CoV-2 spike protein that are targeted by novel mutational variants and antibody-escaping mutations. Atomistic simulations and functional dynamics analysis are combined with alanine scanning and mutational sensitivity profiling for the SARS-CoV-2 spike protein complexes with the ACE2 host receptor are REGN-COV2 antibody cocktail (REG10987+REG10933). Using alanine scanning and mutational sensitivity analysis, we have shown that K417, E484 and N501 residues correspond to key interacting centers with a significant degree of structural and energetic plasticity that allow mutants in these positions to afford the improved binding affinity with ACE2. Through perturbation-based network modeling and community analysis of the SARS-CoV-2 spike protein complexes with ACE2 we demonstrate that E406, N439, K417 and N501 residues serve as effector centers of allosteric interactions and anchor major inter-molecular communities that mediate long-range communication in the complexes. The results provide support to a model according to which mutational variants and antibody-escaping mutations constrained by the requirements for host receptor binding and preservation of stability may preferentially select structurally plastic and energetically adaptable allosteric centers to differentially modulate collective motions and allosteric interactions in the complexes with the ACE2 enzyme and REGN-COV2 antibody combination. This study suggests that SARS-CoV-2 spike protein may function as a versatile and functionally adaptable allosteric machine that exploits plasticity of allosteric regulatory centers to fine-tune response to antibody binding without compromising activity of the spike protein.
CO2 supply modulates lipid remodelling, photosynthetic and respiratory activities in Chlorella species

Microalgae represent potential solutions to reduce the atmospheric CO2 level through photosynthesis. To boost CO2 fixation by microalgae it is essential to understand physiologic and metabolic responses at the base of CO2 assimilation and carbon flow. In this work two Trebouxiophyceae species, Chlorella sorokiniana and Chlorella vulgaris, were investigated for their metabolic responses to high and low CO2 (air level) availability. High CO2 availability resulted in an increase in biomass accumulation in both species but with a different chloroplast and mitochondrial responses. In C. sorokiniana we observed increased polar lipids and protein amount and a balanced NADPH redox state and a similar total respiration in the two conditions analysed. In contrast, in C. vulgaris high CO2 level caused an increase in TAG accumulation and a higher NADPH consumption suggesting a CO2 dependent increase of reducing power consumption in the chloroplast, which in turn influences the redox state of the mitochondria by lowering total dark respiration. Several rearrangements of the photosynthetic machinery were observed in both species, which differ from those described for the model organism Chlamydomonas reinhardtii. In the case of C. reinhardtii, adaptation of the photosynthetic apparatus to different CO2 availability relies on the translational repressor NAB1. NAB1 homologous protein could be identified only in C. vulgaris but lacked the regulation mechanisms previously described in C. reinhardtii. These findings highlight that the acclimation strategies to cope with a fluctuating inorganic carbon supply are diverse among green microalgae and point to new biotechnological strategies to boost CO2 fixation. One sentence summary High/low CO2 availability induces cell responses as lipids remodelling, adaptations of the photosynthetic apparatus and modulation of mitochondrial respiration not conserved among green algae
Cross-sectional analysis of the microbiota of human gut and their direct environment (exposome) in a household cohort in northern Vietnam

Comprehensive insight into the human gut microbiota and the interaction with their environment in communities with a high background of antibiotic use and antibiotic resistance genes is currently largely lacking. In a cohort (Vietnam), individuals within the same household, also individuals within their geographical cluster share more bacterial taxa than individuals from different households or geographical clusters. The microbial diversity among individuals who used antibiotics in the past four months was significantly lower than those who did not. Fecal microbiota of humans was more diverse than non-human samples, shared a small part of its amplicon sequence variants (ASVs) with feces from animals (7.4%), water (2.2%) and food (3.1%). Sharing of ASVs between humans and companion animals was not associated with household. There is a correlation between an Enterobacteriaceae ASV and the presence of blactx-m-2 in feces from humans and animals, hinting towards an exchange of antimicrobial resistant strains between reservoirs.
The Role of Interspecies recombinations in the evolution of antibiotic-resistant pneumococci

The evolutionary histories of the antibiotic-resistant Streptococcus pneumoniae lineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9’s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1 into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout the S. pneumoniae chromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.
Induction of specific antibodies, IgG-secreting plasmablasts and memory B cells following BCG vaccination

Many tuberculosis (TB) vaccine candidates are designed as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does protect may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterised, little is known about the B cell and antibody response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titres in serum versus plasma with modestly higher titres in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a potential contribution of the antibody response to BCG vaccine-mediated control of mycobacterial growth in vitro. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.
Frequency of quorum sensing mutations in Pseudomonas aeruginosa strains isolated from different environments

Pseudomonas aeruginosa uses quorum sensing (QS) to coordinate the expression of multiple genes necessary for establishing and maintaining infection. It has previously been shown that lasR QS mutations frequently arise in cystic fibrosis (CF) lung infections, however, there has been far less emphasis on determining whether other QS system mutations arise during infection or in other environments. To test this, we utilized 852 publicly available sequenced P. aeruginosa genomes from the Pseudomonas International Consortium Database (IPCD) to study P. aeruginosa QS mutational signatures. To study isolates by source, we focused on a subset of 654 isolates collected from CF, wounds, and non-infection environmental isolates, where we could clearly identify their source. We also worked a small collection of isolates in vitro to determine the impact of lasR and pqs mutations on isolate phenotypes. We found that lasR mutations are common across all environments and are not specific to infection nor a particular infection type. We also found that the pqs system proteins PqsA, PqsH, PqsL and MexT, a protein of increasing importance to the QS field, are highly variable. Conversely, RsaL, a negative transcriptional regulator of the las system, was found to be highly conserved, suggesting selective pressure to repress las system activity. Overall, our findings suggest that QS mutations in P. aeruginosa are common and not limited to the las system; however, LasR is unique in the frequency of putative loss-of-function mutations.