Explosive cyclones occurred between 2010 and 2020 in the South Atlantic under the perspective of two detection schemes.

Under two detection schemes, this study analyzes one of the most destructive weather systems - the explosive cyclones - in the South Atlantic, from 2010 to 2020. Then, two methods are presented to study these systems: the Observational Method (OBSM) and the Automated Method (AUTM). The first uses visual analysis of the mean sea level pressure (mslp) fields and functions to identify the local minimums using the Grid Analysis and Display (GrADS) software. The second utilizes a function from OpenGrADS called mfhilo. It shows the local minimum in the grid using laplacian, magnitude, and percentile. Two shell algorithms for data manipulation are used for the AUTM: one to trace the cyclones' trajectories according to a previously defined fixed area and the other to separate them into explosives. The OBSM methodology showed 271 cases averaging 25 yearly and revealed important characteristics regarding the intensities. According to AUTM's methodology, from the 2705 ordinary cyclone cases identified, 299 are explosives. There is a clear seasonality pattern in the systems' distribution along South America, similar to OBSM, but more highlighted. In summer, they concentrate at high latitudes, while in winter and spring, they are assembled near southern Brazilian and Uruguayan coasts.

Detailed Phytochemical Composition, Cyto-/Hepatotoxicity, and Antioxidant/Anti-Inflammatory Profile of Moroccan Spices: A Study on Coriander, Caraway, and Mystical Cumin.

Coriander, caraway, and mystical cumin are famous for their aromatic properties and widely used in Moroccan cuisine. The nutritional/phytochemical composition of their seeds (used for food flavoring and preservation) were compared. Their antioxidant, anti-inflammatory, cytotoxic and hepatotoxic effects were also explored. The fat content was similar among the samples (13%), with monounsaturated fatty acids being predominant. The coriander and mystical cumin seeds were extremely rich in C18:1n9c (81 and 85%, respectively) while, in the caraway, C18:1n12 (25%) was found together with C18:1n9c (32%). The caraway seeds also presented a higher proportion of C18:2n6c (34%) than the other seeds (13 and 8%, correspondingly). γ-Tocotrienol was the major vitamin E form in all the samples. The caraway seeds contained double the amount of protein (~18%) compared to the other seeds (~8%) but, qualitatively, the amino acid profiles among all seeds were similar. The seeds were also rich in dietary fiber (40-53%); however, differences were found in their fiber profiles. Caraway showed the highest antioxidant profile and anti-inflammatory activity and an LC-DAD-ESI/MSn analysis revealed great differences in the phenolic profiles of the samples. Cytotoxicity (NCI-H460, AGS, MCF-7, and CaCo2) and hepatotoxicity (RAW 264.7) were not observed. In sum, besides their flavoring/preservation properties, these seeds are also relevant source of bioactive compounds with health-promoting activities.

Utilization of Fusarium Solani lipase for enrichment of polyunsaturated Omega-3 fatty acids.

Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), offer numerous health benefits. Enriching these fatty acids in fish oil using cost-effective methods, like lipase application, has been studied extensively. This research aimed to investigate F. solani as a potential lipase producer and compare its efficacy in enhancing polyunsaturated omega-3 fatty acids with commercial lipases. Submerged fermentation with coconut oil yielded Lipase F2, showing remarkable activity (215.68 U/mL). Lipase F2 remained stable at pH 8.0 (activity: 93.84 U/mL) and active between 35 and 70 °C, with optimal stability at 35 °C. It exhibited resistance to various surfactants and ions, showing no cytotoxic activity in vitro, crucial for its application in the food and pharmaceutical industries. Lipase F2 efficiently enriched EPA and DHA in fish oil, reaching 22.1 mol% DHA and 23.8 mol% EPA. These results underscore the economic viability and efficacy of Lipase F2, a partially purified enzyme obtained using low-cost techniques, demonstrating remarkable stability and resistance to diverse conditions. Its performance was comparable to highly pure commercially available enzymes in omega-3 production. These findings highlight the potential of F. solani as a promising lipase source, offering opportunities for economically producing omega-3 and advancing biotechnological applications in the food and supplements industry.

Threat directionality modulates defensive reactions in humans: cardiac and electrodermal responses.

Features of threatening cues and the associated context influence the perceived imminence of threat and the defensive responses evoked. To provide additional knowledge about how the directionality of a threat (i.e. directed-towards or away from the viewer) might impact defensive responses in humans, participants were shown pictures of a man carrying a gun (threat) or nonlethal object (neutral) directed-away from or towards the participant. Cardiac and electrodermal responses were collected. Compared to neutral images, threatening images depicting a gun directed-towards the participant induced sustained bradycardia and an increased electrodermal response, interpreted as immobility under attack. This defensive immobility reaction is evoked by high perceived threat and inescapable situations and indicates intense action preparation. Pictures of guns directed-away from the participant induced shorter bradycardia and no significant modulation of the electrodermal response compared to neutral pictures, which might be consistent with the perception of a less threatening situation. The results show that the directionality of threat stimuli is a key factor that prompts different patterns of defensive responses.

Formic acid stability in different solvents by DFT calculations.

CONTEXT: New technologies have been developed toward the use of green energies. The production of formic acid (FA) from carbon dioxide (CO[Formula: see text]) hydrogenation with H[Formula: see text] is a sustainable process for H[Formula: see text] storage. However, the FA adduct stabilization is thermodynamically dependent on the type of solvent and thermodynamic conditions. The results suggest a wide range of dielectric permittivity values between the dimethyl sulfoxide (DMSO) and water solvents to stabilize the FA in the absence of base. The thermodynamics analysis and the infrared and charge density difference results show that the formation of the FA complex with H[Formula: see text]O is temperature dependent and has a major influence on aqueous solvents compared to the FA adduct with amine, in good agreement with the experiment. In these conditions, the stability thermodynamic of the FA molecule may be favorable at non-organic solvents and dielectric permittivity values closer to water. Therefore, a mixture of aqueous solvents with possible ionic composition could be used to increase the thermodynamic stability of H[Formula: see text] storage in CO[Formula: see text] conversion processes. METHODS: Using the Quantum ESPRESSO package, density functional theory (DFT) calculations were performed with periodic boundary conditions, and the electronic wave functions were expanded in plane waves. For the exchange-correlation functional, we use the vdW-DF functional with the inclusion of van der Waals (vdW) forces. Electron-ion interactions are treated by the projector augmented wave (PAW) method with pseudopotentials available in the PSlibrary repository. The wave functions and the electronic densities were expanded employing accurate cut-off energies of 6.80[Formula: see text]10[Formula: see text] and 5.44[Formula: see text]10[Formula: see text] eV, respectively. The electronic density was computed from the wave functions calculated at the [Formula: see text]-point in the first Brillouin-zone. Each structural optimization was minimized according to the Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm, with force and energy convergence criteria of 25 meV[Formula: see text]Å[Formula: see text] and 1.36 meV, respectively. The electrostatic solvation effects were performed by the [Formula: see text] package with the Self-Consistent Continuum Solvation (SCCS) approach.

Silicon attenuates aluminum toxicity in sugarcane plants by modifying growth, roots morphoanatomy, photosynthetic pigments, and gas exchange parameters.

Aluminum (Al) inhibits growth and limits plant productivity in acidic soils. An important strategy to increase Al tolerance is the use of silicon (Si) nutrition. Thus, the aim of this study was to evaluate the interactive role of Si in increasing the growth, physiological and morphoanatomy responses of sugarcane plants under Al toxicity. A 4 × 2 factorial scheme in a completely randomized design was used to study the impact of Si (2 mM) on attenuating Al toxicity (0, 10, 15 and 20 mg L-1, as Al2(SO4)3·18H2O) in sugarcane seedlings. After 45 days, Al toxicity affected sugarcane growth by increasing Al uptake and accumulation, modifying root growth, thickness, and morphoanatomy, and decreasing pigment content, gas exchange parameters, and the number of adaxial and abaxial stomata. However, Si attenuated Al toxicity in the sugarcane seedlings by limiting Al uptake and transport to the shoots, causing positive changes in root morphoanatomy, higher pigment content, improving gas exchange parameters, thereby increased growth. Furthermore, cultivar 'CTC9003' showed beneficial impacts from Si supplementation than 'CTC9002', especially under Al toxicity. The findings of this study suggest that Si plays a notable role in improving anatomical and physiological aspects, particularly the growth of sugarcane seedlings under Al toxicity.

Quinine and chloroquine: Potential preclinical candidates for the treatment of tegumentary Leishmaniasis.

Leishmaniasis is an endemic disease in more than 90 countries, constituting a relevant public health problem. Limited treatment options, increase in resistance, and therapeutic failure are important aspects for the discovery of new treatment options. Drug repurposing may accelerate the discovery of antiLeishmanial drugs. Recent tests indicating the in vitro potential of antimalarials Leishmania resulted in the design of this study. This study aimed at evaluating the susceptibility of Leishmania (L.) amazonensis to chloroquine (CQ) and quinine (QN), alone or in combination with amphotericin B (AFT) and pentamidine (PTN). In the in vitro tests, first, we evaluated the growth inhibition of 50 % of promastigotes (IC50) and cytotoxicity for HepG2 and THP-1 cells (CC50). The IC50 values of AFT and PNT were below 1 µM, while the IC50 values of CQ and QN ranged between 4 and 13 µM. Concerning cytotoxicity, CC50 values ranged between 7 and 30 µM for AFT and PNT, and between 22 and 157 µM for the antimalarials. We also calculated the Selectivity Index (SI), where AFT and PTN obtained the highest values, while the antimalarias obtained values between 5 and 12. Both antimalarials were additive (Æ©FIC 1.05-1.8) in combination with AFT and PTN. For anti-amastigote activity, the drugs obtained the following ICA50 values: AFT (0.26 µM), PNT (2.09 µM), CQ (3.77 µM) and QN (24.5 µM). In the in vivo tests, we observed that the effective dose for the death of 50 % of parasites (ED50) of AFT and CQ were 0.63 mg/kg and 27.29 mg/kg, respectively. When combining CQ with AFT, a decrease in parasitemia was observed, being statistically equal to the naive group. For cytokine quantification, it was observed that CQ, despite presenting anti-inflammatory activity was effective at increasing the production of IFN-γ. Overall, our data indicate that chloroquine will probably be a candidate for repurposing and use in drug combination therapy.

Melon peel flour: utilization as a functional ingredient in bakery products.

Food by-products are a major concern with a direct impact on the economy, society, and environment. The valorisation of these by-products could be an advantageous approach to face the increase in food waste since it can compromise environmental health and food sustainability. On the other hand, this valorisation would allow the development of new food products with health benefits for the population. Cucumis melo L. is a highly consumed fruit all over the world since it has excellent sensory and nutritional qualities, being also a good source of bioactive compounds. However, its peel and seeds are usually discarded. The aim of this study was to evaluate the potential of melon peel flour as a functional ingredient for innovative food products. For that, two different formulations containing melon peel flour were developed (a biscuit and a muffin) by replacing a conventional flour (wheat flour) in different percentages (50% and 100%, respectively). The nutritional composition, total phenolic content, and antioxidant potential of the developed products were studied, showing a high content of fibre, high levels of phenolic compounds and good sensory acceptability. These results show that it is possible to enrich different foods with melon peel flour in order to improve their nutritional properties, contributing to improving public health, simultaneously valorising a usually rejected by-product, reducing food waste and the environmental impact.

Cutaneous Mucormycosis in a Young Immunocompetent Trauma Patient: A Case Report.

Introduction: Mucormycosis, a rare and life-threatening infection, is caused by microorganisms of the Mucorales order. It affects almost exclusively immunocompromised and diabetic patients, requiring extensive surgical debridement and prolonged antifungal therapy. Discussion/Results: We report the case of a 26-year-old immunocompetent woman, presenting with cutaneous mucormycosis after suffering blunt force trauma. This rare occurrence of mucormycosis in an immunocompetent patient reinforces the importance of elevated clinical suspicion and early initiation of adequate surgical and antifungal treatment. Conclusion: Mucormycosis is a challenging condition with potentially devastating consequences. Timely diagnosis and appropriate management are vital to mitigate the morbidity and mortality associated with this condition. LEARNING POINTS: Cutaneous mucormycosis is a rare life-threatening infection that affects mainly immunocompromised patients.Certain circumstances warrant a high index of clinical suspicion in immunocompetent patients, and indicate histopathological examination.Treatment involves a multidisciplinary approach with aggressive surgical debridement, antifungal therapy, and elimination of risk factors.

Incidence and Severity of Post-dural Puncture Headache in Non-obstetric Patients Undergoing Subarachnoid Block.

Background and goal of the study Post-dural puncture headache (PDPH) is a complication of central neuraxial block, either subarachnoid block (SAB) or epidural block. This clinical entity has a wide incidence and is affected by factors such as age, gender, needle gauge, needle shape/type, number of puncture attempts, and previous history of headache. Due to the lack of data in the non-obstetric population, this study assesses the incidence and severity of PDPH after SAB. Materials and methods A prospective observational study was carried out on patients undergoing SAB during the last trimester of 2020. Data were recorded on the day of surgery, 48 hours, and seven days after surgery. Data collected included demographic and medical clinic information, SAB procedure details, and clinical outcomes related to the presence of PDPH. Results and discussion Overall, 143 patients were included (median age: 62 years; 53.1% were women (n=76)). Most patients were aged >60 years (55.9%; n=80) and ASA 2 classification (65.0%; n=93). The incidence of PDPH was 21.7% (n=31), and most cases were from inpatient surgery (58.3%, n=21). The incidence of PDPH was 2.5 times higher with the use of 25 gauge compared to the use of the 27 gauge needle and was more prevalent with the use of the Quincke needles. Conclusion Over 20% of patients undergoing SAB experienced PDPH. Previous history of headache, larger gauge, and the Quincke needle use were associated with a higher incidence of PDPH.

Irrigation level and substrate type on the acclimatization and development of mandacaru (Cereus jamacaru DC.): an emblematic cactus from Brazilian semiarid region.

Mandacaru is a cactus with great socioeconomic potential, but lack of information about its cultivation hinders its domestication. Here, we aimed to evaluate the acclimatization and vegetative development of mandacaru under different substrates and irrigation levels. For this, seeds inoculated in vitro were grown for 120 days, being transplanted to pots containing four types of substrate (S1-caatinga soil + gravel; S2-washed sand + organic matter + soil + charcoal; S3-washed sand + cattle manure + soil + sand; S4-commercial organic substrate). Pots were irrigated with 100% of the field capacity (FC) once-a-week, or with 50% FC twice-a-week, and kept in a greenhouse for six months. The experimental design was completely randomized, in a 4 × 2 factorial scheme, with six replications. Plant height and diameter, axial and radial growth rate, fresh and dry mass of stem and root, water content, and photosynthetic pigments were determined. Growth was affected mainly by the substrate, with S4 resulting in higher growth and pigment content, while S1 was impaired and S2 and S3 resulted in intermediate growth. The use of S4 and 100% FC once per week was the best condition for mandacaru.

CO adsorption on MgO thin-films: formation and interaction of surface charged defects.

Two-dimensional (2D) materials formed by thin-films of metal oxides that grow on metal supports are commonly used in heterogeneous catalysis and multilayer electronic devices. Despite extensive research on these systems, the effects of charged defects at supported oxides on surface processes are still not clear. In this work, we perform spin-polarized density-functional theory (DFT) calculations to investigate formation and interaction of charged magnesium and oxygen vacancies, and Al dopants on MgO(001)/Ag(001) surface. The results show a sizable interface compressive effect that decreases the metal work function as electrons are added on the MgO surface with a magnesium vacancy. This surface displays a larger formation energy in a water environment (O-rich condition) even with additional Al-doping. Under these conditions, we found that a polar molecule such as CO is more strongly adsorbed on the low-coordination oxygen sites due to a larger contribution of the channeled electronic transport with the silver interface regardless of the surface charge. Therefore, these findings elucidate how surface intrinsic vacancies can influence or contribute to charge transfer, which allows one to explore more specific reactions at different surface topologies for more efficient catalysts for CO2 conversion.

Effects of gear modifications in a North Atlantic pelagic longline fishery: A multiyear study.

The threat of population declines caused by pelagic longline fisheries in the Atlantic has increased the concern to find strategies that minimize the bycatch and mortality of non-target marine animals. Gear modification, such as the use of circle hooks instead of conventional J-hooks, has been identified as an effective bycatch reduction strategy in different pelagic longline fisheries around the world. This study aimed to verify the effectiveness of the use of circle hooks by quantifying catch rates, relative size selectivity, and anatomical hooking position for the most common target species (swordfish, Xiphias gladius, and blue shark, Prionace glauca), and some bycatch species (loggerhead sea turtles, Caretta caretta, and shortfin mako, Isurus oxyrinchus) caught by the Azorean longline fishing fleet. The trial was conducted for five consecutive years (2000-2004) using eight different types of hooks. In general, the blue shark catches using circle hooks were significantly higher compared to J (Mustad 9/0). The circle hooks also showed high probabilities of catching juvenile blue sharks. Conversely, the circle hooks were efficient in reducing the loggerhead sea turtle bycatch and were related to fewer catches of small sea turtle individuals. The use of circle hooks was also associated with reduced swordfish catches compared to J (Mustad 9/0), and the effect of hook types on length at capture was only significant for Circle (L. & P. 18/0-CLP18) and Ringed Tuna (RT). No significant differences were observed comparing hook type to either catch rates or size selectivity for shortfin mako. Additionally, circle hooks were more likely to lodge in the mouth than in deeper anatomical positions, when compared to J (Mustad 9/0), for the four species analysed. The present study demonstrated that the use of circle hooks could mitigate the impact of the pelagic longline fisheries in the Azores by decreasing the bycatch of sea turtles and reducing animal injuries caused by deep hooking.

The performance of artificial neural networks for modeling daily concentrations of particulate matter from meteorological data.

The use of techniques based on artificial intelligence and machine learning for the simulation of many processes is becoming increasingly important in environmental sciences, with applications in the study of time series of atmospheric properties, such as pollution levels. The present work aimed to evaluate the efficiency of a model based on Artificial Neural Networks (ANN) in the simulation PM10 from meteorological data observed between 2018 and 2019 in Guaíba, southern Brazil, thus also having an estimate of the influence of atmospheric conditions on local air pollution. For this purpose, meteorological and PM10 data obtained from the stations Parque 35, sustained by Celulose Riograndense (CMPC), and A-801, sustained by the National Institute of Meteorology (INMET), were used. The ANN used for the simulation was of the Multilayer Perceptron type, trained by the backpropagation algorithm with cross-validation. The results obtained indicate that the simulation was satisfactory with a Nash-Sutcliffe index (NSE) of 0.64, a linear correlation coefficient (R) of 0.81, a relative error (Er) of 26% and a root mean square error (RMSE) of 7.40 µg/m3. Thus, even with some difficulty in estimating extreme concentrations, the model was suitable for the largest range observed, of 10 µg/m3 to 50 µg/m3. For this dataset, the model proved to be an useful assessment tool and has the potential to be applied operationally to contribute to the monitoring and control of air quality levels both in the study area and in other regions of Brazil and the world.

A novel approach for lactose determination in cow's milk exploiting smartphone-based digital-image photometry.

Lactose, the main carbohydrate in cow's milk, may cause health problems for consumers with intolerance. Lactose determination in milk is hindered by the matrix complexity and lack of chromophore groups. Chromatography, volumetric, and spectrophotometric approaches involving chemical derivatization are time-consuming and require laborious sample preparation, which is incompatible with the high analytical demand. In this context, a novel approach is presented for lactose determination in milk exploiting smartphone-based digital-image photometry. It was based on a modification of the Benedict's method, involving formation of the violet Cu(I)/2,2'-biquinoline-4,4'-dicarboxylate (BCA) complex instead of the copper(I) oxide precipitate, aiming at improvement of sensitivity and precision. Sample pretreatment and analyte derivatization were performed in Eppendorf tubes with minimal reagent amounts and a smartphone camera was used for image acquisition under controlled conditions. Measurements were based on the RGB color system, taking channel G as the analytical response because of the complementarity with the color of the complex. Under the optimized conditions, the proposed procedure yielded a linear response up to 20 mg L-1 (r = 0.999), with a limit of detection of 1.5 mg L-1, which is compatible with determination of lactose in milk and dairy products categorized with low content of the sugar. The procedure takes less than 10 min, with a coefficient of variation of 3.0% (n = 12) and consumes as low as 160 µg Cu and 430 µg BCA per determination, thus being a more practical, fast, cost-effective, and environmental friendly analytical method.

Exposure levels for carbon monoxide in nuclear submarine atmosphere.

This work proposes exposure limits for carbon monoxide in the nuclear submarine environment. Linear and non-linear forms of the Coburn-Foster-Kane equation were used to evaluate carbon monoxide exposure for an environment with low oxygen content, different exposure times and crew physical activity levels. We evaluated the 90-day Continuous Exposure Guidance Level, 24-h and 1-h Emergency Exposure Guidance Levels and 10-day and 24-h Submarine Escape Action Levels. The results showed that the concentration of carbon monoxide in the environment must not exceed 9 ppm for the 90-day Continuous Exposure Guidance Level, 35 ppm for the 24-h Emergency Exposure Guidance Level, 90 ppm 1-h Emergency Exposure Guidance Level, 60 ppm for the 10-day Submarine Escape Action Level and 80 ppm for the 24-h Submarine Escape Action Level. Comparing these values with those established by the National Research Council for the United States Navy, the limits proposed by this work are verified to be lower, which may indicate a risk to the health of the crew. They also show the impact of the crew's level of physical activity on the formation of carboxyhemoglobin.

Algae Incorporation and Nutritional Improvement: The Case of a Whole-Wheat Pasta.

Algae contain high-quality proteins, dietary fiber, minerals, and phenolic compounds, making them promising alternative ingredients. Since pasta is consumed worldwide, it can be an effective vehicle for incorporating algae. This study compares the nutritional and antioxidant composition of whole-wheat pasta without and with enrichment of an algae mixture (containing Himanthalia elongata and Spirulina) and ascertains the influence of the cooking procedure on their features. Spirulina and H. elongata were also analyzed in parallel for comparison purposes. Macronutrients, chlorides and salt, total and free amino acid profiles, and antioxidant properties (total phenolic content and ferric reducing antioxidant power) were analyzed using AOAC, Mohr's, high performance liquid chromatography with fluorescence detection, and spectrophotometric methods, respectively. The results show a significant increase in fat (70.4%), protein (29.7%), ash (26.5%), and total amino acid (except for serine, tryptophan, isoleucine, and threonine) contents in the raw algae-enriched pasta. The antioxidant activity was also higher (4.15 versus 3.68 g ferrous sulfate eq./g dw, respectively). After cooking, protein, dietary fiber, total amino acids (except threonine) and antioxidant activity were stable in the algae-enriched pasta. Thus, algae can be an excellent ingredient for food applications with health benefits.

Carbon dioxide conversion via reverse water-gas shift reaction: Reactor design.

The reverse water gas shift (RWGS) reaction converts carbon dioxide (CO2) and hydrogen (H2) to syngas, which is used to produce various high-added-value chemicals. This process has attracted great interest from researchers as a way of mitigating the potential environmental impacts of this greenhouse gas, with emphasis on global warming. This work aims to model and simulate an industrial catalytic reactor using kinetic data for the RWGS reaction. The simulation was carried out in Aspen Plus® v10. The thermodynamic analysis showed that the appropriate conditions for the reaction are feed molar ratio (H2/CO2) of 0.8:1, 750 °C, and 20 bar. The RWGS process proceeds in a multi-tubular fixed bed reactor with 36.26% CO2 conversion and 96.41% CO selectivity, at residence times in the order of 2.7 s. These results are at near-equilibrium CO2 conversion with higher CO selectivity.

GATA2 mitotic bookmarking is required for definitive haematopoiesis.

In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.

Restoring tumor immunogenicity with dendritic cell reprogramming.

Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.