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Abstract Noisy Intermediate-Scale Quantum (NISQ) devices lack error correction, limiting scalability for quantum algorithms. In this context, digital-analog quantum computing (DAQC) offers a more resilient alternative quantum computing paradigm that outperforms digital quantum computation by combining the flexibility of single-qubit gates with the robustness of analog simulations. This work explores the impact of noise on both digital and DAQC paradigms and demonstrates DAQC’s effectiveness in error mitigation. We compare the quantum Fourier transform and quantum phase estimation algorithms under a wide range of single and two-qubit noise sources in superconducting processors. DAQC consistently surpasses digital approaches in fidelity, particularly as processor size increases. Moreover, zero-noise extrapolation further enhances DAQC by mitigating decoherence and intrinsic errors, achieving fidelities above 0.95 for 8 qubits, and reducing computation errors to the order of 10−3. These results establish DAQC as a viable alternative for quantum computing in the NISQ era.

Abstract Genetically modified maize MON 95275 was developed to confer protection to certain coleopteran species. These properties were achieved by introducing the mpp75Aa1.1, vpb4Da2 and DvSnf7 expression cassettes. The molecular characterisation data and bioinformatic analyses reveal similarity to known toxins, which was further assessed. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize MON 95275 and its conventional counterpart needs further assessment. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the Mpp75Aa1.1 and Vpb4Da2 proteins and the DvSnf7 dsRNA and derived siRNAs as expressed in maize MON 95275 and finds no evidence that the genetic modification would change the overall allergenicity of maize MON 95275. In the context of this application, the consumption of food and feed from maize MON 95275 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize MON 95275 is as safe as the conventional counterpart and non‐GM maize varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of maize MON 95275 material into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize MON 95275. The GMO Panel concludes that maize MON 95275 is as safe as its conventional counterpart and the tested non‐GM maize varieties with respect to potential effects on human and animal health and the environment.

Abstract Genetically modified (GM) maize DP910521 was developed to confer resistance against certain lepidopteran insect pests as well as tolerance to glufosinate herbicide; these properties were achieved by introducing the mo‐pat, pmi and cry1B.34 expression cassettes. The molecular characterisation data and bioinformatic analyses did not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize DP910521 and its conventional counterpart needs further assessment except for the levels of iron in grain, which do not raise safety and nutritional concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the Cry1B.34, PAT and PMI proteins as expressed in maize DP910521. The GMO panel finds no evidence that the genetic modification impacts the overall safety of maize DP910521. In the context of this application, the consumption of food and feed from maize DP910521 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize DP910521 is as safe as its conventional counterpart and non‐GM maize varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of maize DP910521 material into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize DP910521. The GMO Panel concludes that maize DP910521 is as safe as its conventional counterpart and the tested non‐GM maize varieties with respect to potential effects on human and animal health and the environment.

While hydroponics is considered an efficient vegetable production system, there is a compelling need to investigate the efficiency of the current generic nutrient dosing recommendation primarily based on electrical conductivity (EC) measurements. Such information is critical to fine-tune and optimize the current hydroponic management practices for improved nutrient uptake efficiency. This study investigated the dynamics of some micro and macronutrients (N, P, Ca, Mg, K, Fe, and Mn) in a recirculating nutrient film technique (NFT) hydroponic system under lettuce cultivation. The research was conducted in an indoor controlled environment growth chamber with lettuce grown in different EC levels (1.2 and 1.6 dS m−1). Each treatment had four hydroponic cultivation units, each one with 24 plants. Nutrient solution and tissue samples were collected two to three times per week. Nutrient dynamics, including nutrient uptake efficiencies and environmental losses, were calculated using a mass balance approach. The effects of EC level on fresh and dry lettuce biomass and nutrient uptake were insignificant. Observed variations in nutrient solution composition during lettuce cultivation included the almost complete removal of ammonia nitrogen, nitrate decreases towards the end of the experiment, consistent increases in aqueous Ca concentration, and corresponding decreases in K and Mn. Average N losses ranged between 27 and 40 %, presumably through denitrification, while 10–14 % of N was assimilated into the plant biomass. The remaining N in the recirculating nutrient solution was estimated to be between 50 and 59 %. The average P loss was 11–35 %, likely due to precipitation, while 52–77 % remained in the nutrient solution. Nutrient uptake efficiencies averaged 19–31 % K, 12–21 % P, 9–16 % Mn, 4–6 % Ca, 3–4 % Mg, and 2–4 % Fe. These results suggest that elevated nutrient concentrations in recirculating nutrient solutions led to losses and underutilization. Findings from this study provide a comprehensive dataset critical to improving hydroponic nutrient management beyond N and P. Hydroponic nutrient management should target providing essential nutrients needed by plants at the correct proportions considering the plant growth stage.

Abstract Background Accurately determining the epidemiology of dermatological diseases such as hidradenitis suppurativa (HS), psoriasis (PsO), chronic urticaria (CU) and/or atopic dermatitis (AD) is challenging due to variations in prevalence and disease severity in the reported literature. Objectives The DERMACLEAR study aims to use natural language processing (NLP) to assess the proportions of patients with HS, PsO, CU and/or AD, and obtain information on patient profiles, patient journeys, and disease and healthcare burden in Spain. Here, the study design and objectives of the DERMACLEAR study are described and the precision of the NLP system used is assessed. Methods This study will retrospectively collect patient information from electronic health records (EHRs) at dermatology departments from seven tertiary hospitals in Spain. The NLP system was developed by IOMED Medical Solutions and was verified internally (IOMED scientific team) and externally (principal investigators of each hospital) to determine its precision in identifying patients with HS, PsO, CU and/or AD. Furthermore, internal verification was performed on other medical variables relevant to the study. Results To date, the DERMACLEAR study has retrospectively collected data from 54,458 patients with HS, PsO, CU and/or AD (HS: 5045; PsO: 32,559; CU: 8397; AD: 12,492). The average precision of the NLP system to identify patients diagnosed with HS, PsO, CU, and/or AD across all hospitals exceeded 95% via external and internal verification. Conclusions Results from the DERMACLEAR study will increase the real‐world evidence of clinical practice, obtaining a large amount of information on patients with the studied diseases. The NLP system used is precise in identifying patients diagnosed with HS, PsO, CU and/or AD, and other medical variables from EHRs, highlighting that it is a valid system to use in the DERMACLEAR study.

Abstract Genetically modified (GM) maize MON 94804 was developed to achieve a reduction in plant height by introducing the GA20ox_SUP suppression cassette. The molecular characterisation and bioinformatic analyses do not identify issues requiring food/feed safety assessment. None of the agronomic/phenotypic and compositional differences identified between maize MON 94804 and its conventional counterpart needs further assessment, except for ear height, plant height and levels of carbohydrates in forage, which do not raise safety or nutritional concerns. The Panel on Genetically Modified Organisms (GMO Panel) does not identify safety concerns regarding the toxicity and allergenicity of the GA20ox_SUP precursor‐miRNA and derived mature miRNA as expressed in maize MON 94804 and finds no evidence that the genetic modification would change the overall allergenicity of maize MON 94804. In the context of this application, the consumption of food and feed from maize MON 94804 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize MON 94804 is as safe as the conventional counterpart and non‐GM maize varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of viable maize MON 94804 grains into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize MON 94804. The GMO Panel concludes that maize MON 94804 is as safe as its conventional counterpart and the tested non‐GM maize varieties with respect to potential effects on human and animal health and the environment.

Fluorescence microscopy is a fundamental tool in the life sciences, but the availability of sophisticated equipment required to yield high-quality, quantitative data is a major bottleneck in data production in many laboratories worldwide. This problem has long been recognized and the abundancy of low-cost electronics and the simplification of fabrication through 3D-printing have led to the emergence of open-source scientific hardware as a research field. Cost effective fluorescence microscopes can be assembled from cheaply mass-produced components, but lag behind commercial solutions in image quality. On the other hand, blueprints of sophisticated microscopes such as light-sheet or super-resolution systems, custom-assembled from high quality parts, are available, but require a high level of expertise from the user. Here, we combine the UC2 microscopy toolbox with high-quality components and integrated electronics and software to assemble an automated high-resolution fluorescence microscope. Using this microscope, we demonstrate high resolution fluorescence imaging for fixed and live samples. When operated inside an incubator, long-term live-cell imaging over several days was possible. Our microscope reaches single molecule sensitivity, and we performed single particle tracking and SMLM super-resolution microscopy experiments in cells. Our setup costs a fraction of its commercially available counterparts but still provides a maximum of capabilities and image quality. We thus provide a proof of concept that high quality scientific data can be generated by lay users with a low-budget system and open-source software. Our system can be used for routine imaging in laboratories that do not have the means to acquire commercial systems and through its affordability can serve as teaching material to students.

Anaerobic membrane bioreactors (AnMBR) have been used for treating high-strength industrial wastewater at full-scale and the potential to use them for mainstream municipal wastewater treatment presents an important opportunity to turn energy-intensive plants into net-energy producers. However, several limitations of the AnMBR technology have prevented their adoption in the municipal wastewater industry, namely, high membrane cleaning energy demand and low membrane flux. This study demonstrated a novel AnMBR configuration that uses a commercially available cloth filter technology to address the key limitations of cleaning energy and membrane flux. The cloth filter anaerobic membrane bioreactor (CFAnMBR) is comprised of an anaerobic fixed-film bioreactor coupled with a cloth filter membrane with nominal pore size of 5 µm. The pilot CFAnMBR was operated for 150 days through the winter at a municipal wastewater plant in central Illinois (minimum/average influent temperature 5/13°C). The CFAnMBR increased membrane flux by more than 2 orders of magnitude (3,649 ± 1,246 L per meter squared per hour) and reduced cleaning energy demand by 78%—92% (0.0085 kWh/m3) relative to previously reported AnMBR configurations. With the CFAnMBR, average chemical oxygen demand and total suspended solids removal were 66% and 91%, respectively, and were shown to be increased up to 88% and 96% by in-line coagulant dosing with ferric chloride. Average headspace methane yield was 154 mL CH4/g CODremoved by the end of the study period with influent temperatures of 11°C± 4°C. The CFAnMBR resolves major limitations of AnMBR technology by employing a commercially-available technology already used for other municipal wastewater treatment applications.

Despite emerging evidence and advances in the management of atopic dermatitis there a lack of consensus regarding the diagnostic criteria, therapeutic approach, method to assess severity, and patient follow-up for this condition. An expert consensus study was conducted to provide recommendations on the management of patients with moderate-to-severe atopic dermatitis. The study used Delphi-like methodology based on a literature review, a summary of the scientific evidence, and a 2-round survey. The agreement of 60 panellists on 21 statements was evaluated. Consensus was pre-defined as ≥ 80% agreement of all respondents. In the first round 6 statements reached consensus. Unanimous consensus was achieved regarding therapeutic goals and patient satisfaction (maintained in the long term and periodic goals reassessment recommended every 3–6 months). In the second round, half of the statements reached consensus, all related to patient follow-up, treatment goals, and atopic comorbidities. The statements that did not reach consensus were related to diagnosis (biomarkers, allergy, and food testing) and starting patients on conventional systemic treatment rather than advanced treatment. The study assessed expert opinion regarding a variety of topics related to the clinical approach to patients with moderate-to-severe atopic dermatitis, in order to provide guidance on the diagnosis and management of patients with atopic dermatitis.

Abstract Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling also reduces the ability of stem cells to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to progenitor production is not well understood. Here we combine single‐cell transcriptomics, RiboSeq and mathematical models of interferon to show that this pathway is important for proper stem cell function at all ages in mice. Interferon orchestrates cell cycle and mTOR activity to post‐transcriptionally repress Sox2 and induces quiescence. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC’s main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2’s Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.

The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all cell types. Notably, ERK1/2 are implicated in specific processes in a context-dependent manner as in stem cells and pancreatic β-cells. Alterations in the different components of this cascade result in dysregulation of the effector kinases ERK1/2 which communicate with hundreds of substrates. Aberrant activation of the pathway contributes to a range of disorders, including cancer. This review provides an overview of the structure, activation, regulation, and mutational frequency of the different tiers of the cascade; with a particular focus on ERK1/2. We highlight the importance of scaffold proteins that contribute to kinase localization and coordinate interaction dynamics of the kinases with substrates, activators, and inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues in this field.

Abstract Genetically modified maize GA21 × T25 was developed by crossing to combine two single events: GA21 and T25. The GMO Panel previously assessed the two single maize events and did not identify safety concerns. No new data on the single maize events were identified that could lead to modification of the original conclusions on their safety. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment indicate that the combination of the single maize events and of the newly expressed proteins in maize GA21 × T25 does not give rise to food and feed safety and nutritional concerns. The GMO Panel concludes that maize GA21 × T25, as described in this application, is as safe as its conventional counterpart and the non‐GM reference varieties tested, and no post‐market monitoring of food and feed is considered necessary. In the case of accidental release of viable maize GA21 × T25 grains into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize GA21 × T25. Post‐market monitoring of food and feed is not considered necessary. The GMO Panel concludes that maize GA21 × T25 is as safe as its conventional counterpart and the non‐GM reference varieties tested, with respect to potential effects on human and animal health and the environment.

Abstract Genetically modified maize MON 87419 was developed to confer tolerance to dicamba‐ and glufosinate‐based herbicides. These properties were achieved by introducing the dmo and pat expression cassettes. The molecular characterisation data and bioinformatic analyses do not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize MON 87419 and its conventional counterpart needed further assessment, except for the levels of arginine and protein in grains which did not raise safety and nutritional concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the dicamba mono‐oxygenase (DMO) and phosphinothricin N‐acetyltransferase (PAT) proteins as expressed in maize MON 87419. The GMO Panel finds no evidence that the genetic modification impacts the overall safety of maize MON 87419. In the context of this application, the consumption of food and feed from maize MON 87419 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize MON 87419 is as safe as the conventional counterpart and non‐GM maize varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of viable maize MON 87419 grains into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize MON 87419. The GMO Panel concludes that maize MON 87419 is as safe as its conventional counterpart and the tested non‐GM maize varieties with respect to potential effects on human and animal health and the environment.

The adult mammalian brain entails a reservoir of neural stem cells (NSCs) generating glial cells and neurons. However, NSCs become increasingly quiescent with age, which hampers their regenerative capacity. New means are therefore required to genetically modify adult NSCs for re-enabling endogenous brain repair. Recombinant adeno-associated viruses (AAVs) are ideal gene-therapy vectors due to an excellent safety profile and high transduction efficiency. We thus conducted a high-throughput screening of 177 intraventricularly injected barcoded AAV variants profiled by RNA sequencing. Quantification of barcoded AAV mRNAs identified two synthetic capsids, peptide-modified derivative of wild-type AAV9 (AAV9_A2) and peptide-modified derivative of wild-type AAV1 (AAV1_P5), both of which transduce active and quiescent NSCs. Further optimization of AAV1_P5 by judicious selection of the promoter and dose of injected viral genomes enabled labeling of 30%–60% of the NSC compartment, which was validated by fluorescence-activated cell sorting (FACS) analyses and single-cell RNA sequencing. Importantly, transduced NSCs readily produced neurons. The present study identifies AAV variants with a high regional tropism toward the ventricular-subventricular zone (v-SVZ) with high efficiency in targeting adult NSCs, thereby paving the way for preclinical testing of regenerative gene therapy.

Abstract Maize MON 87429 was developed to confer tolerance to dicamba, glufosinate, quizalofop and 2,4‐D herbicides. The molecular characterisation data and bioinformatic analyses do not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize MON 87429 and its conventional counterpart needs further assessment, except for the levels of phytic acid in grains, which do not raise nutritional and safety concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the DMO, PAT, FT_T and CP4 EPSPS proteins as expressed in maize MON 87429. The GMO Panel finds no evidence that the genetic modification impacts the overall safety of maize MON 87429. In the context of this application, the consumption of food and feed from maize MON 87429 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize MON 87429 is as safe as the conventional counterpart and non‐GM maize reference varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of viable maize MON 87429 grains into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize MON 87429. The GMO Panel concludes that maize MON 87429, as described in this application, is as safe as its conventional counterpart and the tested non‐GM maize reference varieties with respect to potential effects on human and animal health and the environment.

Abstract Genetically modified oilseed rape GT73 was developed to confer herbicide tolerance; this property was achieved by introducing the single insert containing one copy of goxv247 and the CP4 epsps expression cassettes. The scope of the application EFSA‐GMO‐RX‐026/2 is for the modification of the terms of the authorisation regarding the placing on the market of isolated seed protein from oilseed rape GT73 for food. Considering previous opinions on this event of the GMO Panel, the molecular characterisation data do not identify issues requiring additional food safety assessment. Based on previous assessments, no biologically relevant differences were identified in the compositional, agronomic and phenotypic characteristics of oilseed rape GT73 compared with its conventional counterpart, except for the newly expressed proteins. No new agronomic, phenotypic and compositional data in support of the comparative analysis were considered necessary in the context of this application. The GMO Panel did not identify indications of safety concern regarding toxicity, allergenicity or adjuvanticity related to the presence of the newly expressed proteins CP4 EPSPS and GOXv247 in oilseed rape GT73. Therefore, the GMO Panel concludes that in the context of this application, the consumption of oilseed rape GT73 does not represent any nutritional concern and is as safe as the conventional counterpart. No post‐market monitoring of food/feed is considered necessary. In the case of accidental release of viable oilseed rape GT73 into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of oilseed rape GT73. The GMO Panel concludes that oilseed rape GT73 is as safe as its conventional counterpart with respect to potential effects on human and animal health and the environment. These conclusions also apply to the placing on the food market of isolated seed protein produced from oilseed rape GT73.

Abstract Genetically modified maize DP4114 × MON 89034 × MON 87411 × DAS‐40278‐9 was developed by crossing to combine four single events: DP4114, MON 89034, MON 87411 and DAS‐40278‐9. The GMO Panel previously assessed the four single maize events and two of the subcombinations and did not identify safety concerns. No new data on the single maize events or the assessed subcombinations were identified that could lead to modification of the original conclusions on their safety. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment indicate that the combination of the single maize events and of the newly expressed proteins in the four‐event stack maize does not give rise to food and feed safety and nutritional concerns. Therefore, no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of viable four‐event stack maize grains into the environment, this would not raise environmental safety concerns. The GMO Panel assessed the likelihood of interactions among the single events in eight of the maize subcombinations not previously assessed and concludes that these are expected to be as safe as the single events, the previously assessed subcombinations and the four‐event stack maize. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize DP4114 × MON 89034 × MON 87411 × DAS‐40278‐9. Post‐market monitoring of food/feed is not considered necessary. The GMO Panel concludes that the four‐event stack maize and its subcombinations are as safe as its non‐GM comparator and the tested non‐GM maize varieties with respect to potential effects on human and animal health and the environment.

Ligand binding of membrane proteins triggers many important cellular signaling events by the lateral aggregation of ligand-bound and other membrane proteins in the plane of the plasma membrane. This local clustering can lead to the co-enrichment of molecules that create an intracellular signal or bring sufficient amounts of activity together to shift an existing equilibrium towards the execution of a signaling event. In this way, clustering can serve as a cellular switch. The underlying uneven distribution and local enrichment of the signaling cluster’s constituting membrane proteins can be used as a functional readout. This information is obtained by combining single-molecule fluorescence microscopy with cluster algorithms that can reliably and reproducibly distinguish clusters from fluctuations in the background noise to generate quantitative data on this complex process. Cluster analysis of single-molecule fluorescence microscopy data has emerged as a proliferative field, and several algorithms and software solutions have been put forward. However, in most cases, such cluster algorithms require multiple analysis parameters to be defined by the user, which may lead to biased results. Furthermore, most cluster algorithms neglect the individual localization precision connected to every localized molecule, leading to imprecise results. Bayesian cluster analysis has been put forward to overcome these problems, but so far, it has entailed high computational cost, increasing runtime drastically. Finally, most software is challenging to use as they require advanced technical knowledge to operate. Here we combined three advanced cluster algorithms with the Bayesian approach and parallelization in a user-friendly GUI and achieved up to an order of magnitude faster processing than for previous approaches. Our work will simplify access to a well-controlled analysis of clustering data generated by SMLM and significantly accelerate data processing. The inclusion of a simulation mode aids in the design of well-controlled experimental assays.

Abstract Introduction Nitric–zinc complex solution (NZCS) is a topically applied solution containing nitric acid, zinc, copper, and organic acids that induce a painless caustic effect on “difficult-to-treat” warts, including palmoplantar and periungual locations. The objective of the present prospective clinical study was to describe the efficacy and tolerability of NZCS in the treatment of palmoplantar and periungual warts in children. Methods Eligible patients were immunocompetent children and adolescents, with at least one palmoplantar or periungual wart. NZCS was topically applied every 2 weeks in clinic. Efficacy was recorded by clinical evaluation, and acceptability assessments were measured using a visual analogue scale (VAS). Results Pediatric patients (N = 12) were equally distributed by gender, and the mean age was 9.60 ± 3.34 years. The youngest patient was 4 years old. A total of 31 warts were identified: 24 periungual warts (77.4%), 2 palmar warts (6.45%), and 5 plantar warts (16.12%). We observed complete resolution in 83.9% of the warts treated with NZCS, achieving total cure considered as therapy success in 87.5% of periungual warts and 71% of palmoplantar warts, with a mean of 6.0 treatment sessions. The esthetic results evaluated by the investigator were considered excellent in 83.3% of cases and good in 16.7%. In 100% of the completely resolved cases, no scars, erythema, hyperpigmentation, hypopigmentation, or hypertrophy in the area surrounding the treated warts were observed by the investigator. The esthetic results evaluated by the patients or parents/guardians were excellent. Pain and burning sensation were minimal and well tolerated. No clinically relevant adverse events were reported. Conclusion NZCS was an effective treatment of warts in this pediatric population. The painlessness, simplicity, and twice-monthly dosing regimen of this treatment represents an advantage over standard approaches. Funding ISDIN. Trial Registration Retrospectively registered 6 September 2019, ISRCTN90862249.

Axon branching is crucial for proper formation of neuronal networks. Although originally identified as an angiogenic factor, VEGF also signals directly to neurons to regulate their development and function. Here we show that VEGF and its receptor VEGFR2 (also known as KDR or FLK1) are expressed in mouse hippocampal neurons during development, with VEGFR2 locally expressed in the CA3 region. Activation of VEGF/VEGFR2 signaling in isolated hippocampal neurons results in increased axon branching. Remarkably, inactivation of VEGFR2 also results in increased axon branching in vitro and in vivo. The increased CA3 axon branching is not productive as these axons are less mature and form less functional synapses with CA1 neurons. Mechanistically, while VEGF promotes the growth of formed branches without affecting filopodia formation, loss of VEGFR2 increases the number of filopodia and enhances the growth rate of new branches. Thus, a controlled VEGF/VEGFR2 signaling is required for proper CA3 hippocampal axon branching during mouse hippocampus development.

In this paper, we extend the use of disjoint orthogonal components to three-way table analysis with the parallel factor analysis model. Traditional methods, such as scaling, orthogonality constraints, non-negativity constraints, and sparse techniques, do not guarantee that interpretable loading matrices are obtained in this model. We propose a novel heuristic algorithm that allows simple structure loading matrices to be obtained by calculating disjoint orthogonal components. This algorithm is also an alternative approach for solving the well-known degeneracy problem. We carry out computational experiments by utilizing simulated and real-world data to illustrate the benefits of the proposed algorithm.

The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific deletion thereof reduces both neurovascular complexity and synaptic activity in the brain. CD95L-induced neuronal and vascular growth is mediated through src-family kinase (SFK) and PI3K signaling. Together, our study highlights a coordinated neurovascular development instructed by CNS macrophage-derived CD95L, and it underlines the importance of macrophages for the establishment of the neurovascular network during CNS development.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Summary: The death receptor CD95 is expressed in every cancer cell, thus providing a promising tool to target cancer. Activation of CD95 can, however, lead to apoptosis or proliferation. Yet the molecular determinants of CD95’s mode of action remain unclear. Here, we identify an optimal distance between CD95Ligand molecules that enables specific clustering of receptor-ligand pairs, leading to efficient CD95 activation. Surprisingly, efficient CD95 activation leads to apoptosis in cancer cells in vitro and increased tumor growth in vivo. We show that allowing a 3D aggregation of cancer cells in vitro switches the apoptotic response to proliferation. Indeed, we demonstrate that the absence or presence of cell-cell contacts dictates the cell response to CD95. Cell contacts increase global levels of phosphorylated tyrosines, including CD95’s tyrosine. A tyrosine-to-alanine CD95 mutant blocks proliferation in cells in contact. Our study sheds light into the regulatory mechanism of CD95 activation that can be further explored for anti-cancer therapies. : Gülcüler Balta et al. show that CD95 receptor activation is determined through the presentation of its ligand at a certain intermolecular distance. The type of signaling triggered by CD95 is, however, decided by the cellular environment. CD95 triggers survival in cancer cells in contact with other cells and death in isolated ones. Keywords: CD95, CD95 ligand, death receptors, apoptosis, survival, cell-cell contact, cancer, tyrosine kinase, supported membrane

External stimuli such as injury, learning, or stress influence the production of neurons by neural stem cells (NSCs) in the adult mammalian brain. These external stimuli directly impact stem cell activity by influencing areas directly connected or in close proximity to the neurogenic niches of the adult brain. However, very little is known on how distant injuries affect NSC activation state. In this study, we demonstrate that a thoracic spinal transection injury activates the distally located hippocampal-NSCs. This activation leads to a transient increase production of neurons that functionally integrate to improve animal’s performance in hippocampal-related memory tasks. We further show that interferon-CD95 signaling is required to promote injury-mediated activation of remote NSCs. Thus, we identify an immune-CNS axis responsible for injury-mediated activation of remotely located NSCs.

Digital-analog quantum computation aims to reduce the currently infeasible resource requirements needed for near-term quantum information processing by replacing sequences of one- and two-qubit gates with a unitary transformation generated by the systems’ underlying Hamiltonian. Inspired by this paradigm, we consider superconducting architectures and extend the cross-resonance effect, up to first order in perturbation theory, from a two-qubit interaction to an analog Hamiltonian acting on one-dimensional (1D) chains and two-dimensional (2D) square lattices, which, in an appropriate reference frame, results in a purely two-local Hamiltonian. By augmenting the analog Hamiltonian dynamics with single-qubit gates we show how one may generate a larger variety of distinct analog Hamiltonians. We then synthesize unitary sequences, in which we toggle between the various analog Hamiltonians as needed, simulating the dynamics of Ising, XY, and Heisenberg spin models. Our dynamics simulations are Trotter error-free for the Ising and XY models in 1D. We also show that the Trotter errors for 2D XY and 1D Heisenberg chains are reduced, with respect to a digital decomposition, by a constant factor. In order to realize these important near-term speedups, we discuss the practical considerations needed to accurately characterize and calibrate our analog Hamiltonians for use in quantum simulations. We conclude with a discussion of how the Hamiltonian toggling techniques could be extended to derive new analog Hamiltonians, which may be of use in more complex digital-analog quantum simulations for various models of interacting spins.

Pricing interest-rate financial derivatives is a major problem in finance, in which it is crucial to accurately reproduce the time evolution of interest rates. Several stochastic dynamics have been proposed in the literature to model either the instantaneous interest rate or the instantaneous forward rate. A successful approach to model the latter is the celebrated Heath-Jarrow-Morton framework, in which its dynamics is entirely specified by volatility factors. In its multifactor version, this model considers several noisy components to capture at best the dynamics of several time-maturing forward rates. However, as no general analytical solution is available, there is a trade-off between the number of noisy factors considered and the computational time to perform a numerical simulation. Here, we employ the quantum principal component analysis to reduce the number of noisy factors required to accurately simulate the time evolution of several time-maturing forward rates. The principal components are experimentally estimated with the five-qubit IBMQX2 quantum computer for 2×2 and 3×3 cross-correlation matrices, which are based on historical data for two and three time-maturing forward rates. This paper is a step towards the design of a general quantum algorithm to fully simulate on quantum computers the Heath-Jarrow-Morton model for pricing interest-rate financial derivatives. It shows indeed that practical applications of quantum computers in finance will be achievable in the near future.

One of the main drawbacks of the traditional methods for computing components in the three-way Tucker model is the complex structure of the final loading matrices preventing an easy interpretation of the obtained results. In this paper, we propose a heuristic algorithm for computing disjoint orthogonal components facilitating the analysis of three-way data and the interpretation of results. We observe in the computational experiments carried out that our novel algorithm ameliorates this drawback, generating final loading matrices with a simple structure and then easier to interpret. Illustrations with real data are provided to show potential applications of the algorithm.

Sideroxylon obtusifolium, conhecida como quixaba, é utilizada para diversos fins medicinais, dentre eles em casos de inflamações e infecções bacterianas, com isso, o estudo teve por objetivo investigar a atividade antiedematogênica tópica e antibacteriana do extrato metanólico obtido das folhas de S. obtusifolium. Os resultados obtidos através dos testes de microdiluição e modulação mostraram potencial atividade antibacteriana quando associados a gentamicina e amicacina para cepas multirresistentes de Staphylococcus aureus. Para cepas de Escherichia coli, só houve modulação da atividade de aminoglicosídeos frente ao antibiótico amicacina havendo antagonismo para gentamicina, o mesmo efeito foi observado para Pseudomonas aeruginosas em ambos antibióticos. Nos testes para inflamação aguda através dos modelos de edema de orelha induzido por óleo de cróton e fenol, o extrato apresentou um potente efeito antiedematogêncio p < 0,05. A prospecção fitoquímica do extrato foi feita e nela foram verificados diversos metabólitos com inúmeras atividades biológicas. Os polifenóis e flavonóides presentes neste extrato foram quantificados em 150,3 mg equivalentes de ácido gálico/ g de extrato e 98,5 mg equivalentes de quercetina/ g de extrato, respectivamente, o que explica o forte poder antioxidante presente nesta parte da planta. Diante dos resultados, podem-se observar atividades biológicas de S. obtusifolium, o que condiz com seu uso na terapia popular, no entanto como se trata de um extrato, substancias devem ser isoladas e testadas. Sendo assim este trabalho poderá servir como base para futuras pesquisas relacionadas a essa parte da planta.

When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease.

Quantum computers will allow calculations beyond existing classical computers. However, current technology is still too noisy and imperfect to construct a universal digital quantum computer with quantum error correction. Inspired by the evolution of classical computation, an alternative paradigm merging the flexibility of digital quantum computation with the robustness of analog quantum simulation has emerged. This universal paradigm is known as digital-analog quantum computing. Here, we introduce an efficient digital-analog quantum algorithm to compute the quantum Fourier transform, a subroutine widely employed in several relevant quantum algorithms. We show that, under reasonable assumptions about noise models, the fidelity of the quantum Fourier transformation improves considerably using this approach when the number of qubits involved grows. This suggests that, in the noisy intermediate-scale quantum era, hybrid protocols combining digital and analog quantum computing could be a sensible approach to reach useful quantum supremacy.

Adult mammalian central nervous system (CNS) neurons are unable to regenerate following axonal injury, leading to permanent functional impairments. Yet, the reasons underlying this regeneration failure are not fully understood. Here, we studied the transcriptome and translatome shortly after spinal cord injury. Profiling of the total and ribosome-bound RNA in injured and naïve spinal cords identified a substantial post-transcriptional regulation of gene expression. In particular, transcripts associated with nervous system development were down-regulated in the total RNA fraction while remaining stably loaded onto ribosomes. Interestingly, motif association analysis of post-transcriptionally regulated transcripts identified the cytoplasmic polyadenylation element (CPE) as enriched in a subset of these transcripts that was more resistant to injury-induced reduction at the transcriptome level. Modulation of these transcripts by overexpression of the CPE binding protein, Cpeb1, in mouse and Drosophila CNS neurons promoted axonal regeneration following injury. Our study uncovered a global evolutionarily conserved post-transcriptional mechanism enhancing regeneration of injured CNS axons.

Structural imaging studies of borderline personality disorder (BPD) have found regions of reduced cortical volume, but these have varied considerably across studies. Reduced hippocampus and amygdala volume have also been a regular finding in studies using conventional volumetric measurement. How far comorbid major depression, which is common in BPD and can also affect in brain structure, influences the findings is not clear.Seventy-six women with BPD and 76 matched controls were examined using whole-brain voxel-based morphometry (VBM). The hippocampus and amygdala were also measured, using both conventional volume measurement and VBM within a mask restricted to these two subcortical structures. Lifetime history of major depression was assessed using structured psychiatric interview.At a threshold of p = 0.05 corrected, the BPD patients showed clusters of volume reduction in the dorsolateral prefrontal cortex bilaterally and in the pregenual/subgenual medial frontal cortex. There was no evidence of volume reductions in the hippocampus or amygdala, either on conventional volumetry or using VBM masked to these regions. Instead there was evidence of right-sided enlargement of these structures. No significant structural differences were found between patients with and without lifetime major depression.According to this study, BPD is characterized by a restricted pattern of cortical volume reduction involving the dorsolateral frontal cortex and the medial frontal cortex, both areas of potential relevance for the clinical features of the disorder. Previous findings concerning reduced hippocampus and amygdala volume in the disorder are not supported. Brain structural findings in BPD do not appear to be explainable on the basis of history of associated lifetime major depression.

Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells. In myeloid cells, CD95 triggers activation of Syk-Btk/PLCγ2/Rap1 signaling that ultimately leads to integrin activation. Excitingly, CD95-deficient myeloid cells exhibit impaired bacterial clearance in an animal model of sepsis induced by cecal ligation and puncture (CLP). Our data identify the cellular and molecular mechanisms underlying the chemoattractant effect of endothelial cell-derived CD95L in induction of neutrophil recruitment and support the use of therapeutic inhibition of CD95’s activity in inflammatory diseases.

Aim of study: This study was conducted to support fire and forest management planning in eucalypt plantations based on economic, ecological and fire prevention criteria, with a focus on strategic prioritisation of fuel treatments over time. The central objective was to strategically locate fuel treatments to minimise losses from wildfire while meeting budget constraints and demands for wood supply for the pulp industry and conserving carbon. Area of study: The study area was located in Serra do Socorro (Torres Vedras, Portugal, covering ~1449 ha) of predominantly Eucalyptus globulus Labill forests managedcultivated for pulpwood by The Navigator Company. Material and methods: At each of four temporal stages (2015-2018-2021-2024) we simulated: (1) surface and canopy fuels, timber volume (m3 ha-1) and carbon storage (Mg ha-1); (2) fire behaviour characteristics, i.e. rate of spread (m min-1), and flame length (m), with FlamMap fire modelling software; (3) optimal treatment locations as determined by the Landscape Treatment Designer (LTD). Main results: The higher pressure of fire behaviour in the earlier stages of the study period triggered most of the spatial fuel treatments within eucalypt plantations in a juvenile stage. At later stages fuel treatments also included shrublands areas. The results were consistent with observations and simulation results that show high fire hazard in juvenile eucalypt stands. Research highlights: Forest management planning in commercial eucalypt plantations can potentially accomplish multiple objectives such as augmenting profits and sustaining ecological assets while reducing wildfire risk at landscape scale. However, limitations of simulation models including FlamMap and LTD are important to recognise in studies of long term wildfire management strategies. Keywords: Eucalypt plantations; Fire hazard; FlamMap; fuel treatment optimisation; Landscape Treatment Designer; wildfire risk management.

This protocol describes how to visualize neuronal morphology and how to determine neuronal complexity of immature and mature hippocampal neurons in the mouse in vivo including tissue preparation, staining of brain sections and confocal cell analysis.

This protocol shows how to characterize the dynamics of hippocampal neurogenesis in the adult mouse by describing preparation of brain tissue, immunofluorescence of brain sections and confocal stereotactic cell counting.

Dickkopf1 (Dkk1) is a Wnt/β-catenin inhibitor that participates in many processes during embryonic development. One of its roles during embryogenesis is to induce head formation, since Dkk1-null mice lack head structures anterior to midbrain. The Wnt/β-catenin pathway is also known to regulate different aspects of ventral midbrain (VM) dopaminergic (DA) neuron development and, in vitro, Dkk1-mediated inhibition of the Wnt/β-catenin pathway improves the DA differentiation in mouse embryonic stem cells (mESC). However, the in vivo function of Dkk1 on the development of midbrain DA neurons remains to be elucidated. Here we examined Dkk1(+/-) embryos and found that Dkk1 is required for the differentiation of DA precursors/neuroblasts into DA neurons at E13.5. This deficit persisted until E17.5, when a defect in the number and distribution of VM DA neurons was detected. Furthermore, analysis of the few Dkk1(-/-) embryos that survived until E17.5 revealed a more severe loss of midbrain DA neurons and morphogenesis defects. Our results thus show that Dkk1 is required for midbrain DA differentiation and morphogenesis.