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Abstract Background In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. Results In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. Conclusions Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Despite the tremendous advances in aircraft design that led to successful powered flights of aircraft as heavy as the Antonov An-225 Mriya, which weighs 640 tons, or as fast as the NASA-X-43A, which reached a record of Mach 9.6, many characteristics of bird flight have yet to be utilized in aircraft designs. These characteristics enable various species of birds to fly efficiently in gusty environments and rapidly change their momentum in flight without having modern thrust vector control (TVC) systems. Vultures and seagulls, as examples of expert gliding birds, can fly for hours, covering more than 100 miles, without a single flap of their wings. Inspired by the Great Black-Backed Gull (GBBG), this paper presents “CGull”, a non-flapping unmanned aerial vehicle (UAV) with wing and tail morphing capabilities. A coupled two degree-of-freedom (DOF) morphing mechanism is used in CGull’s wings to sweep the middle wing forward and the outer feathered wing backward, replicating the GBBG’s wing deformation. A modular two DOF mechanism enables CGull to pitch and tilt its tail. A computational model was first developed in MachUpX to study the effects of wing and tail morphing on the generated forces and moments. Following the biological construction of birds’ feathers and bones, CGull’s structure is mainly constructed from carbon-fiber composite shells. The successful flight test of the proof-of-concept physical model proved the effectiveness of the proposed morphing mechanisms in controlling the UAV’s path.

Abstract How well a surgery is performed impacts a patient’s outcomes; however, objective quantification of performance remains an unsolved challenge. Deconstructing a procedure into discrete instrument-tissue “gestures” is a emerging way to understand surgery. To establish this paradigm in a procedure where performance is the most important factor for patient outcomes, we identify 34,323 individual gestures performed in 80 nerve-sparing robot-assisted radical prostatectomies from two international medical centers. Gestures are classified into nine distinct dissection gestures (e.g., hot cut) and four supporting gestures (e.g., retraction). Our primary outcome is to identify factors impacting a patient’s 1-year erectile function (EF) recovery after radical prostatectomy. We find that less use of hot cut and more use of peel/push are statistically associated with better chance of 1-year EF recovery. Our results also show interactions between surgeon experience and gesture types—similar gesture selection resulted in different EF recovery rates dependent on surgeon experience. To further validate this framework, two teams independently constructe distinct machine learning models using gesture sequences vs. traditional clinical features to predict 1-year EF. In both models, gesture sequences are able to better predict 1-year EF (Team 1: AUC 0.77, 95% CI 0.73–0.81; Team 2: AUC 0.68, 95% CI 0.66–0.70) than traditional clinical features (Team 1: AUC 0.69, 95% CI 0.65–0.73; Team 2: AUC 0.65, 95% CI 0.62–0.68). Our results suggest that gestures provide a granular method to objectively indicate surgical performance and outcomes. Application of this methodology to other surgeries may lead to discoveries on methods to improve surgery.

Olfaction in mammals relies on a toolbox composed of a varied set of sensory neurons. Here, the authors report in mice that this olfactory neuronal diversity relies both on the chemoreceptor that each neuron expresses and on the experience of this neuron.

Since the inception of the current pandemic, COVID-19 related misinformation has played a role in defaulting control of the situation. It has become evident that the internet, social media, and other communication outlets with readily available data have contributed to the dissemination and availability of misleading information. It has perpetuated beliefs that led to vaccine avoidance, mask refusal, and utilization of medications with insignificant scientific data, ultimately contributing to increased morbidity. Undoubtedly, misinformation has become a challenge and a burden to individual health, public health, and governments globally. Our review article aims at providing an overview and summary regarding the role of media, other information outlets, and their impact on the pandemic. The goal of this article is to increase awareness of the negative impact of misinformation on the pandemic. In addition, we discuss a few recommendations that could aid in decreasing this burden, as preventing the conception and dissemination of misinformation is essential.

Cellulitis is a potentially serious bacterial skin infection. Penile cellulitis refers to the inflammation of the penile shaft and commonly occurs in uncircumcised, sexually active young adults. We reported the case of a 25-year-old heterosexual circumcised male patient with a two-day history of swelling and pain over the penile shaft. Local examination revealed a diffusely swollen penile shaft, erythematous, warm to the touch, and tender. The penile discharge culture was suggestive of a Streptococcus species infection. Ultrasonography of the penis showed increased echogenicity of the left side of the penile shaft soft tissue with a markedly increased Doppler signal, indicating cellulitis. Based on these findings, the patient was diagnosed with cellulitis of the penis and managed with broad-spectrum antibiotics. Though history and clinical examination are sufficient to diagnose penile cellulitis, our case highlighted that ultrasound could also support the diagnosis of penile cellulitis and help rule out differentials.

Amid climate and land use changes, it is important to identify and monitor hotspots of animal activity where disease transmission can occur. Using experimental and observational methods in an East African savannah, this study shows water sources increase the concentration of faecal-oral parasites in the environment and that this effect is amplified in drier areas and following periods of low rainfall.

Palcewska et al. first demonstrated near infrared (NIR) visual response in human volunteers upon two-photon absorption (TPA), in a seminal work of 2014, and assessed the process in terms of wavelength- and power-dependence on murine \textit{ex-vivo} retinas. In the present study, ex-vivo electroretinography (ERG) is further developed to perform a complete characterization of the effect of NIR pulse duration, energy, and focal spot size on the response. The same set of measurements is successively tested on living mice. We discuss how the nonlinear intensity dependence of the photon absorption process is transferred to the amplitude of the visual response acquired by ERG. Finally, we show that the manipulation of the spectral phase of NIR pulses can be translated to predictable change in the two-photon induced response under physiological excitation conditions.

We explored the degree to which political bias in medicine and study authors could explain the stark variation in Hydroxychloroquine (HCQ)/Chloroquine (CQ) study favorability in the US compared to the rest of the world. COVID-19/SARS-CoV-2 preprint and published papers between January 1, 2020-July 26, 2020 with Hydroxychloroquine and/or Chloroquine; 267 met study criteria, 68 from the US. A control subset was selected. HCQ/CQ study result favorability (favorable, unfavorable, or neutral) was noted. First and last main authors of each US study were entered into FollowTheMoney.org Website, extracting any history of political party donation. Of all US studies (68 total), 39/68 (57.4%) were unfavorable, with only 7/68 (10.3%) of US studies yielding favorable results-compared to 199 non-US studies, 66/199 (33.2%) unfavorable, 69/199 (34.7%) favorable, and 64/199 (32.2%) neutral. Studies with at least one US main author were 20.4% (SE 0.053, P < 0.05) more likely to report unfavorable results than non-US studies. US Studies with at least one main author donating to any political party were 25.6% (SE 0.085, P < 0.01) more likely to have unfavorable results. US studies with at least one author donating to the Democratic party were 20.4% (SE 0.045, P < 0.05) more likely to have unfavorable results. US authors were more likely to publish studies with medically harmful conclusions than non-US authors. Cardiology-specific HCQ/CQ studies were 44.2% more likely to yield harmful conclusions (P < 0.01). Inaccurate propagation of HCQ/CQ cardiac adverse effects with individual scientific author political bias has contributed to unfavorable US HCQ/CQ publication patterns and political polarization of the medications.

Currently, assessment of the potential immunotoxicity of a given agent involves a tiered approach for hazard identification and mechanistic studies, including observational studies, evaluation of immune function, and measurement of susceptibility to infectious and neoplastic diseases. These studies generally use costly low-throughput mammalian models. Zebrafish, however, offer an excellent alternative due to their rapid development, ease of maintenance, and homology to mammalian immune system function and development. Larval zebrafish also are a convenient model to study the innate immune system with no interference from the adaptive immune system. In this study, a respiratory burst assay (RBA) was utilized to measure reactive oxygen species (ROS) production after developmental xenobiotic exposure. Embryos were exposed to non-teratogenic doses of chemicals and at 96 h post-fertilization, the ability to produce ROS was measured. Using the RBA, 12 compounds with varying immune-suppressive properties were screened. Seven compounds neither suppressed nor enhanced the respiratory burst; five reproducibly suppressed global ROS production, but with varying potencies: benzo[a]pyrene, 17β-estradiol, lead acetate, methoxychlor, and phenanthrene. These five compounds have all previously been reported as immunosuppressive in mammalian innate immunity assays. To evaluate whether the suppression of ROS by these compounds was a result of decreased immune cell numbers, flow cytometry with transgenic zebrafish larvae was used to count the numbers of neutrophils and macrophages after chemical exposure. With this assay, benzo[a]pyrene was found to be the only chemical that induced a change in the number of immune cells by increasing macrophage but not neutrophil numbers. Taken together, this work demonstrates the utility of zebrafish larvae as a vertebrate model for identifying compounds that impact innate immune function at non-teratogenic levels and validates measuring ROS production and phagocyte numbers as metrics for monitoring how xenobiotic exposure alters the innate immune system.

Motivated by the pervasiveness of artificial intelligence (AI) and the Internet of Things (IoT) in the current “smart everything” scenario, this article provides a comprehensive overview of the most recent research at the intersection of both domains, focusing on the design and development of specific mechanisms for enabling a collaborative inference across edge devices towards the in situ execution of highly complex state-of-the-art deep neural networks (DNNs), despite the resource-constrained nature of such infrastructures. In particular, the review discusses the most salient approaches conceived along those lines, elaborating on the specificities of the partitioning schemes and the parallelism paradigms explored, providing an organized and schematic discussion of the underlying workflows and associated communication patterns, as well as the architectural aspects of the DNNs that have driven the design of such techniques, while also highlighting both the primary challenges encountered at the design and operational levels and the specific adjustments or enhancements explored in response to them.

Poly(ADP-ribose) polymerase 7 (PARP-7) has emerged as a critically important member of a large enzyme family that catalyzes ADP-ribosylation in mammalian cells. PARP-7 is a critical regulator of the innate immune response. What remains unclear is the mechanism by which PARP-7 regulates this process, namely because the protein targets of PARP-7 mono-ADP-ribosylation (MARylation) are largely unknown. Here, we combine chemical genetics, proximity labeling, and proteome-wide amino acid ADP-ribosylation site profiling for identifying the direct targets and sites of PARP-7-mediated MARylation in a cellular context. We found that the inactive PARP family member, PARP-13—a critical regulator of the antiviral innate immune response—is a major target of PARP-7. PARP-13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. Proteome-wide ADP-ribosylation analysis reveals cysteine as a major MARylation acceptor of PARP-7. This study provides insight into PARP-7 targeting and MARylation site preference.

Summary: Reports indicate an association between COVID-19 and anosmia, as well as the presence of SARS-CoV-2 virions in the olfactory bulb. To test whether the olfactory neuroepithelium may represent a target of the virus, we generated RNA-seq libraries from human olfactory neuroepithelia, in which we found substantial expression of the genes coding for the virus receptor angiotensin-converting enzyme-2 (ACE2) and for the virus internalization enhancer TMPRSS2. We analyzed a human olfactory single-cell RNA-seq dataset and determined that sustentacular cells, which maintain the integrity of olfactory sensory neurons, express ACE2 and TMPRSS2. ACE2 protein was highly expressed in a subset of sustentacular cells in human and mouse olfactory tissues. Finally, we found ACE2 transcripts in specific brain cell types, both in mice and humans. Sustentacular cells thus represent a potential entry door for SARS-CoV-2 in a neuronal sensory system that is in direct connection with the brain.

Summary: In rodents, the decrease of felid aversion induced by Toxoplasma gondii, a phenomenon termed fatal attraction, is interpreted as an adaptive manipulation by the neurotropic protozoan parasite. With the aim of understanding how the parasite induces such specific behavioral modifications, we performed a multiparametric analysis of T. gondii-induced changes on host behavior, physiology, and brain transcriptome as well as parasite cyst load and distribution. Using a set of complementary behavioral tests, we provide strong evidence that T. gondii lowers general anxiety in infected mice, increases explorative behaviors, and surprisingly alters predator aversion without selectivity toward felids. Furthermore, we show a positive correlation between the severity of the behavioral alterations and the cyst load, which indirectly reflects the level of inflammation during brain colonization. Taken together, these findings refute the myth of a selective loss of cat fear in T. gondii-infected mice and point toward widespread immune-related alterations of behaviors. : Contradicting the prevailing model of a selective loss of cat fear in Toxoplasma gondii-infected rodents, Boillat et al. show in a multiparametric analysis of host behavior, physiology, and brain transcriptome that the loss of predator fear is not specific to felids and that the severity of behavioral alterations correlates with neuroinflammation. Keywords: Apicomplexa, Toxoplasma gondii, parasites, chronic infection, host-pathogen interaction, effector molecules, innate behavior, predator avoidance, light-sheet microscopy, cat

Ambient Intelligence (AmI) encompasses technological infrastructures capable of sensing data from environments and extracting high-level knowledge to detect or recognize users’ features and actions, as well as entities or events in their surroundings. Visual perception, particularly object detection, has become one of the most relevant enabling factors for this context-aware user-centered intelligence, being the cornerstone of relevant but complex tasks, such as object tracking or human action recognition. In this context, convolutional neural networks have proven to achieve state-of-the-art accuracy levels. However, they typically result in large and highly complex models that typically demand computation offloading onto remote cloud platforms. Such an approach has security- and latency-related limitations and may not be appropriate for some AmI use cases where the system response time must be as short as possible, and data privacy must be guaranteed. In the last few years, the on-device paradigm has emerged in response to those limitations, yielding more compact and efficient neural networks able to address inference directly on client machines, thus providing users with a smoother and better-tailored experience, with no need of sharing their data with an outsourced service. Framed in that novel paradigm, this work presents a review of the recent advances made along those lines in object detection, providing a comprehensive study of the most relevant lightweight CNN-based detection frameworks, discussing the most paradigmatic AmI domains where such an approach has been successfully applied, the different challenges arisen, the key strategies and techniques adopted to create visual solutions for image-based object classification and localization, as well as the most relevant factors to bear in mind when assessing or comparing those techniques, such as the evaluation metrics or the hardware setups used.

Abstract Genetics plays a central role in susceptibility to obesity and metabolic diseases. BALB/c mice are known to be resistant to high fat diet (HFD)-induced obesity, however the genetic cause remains unknown. We report that deletion of the innate immunity antibacterial gene Nod2 abolishes this resistance, as Nod2 −/− BALB/c mice developed HFD-dependent obesity and hallmark features of metabolic syndrome. Nod2 −/− HFD mice developed hyperlipidemia, hyperglycemia, glucose intolerance, increased adiposity, and steatosis, with large lipid droplets in their hepatocytes. These changes were accompanied by increased expression of immune genes in adipose tissue and differential expression of genes for lipid metabolism, signaling, stress, transport, cell cycle, and development in both adipose tissue and liver. Nod2 −/− HFD mice exhibited changes in the composition of the gut microbiota and long-term treatment with antibiotics abolished diet-dependent weight gain in Nod2 −/− mice, but not in wild type mice. Furthermore, microbiota from Nod2 −/− HFD mice transferred sensitivity to weight gain, steatosis, and hyperglycemia to wild type germ free mice. In summary, we have identified a novel role for Nod2 in obesity and demonstrate that Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction.

Repairing bone defects in oral surgery often requires the use of bone regeneration techniques. Silicon is an element that has been employed as regeneration material in several studies. In our study, silicon was combined with autologous bone and platelet-rich fibrin (PRF) membranes to analyse the behaviour of this element in bone regeneration. Four circumferential defects were created in the cranial vault of five New Zealand rabbits. The following elements were applied to the regeneration of the defects: (P): PRF; (S): silicon and (B): autologous bone, with the following distribution of study groups: Group 1 (PSB); Group 2 (PS); Group 3 (SB) and Group 4 (CONTROL): unregenerate group. The animals were sacrificed after 3 weeks. Computed microtomography studies (μ-CT) were carried out, as well as histomorphometric ones. The ANOVA statistical test was used with a Bonferroni post-hoc test to compare the results (p ≤ 0.05). Radiologically, groups PSB and SB were better as far as quantity and percentage of healthy bone observed, but not significantly compared to the control group. The PS group was significantly worse. The histological test revealed that the PSB group was the one to present the largest area, percentage and perimeter of mineralised bone. On evaluating the forming bone (osteoid), no difference was observed across the groups with the exception of the bone perimeter, where the SB group was significantly better. The bone height variable showed no significant differences. In conclusion we can state that the combination of PRF, autologous bone and silicon provides good results at 3 weeks whilst the PS group shows the worst results. This highlights the importance of autologous bone forming part of the graft material in order for the bone to mineralise.

Billfishes are considered to be among the fastest swimmers in the oceans. Previous studies have estimated maximum speed of sailfish and black marlin at around 35 m s−1 but theoretical work on cavitation predicts that such extreme speed is unlikely. Here we investigated maximum speed of sailfish, and three other large marine pelagic predatory fish species, by measuring the twitch contraction time of anaerobic swimming muscle. The highest estimated maximum swimming speeds were found in sailfish (8.3±1.4 m s−1), followed by barracuda (6.2±1.0 m s−1), little tunny (5.6±0.2 m s−1) and dorado (4.0±0.9 m s−1); although size-corrected performance was highest in little tunny and lowest in sailfish. Contrary to previously reported estimates, our results suggest that sailfish are incapable of exceeding swimming speeds of 10-15 m s−1, which corresponds to the speed at which cavitation is predicted to occur, with destructive consequences for fin tissues.

Seeking a more flexible and efficient production, additive manufacturing (AM) has emerged as a major player in the industrial field, streamlining the fabrication of custom tangible assets by directly 3D printing them. However, production still takes too long due to printing, but also due to the product design stage, in which the customer works together with an expert to create a 3D model of the targeted product by means of computer-aided design (CAD) software. Skipping intermediate agents and making customers responsible for the design process will reduce waiting times and speed up the manufacturing process. This work is conceived as a first step towards that optimized AM model, being aimed at bringing CAD tools closer to clients through an enhanced user experience, and consequently at simplifying pre-manufacturing design tasks. Specifically, as an alternative to the traditional user interface operated with the keyboard and mouse duo, standard in CAD and AM, the paper presents a comprehensive multi-touch interaction system conceived as a customer-centric human-machine interface. To depict the proposed solutions, we adopt furniture manufacturing as a case study and, supported by a CAD-like software prototype for 3D modeling of custom cabinets introduced in a previous work of the authors, we assess our approach’s validity in terms of usability by conducting in-lab and remote user studies. The comparison between the designed multi-touch interaction and its desktop alternative yields promising results, showing improved performance and higher satisfaction of the end-user for the touch-based approach, that lay the groundwork for a smarter factory vision based on remotely-operated AM.

Functional brain-imaging techniques used in humans and animals, such as functional MRI and intrinsic optical signal (IOS) imaging, are thought to largely rely on neurovascular coupling and hemodynamic responses. Here, taking advantage of the well-described micro-architecture of the mouse olfactory bulb, we dissected the nature of odor-evoked IOSs. Using in vivo pharmacology in transgenic mouse lines reporting activity in different cell types, we show that parenchymal IOSs are largely independent of neurotransmitter release and neurovascular coupling. Furthermore, our results suggest that odor-evoked parenchymal IOSs originate from changes in light scattering of olfactory sensory neuron axons, mostly due to water movement following action potential propagation. Our study sheds light on a direct correlate of neuronal activity, which may be used for large-scale functional brain imaging.

Biological processes for wastewater treatments are inherently dynamic systems because of the large variations in the influent wastewater flow rate, concentration composition and the adaptive behavior of the involved microorganisms. Moreover, the sludge retention time (SRT) is a critical factor to understand the bioreactor performances when changes in the influent or in the operation conditions take place. Since SRT are usually in the range of 10-30 days, the performance of biological reactors needs a long time to be monitored in a regular laboratory demonstration, limiting the knowledge that can be obtained in the experimental lab practice. In order to overcome this lack, mathematical models and computer simulations are useful tools to describe biochemical processes and predict the overall performance of bioreactors under different working operation conditions and variations of the inlet wastewater composition. The mathematical solution of the model could be difficult as numerous biochemical processes can be considered. Additionally, biological reactors description (mass balance, etc.) needs models represented by partial or/and ordinary differential equations associated to algebraic expressions, that require complex computational codes to obtain the numerical solutions. Different kind of software for mathematical modeling can be used, from large degree of freedom simulators capable of free models definition (as AQUASIM), to closed predefined model structure programs (as BIOWIN). The first ones usually require long learning curves, whereas the second ones could be excessively rigid for specific wastewater treatment systems. As alternative, we present Biological Reactor SIMulator (BioReSIM), a MATLAB code for the simulation of sequencing batch reactors (SBR) and rotating biological contactors (RBC) as biological systems of suspended and attached biomass for wastewater treatment, respectively. This BioReSIM allows the evaluation of simple and complex kinetic biological models, as well as operational conditions of the bioreactors through a friendly and graphic user interface, avoiding the development of complex codes.

Sensory inputs are remarkably organized along all sensory pathways. While sensory representations are known to undergo plasticity at the higher levels of sensory pathways following peripheral lesions or sensory experience, less is known about the functional plasticity of peripheral inputs induced by learning. We addressed this question in the adult mouse olfactory system by combining odor discrimination studies with functional imaging of sensory input activity in awake mice. Here we show that associative learning, but not passive odor exposure, potentiates the strength of sensory inputs up to several weeks after the end of training. We conclude that experience-dependent plasticity can occur in the periphery of adult mouse olfactory system, which should improve odor detection and contribute towards accurate and fast odor discriminations.

The novel immune-type receptors (NITRs), which have been described in numerous bony fish species, are encoded by multigene families of inhibitory and activating receptors and are predicted to be functional orthologs to the mammalian natural killer cell receptors (NKRs). Within the zebrafish NITR family, nitr9 is the only gene predicted to encode an activating receptor. However, alternative RNA splicing generates three distinct nitr9 transcripts, each of which encodes a different isoform. Although nitr9 transcripts have been detected in zebrafish lymphocytes, the specific hematopoietic lineage(s) that expresses Nitr9 remains to be determined. In an effort to better understand the role of NITRs in zebrafish immunity, anti-Nitr9 monoclonal antibodies were generated and evaluated for the ability to recognize the three Nitr9 isoforms. The application of these antibodies to flow cytometry should prove to be useful for identifying the specific lymphocyte lineages that express Nitr9 and may permit the isolation of Nitr9-expressing cells that can be directly assessed for cytotoxic (e.g., NK) function.

Se presenta un sistema de indicadores de sostenibilidad que puede ser empleado en la agroindustria azucarera cubana para evaluar su desempeño ambiental. Para la confección del mismo se tuvo en cuenta las principales iniciativas sobre indicadores de sostenibilidad a escala internacional así como las condiciones económicas y socioculturales donde se ubican dichas instalaciones.

The survival of vertebrate species is dependent on the ability of individuals to adequately interact with each other, a function often mediated by the olfactory system. Diverse olfactory receptor repertoires are used by this system to recognize chemicals. Among these receptors, the V1rs, encoded by a very large gene family in most mammals, are able to detect pheromones. Teleosts, which also express V1r receptors, possess a very limited V1r repertoire. Here, taking advantage of the possibility to unequivocally identify V1r orthologs in teleosts, we analyzed the olfactory expression and evolutionary constraints of a pair of clustered fish V1r receptor genes, V1r1 and V1r2. Orthologs of the two genes were found in zebrafish, medaka, and threespine stickleback, but a single representative was observed in tetraodontidae species. Analysis of V1r1 and V1r2 sequences from 12 different euteleost species indicate different evolutionary rates between the two paralogous genes, leading to a highly conserved V1r2 gene and a V1r1 gene under more relaxed selective constraint. Moreover, positively-selected sites were detected in specific branches of the V1r1 clade. Our results suggest a conserved agonist specificity of the V1R2 receptor between euteleost species, its loss in the tetraodontidae lineage, and the acquisition of different chemosensory characteristics for the V1R1 receptor.

Worst Case Execution Time estimation of software running on parallel platforms is a challenging task, due to resource interference of other tasks and the complexity of the underlying CPU and GPU hardware architectures. Similarly, the increased complexity of the hardware, challenges the estimation of worst case power consumption. In this paper, we employ Measurement Based Probabilistic Timing Analysis (MBPTA), which is capable of managing complex architectures such as multicores. We enable its use by software randomisation, which we show for the first time that is also possible on GPUs. We demonstrate our method on a pedestrian detection use case on an embedded multicore and GPU platform for the automotive domain, the NVIDIA Xavier. Moreover, we extend our measurement based probabilistic method in order to predict the worst case power consumption of the software on the same platform. [ABSTRACT FROM AUTHOR]

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Microwave heating, which is caused by the interaction of electromagnetic radiation and materials, has become an important component in industrial operations across numerous industries. Despite their importance, conventional numerical simulations of microwave heating are computationally intensive. Concurrently, advances in artificial intelligence (AI), particularly machine learning algorithms, have transformed data processing by increasing accuracy while decreasing computational time. This study tackles the difficulty of efficient and accurate modelling in microwave heating by combining convolutional neural networks (CNNs) with traditional simulation techniques. The major goal of this research is to use CNNs to forecast temperature profiles in a variety of industrial materials, including susceptors, semi-transparent, and microwave-transparent materials, under varying power settings and heating periods. This unique strategy greatly reduces prediction times, with up to 60-fold speed increases over standard methods. Our research is based on examining the electromagnetic and thermal responses of these materials under microwave heating. This study’s findings emphasise the need for extensive datasets and show the transformational potential of CNNs in optimising material processing. It uses artificial intelligence to pave the way for more effective and exact simulations, supporting breakthroughs in industrial microwave heating applications.

Assessing the taxonomic status of closely related taxa is crucial in plant systematics and can have important implications for conservation and human plant use. Erica andevalensis Cabezudo & Rivera is a metallophyte endemic species from highly metal-polluted soils of SW Iberian Peninsula, an area with a mining history going back more than 5,000 years. Erica andevalensis is closely related to Erica mackayana Bab., a northern Iberian species also present in western Ireland. The status of E. andevalensis as a species or subspecies subordinated to E. mackayana is subject to debate. Here, we assessed the genetic and phenotypic relationship between both species, including the population structure of E. andevalensis. We used high throughput sequencing to determine genome-wide Single Nucleotide Polymorphisms (SNPs), and morphometric analyses from 35 reproductive and vegetative traits. The morphological analysis showed at least eight characters that can discriminate the two species, from which ovary hairiness and the size of leaf glandular hairs were the most informative. Genetic analyses showed that each species formed a monophyletic cluster with full support, separated by an interspecific genetic distance >4-fold higher than intra-specific distance. Population genetic analyses of E. andevalensis shows that populations are highly structured, with the Portuguese one as the most isolated and less variable. These results support the recognition of E. andevalensis as a distinct species with a highly constrained ecological requirements and a narrow geographic distribution, but with a limited gene flow between populations. We discuss the implications of these outcomes in conservation policies and potential uses of E. andevalensis such as decontamination of polluted soils.

Abstract The aim of this work is to quantitatively assess the wavefront phase of keratoconic eyes measured by the ocular aberrometer t·eyede (based on WaveFront Phase Imaging Sensor), characterized by a lateral resolution of 8.6 µm without requiring any optical element to sample the wavefront information. We evaluated the parameters: root mean square error, Peak-to-Valley, and amplitude of the predominant frequency (Fourier Transform analysis) of a section of the High-Pass filter map in keratoconic and healthy cohorts. Furthermore, we have analyzed keratoconic eyes that presented dark–light bands in this map to assess their period and orientation with the Fourier Transform. There are significant statistical differences (p value

The paper provides an analysis of the difference in the tools adopted in the Spanish urban policies between the two last EU programming cycles (2014–2020 and 2021–2027). After an introduction with references to the policy framework and the literature, a methodological section describes the focus of the research, the source of the data and how this information has been used for the comparative purpose of the work. The following section (Results) provides the comparison of the contents of the policy documents delivered by the Spanish cities involved in the urban agenda, with reference to the type of actions selected, the overlapping of thematic and strategic focus through the two periods, the budget allocated, etc. In the conclusive sections the attempt is to highlights analogies and differences between the two policy periods, pointing out the future investigation needed to provide a more comprehensive outlook on the question addressed in the paper.

Background and objectives Elastography is a technology that has strongly impacted several medical specialties; however, it is not yet applied as part of standard clinical practice in the field of pulmonology. The objective of this systematic review is to analyse the evidence available to date in relation to pleuropulmonary ultrasound elastography, focusing on the three pathologies with the most publications: subpleural consolidations, interstitial lung diseases and pleural effusion. Methods Original in vivo studies published up until 12 August 2023 in the Embase, MEDLINE or Web of Science databases were included. The QUADAS-2 tool was applied to analyse bias. Results We found 613 records in database search. After duplicates removal, we screened 246 records and finally included 18 papers. The average cohort sample size was 109 patients. The elastography modes most frequently used were strain (22.2%), transient elastography (22.2%), point shear-wave elastography (38.9%) and two-dimensional shear-wave elastography (22.2%). The possibility of a meta-analysis was ruled out because of the heterogeneity of the studies included. Discussion The currently available literature indicates that pleuropulmonary ultrasound elastography produces promising and consistent results, although the lack of standardisation in the use of the technique and in the elastography modes employed still impedes its use in daily clinical pneumology practice. The development of a clinical guideline establishing a common nomenclature and standardised techniques for pleuropulmonary elastography will be imperative to generate quality scientific evidence in this field.

BackgroundMedical curricula must provide students with basic and clinical competencies for critical reasoning and diagnosing. These competencies are better acquired when basic and clinical science are taught in an integrated and collaborative manner. In this study, we investigate whether supportive co-teaching (SCT) is an effective approach to promote integrated and reasoned learning as well as to help medical students applying theoretical concepts to clinical scenarios taught in a team-based learning (TBL) framework.MethodsWe conducted a concurrent mixed methods study. For the qualitative part, we performed a focus group and semi-structured interviews to clinical and basic science teachers and medical students. Using conventional content analysis, themes were identified deductively. For the quantitative part, an analytical and descriptive observational study of the 2019–2020 cohort of first-year undergraduate medical students was conducted (107 students out of 220 completed the survey). For the descriptive study, questions were grouped into 5 categories.ResultsDeductive themes from the analysis include relationship between clinical and basic science teachers, knowledge integration, methodology, teamwork and integrated Medicine and curricular design. Basic science and clinical teachers highlighted their relationship as critical to increase their mutual knowledge. This was supported by the student’s opinion who very much valued their joint feedback. Regarding knowledge integration, both teachers and students found that horizontal and vertical integration enhanced applicability of basic knowledge to future clinical practice. The TBL methodology was very well perceived by both students and teachers and was highly motivating for students even though the need for commitment. Students considered that this program presented a great opportunity and expressed their interest in maintaining it in the future. These results were supported by the quantitative data.ConclusionOur work supports the value of co-teaching in basic and clinical sciences within a TBL framework set in real clinical case scenarios. By employing this approach, students can actively apply their theoretical knowledge to clinical practice, enhancing their critical thinking, problem-solving, and clinical reasoning skills. Our findings can inform curriculum design and improved educational practice, leading to enhanced learning experiences for healthcare students and ultimately better patient care.

Introducción: la rehabilitación respiratoria (RR) se recomienda en pacientes con fibrosis quística (FQ). Durante la pandemia de COVID-19 los programas de RR debieron cerrarse o migrar a modalidades de telerehabilitación, imponiendo nuevos desafíos a pacientes y equipos de salud. El objetivo de este estudio fue explorar las percepciones de pacientes, padres y profesionales sobre la transición a la telerehabilitación respiratoria durante la pandemia de COVID-19. Método: estudio cualitativo. Se consideraron pacientes con FQ mayores de 8 años. También a padres y equipos de salud. El tamaño muestral se determinó mediante saturación teórica. Se realizaron entrevistas semiestructuradas y grupos focales vía Zoom ®. El análisis de datos se realizó mediante los métodos de codificación abierta y axial. El análisis se realizó utilizando el software Atlas. Ti 7.5.7. Resultados: se incluyó a 4 pacientes adultos, 1 pediátrico y 2 padres, además de 4 profesionales de equipos de salud. Existió una percepción general positiva respecto a la RR y la telerehabilitación. Entre las barreras destacó la falta de equipamiento para la telerehabilitación en domicilio y la organización diaria de los pacientes. Entre los facilitadores destacó la disponibilidad de equipos y redes que permitieran la conectividad y el apoyo familiar. Existió una valoración positiva hacia la continuidad de la telerehabilitación en la etapa post pandémica. Conclusiones: la telerehabilitación fue percibida como una alternativa viable y efectiva, sin embargo, aspectos de la conectividad, disponibilidad de equipamiento y la rutina diaria de los pacientes debe ser considerada a la hora de implementar modalidades telemáticas de atención.

Oxidative stress is one of the primary instigators of the onset of various human ailments, including cancers, cardiovascular diseases, and dementia. Particularly, oxidative stress severely affects low-density lipid & protein (LDL) oxidation, leading to several detrimental health effects. Therefore, in this study, the effect of beeswax alcohol (BWA) was evaluated in the prevention of LDL oxidation, enhancement of paraoxonase 1 (PON-1) activity of high-density lipid & protein (HDL), and zebrafish embryo survivability. Furthermore, the implication of BWA consumption on the oxidative plasma variables was assessed by a preliminary clinical study on middle-aged and older human subjects (n = 50). Results support BWA augmentation of PON-1 activity in a dose-dependent manner (10–30 μM), which was significantly better than the effect exerted by coenzyme Q10 (CoQ10). Moreover, BWA significantly curtails LDL/apo-B oxidation evoked by CuSO4 (final 0.5 μM) and a causes a marked reduction in lipid peroxidation in LDL. The transmission electron microscopy (TEM) analysis revealed a healing effect of BWA towards the restoration of LDL morphology and size impaired by the exposure of Cu2+ ions (final 0.5 μM). Additionally, BWA counters the toxicity induced by carboxymethyllysine (CML, 500 ng) and rescues zebrafish embryos from development deformities and apoptotic cell death. A completely randomized, double-blinded, placebo-controlled preliminary clinical study on middle- and older-aged human subjects (n = 50) showed that 12 weeks of BWA (100 mg/day) supplementation efficiently diminished serum malondialdehyde (MDA) and total hydroperoxides and enhanced total antioxidant status by 25%, 27%, and 22%, respectively, compared to the placebo-control and baseline values. Furthermore, the consumption of BWA did not exhibit any noteworthy changes in physical variables, lipid profile, glucose levels, and biomarkers pertinent to kidney and liver function, thus confirming the safety of BWA for consumption. Conclusively, in vitro, BWA prevents LDL oxidation, enhances PON-1 activity in HDL, and positively influences oxidative variables in human subjects.

Simple Summary: Treatment failures of acute myeloid leukemia (AML) have been attributed to the persistence of leukemia stem cells (LSCs), which are refractory to conventional treatments. Venetoclax (VEN), currently FDA-approved in combination with low-dose cytarabine or hypomethylating agents, is highly effective in inducing disease remission in patients with de novo AML; however, most of these patients eventually relapse; thus, novel VEN combinations are urgently needed. In this regard, 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets AML cells, including LSCs. We demonstrate that VEN and 8-Cl-Ado cooperate in targeting ribosomal RNA synthesis and mitochondrial metabolism in LSCs, thereby decreasing LSC survival. Given the emerging concept that LSC behavior is strongly associated with protein synthesis regulation and mitochondrial metabolism, our results suggest that the VEN/8-Cl-Ado combination is a promising regimen for the treatment of patients with relapsed AML. It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML. [ABSTRACT FROM AUTHOR]

Canine leishmaniosis, caused by the protozoan parasite Leishmania infantum, is a cosmopolitan vector-borne zoonosis, transmitted principally by Phlebotomus perniciosus in Spain and Portugal, where it is considered an endemic disease. Ecoinformatics tools such as ecological niche models (ENM) have been successfully tested to model the distribution of the risk of infection of different parasitosis as they take into account environmental variables vital for their survival. The risk map proposed in this study combines the potential distribution of Ph. perniciosus in the Iberian Peninsula and the calculation of the infection rate of the parasite in the vector to model the risk of contracting the disease in a more realistic way. In fact, this weighting strategy improves the predictive power of the resulting model (R2 = 0.42, p = 0.05). The places with the highest risk of transmission are the southwest and central peninsular area, as well as the Mediterranean coast, the Balearic Islands and the Ebro basin, places where the ideal habitat of Ph. perniciosus and the infection rate is also high. In the case of future projections under climate change scenarios, an increase in the risk of infection by L. infantum can be observed in most of the territory (4.5% in 2040, 71.6% in 2060 and 63% in 2080), mainly in the northern part of the peninsula. The use of ENMs and their weighting with the infection rate in Ph. perniciosus is a useful tool in predicting the risk of infection for L. infantum in dogs for a given area. In this way, a more complete model can be obtained to facilitate prevention and control.

Animal and human dirofilariosis is a vector-borne zoonotic disease, being one of the most important diseases in Europe. In Serbia, there are extensive studies reporting the presence of Dirofilaria immitis and D. repens, mainly in the north of the country, where the human population is concentrated and where there is a presence of culicid mosquitoes that transmit the disease. Ecological niche modeling (ENM) has proven to be a very good tool to predict the appearance of parasitosis in very diverse areas, with distant orography and climatologies at a local, continental, and global level. Taking these factors into account, the objective of this study was to develop an environmental model for Serbia that reflects the suitability of the ecological niche for the risk of infection with Dirofilaria spp. with which the predictive power of existing studies is improved. A wide set of variables related to the transmission of the parasite were used. The potential number of generations of D. immitis and the ecological niche modeling method (ENM) were used to estimate the potential distribution of suitable habitats for Culex pipiens. The highest probability of infection risk was located in the north of the country, and the lowest in the southern regions, where there is more orographic relief and less human activity. The model was corroborated with the location of D. immitis-infected dogs, with 89.28% of the country having a high probability of infection. In addition, it was observed that the percentage of territory with optimal habitat for Culex spp. will increase significantly between now and 2080. This new model can be used as a tool in the control and prevention of heartworm disease in Serbia, due to its high predictive power, and will serve to alert veterinary and health personnel of the presence of the disease in the animal and human population, respectively.

Antagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A2BAR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (Ki < 100 nM) and outstanding selectivity for A2BAR. From these, five molecules corresponding to the new benzothiazole scaffold were below the Ki < 10 nM threshold, in addition to a novel dual A2A/A2B antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A2BAR. Two A2BAR selective antagonists and the dual A2AAR/A2BAR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A2BAR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A2BAR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A2AAR antagonism in the context of immune checkpoint inhibition.

Heartworm disease caused by Dirofilaria immitis is a vector-borne zoonotic disease responsible for the infection of mainly domestic dogs and cats, or these are those for which the most data are known. Humans are an accidental host where a benign, asymptomatic pulmonary nodule may originate. Dirofilaria immitis also harbours the endosymbiont bacteria of the genus Wolbachia, which play a role in moulting, embryogenesis, inflammatory pathology, and immune response. When Wolbachia sp. is released into the bloodstream, endothelial and pulmonary damage is exacerbated, further encouraging thrombus formation and pulmonary hypertension, facilitating congestive heart failure and death of the animal. Previous studies have shown that parasite excretory/secretory products are able to activate the pro-angiogenic pathway (formation of new vessels) to facilitate parasite survival. The aim of this study was to analyse the role of Wolbachia sp. and its relationship with the cellular processes and the angiogenic pathway in a model of human endothelial cells in vitro. The use of recombinant Wolbachia Surface Protein (rWSP) showed that its stimulation exerted an anti-angiogenic effect by detecting an increase in the production of VEGFR-1/sFlt1 and sEndoglin and did not affect the production of VEGFR-2 and mEndoglin (pro-angiogenic molecules). Furthermore, it did not stimulate cell proliferation or migration, although it did negatively stimulate the formation of pseudocapillaries, slowing down this process. These cellular processes are directly related to the angiogenic pathway so, with these results, we can conclude that Wolbachia sp. is related to the stimulation of the anti-angiogenic pathway, not facilitating the survival of D. immitis in vascular endothelium.