CARTAR: a comprehensive web tool for identifying potential targets in chimeric antigen receptor therapies using TCGA and GTEx data.

Chimeric antigen receptor (CAR) therapy has emerged as a ground-breaking advancement in cancer treatment, harnessing the power of engineered human immune cells to target and eliminate cancer cells. The escalating interest and investment in CAR therapy in recent years emphasize its profound significance in clinical research, positioning it as a rapidly expanding frontier in the field of personalized cancer therapies. A crucial step in CAR therapy design is choosing the right target as it determines the therapy's effectiveness, safety and specificity against cancer cells, while sparing healthy tissues. Herein, we propose a suite of tools for the identification and analysis of potential CAR targets leveraging expression data from The Cancer Genome Atlas and Genotype-Tissue Expression Project, which are implemented in CARTAR website. These tools focus on pinpointing tumor-associated antigens, ensuring target selectivity and assessing specificity to avoid off-tumor toxicities and can be used to rationally designing dual CARs. In addition, candidate target expression can be explored in cancer cell lines using the expression data for the Cancer Cell Line Encyclopedia. To our best knowledge, CARTAR is the first website dedicated to the systematic search of suitable candidate targets for CAR therapy. CARTAR is publicly accessible at https://gmxenomica.github.io/CARTAR/.

Design, synthesis and validation of a new Crimped Head-Piece for DNA-Encoded libraries generation.

Codification of DNA Encoded Libraries (DELs) is critical for successful ligand identification of molecules that bind a protein of interest (POI). There are different encoding strategies that permit, for instance, the customization of a DEL for testing single or dual pharmacophores (single strand DNA) or for producing and screening large diversity libraries of small molecules (double strand DNA). Both approaches challenges, either from the synthetic and encoding point of view, or from the selection methodology to be utilized for the screening. The Head-Piece contains the DNA sequence that is attached to a chemical compound, allowing the encoding of each molecule with a unique DNA tag. Designing the Head-Piece for a DNA-encoded library involves careful consideration of several key aspects including DNA barcode identity, sequence length and attachment chemistry. Here we describe a double stranded DNA versatile Head-Piece that can be used for the generation of single or dual pharmacophore libraries, but also shows other advanced DEL functionalities, stability and enlarged encoding capacity.

The function of wing bullae in mayflies (Insecta: Ephemeroptera) reveals new insights into the early evolution of Pterygota.

BACKGROUND: Mayflies are basal winged insects of crucial importance for the understanding of the early evolution of Pterygota. Unlike all other insects, they have two successive winged stages, the subimago and the imago. Their forewings feature so-called bullae, which are desclerotized spots in the anterior main veins. Up to now, they have been considered to play a major role in wing bending during flight. RESULTS: We investigated bullae by multiple methods to reveal their structure and arrangement and to gain new information on the evolution of insect flight. Bullae are mostly present in the anterior negative wing veins, disrupting the otherwise rigid veins. High-speed videography reveals that mayfly wings do not bend during flight. Likewise, different arrangements of bullae in different species do not correlate with different modes of flying. Observations on the moulting of subimagines unravel that they are essential for wing bending during the extraction of the imaginal wing from the subimaginal cuticle. Bullae define predetermined bending lines, which, together with a highly flexible wing membrane enriched with resilin, permit wing bending during subimaginal moulting. Bullae are only absent in those species that remain in the subimaginal stage or that use modified modes of moulting. Bullae are also visible in fossil mayflies and can be traced back to stemgroup mayflies of the Early Permian, the 270 million years old Protereismatidae, which most probably had bullae in both fore- and hind wings. CONCLUSIONS: Bullae in mayfly wings do not play a role in flight as previously thought, but are crucial for wing bending during subimaginal moulting. Thus, the presence of bullae is a reliable morphological marker for a subimaginal life stage, confirming the existence of the subimago already in Permian Protereismatidae. A thorough search for bullae in fossils of other pterygote lineages may reveal wheather they also had subimagines and at what point in evolution this life stage was lost. In mayflies, however, the subimago may have been retained due to selective advantages in connection with the transition from aquatic to terrestrial life or due to morphological requirements for a specialized mating flight.

Anticonvulsant Effect of Turmeric and Resveratrol in Lithium/Pilocarpine-Induced Status Epilepticus in Wistar Rats.

Epilepsy is a chronic neurological disorder that lacks a cure. The use of plant-derived antioxidant molecules such as those contained in turmeric powder and resveratrol may produce short-term anticonvulsant effects. A total of 42 three-month-old male Wistar rats were divided into six groups (n = 7 in each group): Vehicle (purified water), turmeric (150 and 300 mg/kg, respectively), and resveratrol (30 and 60 mg/kg, respectively), administered per os (p.o.) every 24 h for 35 days. Carbamazepine (300 mg/kg/5 days) was used as a pharmacological control for anticonvulsant activity. At the end of the treatment, status epilepticus was induced using the lithium-pilocarpine model [3 mEq/kg, intraperitoneally (i.p.) and 30 mg/kg subcutaneously (s.c.), respectively]. Seizures were evaluated using the Racine scale. The 300 mg/kg of turmeric and 60 mg/kg of resveratrol groups had an increased latency to the first generalized seizure. The groups treated with 150 and 300 mg/kg of turmeric and 60 mg/kg of resveratrol also had an increased latency to status epilepticus and a decreased number of generalized seizures compared to the vehicle group. The chronic administration of turmeric and resveratrol exerts anticonvulsant effects without producing kidney or liver damage. This suggests that both of these natural products of plant origin could work as adjuvants in the treatment of epilepsy.

Normalization of DNA encoded library affinity selection results driven by high throughput sequencing and HPLC purification.

The output of an affinity selection screening results in a huge amount of valuable data that, after conducting the appropriate analysis, lead to the correct identification of the compounds enriched in the target of interest. The approach chosen to perform these analyses has become a key step in the development of a successful DNA Encoded Library platform. In this paper, we describe the combination of High Performance Liquid Chromatography purification during the library production with the Next Generation Sequencing analysis of the libraries to assess the yield of the chemical reactions prior to the affinity selection. This process allows us, apart from achieving higher quality libraries, to enable a normalization analysis of the affinity selection output, thus minimizing the bias induced by the chemical yield of each reaction as a misleading factor within the analysis and subsequent compound short-listing for off-DNA synthesis.

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential.

BACKGROUND: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. METHODS: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. RESULTS: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. CONCLUSION: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.

Theory of Nonequilibrium Local Search on Random Satisfaction Problems.

We study local search algorithms to solve instances of the random k-satisfiability problem, equivalent to finding (if they exist) zero-energy ground states of statistical models with disorder on random hypergraphs. It is well known that the best such algorithms are akin to nonequilibrium processes in a high-dimensional space. In particular, algorithms known as focused, and which do not obey detailed balance, outperform simulated annealing and related methods in the task of finding the solution to a complex satisfiability problem, that is to find (exactly or approximately) the minimum in a complex energy landscape. A physical question of interest is if the dynamics of these processes can be well predicted by the well-developed theory of equilibrium Gibbs states. While it has been known empirically for some time that this is not the case, an alternative systematic theory that does so has been lacking. In this Letter we introduce such a theory based on the recently developed technique of cavity master equations and test it on the paradigmatic random 3-satisfiability problem. Our theory predicts the qualitative form of the phase boundary between the satisfiable (SAT) and unsatisfiable (UNSAT) region of the phase diagram where the numerics of a focused Metropolis search and cavity master equation cannot be distinguished.

Effect of orange juice and tryptamine on the behavior and c-fos expression of Wistar rats.

Recent reports have shown that commercial orange juice is rich in biogenic amines. Consumption of foods containing large amounts of biogenic amines increase hypertensive crisis and high levels of histamine and tyramine, which have been implicated as causative agents in a number of food poisoning episodes. In addition, accumulation of tryptamine in plasma may be associated with mood disorders. The aim of this study was to determine whether chronic administration of orange juice extract and tryptamine affects the behavior and c-fos expression in the rat. For this purpose, Wistar male rats were injected with saline solution, tryptamine or orange juice extract. Sucrose preference test and elevated plus maze were evaluated to determine hedonic and anxiety behavior, respectively. Rats treated with orange juice extract showed increased anxiety behavior and sucrose consumption, similar to those treated with tryptamine. In addition, dorsal raphe nucleus, accumbens nucleus, and hippocampus showed an increase of c-fos positive cells in rats treated with orange juice extract. In conclusion, the chronic and lengthy consumption of orange juice or their derivatives in the diet could be a factor responsible to induce mood disorders and may promote excess caloric consumption.

Direct analysis of vicariance in Neotropical mayflies (Ephemeroptera).

The distribution of aquatic insects has been poorly explored in quantitative analyses aiming at the historical reconstruction of area relationships in the Neotropics. Ephemeroptera is an ancient group, characterized by its low vagility, and of high richness and endemicity in this region. Systematic knowledge of the group has enormously increased in the last decades, achieving a sufficient background to explore biogeographical historical patterns. Our aim is to reconstruct area history in the Neotropics using the rationale of Barrier biogeography (Hovenkamp protocol). We present eleven mayfly phylogenies, representing groups that evolved independently at least from the Jurassic (i.e., not a one-taxon history). With these groups, we conducted independent biogeographical analyses (using Vicariance Inference Program), and extracted the events that repeated in two or more clades. We found fifty-eight TVEs (Traceable Vicariant Events), from which four were found at least twice, thus constituting SVEs (Supported Vicariant Events).

Antimicrobial Coatings for Food Contact Surfaces: Legal Framework, Mechanical Properties, and Potential Applications.

Food contact surfaces (FCS) in food processing facilities may become contaminated with a number of unwanted microorganisms, such as Listeria monocytogenes, Escherichia coli O157:H7, and Staphylococcus aureus. To reduce contamination and the spread of disease, these surfaces may be treated with sanitizers or have active antimicrobial components adhered to them. Although significant efforts have been devoted to the development of coatings that improve the antimicrobial effectiveness of FCS, other important coating considerations, such as hardness, adhesion to a substrate, and migration of the antimicrobial substance into the food matrix, have largely been disregarded to the detriment of their translation into practical application. To address this gap, this review examines the mechanical properties of antimicrobial coatings (AMC) applied to FCS and their interplay with their antimicrobial properties within the framework of relevant regulatory constraints that would apply if these were used in real-world applications. This review also explores the various assessment techniques for examining these properties, the effects of the deposition methods on coating properties, and the potential applications of such coatings for FCS. Overall, this review attempts to provide a holistic perspective. Evaluation of the current literature urges a compromise between antimicrobial effectiveness and mechanical stability in order to adhere to various regulatory frameworks as the next step toward improving the industrial feasibility of AMC for FCS applications.

Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.

Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means are often required to determine the biologically relevant target (or targets) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3, also known as Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is markedly elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.

Co-authorship networks (and other contextual factors) behind the growth of taxonomy of South American Ephemeroptera: a scientometric approach.

Science carried out in South America has experienced a major rise in the levels of productivity and impact during the last decade. The continuity of this process depends upon strong policy decisions of personnel training and of increasing investments. We study the effects of a new regional paradigm, specifically, an increasing international visibility through knowledge support, using the particular case of taxonomy of an ancient group of insects (Ephemeroptera) in South America. We tracked the number of new species described in scholarly papers along a period of two centuries. We have also mined patterns of connections from the respective co-authorship network. A quantitative framework to analyze historical sequences of scientific output is also proposed. Our results point out three stages of taxonomic development: (i) a pioneering stage (1800's-1970's) where foreign authors coming from Europe and North America account for almost the totality of described species, (ii) a transitional stage (1980's-1990's) where new species are described by both foreign and regional authors, and (iii) an autonomous stage (1999-present) where the bulk of scientific output is performed by regional authors. Remarkably, the transitional stage coincides with the advent of democracy in the region. We hypothesize that conjunction of funding and interactions between researchers act synergistically to foster an autochthonous taxonomy in South America.

White islands in a sea of red.

Dengue is a viral disease caused by a single-stranded RNA virus from the Flaviviridae family, primarily transmitted by the Aedes aegypti mosquito, although Aedes albopictus also plays a role as a vector. Clinical features of dengue range from nonspecific symptoms to severe forms like dengue shock syndrome. Among these clinical features, dermatological manifestations are particularly noteworthy, as they can aid in differentiating dengue from other illnesses.

Perforation of Meckel's diverticulum by an unusual foreign body: A case report and a review of literature.

Key Clinical Message: Perforation of Meckel's diverticulum (MD) is rare, particularly by foreign body. High index of suspicion and thorough intraoperative assessment is needed in patients undergoing surgery for acute appendicitis, specifically when appendix appears normal. Abstract: Meckel's diverticulum is the most common congenital anomaly of the gastrointestinal tract. While often asymptomatic, it can present with several complications. Perforation due to foreign body ingestion is rare but can have severe consequences if late diagnosis occurs. A 13-year-old male, initially suspected of acute appendicitis, was eventually diagnosed with perforation of MD by a wood splinter-like foreign body after intraoperative assessment. Histological analysis revealed ectopic colonic tissue within the MD, a finding whose implications are not well understood, in contrast with the well-established complications associated with ectopic gastric and pancreatic tissues. This case highlights the diagnostic challenges of MD, which can mimic acute appendicitis, emphasizing the need for high suspicion when faced with atypical clinical presentation such as foreign body-induced perforation. Although surgical resection of asymptomatic MD remains controversial, we recommend a case-specific approach based on risk factors to guide decision-making on surgical resection for asymptomatic MD.

Stochastic Syncing in Sinusoidally Driven Atomic Orbital Memory.

Stochastically fluctuating multiwell systems are a promising route toward physical implementations of energy-based machine learning and neuromorphic hardware. One of the challenges is finding tunable material platforms that exhibit such multiwell behavior and understanding how complex dynamic input signals influence their stochastic response. One such platform is the recently discovered atomic Boltzmann machine, where each stochastic unit is represented by a binary orbital memory state of an individual atom. Here, we investigate the stochastic response of binary orbital memory states to sinusoidal input voltages. Using scanning tunneling microscopy, we investigated orbital memory derived from individual Fe and Co atoms on black phosphorus. We quantify the state residence times as a function of various input parameters such as frequency, amplitude, and offset voltage. The state residence times for both species, when driven by a sinusoidal signal, exhibit synchronization that can be quantitatively modeled by a Poisson process based on the switching rates in the absence of a sinusoidal signal. For individual Fe atoms, we also observe a frequency-dependent response of the state favorability, which can be tuned by the input parameters. In contrast to Fe, there is no significant frequency dependence in the state favorability for individual Co atoms. Based on the Poisson model, the difference in the response of the state favorability can be traced to the difference in the voltage-dependent switching rates of the two different species. This platform provides a tunable way to induce population changes in stochastic systems and provides a foundation toward understanding driven stochastic multiwell systems.

High-Throughput DNA-Encoded Libraries Affinity Selection Platform for Binder Identification with Solid Support Protein Immobilization.

DNA-encoded libraries (DELs) have demonstrated to be one of the most powerful technologies within the ligand identification toolbox, widely used either in academia or biotech and pharma companies. DEL methodology utilizes affinity selection (AS) as the approach to interrogate the protein of interest for the identification of binders. Here we present a high-throughput, fully automated AS platform developed to fulfill industrial standards and compatible with different assay formats to improve the reproducibility of the AS process for DEL binders identification. This platform is flexible enough to virtually set aside all kinds of DELs and AS methods and conditions using immobilized proteins. It bears the two main immobilization methods to support of the proteins of interest: magnetic beads or resin tip columns. A combination of a broad variety of protocol options with a wide range of different experimental conditions can be set up with a throughput of 96 samples at the same time. In addition, small modifications of the protocols provide the platform with the versatility to run not only the routine DEL screens, but also test covalent libraries, the successful immobilization of the proteins of interest, and many other experiments that may be required. This versatile AS platform for DEL can be a powerful instrument for direct application of the technology in academic and industry settings.

Emblica officinalis Gaertn as a Potential Alternative Therapy for the Treatment of Epilepsy: An Animal Study.

Introduction: Epilepsy is a neurological disorder characterized by recurrent seizures. Although antiepileptic drugs (AEDs) reduce the frequency of epileptic seizures, they can cause renal and hepatic damage. Several preclinical studies have indicated that Emblica officinalis Gaertn (AMLA) exerts an anticonvulsant effect related to its tannin and polyphenol content. Objective: We aim to evaluate the anticonvulsant effects of chronic oral AMLA administration and its impact on biochemical and hematological parameters in rats. Methods: Twenty-eight male Wistar rats (250 to 300 g) were divided into four experimental groups (n = 7): vehicle (purified water), AMLA (500 and 700 mg/kg), and carbamazepine (CBZ) (300 mg/kg) as the pharmacological control of anticonvulsant activity. Treatments were administered orally every 24 hours for 28 days, while carbamazepine was administered every 48 hours for 5 days before the behavioral, biochemical, and hematological test. On day 29, Status epilepticus (SE) was induced using the lithium-pilocarpine model (3 mEq/kg, i.p. and 30 mg/kg, s.c.), after which the behavioral and biochemical effects were evaluated. Results: The AMLA 500 mg/kg and CBZ 300 mg/kg groups presented fewer phase V seizures than the vehicle group did. None of the treatments modified biochemical or hematological parameters. Conclusion: AMLA could be considered as a potential alternative therapy for the treatment of epilepsy.

Towards a dynamic analysis of weighted networks in biogeography.

An improvement to the Network Analysis Method (NAM) in Biogeography based on weighted inference and dynamic exploration of sympatry networks is proposed. Intricate distributions of species result in a reticulated structure of spatial associations. Species are geographically connected through sympatry links forming an overall natural network in biogeography. Spatial records are the signals that provide evidence to infer these sympatry links in the network. Punctual data are independent of a priori area determination. NAM is oriented to detect groups of species embedded into the global network that are internally sustained by sympatric cohesiveness but weakly connected (or disconnected) to outgroup entities. These groups, called units of co-occurrence (UCs), are segregated through the iterative removal of intermediary species according to their betweenness scores. Instances of analysis of the original NAM are improved through the following changes and extensions: (i) inference of weighted sympatry networks using new measures sensitive to the strength of overlap and topological resemblance between set of points; (ii) construction of a basal network discriminating major from minor sympatry associations; (iii) evaluation of the entire process of iterative removal of intermediary species for the selection of UCs found on different subnetworks; (iv) network partitioning based on the intrinsic cohesiveness of the UCs; (v) production of a graphical tool (cleavogram) depicting the structural changes of the network along the removal process. Improvements are tested using real and hypothetical data sets. Resolution of patterns is notably increased due to a more accurate recognition of allopatric patterns and the possibility of segregating spatially overlapped UCs. As in original NAM, spatial expressions of UCs are building blocks for biogeography supported by strictly endemic and connected species through sympatry paths.

A Comparative Study of Metabolic Syndrome Using NCEP-ATP III and IDF Criteria in Children and Its Relationship with Biochemical Indicators in Huatusco, Veracruz, Mexico.

Metabolic syndrome includes a set of metabolic alterations associated with overweight and obesity. The criteria for its diagnosis are heterogeneous, and there have been few studies about prevalence in the pediatric population. The aim of this study was to describe how the estimated prevalence of metabolic syndrome varies by International Diabetes Federation (IDF) vs. National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP) criteria. We conducted a cross-sectional study in which anthropometric information, triglyceride, cholesterol, glycemia, and insulin levels, among others, were collected. We compared the group potentially misclassified by IDF with the group classified without metabolic syndrome by NCEP-ATP with respect to weight status and biomarkers. Statistical analysis included linear regression, Mann-Whitney U test, Fisher´s exact test, and odds ratio calculation. The IDF criteria missed the association with obesity, although the undetected group differed significantly from the nonmetabolic syndrome group in terms of IBM and weight. The associated biomarkers were ultrasensitive C-reactive protein (Hs-CRP), alanine aminotransferase (ALT) enzyme, insulin, triglycerides, and high-density lipoprotein (HDL) cholesterol. Waist circumference was the parameter with the strongest association for presenting metabolic syndrome, with an odds ratio of 18.33. The results of this study showed the estimated prevalence of MS varies by criteria, due to cutoff points, and how the high prevalence of MS strongly associated with obesity.

The standardized extract of Centella asiatica L. Urb attenuates the convulsant effect induced by lithium/pilocarpine without affecting biochemical and haematological parameters in rats.

BACKGROUND: Status epilepticus (SE) is a type of epileptic activity characterized by a failure of the inhibitory mechanisms that limit seizures, which are mainly regulated by the GABAergic system. This imbalance increases glutamatergic neurotransmission and consequently produces epileptic activity. It is also associated with oxidative stress due to an imbalance between reactive oxygen species (ROS) and antioxidant defences. Unfortunately, long-term treatment with anti-epileptic drugs (AEDs) may produce hepatotoxicity, nephrotoxicity, and haematological alterations. In this way, some secondary metabolites of plants have been used to ameliorate the deterioration of nervous system disorders through their antioxidant properties, in addition to their anticonvulsant effects. An example is Centella asiatica, a plant noted to have a reputed neuroprotective effect related to its antioxidant activity. However, similar to conventional drugs, natural molecules may produce side effects when consumed in high doses, which could occur with Centella asiatica. Therefore, we aimed to evaluate the effect of a standardized extract of Centella asiatica L. Urb with tested anticonvulsant activity on biochemical and haematological parameters in rats subjected to lithium/pilocarpine-induced seizures. METHODS: Twenty-eight adult male Wistar rats were randomly divided into four groups (n = 7 each): vehicle (purified water), Centella asiatica (200 and 400 mg/kg), and carbamazepine (CBZ) (300 mg/kg) as a pharmacological control of anticonvulsant activity. Treatments were administered orally every 24 h for 35 consecutive days. On Day 36, SE was induced using the lithium/pilocarpine model (3 mEq/kg, i.p. and 30 mg/kg s.c., respectively), and the behavioural and biochemical effects were evaluated. RESULTS: Centella asiatica 400 mg/kg increased the latency to the first generalized seizure and SE onset and significantly reduced the time to the first generalized seizure compared to values in the vehicle group. Biochemical parameters, i.e., haematic cytometry, blood chemistry, and liver function tests, showed no significant differences among the different treatments. CONCLUSION: The dose of Centella asiatica that produces anticonvulsant activity in the lithium/pilocarpine model devoid of hepatotoxicity, nephrotoxicity, and alterations in haematological parameters suggests that the standardized extract of this plant could be of utility in the development of new safe therapies for the treatment of convulsions associated with epilepsy.