Detection of the Arabidopsis Proteome and Its Post-translational Modifications and the Nature of the Unobserved (Dark) Proteome in PeptideAtlas.

This study describes a new release of the Arabidopsis thaliana PeptideAtlas proteomics resource (build 2023-10) providing protein sequence coverage, matched mass spectrometry (MS) spectra, selected post-translational modifications (PTMs), and metadata. 70 million MS/MS spectra were matched to the Araport11 annotation, identifying ∼0.6 million unique peptides and 18,267 proteins at the highest confidence level and 3396 lower confidence proteins, together representing 78.6% of the predicted proteome. Additional identified proteins not predicted in Araport11 should be considered for the next Arabidopsis genome annotation. This release identified 5198 phosphorylated proteins, 668 ubiquitinated proteins, 3050 N-terminally acetylated proteins, and 864 lysine-acetylated proteins and mapped their PTM sites. MS support was lacking for 21.4% (5896 proteins) of the predicted Araport11 proteome: the "dark" proteome. This dark proteome is highly enriched for E3 ligases, transcription factors, and for certain (e.g., CLE, IDA, PSY) but not other (e.g., THIONIN, CAP) signaling peptides families. A machine learning model trained on RNA expression data and protein properties predicts the probability that proteins will be detected. The model aids in discovery of proteins with short half-life (e.g., SIG1,3 and ERF-VII TFs) and for developing strategies to identify the missing proteins. PeptideAtlas is linked to TAIR, tracks in JBrowse, and several other community proteomics resources.

Exploring COX-2 inhibitors in tuberculosis: A whole-blood model approach for immune response and adjunt therapy evaluation.

Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.

A Boolean network model of the double-strand break repair pathway choice.

Double strand break (DSB) repair is critical to maintaining the integrity of the genome. DSB repair deficiency underlies multiple pathologies, including cancer, chromosome instability syndromes, and, potentially, neurodevelopmental defects. DSB repair is mainly handled by two pathways: highly accurate homologous recombination (HR), which requires a sister chromatid for template-based repair, limited to S/G2 phases of the cell cycle, and canonical non-homologous end joining (c-NHEJ), available throughout the cell cycle in which minimum homology is sufficient for highly efficient yet error-prone repair. Some circumstances, such as cancer, require alternative highly mutagenic DSB repair pathways like microhomology-mediated end-joining (MMEJ) and single-strand annealing (SSA), which are triggered to attend to DNA damage. These non-canonical repair alternatives are emerging as prominent drivers of resistance in drug-based tumor therapies. Multiple DSB repair options require tight inter-pathway regulation to prevent unscheduled activities. In addition to this complexity, epigenetic modifications of the histones surrounding the DSB region are emerging as critical regulators of the DSB repair pathway choice. Modeling approaches to understanding DSBs repair pathway choice are advantageous to perform simulations and generate predictions on previously uncharacterized aspects of DSBs response. In this work, we present a Boolean network model of the DSB repair pathway choice that incorporates the knowledge, into a dynamic system, of the inter-pathways regulation involved in DSB repair, i.e., HR, c-NHEJ, SSA, and MMEJ. Our model recapitulates the well-characterized HR activity observed in wild-type cells in response to DSBs. It also recovers clinically relevant behaviors of BRCA1/FANCS mutants, and their corresponding drug resistance mechanisms ascribed to DNA repair gain-of-function pathogenic variants. Since epigenetic modifiers are dynamic and possible druggable targets, we incorporated them into our model to better characterize their involvement in DSB repair. Our model predicted that loss of the TIP60 complex and its corresponding histone acetylation activity leads to activation of SSA in response to DSBs. Our experimental validation showed that TIP60 effectively prevents activation of RAD52, a key SSA executor, and confirms the suitable use of Boolean network modeling for understanding DNA DSB repair.

In silico analysis of the interaction of de novo peptides derived from Salvia hispanica with anticancer targets.

Cancer is one of the leading causes of death worldwide. Conventional cancer therapies are not selective to cancer cells resulting in serious side effects on patients. Thus, the need for complementary treatments that improve the patient's response to cancer therapy is highly important. To predict and evaluate the physicochemical characteristics and potential anticancer activity of the peptides identified from S. hispanica protein fraction <1 kDa through the use of in silico tools. Peptides derived from Salvia hispanica's protein fraction <1 kDa were identified and analyzed for the prediction of their physicochemical properties. The characterized peptide sequences were then submitted to a multi-criteria decision analysis to identify the peptides that possess the characteristics to potentially exert anticancer activity. Through molecular docking analysis, the potential anticancer activity of the Potentially Anticancer Peptide (PAP)-1, PAP-2, PAP-3, PAP-4, and PAP-5 was estimated by their binding interactions with cancer and apoptosis-related molecules. All five evaluated PAPs exhibited strong binding interactions (< -100 kcal/mol). However, PAP-3 showed the lowest binding free energies with several of the targets. Thus, PAP-3 shows potential to be used as a nutraceutical or ingredient for functional foods that adjuvate in cancer treatment. Conclusions: Through the molecular docking studies, the binding of the PAPs to target molecules of interest for cancer treatment was successfully simulated, from which PAP-3 exhibited the lowest binding free energies. Further in vitro and in vivo studies are required to validate the predictions obtained by the in silico analysis.Communicated by Ramaswamy H. Sarma.

The Spectrum of Solitary Benign Splenic Lesions-Imaging Clues for a Noninvasive Diagnosis.

Cross-sectional imaging of the upper abdomen, especially if intravenous contrast has been administered, will most likely reveal any acute or chronic disease harbored in the spleen. Unless imaging is performed with the specific purpose of evaluating the spleen or characterizing a known splenic lesion, incidentally discovered splenic lesions pose a small challenge. Solitary benign splenic lesions include cysts, hemangiomas, sclerosing angiomatous nodular transformation (SANT), hamartomas, and abscesses, among others. Sarcoidosis and tuberculosis, although predominantly diffuse micronodular disease processes, may also present as a solitary splenic mass lesion. In addition, infarction and rupture, both traumatic and spontaneous, may take place in the spleen. This review aims to describe the imaging features of the most common benign focal splenic lesions, with emphasis on the imaging findings as these are encountered on routine cross-sectional imaging from a multicenter pool of cases that, coupled with clinical information, can allow a definite diagnosis.

Hemofilia adquirida A en embarazo. Caso clínico de medicina crítica en obstetricia por morbilidad extrema y su abordaje transdisciplinario perioperatorio / Acquired hemophilia A in pregnancy. Clinical case of critical medicine in obstetrics due to extreme morbidity and its perioperative transdisciplinary approach

Resumen: La identificación de múltiples factores de riesgo que predisponen a la hemorragia durante el evento obstétrico, como la hemofilia adquirida que es un trastorno que se desarrolla por la generación de autoanticuerpos inhibidores de factores de la coagulación, la interpretación objetiva de las pruebas de laboratorio rutinarias, el desarrollo de un pensamiento sistematizado en la integración diagnóstico-terapéutica por parte del personal de salud, y la disposición de los recursos farmacológicos hospitalarios, es lo que determina frecuentemente el pronóstico en pacientes obstétricas con morbilidad extrema que requieren atención multidisciplinaria en las diferentes unidades hospitalarias del sector salud de nuestro país. El objetivo es presentar un caso clínico de morbilidad extrema por hemofilia adquirida, su presentación clínica, evolución y desenlace fatal. Se presenta un caso referido de otra unidad del Sector Salud ISEM (Instituto de Salud del Estado de México), atendido en la Unidad de Cuidados Intensivos Obstétricos del Hospital «Mónica Pretelini Sáenz¼, resaltando la importancia en la integración diagnóstico-terapéutica y la interacción multifactorial de variables relacionadas con su desenlace fatal. Conclusiones: Desconocimiento de la patología, retraso en el diagnóstico, múltiples procedimientos condicionantes de hemorragia iatrógena y la limitación en recursos terapéuticos son factores que contribuyen a un desenlace fatal.

Abstract: The identification of multiple risk factors that predispose to bleeding during the obstetric event, such as acquired hemophilia, which is a disorder that develops due to the generation of autoantibodies that inhibit coagulation factors, the objective interpretation of routine laboratory tests , the development of systematized thinking in diagnostic-therapeutic integration by health personnel, and the provision of hospital pharmacological resources, is what frequently determines the prognosis in obstetric patients with extreme morbidity who require multidisciplinary care in the different hospital units of the health sector of our country. The objective is to present a clinical case of extreme morbidity due to acquired hemophilia, its clinical presentation, evolution and fatal outcome. A case referred from another unit of the ISEM (Instituto de Salud del Estado de México) Health Sector, treated at the Obstetric Intensive Care Unit of the «Mónica Pretelini Sáenz¼ Hospital, is presented, highlighting the importance of diagnostic-therapeutic integration, and the multifactorial interaction of variables related to its fatal outcome. Conclusions: Ignorance of the pathology, delay in diagnosis, multiple conditioning procedures of iatrogenic hemorrhage and the limitation in therapeutic resources are factors that contribute to a fatal outcome.

Acute lymphoblastic leukemia-secreted miRNAs induce a proinflammatory microenvironment and promote the activation of hematopoietic progenitors.

Leukemogenesis is proposed to result from the continuous interplay between inducive bone marrow (BM) microenvironments and malignant precursor cells. Recent findings point toward an abnormal production of proinflammatory mediators within the BM from acute lymphoblastic leukemia (ALL) patients, although the mechanism underlying this phenomenon is uncertain. Here, we have identified 3 miRNAs, miR-146a-5p, miR-181b-5p, and miR-199b-3p, as potential candidates for TLR8 ligation, which are overexpressed in ALL and show agonist functional binding. When purified from ALL exosomes, they demonstrated their capacity of inducing cytokine production by both, hematopoietic and stromal BM cells. Of note, the exposure of BM cells from ALL patients to the proinflammatory milieu resulting from these miRNAs agonist activity revealed the proliferation of normal progenitors, while poor effects were recorded in the leukemic counterpart. The unconventional roles of the tumor-secreted miRNAs as TLR8 agonist ligands may provide a novel mechanism contributing a tumor-microenvironment feedback loop by switching on proinflammatory pathways that further activate normal hematopoietic precursors and support ALL progression. Secreted B-ALL TLR8-agonist miRNAs are involved in the promotion of proinflammatory microenvironments that target normal hematopoietic cells. B-lineage ALL cells secrete exosomes containing miRNAs endowed with the ability of functionally binding TLR8 in hematopoietic and BM mesenchymal stromal cells. Upon TLR8 signaling, the activation of the NF-kB pathway induces secretion of proinflammatory cytokines that, in turn, promotes cell proliferation in early hematopoietic cell populations, driving a tumor-microenvironment-hematopoietic activation feedback loop that may reduce the normal hematopoietic stem and progenitor cell compartment and facilitate cancer progression.

In Silico Drug Repositioning to Target the SARS-CoV-2 Main Protease as Covalent Inhibitors Employing a Combined Structure-Based Virtual Screening Strategy of Pharmacophore Models and Covalent Docking.

The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (Mpro) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of Mpro. The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 Mpro in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 Mpro.

Three-Dimensional Additive Manufacturing of Artificial Oil Reservoir Rock Core Plugs for Core Flooding Experimental Tests.

Laboratory tests in which a fluid or combination of fluids that are injected into a core rock are designed to determine oil reservoir rock petrophysical properties, understand the mobility of fluid flow in the porous samples, and calibrate porous media fluid flow models. The core material is extracted from the oil reservoir. However, the manufacture of core plugs is challenging because of the complexity of extracting natural rocks from the reservoir and their morphological and atypical heterogeneity. In addition, core flooding tests are essentially destructive, making it impossible to achieve experimental repeatability by using identical cores. The use of 3D printing in digital rock physics has permitted the production and replication of synthetic rock samples with the morphological characteristics of natural rocks for core analysis and core flooding tests. This study proposes the 3D manufacture of artificial core plugs from microcomputed tomography of Berea sandstone. The digital samples were constructed using a digital particle packing approach by systematically manipulating rock textural parameters, such as the grain size and shape, cementation pattern, and sorting grain, making it possible to obtain a core plug that fulfills experimental requirements. Before the 3D printing of the sample, the flow distribution through the porous media structure was numerically simulated using the Lattice Boltzmann method to obtain the core plug samples' permeability and porosity. The core plug was digitally embedded within a core holder to generate a stereolithography file for 3D printing of the core flooding setup, which can be used directly in conventional experiments. The permeabilities of the 3D printed plugs were experimentally determined to permit a direct comparison to the numerical results and evaluate the utility of printed plugs for displacement experiments.

Gluten-induced RNA methylation changes regulate intestinal inflammation via allele-specific XPO1 translation in epithelial cells.

OBJECTIVES: Coeliac disease (CD) is a complex autoimmune disorder that develops in genetically susceptible individuals. Dietary gluten triggers an immune response for which the only available treatment so far is a strict, lifelong gluten free diet. Human leucocyte antigen (HLA) genes and several non-HLA regions have been associated with the genetic susceptibility to CD, but their role in the pathogenesis of the disease is still essentially unknown, making it complicated to develop much needed non-dietary treatments. Here, we describe the functional involvement of a CD-associated single-nucleotide polymorphism (SNP) located in the 5'UTR of XPO1 in the inflammatory environment characteristic of the coeliac intestinal epithelium. DESIGN: The function of the CD-associated SNP was investigated using an intestinal cell line heterozygous for the SNP, N6-methyladenosine (m6A)-related knock-out and HLA-DQ2 mice, and human samples from patients with CD. RESULTS: Individuals harbouring the risk allele had higher m6A methylation in the 5'UTR of XPO1 RNA, rendering greater XPO1 protein amounts that led to downstream nuclear factor kappa B (NFkB) activity and subsequent inflammation. Furthermore, gluten exposure increased overall m6A methylation in humans as well as in in vitro and in vivo models. CONCLUSION: We identify a novel m6A-XPO1-NFkB pathway that is activated in CD patients. The findings will prompt the development of new therapeutic approaches directed at m6A proteins and XPO1, a target under evaluation for the treatment of intestinal disorders.

Sweet Syndrome in an Adolescent Patient With Differentiation Syndrome Secondary to Promyelocytic Leukemia Treatment With All-Trans Retinoic Acid.

Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis that is histologically characterized by an infiltration of the dermis by neutrophils. A 12-year-old adolescent female patient recently diagnosed with acute promyelocytic leukemia presented with fever and was hospitalized for antibiotic management after 22 days of being treated with a treatment protocol based on daunorubicin, all-trans retinoic acid (ATRA), and prophylaxis with dexamethasone, the patient developed erythematous skin lesions located mostly on the extremities. Lesions evolved into painful subcutaneous nodules, and one lesion evolved into a 2.5-cm blister with a purple and necrotic base. A skin biopsy was performed and showed neutrophilic dermatosis which confirmed the diagnosis of SS. The patient's clinical features complied with criteria for differentiation syndrome complicated by shock. Two days after ATRA was suspended, the patient presented resolution of the fever and skin lesions. SS is a rare neutrophilic dermatosis secondary to an innate immune disorder classified into four categories: classical (idiopathic), para-inflammatory, paraneoplastic or pregnancy-related. SS has been described in patients with acute myeloid leukemia in adults secondary to the use of drugs such as ATRA or as a part of a paraneoplastic syndrome. SS can occur exceptionally in children with myeloid leukemia secondary to the use of drugs such as ATRA.

Continuous Modeling of T CD4 Lymphocyte Activation and Function.

T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes. The regulation of cell metabolism is controlled by the nutrient sensor adenosine monophosphate-activated protein kinase (AMPK), which drives the balance between oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we put forward a 51-node continuous mathematical model that describes the temporal evolution of the early events of activation, integrating a circuit of metabolic regulation into the main routes of signaling. The model simulates the induction of anergy due to defective co-stimulation, the CTLA-4 checkpoint blockade, and the differentiation to effector phenotypes induced by external cytokines. It also describes the adjustment of the OXPHOS-glycolysis equilibrium by the action of AMPK as the effector function of the T cell develops. The development of a transient phase of increased OXPHOS before induction of a sustained glycolytic phase during differentiation to the Th1, Th2 and Th17 phenotypes is shown. In contrast, during Treg differentiation, glycolysis is subsequently reduced as cell metabolism is predominantly polarized towards OXPHOS. These observations are in agreement with experimental data suggesting that OXPHOS produces an ATP reservoir before glycolysis boosts the production of metabolites needed for protein synthesis, cell function, and growth.

The Arabidopsis PeptideAtlas: Harnessing worldwide proteomics data to create a comprehensive community proteomics resource.

We developed a resource, the Arabidopsis PeptideAtlas (www.peptideatlas.org/builds/arabidopsis/), to solve central questions about the Arabidopsis thaliana proteome, such as the significance of protein splice forms and post-translational modifications (PTMs), or simply to obtain reliable information about specific proteins. PeptideAtlas is based on published mass spectrometry (MS) data collected through ProteomeXchange and reanalyzed through a uniform processing and metadata annotation pipeline. All matched MS-derived peptide data are linked to spectral, technical, and biological metadata. Nearly 40 million out of ∼143 million MS/MS (tandem MS) spectra were matched to the reference genome Araport11, identifying ∼0.5 million unique peptides and 17,858 uniquely identified proteins (only isoform per gene) at the highest confidence level (false discovery rate 0.0004; 2 non-nested peptides ≥9 amino acid each), assigned canonical proteins, and 3,543 lower-confidence proteins. Physicochemical protein properties were evaluated for targeted identification of unobserved proteins. Additional proteins and isoforms currently not in Araport11 were identified that were generated from pseudogenes, alternative start, stops, and/or splice variants, and small Open Reading Frames; these features should be considered when updating the Arabidopsis genome. Phosphorylation can be inspected through a sophisticated PTM viewer. PeptideAtlas is integrated with community resources including TAIR, tracks in JBrowse, PPDB, and UniProtKB. Subsequent PeptideAtlas builds will incorporate millions more MS/MS data.

Roles del docente en la evaluación formativa / Teacher´s roles in formative assessment

RESUMEN Introducción: desde hace algunos años existe un creciente interés por la evaluación formativa, el empoderamiento de sus conceptos y las diferentes estrategias para su aplicación; no obstante, los roles que debe cumplir el docente en su aplicación son fundamentales para lograr efectividad, y siguen siendo objeto de diversas opiniones. Objetivo: identificar algunos roles del docente en la implementación de la evaluación formativa para mejorar los aprendizajes. Métodos: se ejecutó la revisión sistemática de la bibliografía para desarrollar un análisis crítico-reflexivo del contenido de documentos, se tomaron en cuenta tesis de doctorado, maestrías, artículos originales, de revisión y editoriales publicados desde 2010 a 2019 en castellano. La búsqueda fue realizada en las bases de datos SciELO y Google Académico de septiembre a diciembre de 2019; las palabras clave utilizadas fueron: "evaluación educacional", "procesos evaluativos" y "rol docente". Tras la identificación de los estudios preseleccionados, se llevó a cabo la lectura de los títulos, resúmenes y palabras clave para comprobar la pertinencia con el estudio. Resultados: la revisión de los diferentes documentos señalados permitió identificar cinco roles del docente en la implementación de la evaluación formativa: planificar los procesos evaluativos, socializar la evaluación, analizar las evidencias, retroalimentar y reajustar la praxis, los que fueron argumentados metodológicamente. Conclusiones: aunque el éxito de la evaluación formativa depende de los componentes personales del proceso docente educativo, sí corresponde al docente cumplir determinados roles para asegurar su eficacia.

ABSTRACT Introduction: for some years there has been a growing interest in formative evaluation, the empowerment of its concepts and the different strategies for its application; however, the roles that the teacher must fulfill in its application are fundamental to achieve effectiveness, and they continue to be the subject of different opinions. Objective: to identify some roles of the teacher in the implementation of formative assessment to improve learning. Methods: a systematic review of the bibliography was carried out to develop a critical-reflective analysis of the content of documents; doctoral theses, master's degrees, original, review and editorial articles published from 2010 to 2019 in Spanish were taken into account. The search was carried out in the SciELO and Google Academic databases from September to December 2019; the keywords used were: "educational evaluation", "evaluation processes" and "teaching role". After the identification of the preselected studies, the titles, abstracts and keywords were read to check their relevance to the study. Results: the review of the different documents indicated allowed identifying five roles of the teacher in the implementation of the formative evaluation: planning the evaluation processes, socializing the evaluation, analyzing the evidence, providing feedback and readjusting the praxis, which were methodologically argued. Conclusions: although the success of the formative assessment depends on the personal components of the educational teaching process, it does correspond to the teacher to fulfill certain roles to ensure its effectiveness.

Notas sobre los factores naturales y culturales en el desarrollo sociopolítico prehispánico en el extremo noroeste de Guanacaste, Costa Rica

Introducción: El estudio interdisciplinario de los patrones de ocupación y desarrollo de la sociedad humana en tiempos prehispánicos es tenue en la zona del volcán Orosí. El contexto ambiental es usualmente descrito para ilustrar patrones de subsistencia, sin mayor propósito de establecer formas de relación con los cambios que se vislumbran en la composición sociopolítica de los pobladores. Objetivo: En este trabajo, se explora la posibilidad de ilustrar instancias de relación entre los cambios que detecta el registro arqueológico, con potenciales factores naturales y culturales, según se destacan en los aportes de otras disciplinas científicas. Métodos: Una muestra de 111 componentes culturales identificados en sitios arqueológicos fue examinada en cuanto a su localización geográfica en diversos ecosistemas y su posición cronológica, respecto de los períodos culturales definidos en la región de Guanacaste. Resultados: Los componentes arqueológicos se confrontan con diversos factores naturales y culturales que habría incidido como agentes de cambio. Se analizaron las instancias de relación y se valoraron sus efectos por períodos, cubriendo tiempos precerámicos y cerámicos. Conclusiones: Se identifica como agentes naturales de cambio a la calidad de suelos, el tipo de clima, pero, ante todo, destacan los procesos culturales como el intercambio de productos, desarrollo de la agricultura y los movimientos migratorios de la población.

Introduction: Interdisciplinary studies on ancient occupation patterns and the development of human society in the Orosí Volcano region are few. Environmental data are included in archaeological studies of specific sites, mainly to illustrate the likely availability of local subsistence resources, with little regard for biodiversity linked to altitude and an array of different geomorphic areas. Effects surging from volcanic activity and tectonics are largely dispensed. Incidence of all these natural phenomena is rarely considered as agents of sociopolitical changes. Objective: Herein a search is performed in order to detect and illustrate instances of the relationship between sociopolitical change detected by archaeology and diverse natural and cultural factors as described by other scientific disciplines. Methods: A sample of 111 cultural components in archaeological sites were examined in terms of their geographical location, ecological context and chronological position along the periods of the cultural sequence in the Guanacaste region. Results: As settlement models, the archaeological data are confronted with diverse natural and cultural factors looking for their potential incidence as agents for sociopolitical change. Instances of relationship are examined and their apparent effects are evaluated for each period, both in preceramic and ceramic times. Conclusions: Both soil quality and climate are identified as important factors for change and development. Yet, largely salient are distinct cultural factors, namely the exchange of products, agriculture and migration processes.

Translucent Customized Cranial Implants Made of Clear Polymethylmethacrylate: An Early Outcome Analysis of 55 Consecutive Cranioplasty Cases.

BACKGROUND: Large skull reconstruction, with the use of customized cranial implants, restores cerebral protection, physiologic homeostasis, and one's preoperative appearance. Cranial implants may be composed of either bone or a myriad of alloplastic biomaterials. Recently, patient-specific cranial implants have been fabricated using clear polymethylmethacrylate (PMMA), a visually transparent and sonolucent variant of standard opaque PMMA. Given the new enhanced diagnostic and therapeutic applications of clear PMMA, we present here a study evaluating all outcomes and complications in a consecutive patient series. METHODS: A single-surgeon, retrospective, 3-year study was conducted on all consecutive patients undergoing large cranioplasty with clear PMMA implants (2016-2019). Patients who received clear PMMA implants with embedded neurotechnologies were excluded due to confounding variables. All outcomes were analyzed in detail and compared with previous studies utilizing similar alloplastic implant materials. RESULTS: Fifty-five patients underwent cranioplasty with customized clear PMMA implants. Twenty-one (38%) were performed using a single-stage cranioplasty method (ie, craniectomy and cranioplasty performed during the same operation utilizing a prefabricated, oversized design and labor-intense, manual modification), whereas the remaining 34 (62%) underwent a standard, 2-stage reconstruction (craniectomy with a delayed surgery for cranioplasty and minimal-to-no implant modification necessary). The mean cranial defect size was 101.8 cm. The mean follow-up time was 9 months (range, 1.5-39). Major complications requiring additional surgery occurred in 7 patients (13%) consisting of 2 (4%) cerebrospinal fluid leaks, 2 (4%) epidural hematomas, and 3 (4%) infections. In addition, 3 patients developed self-limiting or nonoperative complications including 2 (4%) with new onset seizures and 1 (2%) with delayed scalp healing. CONCLUSIONS: This is the first reported consecutive case series of cranioplasty reconstruction using customized clear PMMA implants, demonstrating excellent results with regard to ease of use, safety, and complication rates well below published rates when compared with other alloplastic materials. Clear PMMA also provides additional benefits, such as visual transparency and sonolucency, which is material specific and unavailable with autologous bone. Although these early results are promising, further studies with multicenter investigations are well justified to evaluate long-term outcomes.

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies.

BACKGROUND: The blockage at the early B lymphoid cell development pathway within the bone marrow is tightly associated with hematopoietic and immune diseases, where the disruption of basal regulatory networks prevents the continuous replenishment of functional B cells. Dynamic computational models may be instrumental for the comprehensive understanding of mechanisms underlying complex differentiation processes and provide novel prediction/intervention platforms to reinvigorate the system. METHODS: By reconstructing a three-module regulatory network including genetic transcription, intracellular transduction, and microenvironment communication, we have investigated the early B lineage cell fate decisions in normal and pathological settings. The early B cell differentiation network was simulated as a Boolean model and then transformed, using fuzzy logic, to a continuous model. We tested null and overexpression mutants to analyze the emergent behavior of the network. Due to its importance in inflammation, we investigated the effect of NFkB induction at different early B cell differentiation stages. RESULTS: While the exhaustive synchronous and asynchronous simulation of the early B cell regulatory network (eBCRN) reproduced the configurations of the hematopoietic progenitors and early B lymphoid precursors of the pathway, its simulation as a continuous model with fuzzy logics suggested a transient IL-7R+ ProB-to-Pre-B subset expressing pre-BCR and a series of dominant B-cell transcriptional factors. This conspicuous differentiating cell population up-regulated CXCR7 and reduced CXCR4 and FoxO1 expression levels. Strikingly, constant but intermediate NFkB signaling at specific B cell differentiation stages allowed stabilization of an aberrant CXCR7+ pre-B like phenotype with apparent affinity to proliferative signals, while under constitutive overactivation of NFkB, such cell phenotype was aberrantly exacerbated from the earliest stage of common lymphoid progenitors. Our mutant models revealed an abnormal delay in the BCR assembly upon NFkB activation, concomitant to sustained Flt3 signaling, down-regulation of Ebf1, Irf4 and Pax5 genes transcription, and reduced Ig recombination, pointing to a potential lineage commitment blockage. DISCUSSION: For the first time, an inducible CXCR7hi B cell precursor endowed with the potential capability of shifting central lymphoid niches, is inferred by computational modeling. Its phenotype is compatible with that of leukemia-initiating cells and might be the foundation that bridges inflammation with blockage-related malignancies and a wide range of immunological diseases. Besides the predicted differentiation impairment, inflammation-inducible phenotypes open the possibility of newly formed niches colonized by the reported precursor. Thus, emergent bone marrow ecosystems are predicted following a pro-inflammatory induction, that may lead to hematopoietic instability associated to blockage pathologies.

Potential effect of probiotics in the treatment of breast cancer.

Breast cancer is one of the most important causes of cancerrelated morbidity and mortality in the world. Probiotics, as functional food, have the potential to act against breast cancer, as evidenced by cell-based and animal model experiments. Probiotic may be useful in prevention or treatment of breast cancer by modulating the gastrointestinal bacteria and the systemic immune system. However, large-scale clinical trials and intensive research are mandatory to confirm the in vitro and in vivo results and exploring the probiotics-related metabolic, immune, and molecular mechanisms in breast cancer. This current review summarizes the available data related to probiotics and their potential role in the treatment of breast cancer.

Abundancia, distribución espacial y temporal de aves playeras (Orden: Charadriiformes) en Marismas Nacionales, México

El noroeste de México alberga las mayores abundancias de aves playeras del país. Sin embargo, para muchos de estos humedales, información sobre comunidades de aves playeras, como abundancia, tendencias poblacionales y riqueza es limitada. Actualmente, los sitios de descanso son críticos para la conservación porque las poblaciones de aves playeras han decaído en las últimas décadas. Marismas Nacionales (MN) es un humedal tropical importante con un ecosistema dinámico donde los estudios de aves playeras están limitados a unos pocos censos aéreos y terrestres. Así el objetivo del trabajo fue describir la abundancia y distribución espacial y temporal de las aves playeras en MN (temporada 2010-2011). Se seleccionaron ocho unidades de muestreo en las que se llevaron a cabo censos mensuales (noviembre 2010 a junio 2011). Se determinaron las riquezas y abundancias por sitio-mes, además se realizó un análisis espacial y temporal de las especies dominantes. Se registraron 27 especies de aves playeras y un género, con un estimado mínimo de 136 236 individuos. Este número hace a MN uno de los humedales prioritarios para la conservación en México, pues alberga al 10 % de la abundancia general del noroeste. Las especies dominantes fueron el Playerito occidental (Calidris mauri, 33 % del total), la Avoceta americana (Recurvirostra americana, 31 %) y los Costureros (Limnodromus spp., 17 %). Espacialmente las lagunas de mayor importancia fueron: Chumbeño (37 % del total registrado), Las Garzas-Chahuin (24 %) y La Polca (24 %). Este trabajo actualiza la información sobre aves playeras que utilizan MN y podría permitir el establecimiento de un programa de monitoreo, lo cual es prioritario sobre todo porque el área es un Sitio de Importancia Internacional por parte de la Red Hemisférica de Reserva para las Aves Playeras.

Northwest Mexico is an important region for shorebirds associated with an extensive series of wetlands. However, for many of these wetlands, basic information about shorebirds communities like abundance, population trends, and richness are limited. Currently, wintering and stopover sites are critical for conservation because many populations of shorebirds have declined in the last decades. Marismas Nacionales (MN) is an important tropical wetland with a dynamic ecosystem and where shorebirds studies are limited to few wintering aerial and ground surveys. Our goals were analyzing shorebirds abundance and spatial and temporal distribution patterns in 2010-2011 season. We selected eight monitoring sites from two prospective visits to the study area. We observed shorebirds monthly between November 2010 and June 2011 to analyze richness and abundance patterns by site and month. Additionally, we describe specific spatial and temporal distribution for dominant species. A total of 27 shorebirds species and one genus, with a minimum global abundance of 136 236 individuals were found. Shorebird abundance at MN is among the most important in the region with around 10 % of total abundance in northwest Mexico; therefore, MN is a priority conservation site for this group of birds. Additionally, MN presents a suitable habitat for breeding of some shorebirds species such as Snowy and Wilson' Plover, Killdeer, Northern Jacana, Black-necked Stilt and Pacific American Oystercatcher. Dominant species were: Western Sandpiper (33.5 % of total in MN), American Avocet (31 %) and Dowitchers (17 %). These taxa are very common in others wetlands in Northwest Mexico region. Spatially, shorebirds were distributed in three sites: Chumbeño lagoon (37 % of abundance total), Las Garzas-Chihuin lagoons (24.2 %) and La Polca lagoon (24 %). The less used sites by shorebirds are located in the southern part of MN. Our results update MN information and can help to establish monitoring programs in the area.

Spatial Distribution of Soybean Cyst Nematode in Research Plots.

Soybean cyst nematode (SCN; Heterodera glycines Ichinohe) is a major pathogen of soybean [Glycine max (L.) Merr.] in the United States. The spatial distribution of SCN in 10 naturally infested research sites in North Dakota was examined between 2006 and 2009. Egg densities were measured in plots and expressed as arithmetic means or grouped into classes using two categorical scales based on the effect of SCN on yield. Data were used to determine spatial distribution, egg cluster sizes, minimum plot sizes, and replications in field experiments. SCN populations varied among plots from undetected to 25,800 eggs/100 cm3 of soil, and differences between adjacent plots were as high as sixfold. Mean to median ratios and Lloyd's index of patchiness suggested an aggregated distribution in nine of the 10 sites. SCN cluster sizes varied in five of the 10 sites and optimum plot size over all sites varied depending on calculation methods. The minimum number of replications needed to detect specific differences among plots varied between field sites. Grouping data into either of the two categories generally increased the ability to detect differences between plots. The spatial distribution of SCN can be a critical factor affecting design and outcomes of field experiments.