Unveiling Tst3, a Multi-Target Gating Modifier Scorpion α Toxin from Tityus stigmurus Venom of Northeast Brazil: Evaluation and Comparison with Well-Studied Ts3 Toxin of Tityus serrulatus.

Studies on the interaction sites of peptide toxins and ion channels typically involve site-directed mutations in toxins. However, natural mutant toxins exist among them, offering insights into how the evolutionary process has conserved crucial sequences for activities and molecular target selection. In this study, we present a comparative investigation using electrophysiological approaches and computational analysis between two alpha toxins from evolutionarily close scorpion species of the genus Tityus, namely, Tst3 and Ts3 from T. stigmurus and T. serrulatus, respectively. These toxins exhibit three natural substitutions near the C-terminal region, which is directly involved in the interaction between alpha toxins and Nav channels. Additionally, we characterized the activity of the Tst3 toxin on Nav1.1-Nav1.7 channels. The three natural changes between the toxins did not alter sensitivity to Nav1.4, maintaining similar intensities regarding their ability to alter opening probabilities, delay fast inactivation, and induce persistent currents. Computational analysis demonstrated a preference for the down conformation of VSD4 and a shift in the conformational equilibrium towards this state. This illustrates that the sequence of these toxins retained the necessary information, even with alterations in the interaction site region. Through electrophysiological and computational analyses, screening of the Tst3 toxin on sodium isoform revealed its classification as a classic α-NaTx with a broad spectrum of activity. It effectively delays fast inactivation across all tested isoforms. Structural analysis of molecular energetics at the interface of the VSD4-Tst3 complex further confirmed this effect.

Spatial and Temporal Dynamics of the Vegetation Cover from the Bijagual Massif, Boyacá, Colombia, during the 1986-2021 Period.

Landscape changes based on spectral responses allow showing plant cover changes through diversity, composition, and ecological connectivity. The spatial and temporal vegetation dynamics of the Bijagual Massif from 1986 to 2021 were analyzed as a measure of ecological integrity, conservation, and territory. The covers identified were high open forest (Hof), dense grassland of non-wooded mainland (Dgnm), a mosaic of pastures and crops (Mpc), lagoons (Lag), and bare and degraded lands (Bdl). The Bijagual Massif has 8574.1 ha. In 1986, Dgnm occupied 42.6% of the total area, followed by Mpc (32.8%) and Hof (24.5%); by 2000, Mpc and Hof increased (43.7 and 28.1%, respectively), while Dgnm decreased (28%); by 2021, Dgnm was restricted to the northeastern zone and continued to decrease (25.2%), Mpc occupied 52.9%, Hof 21.7% and Bdl 0.1%. Of the three fractions of the connectivity probability index, only dPCintra and dPCflux contribute to ecological connectivity. Hof and Dgnm show patches with biota habitat quality and availability. Between 1986 and 2021, Dgnm lost 1489 ha (41%) and Hof 239.5 ha (11%). Mpc replaced various covers (1722.2 ha; 38%) in 2021. Bijagual has a valuable biodiversity potential limited by Mpc. Territorial planning and sustainable agroecological and ecotourism proposals are required due to the context of the ecosystems.

Matrix Metalloproteinase-9 Expression Is Associated with the Absence of Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients.

Triple-negative breast cancer (TNBC) is particularly challenging due to the weak or absent response to therapeutics and its poor prognosis. The effectiveness of neoadjuvant chemotherapy (NAC) response is strongly influenced by changes in elements of the tumor microenvironment (TME). This work aimed to characterize the residual TME composition in 96 TNBC patients using immunohistochemistry and in situ hybridization techniques and evaluate its prognostic implications for partial responders vs. non-responders. Compared with non-responders, partial responders containing higher levels of CD83+ mature dendritic cells, FOXP3+ regulatory T cells, and IL-15 expression but lower CD138+ cell concentration exhibited better OS and RFS. However, along with tumor diameter and positive nodal status at diagnosis, matrix metalloproteinase-9 (MMP-9) expression in the residual TME was identified as an independent factor associated with the impaired response to NAC. This study yields new insights into the key components of the residual tumor bed, such as MMP-9, which is strictly associated with the lack of a pathological response to NAC. This knowledge might help early identification of TNBC patients less likely to respond to NAC and allow the establishment of new therapeutic targets.

Application of Phytosociological Information in the Evaluation of the Management of Protected Areas.

The classification system of plant communities using phytosociological methods can be applied to their conservation in protected areas, as well as in establishing adequate protections and granting legal status to such areas. A new integrative index is developed to classify plant communities for the evaluation of the conservation status of protected areas, obtained from the product of three statistical indices of diversity: Syntaxonomic Distinctness, Rarefaction and Areas Prioritisation, which has been named DRA (acronym of the three indices used). The DRA is used to assess whether the status granted to Protected Areas matches the values provided by the plant communities within them and which were the basis for the identification and description of the Habitats of Community Interest (Habitats Directive-92/43/CEE). The proposed method was applied to the network of protected natural areas on the Andalusian coast, including 14 areas with different protection status, where, once the plant communities they contain were identified, the DRA index was applied to each of them and compared with the Legal Protection Index, i.e., the current protection regime; it becomes clear, objectively, that not all the statuses assigned, whether the IUCN criteria or those of the Andalusian government, correspond to the real levels of protection they should have on the basis of their plant communities.

Ts17, a Tityus serrulatus ß-toxin structurally related to α-scorpion toxins.

Ts17 was purified from the venom of the scorpion Tityus serrulatus, the most dangerous scorpion species in Brazil. The activity on Nav1.1-Nav1.7 channels was electrophysiologically characterized by patch-clamp technique. Ts17 amino acid sequence indicated high similarity to alpha-scorpion toxins; however, it presented beta-toxin activity, altering the kinetics of the Na+-channels. The most affected subtypes during activation (with and without prepulse) and inactivation phases were Nav1.2 and Nav1.5, respectively. For recovery from inactivation, the most affected voltage-gated sodium channel was Nav1.5. Circular dichroism spectra showed that Ts17 presents mainly ß-sheet and unordered structures at all analyzed pHs, and the maximum value of α-helix was found at pH 4.0 (13.3 %). Based on the results, Ts17 might be used as a template to develop a new cardiac drug. Key contribution Purification of Ts17 from Tityus serrulatus, electrophysiological characterization of Ts17 on voltage-gated sodium channel subtypes, ß-toxin classification.

Modulation of hNav by Tst1, a ß-toxin purified from the scorpion Tityus stigmurus.

Scorpion venoms are known as a rich mixture of components, including peptides that can interact with different ion channels, particularly voltage-gated potassium channels (Kv), calcium channels (Cav) and sodium channels (Nav), essential membrane proteins for various physiological functions in organisms. The present work aimed to characterize the modulation of hNa+-channels by Tst1, a peptide purified from the venom of Tityus stigmurus, using whole-cell patch clamp. Tst1 at 100 nM provoked current inhibition in Nav 1.3 (85.23%), Nav 1.2 (67.26%) and Nav 1.4 (63.43%), while Nav 1.1, 1.5, 1.6, and 1.7 were not significantly affected. Tst1 also shifted the voltage of activation and steady-state inactivation to more hyperpolarized states and altered the recovery from inactivation of the channels, reducing repetitive firing of cells, which was more effective in Nav 1.3. Tst1 also demonstrated that the effect on Nav 1.3 is dose-dependent, with an IC50 of 8.79 nM. Taken together, these results confirmed that Tst1, the first Tityus stigmurus NaScTx assayed in relation to Nav channels, is a ß-toxin, as was previously suggested due to its amino acid sequence. KEY CONTRIBUTION: First ß-toxin purified from the venom of Tityus stigmurus scorpion broadly characterized in hNa+-channels.

Slums and pandemics.

How do slums shape the economic and health dynamics of pandemics? A difference-in-differences analysis using millions of mobile phones in Brazil shows that residents of overcrowded slums engaged in less social distancing after the outbreak of Covid-19. We develop and calibrate a choice-theoretic equilibrium model in which individuals are heterogeneous in income and some people live in high-density slums. Slum residents account for a disproportionately high number of infections and deaths and, without slums, deaths increase in non-slum neighborhoods. Policy analysis of reallocation of medical resources, lockdowns and cash transfers produce heterogeneous effects across groups. Policy simulations indicate that: reallocating medical resources cuts deaths and raises output and the welfare of both groups; mild lockdowns favor slum individuals by mitigating the demand for hospital beds, whereas strict confinements mostly delay the evolution of the pandemic; and cash transfers benefit slum residents to the detriment of others, highlighting important distributional effects.

CD68 and CD83 immune populations in non-metastatic axillary lymph nodes are of prognostic value for the survival and relapse of breast cancer patients.

BACKGROUND: The foremost cause of death of breast cancer (BC) patients is metastasis, and the first site to which BC predominantly metastasizes is the axillary lymph node (ALN). Thus, ALN status is a key prognostic indicator at diagnosis. The immune system has an essential role in cancer progression and dissemination, so its evaluation in ALNs could have significant applications. In the present study we aimed to investigate the association of clinical-pathological and immune variables in the primary tumour and non-metastatic ALNs (ALNs-) of a cohort of luminal A and triple-negative BC (TNBC) patients with cancer-specific survival (CSS) and time to progression (TTP). METHODS: We analysed the differences in the variables between patients with different outcomes, created univariate and multivariate Cox regression models, validated them by bootstrapping and multiple imputation of missing data techniques, and used Kaplan-Meier survival curves for a 10-years follow-up. RESULTS: We found some clinical-pathological variables at diagnosis (tumour diameter, TNBC molecular profile and presence of ALN metastasis), and the levels of several immune markers in the two studied sites, to be associated with worse CSS and TTP. Nevertheless, only CD68 and CD83 in ALNs- were confirmed as independent prognostic factors for TTP. CONCLUSIONS: The study identified the importance of macrophage and dendritic cell markers as prognostic factors of relapse for BC. We highlight the importance of studying the immune response in ALNs-, which could be relevant to the prediction of BC patients' outcome.

Annual Nitrogen Balance from Dairy Barns, Comparison between Cubicle and Compost-Bedded Pack Housing Systems in the Northeast of Spain.

The aim of this study was to determine N recovery and irreversible losses (i.e., through NH3-N volatilization) from manure in two different housing systems throughout a year using an N mass balance approach. Dietary, milk, and manure N were monitored together with outside temperatures in six dairy barns during six months, comprising two different seasons. Three barns were designed as conventional free stalls (cubicle, CUB) and the other three barns as compost-bedded packs (CB). All the barns were located in the Ebro's valley, in the northeast of Spain. Mass N balance was performed simultaneously in the six barns, during two three-month periods (Season I and II) and sampling at a 15-day interval. Results of ANOVA analysis showed that annual N retained in manure (kg/head per year) from cows housed in CUB barns was significantly higher than in manure from cows housed in CB (133.5 vs. 70.9, p < 0.001), while the opposite was observed for N losses (26.9 vs. 84.8, for CUB and CB barn, respectively; p < 0.005). The annual mean proportion of irreversible N loss from manure in relation to N intake was much lower in barns using conventional free-stall cubicles than the mean ratio registered in bedded pack systems barns.

Osteosarcoma of the Trapezium.

Osteogenic sarcoma is a malignant tumor that rarely affects the hand. When it does, it most often involves the phalanges or metacarpal heads. We present the case of a 51-year-old woman with a low-grade osteosarcoma affecting the trapezium bone of her left hand. A total trapeziectomy with partial removal of the first metatarsal, scaphoid, trapezoid, and capitate bones was performed, and no adjuvant therapy was administered. Six years after the intervention, the patient is disease-free, with excellent functionality and yearly imaging tests showing no signs of recurrence.

Avoidable environmental disasters and infant health: Evidence from a mining dam collapse in Brazil.

We study the health consequences of one of the largest environmental disasters of the world mining industry, which largely stemmed from regulatory failure. Exploiting the timing and location of the Mariana mine tailings dam collapse in Brazil, we show that in utero exposure to the tragedy significantly reduced birth weight and increased infant mortality. The adverse effects were stronger for infants born to less educated and nonmarried mothers. These findings indicate that poorly enforced environmental regulation may have long-term welfare impacts on local communities.

Tumor de células de la granulosa extraovárico con mutación FOXL2. Diagnóstico diferencial morfológico e inmunohistoquímico / Extraovarian granulosa cell tumor with FOXL2 mutation. Morphological and immunohistochemical differential diagnosis

El tumor de células de la granulosa extraovárico es una neoplasia infrecuente donde la identificación de la mutación de FOXL2 puede ser utilizada como una herramienta diagnóstica adicional complementaria a los hallazgos histopatológicos e inmunohistoquímicos clásicos. Presentamos un nuevo caso de tumor de células de la granulosa extraovárico en una paciente femenina de 57 años de edad con una masa tumoral subhepática y dolor abdominal. En el estudio histopatológico del tumor resecado se encontraron características morfológicas sugestivas de tumor de células de la granulosa del adulto con positividad inmunohistoquímica para α-inhibina, calretinina, WT1, S100, CD99 y receptores de progesterona. En el estudio por biología molecular se encontró mutación en FOXL2. El diagnóstico final fue de tumor de células de la granulosa del adulto extraovárico. Discutimos el diagnóstico diferencial histopatológico e inmunohistoquímico

Extraovarian granulosa cell tumor is a very uncommon tumor and the identification of a recurrent mutation in FOXL2 may be used as another diagnostic tool along with the classical morphological and immunohistochemical findings. Here, we report a new case of extraovarian granulosa cell tumor in a 57 years old female patient presented with a sub-hepatic mass and abdominal pain. Histopathological examination of the excised mass showed features of adult-type granulosa cell tumor with α-inhibin, calretinin, WT1, S100, CD99 and progesterone receptor immunoreactivity. A FOXL2 mutation was detected on molecular biology study. A final diagnosis was an extraovarian adult-type granulosa cell tumor. We discuss the histopathological and immunohistochemical differential diagnosis

Congenital Supravalvar Mitral Ring - A Case Report.

Congenital mitral valve stenosis is a rare and severe disease, usually associated with other heart defects. The appropriate intervention depends on the site and mechanism of valvular obstruction and the aim is to avoid or delay valve replacement since it is associated with significant morbidity and mortality. Early single-stage complete repair is associated with better prognosis. We report the case of a 20-month-old child with a supravalvar mitral ring combined with a ventricular septal defect; pulmonary arterial systolic pressure before the surgery was 79 mmHg. The patient underwent a successful surgical repair with good clinical resolution.

Conexión de registros sanitarios: base poblacional de salud de Andalucía / Health record linkage: Andalusian health population database

OBJETIVO: Describir el desarrollo de un sistema de información que conecta datos procedentes de múltiples registros, sanitarios y otros, para su uso con fines asistenciales, de administración, gestión, evaluación, inspección, investigación y salud pública. MÉTODO: Conexión determinística de datos pseudonimizados de una población de 8,5 millones de habitantes, procedentes de Base de datos de usuarios, Historia clínica electrónica DIRAYA, Conjunto mínimo básico de datos (hospitalización, cirugía mayor ambulatoria, urgencias hospitalarias y hospital de día médico) y sistemas de información de salud mental, pruebas de imagen, pruebas analíticas, vacunas, pacientes renales y farmacia. Se utilizó un codificador automático para los diagnósticos clínicos y se definieron 80 enfermedades crónicas para su seguimiento. La arquitectura del sistema de información constó de tres capas: datos (base de datos Oracle 11g), aplicaciones (MicroStrategy BI) y presentación (MicroStrategy Web, librerías JavaScript, HTML 5 y hojas de estilo CSS). Se implantaron medidas para la gobernanza del sistema. RESULTADOS: Se incluyeron datos de 12,5 millones de personas que fueron usuarias entre los años 2001 y 2017, con 435,5 millones de diagnósticos. El 88,7% de estos diagnósticos fueron generados por el codificador automático. Los datos se presentan mediante informes predefinidos o consultas dinámicas, ambos exportables a ficheros CSV para su tratamiento fuera del sistema. Analistas expertos pueden acceder directamente a las bases de datos y realizar extracciones mediante SQL o tratar directamente los datos con herramientas externas. CONCLUSIÓN: El trabajo ha mostrado cómo la conexión de registros sanitarios abre nuevas posibilidades en el análisis de datos

OBJECTIVE: To describe the development of an information system that connects data from multiple health records to improve assistance to patients, health services administration, management, evaluation, and inspection, as well as public health and research. METHOD: Deterministic connection of pseudonymized data from a population of 8.5 million inhabitants provided by: a users database, DIRAYA electronic medical records, minimum basic data sets (inpatients, outpatient mayor surgery, hospital emergencies and medical day hospital), mental health information systems, analytical and image tests, vaccines, renal patients, and pharmacy. An automatic coder was used to code clinical diagnoses and 80 chronic pathologies were identified to follow-up. The architecture of the information system consisted of three layers: data (Oracle Database 11g), applications (MicroStrategy BI) and presentation (MicroStrategy Web, JavaScript libraries, HTML 5 and CSS style sheets). Measures for the governance of the system were implemented. RESULTS: Data from 12.5 million health system users between 2001 and 2017 were gathered, including 435.5 million diagnoses, 88.7% of which were generated by the automatic coder. Data can be accessed through predefined reports or dynamic queries, both exportable to CSV files for processing outside the system. Expert analysts can directly access the databases and perform queries using SQL or directly treat the data with external tools. CONCLUSION: The work has shown that the connection of health records opens new possibilities for data analysis

Changes in Foliar Functional Traits of S. pyrenaicus subsp. carpetanus under the Ongoing Climate Change: A Retrospective Survey.

The sensitivity of stomatal behavior and patterning (i.e., distribution, density, size) to environmental stimuli, renders them crucial for defining the physiological performance of leaves. Thus, assessing long-term modifications in stomatal traits in conserved specimens arises as a valuable eco-physiological approach to predict how the rising trend of warmer, drier summers could affect plant fitness; particularly in mountain areas already experiencing climate aggravation and lacking the related monitoring schemes like Mediterranean high-mountains. Variations in foliar and stomatal traits were studied in conserved specimens of Senecio pyrenaicus subsp. carpetanus from Sierra de Guadarrama over the past 71 years. Our findings revealed decreasing trends in leaf width, stomatal size, and increasing tendency in stomatal density, all correlated with the recent 30-year climate exacerbation in these mountains. This evidenced a positive selection favoring traits that allow safeguarding plant performance under drier, hotter weather conditions. The significant relation between stomatal traits and climatic variables upholds the role of stomatal patterning in sensing environmental cues in this species, feasibly optimizing physiological responses involved in the growth-water loss trade-off. The transition to smaller, densely packed stomata observed in recent decades could indicate local-adaptive plasticity in this species, enhancing stomatal response, as coarser environmental conditions take place in Sierra de Guadarrama.

[Extraovarian granulosa cell tumor with FOXL2 mutation. Morphological and immunohistochemical differential diagnosis]. / Tumor de células de la granulosa extraovárico con mutación FOXL2. Diagnóstico diferencial morfológico e inmunohistoquímico.

Extraovarian granulosa cell tumor is a very uncommon tumor and the identification of a recurrent mutation in FOXL2 may be used as another diagnostic tool along with the classical morphological and immunohistochemical findings. Here, we report a new case of extraovarian granulosa cell tumor in a 57 years old female patient presented with a sub-hepatic mass and abdominal pain. Histopathological examination of the excised mass showed features of adult-type granulosa cell tumor with α-inhibin, calretinin, WT1, S100, CD99 and progesterone receptor immunoreactivity. A FOXL2 mutation was detected on molecular biology study. A final diagnosis was an extraovarian adult-type granulosa cell tumor. We discuss the histopathological and immunohistochemical differential diagnosis.

Congenital supravalvar mitral ring - a case report

Abstract Congenital mitral valve stenosis is a rare and severe disease, usually associated with other heart defects. The appropriate intervention depends on the site and mechanism of valvular obstruction and the aim is to avoid or delay valve replacement since it is associated with significant morbidity and mortality. Early single-stage complete repair is associated with better prognosis. We report the case of a 20-month-old child with a supravalvar mitral ring combined with a ventricular septal defect; pulmonary arterial systolic pressure before the surgery was 79 mmHg. The patient underwent a successful surgical repair with good clinical resolution.

Cardiac metastasizing leiomyoma: A case report.

INTRODUCTION: Cardiac intracavitary growth of metastasizing tumour is unusual. Benign Metastasizing Leiomyoma (BML) from the uterus to the heart is extremely rare. It affects premenopausal women with a history of uterine leiomyoma. PRESENTATION OF CASE: We report a case of a 42-year-old woman who presented three tumours in the right side of the heart, two years after a hysterectomy due to leiomyomatosis. The cardiac tumours were resected and the diagnosis was uterine leiomyoma. DISCUSSION: The patient developed cardiac failure due to three masses at the right side of the heart. Cardiac involvement in BML is usually asymptomatic and rare. The heart masses were surgically removed and a peri ovarian mass was detected and also removed. Although histologically benign, BML exhibits metastatic qualities. CONCLUSION: It suggests that BML should be included as a differential diagnosis when a female patient presents an intra cardiac mass and a history of hysterectomy.

[Health record linkage: Andalusian health population database]. / Conexión de registros sanitarios: base poblacional de salud de Andalucía.

OBJECTIVE: To describe the development of an information system that connects data from multiple health records to improve assistance to patients, health services administration, management, evaluation, and inspection, as well as public health and research. METHOD: Deterministic connection of pseudonymized data from a population of 8.5 million inhabitants provided by: a users database, DIRAYA electronic medical records, minimum basic data sets (inpatients, outpatient mayor surgery, hospital emergencies and medical day hospital), mental health information systems, analytical and image tests, vaccines, renal patients, and pharmacy. An automatic coder was used to code clinical diagnoses and 80 chronic pathologies were identified to follow-up. The architecture of the information system consisted of three layers: data (Oracle Database 11g), applications (MicroStrategy BI) and presentation (MicroStrategy Web, JavaScript libraries, HTML 5 and CSS style sheets). Measures for the governance of the system were implemented. RESULTS: Data from 12.5 million health system users between 2001 and 2017 were gathered, including 435.5 million diagnoses, 88.7% of which were generated by the automatic coder. Data can be accessed through predefined reports or dynamic queries, both exportable to CSV files for processing outside the system. Expert analysts can directly access the databases and perform queries using SQL or directly treat the data with external tools. CONCLUSION: The work has shown that the connection of health records opens new possibilities for data analysis.

Subtype Specificity of ß-Toxin Tf1a from Tityus fasciolatus in Voltage Gated Sodium Channels.

Scorpion venoms are a complex mixture of components. Among them the most important are peptides, which presents the capacity to interact and modulate several ion channel subtypes, including voltage-gated sodium channels (NaV). Screening the activity of scorpion toxins on different subtypes of NaV reveals the scope of modulatory activity and, in most cases, low channel selectivity. Until now there are approximately 60 scorpion toxins experimentally assayed on NaV channels. However, the molecular bases of interaction between scorpion toxins and NaV channels are not fully elucidated. The activity description of new scorpion toxins is crucial to enhance the predictive strength of the structural⁻function correlations of these NaV modulatory molecules. In the present work a new scorpion toxin (Tf1a) was purified from Tityus fasciolatus venom by RP-HPLC, and characterized using electrophysiological experiments on different types of voltage-gated sodium channels. Tf1a was able to modify the normal function of NaV tested, showing to be a typical ß-NaScTx. Tf1a also demonstrated an unusual capability to alter the kinetics of NaV1.5.