Postweaning Development Influences Endogenous VPAC1 Modulation of LTP Induced by Theta-Burst Stimulation: A Link to Maturation of the Hippocampal GABAergic System.

Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) undergoes postweaning developmental changes partially linked to GABAergic circuit maturation. Endogenous vasoactive intestinal peptide (VIP) acting on its VPAC1 receptor strongly influences LTP induced by theta-burst stimulation (TBS), an effect dependent on GABAergic transmission. Although VPAC1 receptor levels are developmentally regulated during embryogenesis, their variation along postweaning development is unknown, as is the VPAC1 modulation of LTP or its relation to hippocampal GABAergic circuit maturation. As such, we investigated how VPAC1 modulation of LTP adjusts from weaning to adulthood along with GABAergic circuit maturation. As described, LTP induced by mild TBS (5 bursts, 4 pulses delivered at 100 Hz) was increasingly greater from weaning to adulthood. The influence of the VPAC1 receptor antagonist PG 97-269 (100 nM) on TBS-induced LTP was much larger in juvenile (3-week-old) than in young adult (6-7-week-old) or adult (12-week-old) rats. This effect was not associated with a developmental decrease in synaptic VPAC1 receptor levels. However, an increase in pre and post-synaptic GABAergic synaptic markers suggests an increase in the number of GABAergic synaptic contacts that is more prominent than the one observed in glutamatergic connections during this period. Conversely, endogenous VPAC2 receptor activation did not significantly influence TBS-induced LTP. VPAC2 receptor levels enhance pronouncedly during postweaning development, but not at synaptic sites. Given the involvement of VIP interneurons in several aspects of hippocampal-dependent learning, neurodevelopmental disorders, and epilepsy, this could provide important insights into the role of VIP modulation of hippocampal synaptic plasticity during normal and altered brain development potentially contributing to epileptogenesis.

Marine macroinvertebrate ecosystem services under changing conditions of seagrasses and mangroves.

This study aimed to investigate the impact of changing environmental conditions on MMI ES in seagrasses and mangroves. We used data from satellite and biodiversity platforms combined with field data to explore the links between ecosystem pressures (habitat conversion, overexploitation, climate change), conditions (environmental quality, ecosystem attributes), and MMI ES (provisioning, regulation, cultural). Both seagrass and mangrove extents increased significantly since 2016. While sea surface temperature showed no significant annual variation, sea surface partial pressure CO2, height above sea level and pH presented significant changes. Among the environmental quality variables only silicate, PO4 and phytoplankton showed significant annual varying trends. The MMI food provisioning increased significantly, indicating overexploitation that needs urgent attention. MMI regulation and cultural ES did not show significant trends overtime. Our results show that MMI ES are affected by multiple factors and their interactions can be complex and non-linear. We identified key research gaps and suggested future directions for research. We also provided relevant data that can support future ES assessments.

Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors.

Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

Opposing reduced VPAC1 and enhanced VPAC2 VIP receptors in the hippocampus of the Li2+-pilocarpine rat model of temporal lobe epilepsy.

VIP binding sites are upregulated in mesial temporal lobe epilepsy (MTLE) patients, also suffering from severe cognitive deficits. Although altered VIP and VIP receptor levels were described in rodent models of epilepsy, the VIP receptor subtype(s) were never identified. We now investigated how VPAC1 and VPAC2 receptor levels change in the Li2+-pilocarpine rat model of MTLE. Cognitive decline and altered synaptic plasticity as estimated from phosphorylation of AMPA GluA1 subunit on Ser831 and Ser845 and AMPA GluA1/GluA2 ratio was also probed. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks showed impaired learning in the radial arm maze (RAM) and presented decreased VPAC1 and increased VPAC2 receptor levels. In addition, SRSs rats showed increased AMPA GluA1 phosphorylation in Ser831 and Ser845, marked decrease in GluA1 levels and a milder decrease in GluA2 levels. Consequently, the GluA1/GluA2 ratio was also decreased in SRSs rats. Altered VIP receptor levels may differentially prevent or contribute to MTLE pathology, since VPAC1 receptors promote the endogenous control of LTP, mediate endogenous VIP neuroprotection against altered synaptic plasticity following epileptiform activity, and mediate anti-inflammatory actions in microglia, while VPAC2 receptors mediate VIP endogenous neuroprotection against neonatal excitotoxicity and prevent reactive astrogliosis. This discovery imposes a different mindset for considering VIP receptors as therapeutic targets in MTLE, allowing a differential targeting of the cellular events contributing to epileptogenesis.

Necrotizing fasciitis of the vulva due to carbapenem-resistant Enterobacteriaceae as a complication of acute myeloid leukemia treatment: a case report.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae strains have been reported in healthcare facilities with a rising incidence and are a major concern owing to infections that are often severe and can be potentially fatal, with limited therapeutic options. Klebsiella pneumonia represents the most frequently isolated microorganism. CASE PRESENTATION: We report the case of a Caucasian 52-year old Caucasian woman with acute myeloid leukemia was admitted to the inpatient hematology unit at a university referral hospital in Portugal. This hospital has endemic colonization of Carbapenem-resistant Enterobacteriaceae and contention measures are being implemented to reduce spreading of these multidrug resistant bacteria. After receiving first line chemotherapy according to the intermediate-dose cytarabine regimen, in context of deep medullary aplasia, the patient developed a localized infection of the vulva, which progressed to a necrotizing fasciitis. This is a rare, life-threatening, and fulminant infection. Carbapenem-resistant Klebsiella was isolated in both vulvar exudate and blood cultures. The patient underwent multiple schemes of antimicrobials, but progressed with multiorgan compromise and was admitted to the intensive care unit for a short period for stabilization. Surgical debridement was performed twice with clinical improvement and, after 6 weeks, a skin graft was executed with good response. Reevaluation of the hematologic disease showed a complete response to first cycle of induction therapy. Despite success in resolving this complex infection, decisions regarding antibiotic treatment represented a tremendous challenge for the whole team. The importance of multidisciplinary collaboration was key for the patient's recovery and survival, and therefore, needs to be acknowledged. CONCLUSIONS: This clinical case raises awareness on a clinical entity that can be life threatening and, therefore, requires a high level of suspicion to assure an early integrated approach to avoid complications. Endemic spreading of carbapenem-resistant Enterobacteriaceae is becoming a reality, and health policies need to be urgently undertaken at the national level to decrease morbidity and mortality because of health facilities-related infections.

A picture is worth a thousand words: using digital tools to visualise marine invertebrate diversity data along the coasts of Mozambique and São Tomé & Príncipe.

The amount of biological data available in online repositories is increasing at an exponential rate. However, data on marine invertebrate biodiversity resources from Mozambique and São Tomé and Príncipe are still sparse and scattered. Online repositories are useful instruments for biodiversity research, as they provide a fast access to data from different sources. The use of interactive platforms comprising web mapping are becoming more important, not only for the scientific community, but also for conservation managers, decision-makers and the general public as they allow data presentation in simple and understandable visual schemes. The main goal of this study was to create an interactive online digital map (hosted and available at MARINBIODIV Atlas), through the collection of data from various sources, to visualise marine invertebrate occurrences and distribution across different habitats, namely mangroves, seagrasses, corals and other coastal areas, in Mozambique and São Tomé and Príncipe. The acquired biodiversity data were managed and structured to be displayed as spatial data and to be disseminated using the geographic information system ArcGIS, where data can be accessed, filtered and mapped. The ArcGIS web mapping design tools were used to produce interactive maps to visualise marine invertebrate diversity information along the coasts of Mozambique and São Tomé and Príncipe, through different habitats, offering the foundation for analysing species incidence and allocation information. Understanding the spatial occurrences and distribution of marine invertebrates in both countries can provide a valuable baseline, regarding information and trends on their coastal marine biodiversity.

MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease.

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions.

Delirium: intervenciones de enfermería en el adulto hospitalizado - una revisión bibliográfica / Delirium: intervenções de enfermagem dirigidas ao adulto hospitalizado - uma revisão bibliográfica / Delirium: nursing interventions directed to the hospitalized adult patient - a bibliographic review

El delirio es un síndrome neuropsiquiátrico, caracterizado por un trastorno agudo de la atención y de la cognición, de etiología multifactorial. Tiene una elevada prevalencia en la población mayor y se trata de un indicador de mal pronóstico. Incita a un impacto negativo, conduciendo a un deterioro de la calidad de vida de la persona. Objetivos: Identificar las intervenciones de enfermería dirigidas al adulto/ mayor hospitalizado, para el control del delirio. Metodología: Utilizando como referencia una cuestión PICO, se ha realizado la revisión de artículos publicados entre 2012 y 2017, que identificaron las intervenciones de enfermería dirigidas a la persona adulta/mayor hospitalizada presentando delirio. Resultados: Se identificaron 5 estudios en esta revisión bibliográfica que presentan estrategias dinámicas, de carácter preventivo y tendencialmente no farmacológicas, ante el delirio. Esto evidencia el papel del enfermero en el desempeñar acciones de prevención (dirigidas preferentemente a los factores de riesgo desencadenantes de esta alteración neurológica), en el mantenimiento del equilibrio sensorial, gestión del ambiente, nutrición/alimentación adecuadas, monitorización del dolor, sueño y fomentando la movilidad precoz. Conclusión: El abordaje ante al delirio debe incluir la identificación de factores predisponentes, precipitadores y el recurso a acciones adecuadas, con el fin de la resolución del cuadro. La investigación es imperativa en el sentido de reconocer y validar, qué acciones permiten controlar (prevenir/tratar) el delirio y, de esta forma, disminuir sus consecuencias

O delirium é uma síndrome neuropsiquiátrica, caracterizada por um transtorno agudo da atenção e cognição de etiologia multifactorial. Tem uma elevada prevalência na população idosa e trata-se de um indicador de mau prognóstico. Incita a um impacto negativo, conduzindo à deterioração da qualidade de vida da pessoa. Objetivos: Identificar as intervenções de enfermagem, dirigidas ao adulto/idoso hospitalizado, para o controlo do delirium. Metodologia: Utilizando como referência uma questão PICO, realizou-se a revisão de artigos publicados entre 2012 e 2017, que identificaram quais as intervenções de enfermagem dirigidas à pessoa adulta/idoso, hospitalizada apresentando delirium. Resultados: Identificaram-se 5 estudos nesta revisão bibliográfica que apresentam estratégias dinâmicas, de carácter preventivo e tendencialmente não farmacológicas, perante o delirium. Tal, evidencia o papel do enfermeiro em desempenhar acções de prevenção (dirigidas essencialmente, aos fatores de risco desencadeantes desta alteração neurológica) na manutenção do equilíbrio sensorial, gestão do ambiente, nutrição/hidratação adequadas, monitorização da dor, sono e estimulação da mobilidade precoce. Conclusão: A intervenção face ao delirium, deve incluir a identificação de fatores predisponentes, precipitantes e o recurso a acções adequadas, visando assim a resolução do quadro. A investigação torna-se imperativa, no sentido de reconhecer e validar quais as acções, que permitem controlar o delirium(prevenir/tratar) e desta forma diminuir as suas consequências

Delirium is a neuropsychiatric syndrome, characterized by an acute attention and cognition deficit disorder, of multifactorial etiology. It has a high prevalence in the elderly population and it’s an indicator of a poor prognosis. It leads to a negative impact, provoking deterioration in the person's quality of life. Objectives: This study aimed to identify the nursing interventions directed to the hospitalized adult / elderly, for the control of delirium. Methodology: Using a PICO question as a reference, a review of articles published between 2012 and 2017 was carried out. That identified, which nursing interventions aimed at the adult / elderly person hospitalized with delirium. Results: In this bibliographic review 5 studies were selected, in common, they present tendentially, non-pharmacological dynamic strategies of preventive character towards the delirium. This evidences the role of nursing in carrying out preventive actions (preferentially directed to risk factors, which may trigger this neurological alteration), such as the maintenance of the sensorial balance, assessing the local environment, monitoring pain, sleep and the stimulation of the early mobility. Conclusion: The interventions for delirium should include the identification of predisposing and precipitating factors with adequate actions, for its resolution. Research is imperative, to recognize and validate witch interventions may control delirium (prevent/ treat) and thus reduce its consequences

Evaluation of linkage disequilibrium on the Xq13.3 region: comparison between the Azores islands and mainland Portugal.

The design of genetic studies of complex diseases is dependent on the extent and distribution of linkage disequilibrium (LD) across the genome in different populations. Here, we characterize the extent of LD in the Azores (Western, Central, and Eastern island groups) and mainland Portugal populations. LD was evaluated in the Xq13.3 region by genotyping eight STR markers spanning 20.9 Mb. Standardized multiallelic disequilibrium coefficient (D') analysis indicates that the Western group presents higher values when compared with the Central and Eastern groups. However, all island groups show values of D' lower than 0.5 and 0.33, suggesting no extensive LD in these populations. Taken together, the data show that the Azorean population presents a lower D' (0.142) than mainland Portugal (0.226). Although, both populations do not show extensive LD, the easy reconstruction of large pedigrees in the Azorean population is a valuable resource for the fine mapping of disease genes.

Azores Islands: genetic origin, gene flow and diversity pattern.

BACKGROUND: The Azores are an archipelago located in the North Atlantic Ocean (parallel 38) composed of nine islands, dispersed over three geographical groups: The Eastern group (São Miguel and Santa Maria), the Central group (Terceira, Graciosa, Pico, São Jorge and Faial) and the Western group (Flores and Corvo). Taking into consideration the geographical and settlement history differences of the archipelago, the genetic diversity pattern and the internal migration of the Azorean population were assessed, based on the analysis of 15 STR loci in 592 unrelated individuals. RESULTS: The results of this evaluation reveal that Terceira displays the highest value of gene diversity (0.7979) and Corvo the lowest (0.7717). Gene flow analysis indicates that Corvo has the lowest value for migration, 23.35, where as São Miguel and Terceira have the highest values for emigration, 108.14 and 87.66, respectively. Taken together, the data demonstrate that, despite settlement diversity, no genetic difference between the populations of the nine islands is observable today. This may be explained by internal migration. CONCLUSION: Overall, the Azorean population can be analysed as a homogeneous genetic group, which consequently, would present, possibly, the same drug-reaction profile. In terms of genomic medicine, these results will have a significant impact on the design of future genetic and pharmacogenomic studies in the Azorean population.

Screening of synthetic and plant-derived compounds for (anti)estrogenic and (anti)androgenic activities.

Recently we constructed yeast cells that either express the human estrogen receptor alpha or the human androgen receptor in combination with a consensus ERE or ARE repeat in the promoter region of a green fluorescent protein (yEGFP) read-out system. These bioassays were proven to be highly specific for their cognate agonistic compounds. In this study the value of these yeast bioassays was assessed for analysis of compounds with antagonistic properties. Several pure antagonists, selective estrogen receptor modulators (SERMs) and plant-derived compounds were tested. The pure antiestrogens ICI 182,780 and RU 58668 were also classified as pure ER antagonists in the yeast estrogen bioassay and the pure antiandrogen flutamide was also a pure AR antagonist in the yeast androgen bioassay. The plant-derived compounds flavone and guggulsterone displayed both antiestrogenic and antiandrogenic activities, while 3,3'-diindolylmethane (DIM) and equol combined an estrogenic mode of action with an antiandrogenic activity. Indol-3-carbinol (I3C) only showed an antiandrogenic activity. Coumestrol, genistein, naringenin and 8-prenylnaringenin were estrogenic and acted additively, while the plant sterols failed to show any effect. Although hormonally inactive, in vitro and in vivo metabolism of the aforementioned plant sterols may still lead to the formation of active metabolites in other test systems.