Greater Expression Research Articles

BSBM-19 CROSS-PRESENTATION BY TUMOR-ASSOCIATED MACROPHAGES MEDIATES THE TRANSITION FROM PROGENITOR TO TERMINAL T CELL EXHAUSTION IN PRIMARY AND METASTATIC BRAIN TUMORS

Abstract Glioblastoma (GBM) and brain metastases remain largely resistant to immunotherapeutic intervention. T cell exhaustion, a differentiation state characterized by loss of function and persistence, contributes to this resistance. Two exhaustion subsets, progenitor (Tex_prog) and terminal (Tex_term), have been identified, where only Tex_prog remain responsive to immunotherapy. To date, the dynamics and characteristics of these exhausted populations in GBM and brain metastases remain unclear. Herein, we identify a striking loss of Tex_prog in a murine model of GBM throughout tumor progression. We elucidate the requirements for Tex_prog to Tex_term transition through characterization of T cell exhaustion progression at the RNA (paired scRNA and TCR sequencing) and protein level (flow-cytometry). Tex_prog are enriched for pathways of migration, cell-cell adhesion, and differentiation, whereas Tex_term primarily upregulate cytotoxic pathways. TCRseq revealed that clonal expansion is concentrated to the Tex_term cluster, suggesting a link between Tex_prog transition and proliferation in response to antigen. Likewise, we defined the necessity of hematopoietic antigen presentation, but not tumor-derived antigen presentation for the Tex_prog to Tex_term transition. Of the antigen presenting cells in the TME, tumor-associated macrophages (TAM) had the greatest expression of tumor-antigen loaded MHC I, illustrating their capacity to cross-present. By depleting TAM, we observed disruption of the Tex_prog transition. Similar results were seen in subcutaneous and intracranial melanoma, highlighting the role of TAM in this process across tumor histology and location. Lastly, we identified additional inflammatory cell-cell interactions between T cells and TAM in mice and humans that may contribute to this phenomenon. Taken together, we define T cell exhaustion dynamics in models of primary and metastatic brain tumors, where tumor-antigen presentation by TAM is a critical mediator of the loss of Tex_prog. We extend these findings to human data to better define these complex interactions, which we aim to leverage to overcome immunotherapy resistance.

Therapeutic effects of cinnamon bark oil on sciatic nerve injury in rats.

The aim of this study was to investigate the effects of cinnamon bark essential oil (CBO) on analgesia, motor activity, balance, and coordination in rats with sciatic nerve damage. Rats were divided into three groups as simply randomized. The right sciatic nerve (RSN) of the Sham group was explored. Only vehicle solution was applied for 28 days. The RSN of the sciatic nerve injury (SNI) group was explored. Damage was created by unilateral clamping, and vehicle solution was applied for 28 days. The RSN of the sciatic nerve injury+cinnamon bark essential oil (SNI+CBO) group was explored. SNI was created by unilateral clamping and CBO was applied for 28 days. In the experiment study, motor activity, balance, and coordination measurements were made with rotarod and accelerod tests. A hot plate test was performed for analgesia measurements. Histopathology studies were carried out with the sciatic nerve tissues. In the rotarod test, there was a statistically significant difference between the SNI group and the SNI+CBO group (p<0.05). According to the accelerod test findings, there was a statistically significant difference between the SNI group with the Sham and SNI+CBO groups. In the hot plate test, there was a statistically significant difference between the SNI group with the Sham and SNI+CBO groups (p<0.05). In comparison to the Sham group and the SNI group, the SNI+CBO group was shown to have the greatest expression level of vimentin. We have concluded that CBO can be used as an adjuvant treatment in cases of SNI, increased pain, nociception, impaired balance, motor activity, and coordination. Our results will be supported by further studies.

SCLang: Graphical Domain-Specific Modeling Language for Stream Cipher

Abstract A Stream Cipher (SC) is a symmetric-key encryption type that scrambles each piece of data in clear text to conceal it from hackers. Despite its advantages, it has a substantial challenge. Correct handwriting of the script code for the cipher scheme is a challenge for programmers. In this paper, we propose a graphical Domain-Specific Modeling Language (DSML) to make it easier for non-technical users and domain specialists to implement an SC domain. The proposed language, SCLang, offers great expressiveness and flexibility. Six different methods of keystream generation are provided to obtain a random sequence. In addition, fifteen tests in the NIST suite are provided for random statistical analysis. The concepts of the SC domain and their relationships are presented in a meta-model. The evaluation of SCLang is based on qualitative analysis and is presented to demonstrate its effectiveness and efficiency.

An integrated in silico-in vitro investigation to assess the skin sensitization potential of 4-Octylphenol

One of the major challenges in chemical toxicity testing is the possibility to protect human health against adverse effects with non-animal methods. In this paper, 4-Octylphenol (OP) was tested for skin sensitization and immunomodulatory effects using an integrated in silico-in vitro test approach. In silico tools (QSAR TOOLBOX 4.5, ToxTree and VEGA) were used together with several in vitro tests including HaCaT cells (quantification of IL-6; IL-8; IL-1α and IL-18 by ELISA and expression of genes TNF, IL1A, IL6 and IL8 by RT- qPCR), RHE model (quantification of IL-6; IL-8; IL-1α and IL-18 by ELISA) and THP-1 activation assay (CD86/CD54 expression and IL-8 release). Additionally, the immunomodulatory effect of OP was investigated using lncRNAs MALAT1 and NEAT1 expression and LPS-induced THP-1 activation (CD86/CD54 expression and IL-8 release). The in silico tools predicted OP as a sensitizer. In vitro tests are also concordant with the in silico prediction. OP increased IL-6 expression (HaCaT cells); IL-18 and IL-8 expressions (RHE model). An irritant potential was also shown by a great expression of IL-1α (RHE model); and increased expression of CD54 marker and IL-8 in THP-1 cells. Immunomodulatory effects of OP were demonstrated by the downregulation of NEAT1, MALAT1 (epigenetic markers), IL6 and IL8; and an increase in LPS-induced CD54 and IL-8 expressions. Overall, results indicate that OP is a skin sensitizer, being positive in three key events of the AOP for skin sensitization, also showing immunomodulatory effects.

Screening and Constructing a Library of Promoter-5'-UTR Complexes with Gradient Strength in Pediococcus acidilactici.

The GRAS (generally recognized as safe) strain Pediococcus acidilactici is well known for its antibacterial and probiotic functions. Furthermore, as P. acidilactici has excellent high temperature and salt resistance, it is an ideal host for the production of food enzymes, food additives, and pharmaceuticals. In this regard, it is desirable and feasible to enhance the production of these products through the metabolic engineering of P. acidilactici. However, the rare gene expression elements greatly obstruct the development of engineering P. acidilactici. In this study, we screened and constructed a library of promoter-5'-UTR (PUTR) complexes in P. acidilactici DY15 for regulating gene expression at the transcription and translation levels. In the post-log phase, the mRNA and protein expression level ranges of the 90 screened native PUTRs were 0.059-2010% and 0.77-245%, respectively, of the P32 promoter. Besides, several PUTRs exhibited great expression stability under high temperature, salt, and ethanol stress. We analyzed the structure of PUTRs and obtained the conserved regions of the promoter and 5'-UTR. Based on the identified core regions of PUTRs, we constructed a panel of combinatorial PUTRs with higher and stable protein expression levels. The strongest combinatorial PUTR was 853% of the P32 promoter in the protein expression level. Finally, the obtained PUTRs were applied to optimize the expression level of aminotransferase and improve the phenyllactic acid (PLA) production in P. acidilactici DY15. The achieved yield was 950.6 mg/L, which was 79.2% higher than the wild-type strain. These results indicated that the obtained PUTRs with gradient strength had great potential for precisely regulating gene expression to achieve various goals in P. acidilactici.

Multi-scale systems genomics analysis predicts pathways, cell types, and drug targets involved in normative variation in peri-adolescent human cognition.

An open challenge in human genetics is to better understand the systems-level impact of genotype variation on developmental cognition. To characterize the genetic underpinnings of peri-adolescent cognition, we performed genotype-phenotype and systems analysis for binarized accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (~2,200 individuals of European continental ancestry aged 8-21years). We report a region of genome-wide significance within the 3' end of the Fibulin-1 gene (P= 4.6 × 10-8), associated with accuracy in nonverbal reasoning, a heritable form of complex reasoning ability. Diffusion tensor imaging data from a subset of these participants identified a significant association of white matter fractional anisotropy with FBLN1 genotypes (P< 0.025); poor performers show an increase in the C and A allele for rs77601382 and rs5765534, respectively, which is associated with increased fractional anisotropy. Integration of published human brain-specific 'omic maps, including single-cell transcriptomes of the developing human brain, shows that FBLN1 demonstrates greatest expression in the fetal brain, as a marker of intermediate progenitor cells, demonstrates negligible expression in the adolescent and adult human brain, and demonstrates increased expression in the brain in schizophrenia. Collectively these findings warrant further study of this gene and genetic locus in cognition, neurodevelopment, and disease. Separately, genotype-pathway analysis identified an enrichment of variants associated with working memory accuracy in pathways related to development and to autonomic nervous system dysfunction. Top-ranking pathway genes include those genetically associated with diseases with working memory deficits, such as schizophrenia and Parkinson's disease. This work advances the "molecules-to-behavior" view of cognition and provides a framework for using systems-level organization of data for other biomedical domains.

Burnout in Nurses of an Intensive Care Unit during COVID-19: A Pilot Study in Portugal.

This study aimed to evaluate burnout in intensive care unit nurses and describe the relationship between burnout dimensions and sociodemographic and professional variables. A pilot study was carried out with 29 intensive care nurses during the COVID-19 pandemic. The data were collected using an online questionnaire consisting of a sociodemographic characterization and the Maslach Burnout Inventory Human Services Survey. In the comparative statistical analysis, the nonparametric Mann-Whitney and Kruskal-Wallis tests were used (p < 0.05). The Emotional Exhaustion dimension represented an average of 27.9 ± 10.4, and the Personal Fulfillment of 30.8 ± 7.0 was considered high. Regarding Depersonalization, medium-level results (8.1 ± 6.0) were found. There was a prevalence of 41.3% of high levels of burnout. There was no statistically significant difference in the comparison between the three dimensions and sociodemographic and professional variables (p > 0.05). The global results point to high levels of burnout in nurses, with greater expression in the Emotional Exhaustion and Professional Fulfillment domains. There were no differences between groups, demonstrating homogeneity in the team's level of burnout. The incidence of burnout in this study was higher than that identified in other studies carried out in Portugal with health professionals. This pilot study will allow the defining of strategies for reducing burnout and, consequently, a proposed extension of the study to other organization wards.

A critical review of effects on ethanol intake of the dynorphin/kappa opioid receptor system in the extended amygdala: From inhibition to stimulation.

The dynorphin (DYN)/kappa opioid receptor (KOR) system has increasingly been investigated as a possible pharmacotherapeutic target for alcohol use disorder, but findings on the direction of its effects have been mixed. Activation of KORs by DYN has been shown to elicit dysphoric effects, and the DYN/KOR system has canonically been considered particularly important in driving alcohol intake through negative reinforcement in dependent states. However, this review also highlights its activity in opposing the positive reinforcement that drives alcohol intake at earlier stages. Both DYN and KORs are concentrated in the extended amygdala, a set of interconnected regions that includes the bed nucleus of the stria terminalis, central nucleus of the amygdala, and nucleus accumbens shell. This review focuses on the role of the DYN/KOR system in the extended amygdala in ethanol use. It begins by examining the effects of ethanol on the expression of DYN/KOR in the extended amygdala, expression of DYN/KOR in alcohol-preferring and alcohol-avoiding animals, and the effects of knocking out DYN/KOR genes on ethanol intake. Then, it examines the effects on ethanol use in both dependent and nondependent states from systemic pharmacological manipulations of DYN/KOR and from specific manipulation of this system in regions of the extended amygdala. We propose that greater expression and binding of DYN/KOR, by reducing the positive reinforcement that drives early stages of intake, initially acts to prevent the escalation of ethanol drinking. However, prolonged, binge-like, or intermittent ethanol intake enhances levels of DYN/KOR in the extended amygdala such that the system ultimately facilitates the negative reinforcement that drives later stages of ethanol drinking. This review highlights the potential of the DYN/KOR system as a target that can affect different outcomes across different stages of ethanol drinking and the development of alcohol use disorder.

Optimal Reference Genes for RT-qPCR Experiments in Hippocampus and Cortex of Rats Chronically Exposed to Excessive Fluoride.

Normalization of the quantitative real-time PCR (RT-qPCR) data to the stably expressed reference genes is critically important for obtaining reliable results. However, all previous studies focused on F- toxicity for brain tissues used a single, non-validated reference gene, what might be a cause of contradictory or false results. The present study was designed to analyze the expression of a series of reference genes to select optimal ones for RT-qPCR analysis in cortex and hippocampus of rats chronically exposed to excessive fluoride (F-) amounts. Six-week-old male Wistar rats randomly assigned to four groups consumed regular tap water with 0.4 (control), 5, 20, and 50 ppm F- (NaF) for 12 months. The expression of six genes (Gapdh, Pgk1, Eef1a1, Ppia, Tbp, Helz) was compared by RT-qPCR in brain tissues from control and F--exposed animals. The stability of candidate reference genes was evaluated by coefficient of variation (CV) analysis and RefFinder online program summarizing the results of four well-acknowledged statistical methods (Delta-Ct, BestKeeper, NormFinder, and GeNorm). In spite of some discrepancies in gene ranking between these algorisms, Pgk1, Eef1a1, and Ppia were found to be most valid in cortex, while Ppia, Eef1a1, and Helz showed the greatest expression stability in hippocampus. Tbp and Helz were identified as the least stable genes in cortex, whereas Gapdh and Tbp are unsuitable for hippocampus. These data indicate that reliable mRNA quantification in the cortex and hippocampus of F--poisoned rats is possible using normalization to geometric mean of Pgk1+Eef1a1 or Ppia+Eef1a1 expression, respectively.

Physical-geographical characterization of the sedimentary plateau of Ibiapaba-Ceará and its morphsculpture

Belonging to the group of exception areas in the middle of the semi-arid northeast, important geomorphological features for the state of Ceará and for the Northeast region of Brazil, Ibiapaba presents forms of lush and particular landscapes. The Sedimentary Plateau of Ibiapaba represents a geomorphological compartmentalization of great expressiveness in northeastern Brazil, with an extension of approximately 380 km in the western part of Ceará. This work aims to present the physical aspects of the area through the physical-geographical characterization of these elements and their reflexes and their interaction with the morphosculpture of Ibiapaba in its northern part based on Ross's methodology (1992) for classification and systemic perspective as a subsidy. The materials and methods are constituted by the stage of bibliographic review, cartographic preparation, fieldwork and analysis of data and information. The results present the physical-geographic picture (geological, pedological, geomorphological, morphostructural and climatic aspects of the area and its interactions). Associated with the proposed objective, the physical-geographical framework of the area and morphostructure characteristics, it is understood that this level of approach may be essential to understand the geomorphological particularities of the region, as well as present in itself as a contribution to scientific studies in the area, serving as the basis for future studies.

Plasma Exosome Gene Signature Differentiates Colon Cancer from Healthy Controls

BackgroundLiquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls.MethodsPlasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas.ResultsUnsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors.ConclusionsPlasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.

Isolation and characterization of apical papilla cells from root end of human third molar and their differentiation into cementoblast cells: an in vitro study

BackgroundPeriodontal regeneration, treatment of periodontal-related diseases and improving the function of implants are global therapeutic challenges. The differentiation of human stem cells from apical papilla into cementoblasts may provide a strategy for periodontitis treatment. This study aimed to evaluate the differentiation of primary human stem cells apical papilla (hSCAPs) to cementoblast cells.Material and methodsSCAPs cells were isolated from human third molar and then incubated for 21 days in a differentiation microenvironment. Alkaline phosphatase (ALP) and Alizarin red S staining assays were performed to evaluate the calcium deposition and formation of hydroxyapatite in the cultured hSCAPs microenvironment. Real-time polymerase chain reaction (RT-PCR) assay was performed for cementum protein 1 (CEMP1), collagen type I (COL1), F-Spondin (SPON1), osteocalcin (OCN), and osteopontin (OPN) as specific markers of cementoblasts and their progenitors.ResultsALP phosphatase activity in day 21 of treatment demonstrated a significant increase in ALP compared to the control. Alizarin red S staining assay showed that the differentiated hSCAPs offered a great amount of calcium deposition nodules compared to the control. The increased expression level of CEMP1, OCN, OPN, COL1 and Spon1 was observed in days 7, 14 and 21 compared to the control, while greatest expression level was observed in day 21.ConclusionIn conclusion, the differentiation microenviroment is convenient and useful for promoting the differentiation of hSCAPs into cementoblast.

Sintomas de transtorno de estresse pós-traumático e afetos em profissionais da saúde durante a pandemia da COVID-19

Abstract Objective: This study aimed to evaluate symptoms of post-traumatic stress disorder and affects in health professionals during the COVID-19 pandemic. Method: Three hundred and seventy-four health professionals, among which 235 were front-line and 139 non-front-line workers, answered an online questionnaire consisting of socio-demographic data, identification of past mental disorders, personal experience facing the pandemic, the Impact of Event Scale, and the Positive and Negative Affect Schedule. The sample consisted mainly of physicians and nursing staff aged between 30 and 49 years. Results: The results demonstrate high scores of symptoms related to post-traumatic stress disorder, with greater expressiveness among front-line professionals, especially in the nursing staff, and a strong correlation of these results with negative affects. Conclusion: Psychological assistance and interventions directed to health professionals are urgent to mitigate the impacts caused by the COVID-19 pandemic.

The metabolic response of Araucaria angustifolia embryogenic cells to heat stress is associated with their maturation potential.

Araucaria angustifolia is a critically endangered species and its distribution can be affected by an increase in temperature. In this study, we evaluated the effects of heat stress (30°C) on Araucaria angustifolia cell lines responsive (SE1) and non-responsive (SE6) to the development of somatic embryos. The viability of both cell lines was reduced by heat stress and mitochondria were the organelles most affected. Heat stress for 24h increased the reactive oxygen species (ROS) levels in SE1 cells, followed by a reduction at 48 and 72h. In SE6 cells, an increase occurred after 24 and 48h of stress, returning to control levels at 72h. H2 O2 levels were increased after 24h for both SE1 and SE6 cells, being higher for SE6. Interestingly, at 48 and 72h, H2 O2 levels decreased in SE1 cells, while in SE6, the values returned to the control levels. The respiration of SE6 cells in the presence of oxidisable substrates was inhibited by heat stress, in agreement with the high lipid peroxidation levels. The AaSERK1 gene was identified in both cultures, with greater expression in the SE1 line. Heat stress for 24 and 48h increased gene expression only in this cell line. The activity of peroxidase, superoxide dismutase and enzymes of the glutathione/ascorbate cycle was increased in both cell lines subjected to heat stress. Catalase activity was increased only in SE6 cells at 72h of exposure. These results show that responsive SE1 cells can modulate ROS levels more efficiently than SE6 when these cells are stressed by heat. This ability may be related to the maturation capacity of these cells.

Senescence in oral lichen planus as assessed by the immunohistochemical evaluation of senescence marker protein-30 (Regucalcin).

Oral lichen planus is a T-cell-mediated chronic inflammatory disease affecting approximately 1% to 2% of the population, the etiology of which is currently unknown. The objectives of this study were to observe if senescence occurs in oral lichen planus, through the assessment of the immunohistochemical expression of a novel marker for senescence called Senescence marker protein-30 or regucalcin, and compare the expression to that in oral lichenoid reaction and non-specific inflammation. The study material consisted of 30 cases of oral lichen planus, 15 cases of oral lichenoid reaction and 15 cases of non-specific inflammation. The number of positive cells in ten randomly selected high power fields were counted in the epithelium and the connective tissue separately and the mean was determined. Mann-Whitney U test was used to statistically analyze if there was any significant difference in the expression of Senescence marker protein-30 between oral lichen planus, oral lichenoid reaction and non-specific inflammation. Even though a greater expression was seen in the oral lichen planus cases than oral lichenoid reaction, the difference in both the epithelium and connective tissue was not statistically significant. This study shows that in addition to the already known mechanisms like apoptosis and increased cell proliferation rates, the activated T-lymphocytes may also trigger a senescent change in the cells of oral lichen planus. As with the other mechanisms, this is also seen only in a small proportion of the cases.

The Invisibility of the Soul and the Rhetoric of Dissent: Conscience and the Wycliffite Heresy

This essay argues that the use of conscience as a justification for dissent has an even longer history than has often been assumed by intellectual historians of the Reformation. Through a close examination of the English Wycliffite Sermons (c.1380s–1390s) and the Testimony of William Thorpe (1407), it offers the first extended consideration of the use of the word “conscience” in Wycliffite texts, using this as the point of departure for an assessment of Lollard characterisations of human interiority more generally. Wycliffite writers repeatedly emphasise the opacity of the inner life and its consequent authority, a rhetorical tendency inherited and adapted from Wyclif’s own writings and other Latinate discourses. This not only provides Lollards with a helpful strategy in their attempts to avoid prosecution for heresy, but also provides the somewhat shaky ground upon which a number of their doctrinal convictions rest—especially those pertaining to oral confession and membership of the Church. Conscience also provides an obvious connection between religious dissent and political rebellion, which is why it must be central to any future account of Lollardy’s relationship to class struggle or sedition more generally conceived. When writers like Thorpe refer to the soul as invisible, or to God as their only judge, they invoke a fundamental, if unstable, aspect of Wycliffite belief: an incipient but dynamic account of the relationship between individual conscience, interiority, and authority that was to find even greater expression in figures such as Martin Luther, Jan Huss, and Henry VIII.

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, severely distressing clinical syndrome characterized by bladder pain and pressure perceptions. The origin and pathophysiology of IC/BPS are currently unclear, making it difficult to diagnose and formulate successful treatments. Our study is aimed at investigating the role of immune-related genes in the diagnosis, progression, and therapy of IC/BPS. The gene expression datasets GSE11783, GSE11839, GSE28242, and GSE57560 were retrieved from the GEO database for further analysis. Immune-related IC/BPS differentially expressed genes (DEGs) were identified by limma. Three distinct machine learning approaches, least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF), were used to find the immune-related IC characteristic genes. Nomogram and receiving operator curves (ROC) were plotted to measure characteristic effectiveness. Using the CMap database and the molecular docking approach, potential small-molecule medicines were found and verified. Consensus cluster analysis was also performed to separate the IC/BPS samples into immunological subtypes. A total of 24 immune-related IC/BPS-DEGs were identified. When compared to the normal control group, the IC/BPS cohort had significantly more immune cell infiltration. Integrative machine learning methods discovered 5 IC/BPS characteristic genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) that may predict IC/BPS diagnosis and immune cell infiltration. Furthermore, two immunological subgroups with substantial variations in immune cell infiltration across IC/BPS samples were identified, which were named cluster1 and cluster2, with the hallmark genes having greater expression in cluster2. Finally, bumetanide was shown to have the potential to be a medication for the treatment of IC/BPS, and it performed well in terms of its molecular binding with RASGRP1. We found and validated 5 immune-related IC/BPS genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) and 2 IC/BPS immune subtypes. In addition, bumetanide was discovered to be a potential drug for treating IC/BPS, which may provide new insight into the diagnosis and immune therapy of IC/BPS patients.

Investigating the role of glycoprotein hormone GPA2/GPB5 signaling in reproduction in adult female Rhodnius prolixus.

Glycoprotein hormones are essential for regulating various physiological activities in vertebrates and invertebrates. In vertebrates, the classical glycoprotein hormones include follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) and chorionic gonadotropin (CG), which have crucial roles in growth, development, metabolism, and reproduction. In female mammals, FSH stimulates egg production in the ovaries, whereas LH and CG act as the triggers for follicular ovulation. The more recently discovered heterodimeric glycoprotein hormone GPA2/GPB5 (called thyrostimulin in vertebrates) is suggested to be involved in reproductive processes in arthropods. Here, we focus on understanding the role of GPA2/GPB5 and its receptor, LGR1, in the reproductive success of adult female Rhodnius prolixus, a vector of Chagas disease. qPCR was used to monitor the expression of GPA2 and GPB5 transcripts and their receptor in different tissues. Immunohistochemistry was used to show the distribution of GPB5 in the nervous system and reproductive system, and RNA interference was used to disrupt the glycoprotein hormone signaling pathway. Both subunit transcripts, GPA2 and GPB5, are present in a variety of tissues, with the greatest expression in the central nervous system; whereas the LGR1 transcript is present in peripheral tissues, including the fat body and the reproductive system of adult females. In the adult female, GPB5-like immunoreactive axonal projections are present in the trunk nerves extending onto the reproductive tissues, with processes overlaying the ovaries, oviducts, spermatheca, and bursa, indicating the possibility of neural control by neurons containing GPA2/GPB5. In addition, GPB5-like immunostaining is present in muscles encircling the ovarioles, and in the cytoplasm of trophocytes (nurse cells) located in the tropharium. GPB5-like immunoreactive processes and blebs are also localized to the previtellogenic follicles, suggesting an involvement of this glycoprotein hormone signaling in oocyte development. LGR1 transcript expression increases in the adult female reproductive system post-feeding, a stimulus that initiates reproductive development, adding further support to an involvement in reproduction. We have investigated the effect of LGR1 downregulation on reproductive processes, monitoring the number and the quality of eggs laid, hatching ratio, and production of vitellogenin (Vg), the major yolk protein for developing eggs. Downregulation of LGR1 leads to increases in transcript expression of vitellogenin, RhoprVg1, in the fat body and the vitellogenin receptor, RhoprVgR, in the ovaries. Total protein in the fat body and hemolymph of dsLGR1-injected insects increased compared to controls and associated with this effect was a significant increase in vitellogenin in these tissues. dsLGR1-injection leads to accelerated oogenesis, an increase in the number of eggs produced and laid, an increase in egg size and a reduction in hatching rate. Our results indicate that GPA2/GPB5 signaling acts to delay egg production in adult female R. prolixus.

Technological Innovation in the Traditional Olive Orchard Management: Advances and Opportunities to the Northeastern Region of Portugal

In Portugal, the olive orchard is the most representative agricultural crop and one of the most impactful on the national economy. Therefore, a production structure accompanying the technological advances in this field would be expected; however, such a structure has not yet been realized, especially within traditional systems. Thus, taking northeastern Portugal as a case study, where a great expression of traditional orchards is visible, the following aspects are addressed within this paper: the region’s biophysical framework, the olive orchard’s environmental and socio-economic importance and its current management practices and associated pressures. As a result of that assessment, which demonstrates a low level of sustainability for traditional olive orchards, mainly in terms of economic viability, the most effective and simple solution is to act appropriately on factors that interfere with the crop yield, namely, irrigation and fertilization issues. With that purpose, a multiscale precision oliviculture system is also presented that is being developed in order to support decision making in traditional olive orchard management, aiming to obtain economically efficient productions based on eco-friendly cultural practices. Throughout the entire process, it is essential to ensure stakeholder engagement, in particular, olive growers, so that they recognize the effectiveness of potential measures that may avoid the reconversion/abandonment of the traditional olive production system.

Moving toward a standardized diagnostic statement of pituitary adenoma using an information extraction model: a real-world study based on electronic medical records

PurposeDiagnostic statements for pituitary adenomas (PAs) are complex and unstandardized. We aimed to determine the most commonly used elements contained in the statements and their combination patterns and variations in real-world clinical practice, with the ultimate goal of promoting standardized diagnostic recording and establishing an efficient element extraction process.MethodsPatient medical records from 2012 to 2020 that included PA among the first three diagnoses were included. After manually labeling the elements in the diagnostic texts, we obtained element types and training sets, according to which an information extraction model was constructed based on the word segmentation model “Jieba” to extract information contained in the remaining diagnostic texts.ResultsA total of 576 different diagnostic statements from 4010 texts of 3770 medical records were enrolled in the analysis. The first ten diagnostic elements related to PA were histopathology, tumor location, endocrine status, tumor size, invasiveness, recurrence, diagnostic confirmation, Knosp grade, residual tumor, and refractoriness. The automated extraction model achieved F1-scores that reached 100% for all ten elements in the second round and 97.3–100.0% in the test set consisting of an additional 532 diagnostic texts. Tumor location, endocrine status, histopathology, and tumor size were the most commonly used elements, and diagnoses composed of the above elements were the most frequent. Endocrine status had the greatest expression variability, followed by Knosp grade. Among all the terms, the percentage of loss of tumor size was among the highest (21%). Among statements where the principal diagnoses were PAs, 18.6% did not have information on tumor size, while for those with other diagnoses, this percentage rose to 48% (P < 0.001).ConclusionStandardization of the diagnostic statement for PAs is unsatisfactory in real-world clinical practice. This study could help standardize a structured pattern for PA diagnosis and establish a foundation for research-friendly, high-quality clinical information extraction.