Drought Responses in Poaceae: Exploring the Core Components of the ABA Signaling Pathway in Setaria italica and Setaria viridis.

Drought severely impacts plant development and reproduction, reducing biomass and seed number, and altering flowering patterns. Drought-tolerant Setaria italica and Setaria viridis species have emerged as prominent model species for investigating water deficit responses in the Poaceae family, the most important source of food and biofuel biomass worldwide. In higher plants, abscisic acid (ABA) regulates environmental stress responses, and its signaling entails interactions between PYR/PYL/RCAR receptors and clade A PP2C phosphatases, which in turn modulate SnRK2 kinases via reversible phosphorylation to activate ABA-responsive genes. To compare the diversity of PYR/PYL/RCAR, PP2C, and SnRK2 between S. italica and S. viridis, and their involvement in water deficit responses, we examined gene and regulatory region structures, investigated orthology relationships, and analyzed their gene expression patterns under water stress via a meta-analysis approach. Results showed that coding and regulatory sequences of PYR/PYL/RCARs, PP2Cs, and SnRK2s are highly conserved between Setaria spp., allowing us to propose pairs of orthologous genes for all the loci identified. Phylogenetic relationships indicate which clades of Setaria spp. sequences are homologous to the functionally well-characterized Arabidopsis thaliana PYR/PYL/RCAR, PP2C, and SnRK2 genes. Gene expression analysis showed a general downregulation of PYL genes, contrasting with upregulation of PP2C genes, and variable expression modulation of SnRK2 genes under drought stress. This complex network implies that ABA core signaling is a diverse and multifaceted process. Through our analysis, we identified promising candidate genes for further functional characterization, with great potential as targets for drought resistance studies, ultimately leading to advances in Poaceae biology and crop-breeding strategies.

Evaluation of the Effectiveness of Geogrids Manufactured from Recycled Plastics for Slope Stabilization-A Case Study.

This study aimed to investigate the sustainable use of recycled plastics, specifically polypropylene (PP) and high-density polyethylene (HDPE), in the manufacture of geogrids for geotechnical and civil engineering applications. Plastics were collected from a recycling center, specifically targeting containers used for food, cleaning products, and other domestic packaging items. These plastics were sorted according to the Möbius triangle classification system, with HDPE (#2) and PP (#5) being the primary categories of interest. The research methodologically evaluates the mechanical properties of PP/HDPE (0/100, 25/75, 50/50, 75/25 and 100/0% w/w) composites through tensile and flexural tests, exploring various compositions and configurations of geogrids. The results highlight the superiority of pure recycled HDPE processed into 1.3 mm thick laminated yarns and hot air welded for 20 to 30 s, exhibiting a deformation exceeding 60% in comparison to the PP/HDPE composites. Through SolidWorks® Simulation, it was shown that the adoption of a trigonal geogrid geometry optimizes force distribution and tensile strength, significantly improving slope stabilization efficiency. Based on the results obtained, a laboratory-scale prototype geogrid was developed using an extrusion process. The results underscore the importance of careful composite design and yarn configuration selection to achieve the desired mechanical properties and performance in geogrid applications. It emphasizes the potential of recycled plastics as a viable and environmentally friendly solution for stabilizing slopes, contributing to the reduction in plastic waste and promoting sustainable construction practices.

Relevance of acquired T cell molecular defects in the immunopathogenesis of SLE.

Systemic lupus erythematosus (SLE) and other autoimmune diseases are thought to develop in genetically predisposed individuals when triggered by environmental factors. This paradigm does not fully explain disease development, as it fails to consider the delay between birth and disease expression. In this review, we discuss observations described in T cells from patients with SLE that are not related to hereditary factors and have therefore been considered secondary to the disease process itself. Here, we contextualize some of those observations and argue that they may represent a pathogenic layer between genetic factors and disease development. Acquired changes in T cell phenotype and function in the setting of SLE may affect the immune system, creating a predisposition towards a more inflammatory and pathogenic system that amplifies autoimmunity and facilitates disease development.

Structural modifications of INGAP-PP present in HTD4010 peptide potentiate its effect on rat islet gene expression and insulin secretion.

Type 2 diabetes (T2D) is characterized by peripheral insulin resistance and altered insulin secretion due to a progressive loss of ß-cell mass and function. Today, most antidiabetic agents are designed to resolve impaired insulin secretion and/or insulin resistance, and only GLP-1-based formulations contribute to stopping the decline in ß-cell mass. HTD4010, a peptide carrying two modifications of the amino acid sequence of INGAP-PP (N-terminus acetylation and substitution of Asn13 by Ala) showed greater plasma stability and could be a good candidate for proposal as a drug that could improve ß cell mass and function lost in T2D. In the present study, we showed that HTD4010 included in the culture media of normal rat islets at a dose 100 times lower than that used for INGAP-PP was able to modulate, in the same way as the original peptide, both insulin secretion in response to glucose and the expression of key genes related to insular function, insulin and leptin intracellular pathways, neogenesis, apoptosis, and inflammatory response. Our results confirm the positive effect of HTD4010 on ß-cell function and gene expression of factors involved in the maintenance of ß-cell mass. Although new assays in animal models of prediabetes and T2D must be performed to be conclusive, our results are very encouraging, and they suggest that the use of HTD4010 at a dose 100 times lower than that of INGAP-PP could minimize its side effects in a future clinical trial.

SET protein as an epigenetics target.

The SET gene has four transcripts reported in NCBI, coding two isoforms of SET proteins. The most known function of SET protein is inhibiting protein phosphatase 2A, a tumor suppressor, which has been associated with different biological processes. In this review, our focus was on exploring the other SET functions related to epigenetic mechanisms, which impact cellular migration, cell cycle and apoptosis.

Development of a highly cytotoxic, clinical-grade virus-specific T cell product for adoptive T cell therapy.

At present, recipients of allogeneic hematopoietic stem-cells are still suffering from recurrent infections after transplantation. Infusion of virus-specific T cells (VST) post-transplant reportedly fights several viruses without increasing the risk of de novo graft-versus-host disease. This study targeted cytomegalovirus (CMV) for the development of an innovative approach for generating a very specific VST product following Good Manufacturing Practices (GMP) guidelines. We used a sterile disposable compartment named the Leukoreduction System Chamber (LRS-chamber) from the apheresis platelet donation kit as the starting material, which has demonstrated high levels of T cells. Using a combination of IL-2 and IL-7 we could improve expansion of CMV-specific T cells. Moreover, by developing and establishing a new product protocol, we were able to stimulate VST proliferation and favors T cell effector memory profile. The expanded VST were enriched in a closed automated system, creating a highly pure anti-CMV product, which was pre-clinically tested for specificity in vitro and for persistence, biodistribution, and toxicity in vivo using NOD scid mice. Our results demonstrated very specific VST, able to secrete high amounts of interferon only in the presence of cells infected by the human CMV strain (AD169), and innocuous to cells partially HLA compatible without viral infection.

Assessment of Prickly Pear Fruit Peel Mucilage in Form of Gel as a Green Coagulant for the Tertiary Treatment of Domestic Wastewater.

The application of natural coagulants derived from food byproducts in domestic wastewater tertiary treatment, which contains a number of impurities as suspended colloidal particles, has a potential use as essential substitutes for traditional inorganic coagulants. These biomaterials are a sustainable and environmentally friendly alternative that can be used to improve water quality and human health. In this study, prickly pear (PP) fruit peel mucilage gel was evaluated as a novel coagulant for the tertiary stage of domestic wastewater treatment. Jar tests were performed on residual raw water at the inlet (influent) and outlet (effluent) of the tertiary wastewater treatment (constructed wetland) with a coagulant dose of 12 mg L-1 at a pH of 13. The efficiency of green (i.e., mucilage) and inorganic chemical (i.e., FeCl3) coagulants was compared on the basis of turbidity and color removal. The flocs produced by the coagulants were characterized structurally by FTIR spectroscopy and Zeta potential analysis and morphologically by scanning electron microscopy (SEM). The results showed that the turbidity and the color removal efficiency of the mucilage compared to the FeCl3 at the outlet of the treatment (effluent) were practically the same, reaching 94% turbidity and 85-87% color removal efficiency with both coagulants. The structure and morphology of the flocs generated by the coagulants showed a higher content of organic matter trapped in the flocs. The floc formation observed mechanisms were adsorption/bridging for mucilage and charge neutralization for FeCl3. The results of this study demonstrated that the PP mucilage green coagulant can be used to enhance the quality of treatment of domestic wastewater in an eco-friendly and biodegradable manner.

Genome-wide identification of core components of ABA signaling and transcriptome analysis reveals gene circuits involved in castor bean (Ricinus communis L.) response to drought.

Castor bean (Ricinus communis L.) can withstand long periods of water deficit and high temperatures, and therefore has been recognized as a drought-resistant plant species, allowing the study of gene networks involved in drought response and tolerance. The identification of genes networks related to drought response in this plant may yield important information in the characterization of molecular mechanisms correlating changes in the gene expression with the physiological adaptation processes. In this context, gene families related to abscisic acid (ABA) signaling play a crucial role in developmental and environmental adaptation processes of plants to drought stress. However, the families that function as the core components of ABA signaling, as well as genes networks related to drought response, are not well understood in castor bean. In this study 7 RcPYL, 63 RcPP2C, and 6 RcSnRK2 genes were identified in castor bean genome, which was further supported by chromosomal distribution, gene structure, evolutionary relationships, and conserved motif analyses. The castor bean general expression profile was investigated by RNAseq in root and leaf tissues in response to drought stress. These analyses allowed the identification of genes differentially expressed, including genes from the ABA signaling core, genes related to photosynthesis, cell wall, energy transduction, antioxidant response, and transcription factors. These analyses provide new insights into the core components of ABA signaling in castor bean, allow the identification of several molecular responses associated with the high physiological adaptation of castor bean to drought stress, and contribute to the identification of candidate genes for genetic improvement.

3D-Printed Gastroretentive Tablets Loaded with Niclosamide Nanocrystals by the Melting Solidification Printing Process (MESO-PP).

Niclosamide (NICLO) is a recognized antiparasitic drug being repositioned for Helicobacter pylori. The present work aimed to formulate NICLO nanocrystals (NICLO-NCRs) to produce a higher dissolution rate of the active ingredient and to incorporate these nanosystems into a floating solid dosage form to release them into the stomach slowly. For this purpose, NICLO-NCRs were produced by wet-milling and included in a floating Gelucire l3D printed tablet by semi-solid extrusion, applying the Melting solidification printing process (MESO-PP) methodology. The results obtained in TGA, DSC, XRD and FT-IR analysis showed no physicochemical interactions or modifications in the crystallinity of NICLO-NCR after inclusion in Gelucire 50/13 ink. This method allowed the incorporation of NICLO-NCRs in a concentration of up to 25% w/w. It achieved a controlled release of NCRs in a simulated gastric medium. Moreover, the presence of NICLO-NCRs after redispersion of the printlets was observed by STEM. Additionally, no effects on the cell viability of the NCRs were demonstrated in the GES-1 cell line. Finally, gastroretention was demonstrated for 180 min in dogs. These findings show the potential of the MESO-PP technique in obtaining slow-release gastro-retentive oral solid dosage forms loaded with nanocrystals of a poorly soluble drug, an ideal system for treating gastric pathologies such as H. pylori.

Design and Development of Sublingual Printlets Containing Domperidone Nanocrystals Using 3D Melting Solidification Printing Process (MESO-PP).

Domperidone (DOM) is a drug commonly used to treat nausea and vomiting, as well as gastrointestinal disorders. However, its low solubility and extensive metabolism pose significant administration challenges. In this study, we aimed to improve DOM solubility and avoid its metabolism by developing nanocrystals (NC) of DOM through a 3D printing technology-melting solidification printing process (MESO-PP)-to be delivered via a solid dosage form (SDF) that can be administered sublingually. We obtained DOM-NCs using the wet milling process and designed an ultra-rapid release ink (composed of PEG 1500, propylene glycol, sodium starch glycolate, croscarmellose sodium, and sodium citrate) for the 3D printing process. The results demonstrated an increase in the saturation solubility of DOM in both water and simulated saliva without any physicochemical changes in the ink as observed by DSC, TGA, DRX, and FT-IR. The combination of nanotechnology and 3D printing technology enabled us to produce a rapidly disintegrating SDF with an improved drug-release profile. This study demonstrates the potential of developing sublingual dosage forms for drugs with low aqueous solubility using nanotechnology and 3D printing technology, providing a feasible solution to the challenges associated with the administration of drugs with low solubility and extensive metabolism in pharmacology.

The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter.

The activity of the Na+-Cl- cotransporter (NCC) in the distal convoluted tubule (DCT) is finely tuned by phosphorylation networks involving serine/threonine kinases and phosphatases. While much attention has been paid to the With-No-lysine (K) kinase (WNK)- STE20-related Proline Alanine rich Kinase (SPAK)/Oxidative Stress Responsive kinase 1 (OSR1) signaling pathway, there remain many unanswered questions regarding phosphatase-mediated modulation of NCC and its interactors. The phosphatases shown to regulate NCC's activity, directly or indirectly, are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), calcineurin (CN), and protein phosphatase 4 (PP4). PP1 has been suggested to directly dephosphorylate WNK4, SPAK, and NCC. This phosphatase increases its abundance and activity when extracellular K+ is increased, which leads to distinct inhibitory mechanisms towards NCC. Inhibitor-1 (I1), oppositely, inhibits PP1 when phosphorylated by protein kinase A (PKA). CN inhibitors, like tacrolimus and cyclosporin A, increase NCC phosphorylation, giving an explanation to the Familial Hyperkalemic Hypertension-like syndrome that affects some patients treated with these drugs. CN inhibitors can prevent high K+-induced dephosphorylation of NCC. CN can also dephosphorylate and activate Kelch-like protein 3 (KLHL3), thus decreasing WNK abundance. PP2A and PP4 have been shown in in vitro models to regulate NCC or its upstream activators. However, no studies in native kidneys or tubules have been performed to test their physiological role in NCC regulation. This review focuses on these dephosphorylation mediators and the transduction mechanisms possibly involved in physiological states that require of the modulation of the dephosphorylation rate of NCC.

Increased expression of the pathological O-glycosylated form of oncofetal fibronectin in the multidrug resistance phenotype of cancer cells.

Changes in protein glycosylation are a hallmark of transformed cells and modulate numerous phenomena associated with cancer progression, such as the acquisition of multidrug resistance (MDR) phenotype. Different families of glycosyltransferases and their products have already been described as possible modulators of the MDR phenotype. Among the glycosyltransferases intensively studied in cancer research, UDP-N-acetyl-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase-6 (pp-GalNAc-T6), which is widely expressed in many organs and tissues, stands out. Its influence in several events associated with kidney, oral, pancreatic, renal, lung, gastric and breast cancer progression has already been described. However, its participation in the MDR phenotype has never been studied. Here, we demonstrate that human breast adenocarcinoma MCF-7 MDR cell lines, generated by chronic exposure to doxorubicin, in addition to exhibiting increased expression of proteins belonging to the ABC superfamily (ABCC1 and ABCG2), and anti-apoptotic proteins (Blcl-2 and Bcl-xL), also present high expression of pp-GalNAc-T6, the enzyme currently proposed as the main responsible for the biosynthesis of oncofetal fibronectin (onf-FN), a major extracellular matrix component expressed by cancer cells and embryonic tissues, but absent in healthy cells. Our results show that onf-FN, which is generated by the addition of a GalNAc unit at a specific threonine residue inside the type III homology connective segment (IIICS) domain of FN, is strongly upregulated during the acquisition of the MDR phenotype. Also, the silencing of pp-GalNAc-T6, not only compromises the expression of the oncofetal glycoprotein, but also made the MDR cells more sensitive to all anticancer drugs tested, partially reversing the MDR phenotype. Taken together, our results demonstrate for the first time the upregulation of the O-glycosylated oncofetal fibronectin, as well as the direct participation of pp-GalNAc-T6 during the acquisition of a MDR phenotype in a breast cancer model, giving credence to the hypothesis that in transformed cells, glycosyltransferases and/or their products, such as unusual extracellular matrix glycoproteins can be used as potential therapeutic targets for the treatment of cancer.

Exercise volume load in women with breast cancer: Study protocol for the ABRACE randomized clinical trial.

Background: An increased number of breast cancer patients are challenged by acute and persistent treatment side effects. Oncology guidelines have been establishing physical exercise to counteract several treatment-related toxicities throughout cancer care. However, evidence regarding the optimal dose-response, feasibility, and the minimal resistance exercise volume and/or intensity remains unclear. The ABRACE Study will assess the impact of different resistance training volumes (i.e., single or multiple sets) combined with aerobic exercise on physical and psychological outcomes of breast cancer patients undergoing primary treatment. Methods: This study is a randomized, controlled, three-armed parallel trial. A total of 84 participants, aged ≥18 years, with breast cancer stages I-III, initiating adjuvant or neoadjuvant chemotherapy (≤50% of sessions completed) will be randomized to multiple sets resistance training plus aerobic training group, single set resistance training plus aerobic training group or control group. Neuromuscular and cancer-related fatigue (primary outcomes), muscle strength, muscle thickness, muscle quality by echo intensity, body composition, cardiorespiratory capacity, functional performance, upper-body endurance and quality of life will be measured before and after the 12-week intervention. Our analysis will follow the intention-to-treat approach and per-protocol criteria, with additional sub-group analysis. Discussion: Findings support prescribing exercise during chemotherapy for breast cancer and elucidate the potential role of different resistance training volumes as a management strategy for physical and psychological impairments in women with early-stage breast cancer. Our main hypothesis is for superiority in physical and psychological outcomes for both training groups compared to the control group, with no difference between single or multiple sets groups. Trial registration: Clinical trials NCT03314168.

SMEK1 promotes lung adenocarcinoma proliferation and invasion by activating Wnt/ß-catenin signaling pathway.

PURPOSE: SMEK1, also known as PP4R3α, the regulatory subunit 3α of serine and threonine phosphatase PP4, participates in diversely critical biological processes such as the integration of centromere, deacetylation of histones, asymmetric divisions of neuroblast, and other crucial cellular activities. SMEK1 was formerly reported to play a part in carcinogenesis. This study aims to reveal the role of SMEK1 in lung adenocarcinoma and the underlying molecular mechanism. METHODS: Using immunohistochemical (IHC) staining, the protein level of SMEK1 in lung adenocarcinoma and adjacent non-tumor tissue was detected. The functional role of SMEK1 in cell proliferation and invasion was explored using cell counting kit-8 and Transwell assay, respectively. Xenograft tumor experiment was used to investigate the effect of SMEK1 on tumor growth in vivo. The alteration of Wnt/ß-catenin signaling pathway was detected by Western blotting, quantitative PCR, and dual-luciferase reporter assays. RESULTS: SMEK1 was highly expressed at the protein level in lung adenocarcinoma compared to the adjacent non-tumor tissue. In vitro, suppression of SMEK1 significantly decreased the proliferation, migration, and invasion of lung adenocarcinoma cell lines, while overexpression of SMEK1 enhanced above abilities. The xenograft model demonstrated that down-regulation of SMEK1 significantly inhibited tumor growth in vivo. In addition, we found that SMEK1 could positively regulate Wnt/ß-catenin signaling in lung adenocarcinoma cell lines. CONCLUSIONS: SMEK1 exerts a cancer-promoting effect in lung adenocarcinoma by activating Wnt/ß-catenin signaling.

miR-18a-5p Is Involved in the Developmental Origin of Prostate Cancer in Maternally Malnourished Offspring Rats: A DOHaD Approach.

The Developmental Origins of Health and Disease (DOHaD) concept correlates early life exposure to stressor conditions with the increased incidence of non-communicable chronic diseases, including prostate cancer (PCa), throughout the life span. However, the molecular mechanisms involved in this process remain poorly understood. In this study, the deregulation of two miRNAs (rno-miR-18a-5p and rno-miR-345-3p) was described in the ventral prostate VP of old rats born to dams fed with a low protein diet (LPD) (6% protein in the diet) during gestational and lactational periods. Integrative analysis of the (VP) transcriptomic and proteomic data revealed changes in the expression profile of 14 identified predicted targets of these two DE miRNAs, which enriched terms related to post-translational protein modification, metabolism of proteins, protein processing in endoplasmic reticulum, phosphonate and phosphinate metabolism, the calnexin/calreticulin cycle, metabolic pathways, N-glycan trimming in the ER and the calnexin/calreticulin cycle, hedgehog ligand biogenesis, the ER-phagosome pathway, detoxification of reactive oxygen species, antigenprocessing-cross presentation, RAB geranylgeranylation, collagen formation, glutathione metabolism, the metabolism of xenobiotics by cytochrome P450, and platinum drug resistance. RT-qPCR validated the deregulation of the miR-18a-5p/P4HB (prolyl 4-hydroxylase subunit beta) network in the VP of older offspring as well as in the PNT-2 cells transfected with mimic miR-18a-5p. Functional in vitro studies revealed a potential modulation of estrogen receptor α (ESR1) by miR-18a-5p in PNT-2 cells, which was also confirmed in the VP of older offspring. An imbalance of the testosterone/estrogen ratio was also observed in the offspring rats born to dams fed with an LPD. In conclusion, deregulation of the miR-18a-5p/P4HB network can contribute to the developmental origins of prostate cancer in maternally malnourished offspring, highlighting the need for improving maternal healthcare during critical windows of vulnerability early in life.

Possível caso autóctone de dirofilarioseem cão residente decambé, norte do paraná: relato de caso / Possible autochthonous case of heartwormdisease in a dog residing in cambé, northern of paraná: case report

A dirofilariose é uma enfermidade antropozoonótica que acomete, frequentemente, cães em regiões litorâneas, locais que favorecem a multiplicação de vetores transmissores de Dirofilariaspp. O objetivo deste trabalho foi relatar a possível ocorrência do primeiro caso autóctone de dirofilariose em cão doméstico, no município de Cambé, Paraná, distante cerca de 500 km do litoral. O paciente, um Lhasa Apso de 9 meses de idade e 4,8 Kg, foi atendido em clínica particular com histórico de apatia, hiporexia, êmese ecansaço intenso após exercício. O diagnóstico de dirofilariose foi confirmado a partir do Teste SNAP 4Dx Plus. O animal foi tratado com Doxiciclina 50 mg/kg/SID durante 30 dias, Moxidectina injetável e omeprazol 10 mg/kg uma vez ao dia, durante 30 dias. No retorno, um mês após o início do tratamento, o canino apresentou melhoras nas condições gerais e remissão de todos os sinais clínicos antes apresentados, evidenciando sucesso no protocolo farmacológico adotado. A ocorrência dessa doença em região não endêmica é preocupante, pois revela expansão da área de ocorrência, acompanhada, possivelmente, do número de insetos transmissores, responsáveis, também, pela disseminação de arboviroses, como a dengue. Assim, medidas de controle contra esses vetores e pesquisas a respeito da ocorrência de dirofilariose em áreas não endêmicas fazem-se necessárias.(AU)

Heartworm is a zoonotic disease that often affects dogs in coastal regions, places with favorable temperature conditions and humidity for Dirofilariaspp.' vectors replication. The aim of this study was to report the possible occurrence of the first autochthonous case of heartworm disease in a domestic dog, in the municipality of Cambé, Paraná, about 500 km from the coast. The patient, a 9-month-old Lhasa Apso weighing 4.8 Kg, was attended at a private clinic with a medical history of apathy, hyporexia, emesis and intense tiredness after exercise. The diagnosis of heartworm was confirmed by the SNAP 4Dx Plus Test. The animal was treated with Doxycycline 50 mg/kg/once a day for 30 days, injectable Moxidectin every six months and omeprazole 10 mg/kg once a day for 30 days. On return, 30 days after the start of treatment, the canine showed improvement in general conditions and remission of all clinical signs previously presented, evidencing success in the pharmacological protocol adopted. The occurrence of this disease in a non-endemic region is worrying and revels an expansion of the occurrence area, possibly accompanied by the number of transmitting insects, which are also responsible for the arboviruses spread, such as dengue. Therefore, control measures against this vectors and research on the occurrence of heartworm disease in non-endemic areas are necessary.(AU)

La dirofilariosis es una enfermedad antropozoótica que afecta, frecuentemente, a perros en regiones costeras, lugares que favorecen la multiplicación de vectores transmisores de Dirofilaria spp. El objetivo de este trabajo fue informar la posible ocurrencia del primer caso autóctono de dirofilariosis en perro doméstico, en la ciudad de Cambé, Paraná, distante cerca de 500 km del litoral. El paciente, un Lhasa Apso de 9 meses y 4,8 kg de peso, fue atendido en una clínica privada con una historia de apatía, hiporexia, emesis y cansancio intenso después del ejercicio. El diagnóstico de dirofilariosis se confirmó con la prueba SNAP 4Dx Plus. El animal fue tratado con Doxiciclina 50 mg/kg/SID durante 30 días, Moxidectina inyectable y omeprazol 10 mg/kg una vez al día durante 30 días. A su regreso, un mes después del inicio del tratamiento, el canino presentó una mejoría en su estado general y la remisión de todos los signos clínicos que presentaba anteriormente, lo que demuestra el éxito del protocolo farmacológico adoptado. La aparición de esta enfermedad en una región no endémica es preocupante, ya que revela una expansión del área de ocurrencia, posiblemente acompañada de un aumento del número de insectos que transmiten la enfermedad, que también son responsables de la diseminación de arbovirosis, como el dengue. Por ello, es necesario adoptar medidas de control contra estos vectores e investigar la aparición de la dirofilariosis en zonas no endémicas.(AU)

The protein phosphatase 2A catalytic subunit StPP2Ac2b is involved in the control of potato tuber sprouting and source-sink balance in tubers and sprouts.

Sprouting negatively affects the quality of stored potato tubers. Understanding the molecular mechanisms that control this process is important for the development of potato varieties with desired sprouting characteristics. Serine/threonine protein phosphatase type 2A (PP2A) has been implicated in several developmental programs and stress responses in plants. PP2A comprises a catalytic (PP2Ac), a scaffolding (A), and a regulatory (B) subunit. In cultivated potato, six PP2Ac isoforms were identified, named StPP2Ac1, 2a, 2b, 3, 4, and 5. In this study we evaluated the sprouting behavior of potato tubers overexpressing the catalytic subunit 2b (StPP2Ac2b-OE). The onset of sprouting and initial sprout elongation is significantly delayed in StPP2Ac2b-OE tubers; however, sprout growth is accelerated during the late stages of development, due to a high degree of branching. StPP2Ac2b-OE tubers also exhibit a pronounced loss of apical dominance. These developmental characteristics are accompanied by changes in carbohydrate metabolism and response to gibberellic acid, and a differential balance between abscisic acid, gibberellic acid, cytokinins, and auxin. Overexpression of StPP2Ac2b alters the source-sink balance, increasing the source capacity of the tuber, and the sink strength of the sprout to support its accelerated growth.

Increased TNF-α production in response to IL-6 in patients with systemic inflammation without infection.

Acute systemic inflammation can lead to life-threatening organ dysfunction. In patients with sepsis, systemic inflammation is triggered in response to infection, but in other patients, a systemic inflammatory response syndrome (SIRS) is triggered by non-infectious events. IL-6 is a major mediator of inflammation, including systemic inflammatory responses. In homeostatic conditions, when IL-6 engages its membrane-bound receptor on myeloid cells, it promotes pro-inflammatory cytokine production, phagocytosis, and cell migration. However, under non-physiologic conditions, such as SIRS and sepsis, leucocyte dysfunction could modify the response of these cells to IL-6. So, our aim was to evaluate the response to IL-6 of monocytes from patients diagnosed with SIRS or sepsis. We observed that monocytes from patients with SIRS, but not from patients with sepsis, produced significantly more TNF-α than monocytes from healthy volunteers, after stimulation with IL-6. Monocytes from SIRS patients had a significantly increased baseline phosphorylation of the p65 subunit of NF-κB, with no differences in STAT3 phosphorylation or SOCS3 levels, compared with monocytes from septic patients, and this increased phosphorylation was maintained during the IL-6 activation. We found no significant differences in the expression levels of the membrane-bound IL-6 receptor, or the serum levels of IL-6, soluble IL-6 receptor, or soluble gp130, between patients with SIRS and patients with sepsis. Our results suggest that, during systemic inflammation in the absence of infection, IL-6 promotes TNF-α production by activating NF-κB, and not the canonical STAT3 pathway.

Nanocrystal-based 3D-printed tablets: Semi-solid extrusion using melting solidification printing process (MESO-PP) for oral administration of poorly soluble drugs.

This is the first report on the inclusion of nanocrystals (NCs) within 3D-printed oral solid dosage forms -3D-printed tablets or printlets- produced by the Melting Solidification Printing Process (MESO-PP) 3D printing technique. This method allowed the incorporation of albendazole (ABZ) nanocrystals in a concentration of up to 50% w/w, something not achieved in conventional tablets. An ink of PEG 1500/propylenegycol was used as a carrier and no physicochemical interactions or crystallinity modifications were observed due to the inclusion of ABZ-NCs into the ink, as demonstrated by TGA, DSC, XRD and FT-IR. In particular, the relative crystallinity of the ink loaded with NCs was 97.8% similar to the physical mixture of the components. Moreover, the presence of NCs was observed in the surface and matrix of the printlets by SEM. In addition, the printlet NCs demonstrated to be more effective than NCs included in hard gelatin capsules in improving drug dissolution in HCl 0.1 N. The particle size, crystallinity and chemical stability of the nanocrystals was maintained before and after 180 days of storage. Thus, these findings exhibit relevant pharmaceutical potential for developing stable, fast-release, oral, solid dosage forms of poorly soluble drugs combining 3D printing and nanocrystals. Additionally, this technique could be applied for printing objects using different types of nanocrystals embedded in low melting temperature polymers.

Berberine increases the expression of cytokines and proteins linked to apoptosis in human melanoma cells.

BACKGROUND: Melanoma is the most lethal form of skin cancer, and its incidence has increased considerably in the last decades. Melanoma presents difficult treatment with strong resistance of tumor cells, due to its extremely invasive nature with high capacity to metastases. Berberine (BBR), an isoquinoline alkaloid, is a molecule found in several medicinal plants, and has been studied in several diseases, demonstrating antimicrobial, antidiabetic and anti-inflammatory properties and anti-tumorigenic effects. METHODS AND RESULTS: In SK-MEL-28 cells, 50 µM BBR treatment for 24 h decreased cell viability by 50 percent. This concentration generated cell death both by early apoptosis and necrosis, with an increase in the DNA damage index. BBR increased (*p < 0.05) the proportion of cells in G1/G0 phase and decreased (###p < 0.005) the percentage of cells in S phase. The alcaloid increased (****p < 0.001) ROS production compared to untreated controls with an increase in activated caspase 3 and phosphorylated p53 protein levels. In addition, BBR significantly enhanced ERK as well as both pro- and anti-inflammatory cytokine expression compared to untreated controls. CONCLUSIONS: BBR has important antiproliferative effects and may be alone or in adjunct therapy a promising candidate for melanoma treatment, a cancer with great incidence and high lethality.