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Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5–15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL’s mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL’s molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.

Lucyna &Sacute;cis&lstrok;o,1 Magdalena Staszkiewicz,1 El&zdot;bieta Walewska,1 Ma&lstrok;gorzata Paplaczyk-Serednicka,1 Iwona Bodys-Cupak,2 Paulina Zawieja3 1Department of Clinical Nursing, Institute of Nursing and Midwifery, Faculty of Health Sciences, Jagiellonian University, Medical College, Kraków, 31-501, Poland; 2Laboratory of Theory and Fundamentals of Nursing, Institute of Nursing and Midwifery, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, 31-126, Poland; 3Faculty of Health Sciences, Jagiellonian University, Medical College, Kraków, 31-501, PolandCorrespondence: Lucyna &Sacute;cis&lstrok;o, Department of Clinical Nursing, Institute of Nursing and Midwifery, Faculty of Health Sciences, Jagiellonian University, Medical College, 25 M. Kopernik street, Kraków, 31-501, Poland, Email lucyna.scislo@uj.edu.pl Magdalena Staszkiewicz, Department of Clinical Nursing, Institute of Nursing and Midwifery, Faculty of Health Sciences, Jagiellonian University, Medical College, 25 M. Kopernik street, Kraków, 31-501, Poland, Email m.staszkiewicz@uj.edu.plIntroduction: The factors determining the level of functional efficiency in patients after ischemic stroke are: age, sex, physical condition, mental activity before stroke, previous neurological deficits, comorbidities, nutritional status and the course of the stroke.Aim: Assessment of the functional efficiency of patients before and after rehabilitation due to ischemic stroke and determination of the influence of selected factors on the effects of rehabilitation measured by functional efficiency.Material and Methods: The study was conducted in neurological rehabilitation centers among 82 people diagnosed with ischemic stroke. The examination was performed twice: on admission to the ward and after a month of neurological rehabilitation. The diagnostic survey method, the Barthel scale, the NRS 2002 scale were used, and the BMI was calculated.Results: The functional efficiency level of the patients was varied, higher after one month of rehabilitation (p < 0.05). Among the patients who achieved a lower level of functional efficiency, the following factors had a significant influence: underweight and overweight (p = 0.002), risk of malnutrition (p = 0.002), right-sided paresis (p = 0.016), limited physical activity before stroke (p = 0.01) and the later rehabilitation period (p = 0.01). There was no correlation between sociodemographic data and the level of efficiency of patients after a stroke after one month of rehabilitation.Conclusion: The level of functional efficiency after rehabilitation improved in all patients, however, to a different extent depending on the nutritional status and physical activity. Therefore, it is important to to undertake rehabilitation in the shortest possible time.Keywords: ischemic stroke, functional efficiency, Barthel scale

Abstract Mesenchymal stem cells (mesenchymal stromal cells, MSC) are multipotent stem cells that can differentiate into cells of at least three mesodermal lineages, namely adipocytes, osteoblasts, and chondrocytes, and have potent immunomodulatory properties. Epigenetic modifications are critical regulators of gene expression and cellular differentiation of mesenchymal stem cells (MSCs). Epigenetic machinery controls MSC differentiation through direct modifications to DNA and histones. Understanding the role of epigenetic machinery in MSC is crucial for the development of effective cell-based therapies for degenerative and inflammatory diseases. In this review, we summarize the current understanding of the role of epigenetic control of MSC differentiation and immunomodulatory properties.

Feline injection-site sarcomas (FISSs) are aggressive neoplasms that have been associated mostly with vaccination. Feline noninjection-site sarcomas (non-FISSs) are less frequently observed in cats and may arise in any anatomic site. This study aimed to determine the differences in the expression of the selected proteins (matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), and P-glycoprotein (PGP)) and their correlation with the mitotic count in FISS and non-FISS, in order to characterize their immunohistochemical features. A preliminary study of eleven samples of FISS and eight samples of non-FISS was performed using immunohistochemistry. Among all the tested sarcomas, 80.4% of the tumors were positive for COX-2, 90.2% were positive for MMP-9, and 100% were positive for PGP. The results showed that the expressions of COX-2, MMP-9, and PGP were significantly higher in FISS than in non-FISS (COX-2—p ≤ 0.001; MMP-9—p ≤ 0.05; and PGP—p ≤ 0.05). A Spearman rank correlation analysis showed a moderate negative correlation between the expression of COX-2 and MMP-9 in FISS (r = −0.52). A strong negative correlation between COX-2 and PGP (r = −0.81), a moderate positive correlation between MMP-2 and MMP-9 (r = +0.69), and a moderate negative correlation between MMP-2 and PGP (r = −0.44) were observed in non-FISS. In summary, our study presents the immunohistochemical profile of the proteins involved with inflammation and carcinogenesis in FISS and non-FISS, which can contribute to expanding the knowledge of tumor biology.

Assisted Reproductive Technologies (ART) have revolutionized infertility treatment and animal breeding, but their success largely depends on selecting high-quality oocytes for fertilization and embryos for transfer. During preimplantation development, embryos undergo complex morphogenetic processes, such as compaction and cavitation, driven by cellular forces dependent on cytoskeletal dynamics and cell-cell interactions. These processes are pivotal in dictating an embryo’s capacity to implant and progress to full-term development. Hence, a comprehensive grasp of the biomechanical attributes characterizing healthy oocytes and embryos is essential for selecting those with higher developmental potential. Various noninvasive techniques have emerged as valuable tools for assessing biomechanical properties without disturbing the oocyte or embryo physiological state, including morphokinetics, analysis of cytoplasmic movement velocity, or quantification of cortical tension and elasticity using microaspiration. By shedding light on the cytoskeletal processes involved in chromosome segregation, cytokinesis, cellular trafficking, and cell adhesion, underlying oogenesis, and embryonic development, this review explores the significance of embryo biomechanics in ART and its potential implications for improving clinical IVF outcomes, offering valuable insights and research directions to enhance oocyte and embryo selection procedures.

Malnutrition is a significant issue among elderly individuals in 24-hour care facilities, leading to increased morbidity. The aim of the study was to compare the nutritional status before and after nutritional intervention based on selected indicators of nutritional status among residents of a 24-hour care institution. The study included a group of 104 people aged 65 to 97 years. Nutritional status was assessed before and after the nutritional intervention based on indicators: levels of prealbumin, albumin, transferrin, total lymphocyte count, BMI, and MNA scale. The nutritional intervention consisted of administering oral nutritional supplements (ONS) to patients, regardless of nutritional status. The method of retrospective analysis of patients' medical records was used. Statistical analysis was performed using IBM SPSS Statistics 24 for Windows. Improvements in nutritional status occurred among patients with malnutrition based on MNA and prealbumin indices, and in groups of patients with moderate or mild malnutrition as determined by transferrin, prealbumin and albumin. The mean levels of nutritional indices significantly increased: MNA ( p = .001), BMI ( p = .001), prealbumin ( p = .001), and albumin ( p

Appendicular osteosarcoma (OSA) is a highly aggressive and metastatic primary bone tumour in dogs. Standard therapy is amputation and adjuvant chemotherapy (e.g. with doxorubicin). Liposomal drug delivery may augment therapeutic efficacy and reduce negative side effects. Polyethylene glycol (PEG)-liposomal doxorubicin treats human metastatic cancers effectively. The study aimed was to evaluate PEG-liposomal doxorubicin’s inhibitory effect on canine metastatic proliferation and migration in vitro. It also aimed to appraise the drug’s extravasation inhibition in vivo using the human medicine–proven chick embryo chorioallantoic membrane ex ovo model.

Summary: Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79–4.91; p

Venetoclax, a highly selective, oral B-cell lymphoma 2 inhibitor, provides a robust targeted-therapy option for the treatment of chronic lymphocytic leukemia (CLL), including patients with high-risk del(17p)/mutated-TP53 and immunoglobulin heavy variable region unmutated CLL and those refractory to chemoimmunotherapy across all age groups. Due to the potent pro-apoptotic effect of venetoclax, treatment initiation carries a risk of tumor lysis syndrome (TLS). Prompt and appropriate management is needed to limit clinical TLS, which may entail serious adverse events and death. Venetoclax ramp-up involves gradual, stepwise increases in daily venetoclax dosing from 20 mg to 400 mg (target dose) over 5 weeks; adherence to on-label scheduling provides a tumor debulking phase, reducing the risk of TLS. The key components of safe venetoclax therapy involve assessment (radiographic evaluation and baseline blood chemistry), preparation (adequate hydration), and initiation (blood chemistry monitoring). In addition to summarizing the evidence for venetoclax’s efficacy and safety, this review uses hypothetical patient scenarios based on risk level for TLS (high, medium, low) to share the authors’ clinical experience with venetoclax initiation and present global approaches utilized in various treatment settings. These hypothetical scenarios highlight the importance of a multidisciplinary approach and shared decision-making, outlining best practices for venetoclax initiation and overall optimal treatment strategies in patients with CLL.

Despite substantial progress in the diagnostic and therapeutic procedures, acute myeloid leukaemia (AML) still constitutes a significant problem for patients suffering from its relapses. A comprehensive knowledge of the disease’s molecular background has led to the development of targeted therapies, including immune checkpoint inhibitors, and demonstrated beneficial effects on several types of cancer. Here, we aimed to assess in vitro the potential of the immune checkpoint blockage for supporting anti-cancer responses to the AML backbone therapy with cytarabine. PBMCs of AML patients were collected at admission and, following the therapy, eight complete remission (CR) and eight non-responders (NR) subjects were selected. We assessed the effects of the in vitro treatment of the cells with cytarabine and the immune checkpoint inhibitors: anti-CTLA-4, anti-PD-1, anti-PD-L1. The study protocol allowed us to evaluate the viability of the cancer and the immune cells, proliferation status, phenotype, and cytokine release. Anti-PD-L1 antibodies were found to exert the most beneficial effect on the activation of T cells, with a concomitant regulation of the immune balance through Treg induction. There was no direct influence on the blast cells; however, the modulation of the PD-1/PD-L1 axis supported the expansion of lymphocytes. Changes in the response between CR and NR patients might result from the differential expression of PD-1 and PD-L1, with lower levels in the latter group. The tested blockers appear to support the anti-cancer immune responses rather than directly improve the effects of cytarabine. In conclusion, checkpoint proteins’ modulators might improve the anti-cancer responses in the tumour environment.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Brutons tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and

Glioblastoma (GBM) is an aggressive and highly heterogeneous primary brain tumor. Glioma stem cells represent a subpopulation of tumor cells with stem cell traits that are presumed to be the cause of tumor relapse. There exists complex tumor heterogeneity in drug sensitivity patterns between glioma stem cell (GSC) cultures derived from different patients. Here, we describe that heterogeneity also exists between GSC cultures derived from multiple biopsies within a single tumor. From biopsies harvested within spatially distinct regions representing the entire tumor mass, we established seven GSC cultures and compared their stem cell properties, mutations, gene expression profiles, and drug sensitivity patterns against 115 different anticancer drugs. The results were compared to 14 GSC cultures derived from other patients. Between the multiregional-derived GSC cultures, we observed only minor differences in their phenotype, proliferative capacity, and global gene expression. Further, they displayed intratumoral heterogeneity in mutational profiles and sensitivity patterns to anticancer drugs. This heterogeneity, however, did not exceed the extensive heterogeneity found between GSC cultures derived from other GBM patients. Our results suggest that the use of GSC cultures from one single focal biopsy may underestimate the overall complexity of the GSC population and display the importance of including GSC cultures reflecting the entire tumor mass in drug screening strategies.

Simple Summary: Simple Summary: The aim of our research was to assess the expression of the selected proteins involved with inflammation and carcinogenesis, in order to expand knowledge of FISS and non-FISS. Matrix metalloproteinase-2, matrix metalloproteinase-9, cyclooxygenase-2, and P-glycoprotein were evaluated with the immunohistochemistry method. Our results showed that the expressions of COX-2, MMP-9, and PGP were significantly higher in FISS than in non-FISS Feline injection-site sarcomas (FISSs) are aggressive neoplasms that have been associated mostly with vaccination. Feline noninjection-site sarcomas (non-FISSs) are less frequently observed in cats and may arise in any anatomic site. This study aimed to determine the differences in the expression of the selected proteins (matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), and P-glycoprotein (PGP)) and their correlation with the mitotic count in FISS and non-FISS, in order to characterize their immunohistochemical features. A preliminary study of eleven samples of FISS and eight samples of non-FISS was performed using immunohistochemistry. Among all the tested sarcomas, 80.4% of the tumors were positive for COX-2, 90.2% were positive for MMP-9, and 100% were positive for PGP. The results showed that the expressions of COX-2, MMP-9, and PGP were significantly higher in FISS than in non-FISS (COX-2—p ≤ 0.001; MMP-9—p ≤ 0.05; and PGP—p ≤ 0.05). A Spearman rank correlation analysis showed a moderate negative correlation between the expression of COX-2 and MMP-9 in FISS (r = −0.52). A strong negative correlation between COX-2 and PGP (r = −0.81), a moderate positive correlation between MMP-2 and MMP-9 (r = +0.69), and a moderate negative correlation between MMP-2 and PGP (r = −0.44) were observed in non-FISS. In summary, our study presents the immunohistochemical profile of the proteins involved with inflammation and carcinogenesis in FISS and non-FISS, which can contribute to expanding the knowledge of tumor biology. [ABSTRACT FROM AUTHOR]

The development of novel drugs with different mechanisms of action has dramatically changed the treatment landscape of AML patients in recent years. Considering a significant dysregulation of the immune system, inhibitors of immune checkpoint (ICI) proteins provide a substantial therapeutic option for those subjects. However, use of ICI in haematological malignancies remains very limited, in contrast to their wide use in solid tumours. Here, we analysed expression patterns of the most promising selected checkpoint-based therapeutic targets in AML patients. Peripheral blood of 72 untreated AML patients was used for flow cytometric analysis. Expression of PD-1, PD-L1, CTLA-4, and B7-H3 was assessed within CD4+ (Th) lymphocytes and CD33+ blast cells. Patients were stratified based on therapy outcome and cytogenetic molecular risk. AML non-responders (NR) showed a higher frequency of PD-1 in Th cells compared to those with complete remission (CR). Reduced blast cell level of CTLA-4 was another factor differentiating CR from NR subjects. Elevated levels of PD-1 were associated with a trend for poorer patients’ survival. Additionally, prognosis for AML patients was worse in case of a higher frequency of B7-H3 in Th lymphocytes. In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data.

Background and objective: The study was to compare the severity of male depression symptoms, suicidal behaviors, the use of psychoactive substances (alcohol, nicotine), and evaluate personal resources (self-efficacy, coping strategies and resilience) among men from three different groups. Material and methods: The clinical group contained men with depression disorders diagnosed by psychiatrists and treated in psychiatric hospitals (n = 197). The control groups contained men with physical disorders treated in general hospitals in Warsaw, Poland (n = 198) and men who self-evaluated themselves as healthy without physical or mental disorders (n = 203). Several tests were used for evaluation: a test with sociodemographic variables, the AUDIT Test, the Fagerstrom Test, the Generalized Self-Efficacy Scale (GSES), the MINI-COPE Questionnaire, the Resilience Evaluation Questionnaire (KOP-26), the Suicide Behaviors Questionnaire-Revised by Osman (SBQ-R) and the Gotland Male Depression Scale (GMDS). Results: Most of the men with depression disorders presented non-typical symptoms of depression which are not included in diagnostic criteria. It allows us to assume that a large percentage of men who suffer from depression are not properly being diagnosed. Moreover, we found that men with any type of physical disorder have the greatest severity of male depression symptoms than healthy men. Men with depression disorders have suicidal thoughts and have made efforts in the past more often, as well as having higher alcohol and nicotine addictions. Patients who overuse or are addicted to alcohol or nicotine should be additionally screened for the possible occurrence of depressive disorders, and substance usage should be treated as a symptom of male depression. Men with depression present low resilience and low self-efficacy. They also use negative strategies in dealing with stress. Conclusion: There is a need to plan and implement effective prevention actions that will take the conditioning of these groups into account.

BackgroundSymptomatic intracranial hemorrhage (sICH) and malignant brain edema (MBE) are well-known deleterious endovascular treatment (EVT) complications that some studies found to be associated with postprocedural blood pressure (BP) variability. We aimed to evaluate their association with periprocedural BP changes, including its intraprocedural decrease.MethodsWe retrospectively analyzed the data of 132 consecutive patients that underwent EVT between 1 December 2018 and 31 December 2019, for anterior circulation ischemic stroke. Analyzed predictors of sICH and MBE included non-invasively obtained BP before and 5-min after treatment, intraprocedural relative decreases of BP from baseline, and its post-treatment increases. SICH was defined in accordance with the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria and MBE as brain edema with midline shift on the follow-up imaging. We used binary logistic regression analysis to investigate the association of BP parameters and the incidence of sICH and MBE.ResultsAmong the included patients, 11 (8.3%) developed sICH and 31 (23.5%) MBE. The intraprocedural decrease of mean arterial blood pressure (MAP) was independently associated with MBE occurrence (aOR per 10 mmHg drop from baseline 1.27; 95% CI 1.01–1.60; P = 0.040). Over 40% MAP drop was associated with a higher risk of sICH in the entire cohort (aOR 4.24; 95% CI 1.33–13.51; P = 0.015), but not in the subgroup with successful reperfusion (aOR 2.81; 95% CI 0.64–12.23; P = 0.169). Post-treatment systolic blood pressure (SBP) and MAP elevation above their minimal values during MT are significantly associated with the development of sICH (aOR per 10 mmHg SBP increase 1.78; 95% CI 1.15–2.76; P = 0.010 and aOR per 10 mmHg MAP increase 1.78; 95% CI 1.04–3.03; P = 0.035).ConclusionsIn the anterior circulation ischemic stroke patients relative MAP decrease during EVT is associated with a higher risk of MBE occurrence, and over 40% MAP drop with a higher incidence of both MBE and sICH. Post-treatment elevation of SBP and MAP increased the risk of sICH.

Rheumatoid arthritis (RA) synovitis is dominated by monocytes/macrophages with inflammatory patterns resembling microbial stimulation. In search of triggers, we reduced the intestinal microbiome in 20 RA patients (open label study DRKS00014097) by bowel cleansing and 7-day fasting (≤250 kcal/day) and performed immune monitoring and microbiome sequencing. Patients with metabolic syndrome (n = 10) served as a non-inflammatory control group. Scores of disease activity (DAS28/SDAI) declined within a few days and were improved in 19 of 20 RA patients after breaking the fast (median ∆DAS28 = −1.23; ∆SDAI = −43%) or even achieved remission (DAS28 < 2.6/n = 6; SDAI < 3.3/n = 3). Cytometric profiling with 46 different surface markers revealed the most pronounced phenomenon in RA to be an initially increased monocyte turnover, which improved within a few days after microbiota reduction and fasting. Serum levels of IL-6 and zonulin, an indicator of mucosal barrier disruption, decreased significantly. Endogenous cortisol levels increased during fasting but were insufficient to explain the marked improvement. Sequencing of the intestinal microbiota indicated that fasting reduced potentially arthritogenic bacteria and changed the microbial composition to species with broader metabolic capabilities. More eukaryotic, predominantly fungal colonizers were observed in RA, suggesting possible involvement. This study demonstrates a direct link between the intestinal microbiota and RA-specific inflammation that could be etiologically relevant and would support targeted nutritional interventions against gut dysbiosis as a causal therapeutic approach.

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for β-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson’s disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

O Curso de Treinamento para Operadores de Reatores de Pesquisa (Ctorp) é ministrado no Centro de Desenvolvimento de Tecnologia Nuclear (CDTN), desde 1974. Aproximadamente 250 trabalhadores foram certificados pela CDTN. Um sistema de simulação digital para o reator de pesquisa TRIGA® IPR-R1 foi desenvolvido no CDTN. A intenção é fornecer uma ferramenta para apoiar o ensino e treinamento em estudos teóricos e práticos, abordados nos cursos de operação de reatores. Destina-se à educação de princípios básicos de neutrônica de reator, como: multiplicação subcrítica (M), fator de multiplicação (k), massa crítica, reatividade (r), período (T), fluxo neutrônico, nêutrons prontos e produtos de fissão. O sistema de simulação foi projetado utilizando o programa LabVIEW® (Laboratory Virtual Instruments Engineering Workbench), considerando o recente conceito de instrumentos virtuais (VI’s) usando processador eletrônico e interface de visualização em monitor de vídeo. Este artigo apresenta o projeto e os resultados das interfaces visuais do usuário desenvolvidas para o simulador de operação do reator. Essa é a parte equivalente da programação de texto estruturada e, portanto, a parte mais significativa do simulador desenvolvido.

The mitochondrial large-conductance calcium-activated potassium channel (mitoBKCa) is located in the inner mitochondrial membrane and seems to play a crucial role in cytoprotection. The mitoBKCa channel is regulated by many modulators, including activators, such as calcium ions and inhibitors, such as heme and its oxidized form hemin. Heme/hemin binds to the heme-binding motif (CXXCH) located between two RCK domains present in the mitochondrial matrix. In the present study, we used the patch-clamp technique in the outside-out configuration to record the activity of mitoBKCa channels. This allowed for the application of channel modulators to the intermembrane-space side of the mitoBKCa. We found that hemin applied in this configuration inhibits the activity of mitoBKCa. In addition, we proved that the observed hemin effect is specific and it is not due to its interaction with the inner mitochondrial membrane. Our data suggest the existence of a new potential heme/hemin binding site in the structure of the mitoBKCa channel located on the mitochondrial intermembrane space side, which could constitute a new way for the regulation of mitoBKCa channel activity.

This study investigates short cationic antimicrobial lipopeptides composed of 2–4 amino acid residues and C12-C18 fatty acids attached to the N-terminal part of the peptides. The findings were discussed in the context of the relationship among biological activity, self-assembly, stability, and membrane interactions. All the lipopeptides showed the ability to self-assemble in PBS solution. In most cases, the critical aggregation concentration (CAC) much surpassed the minimal inhibitory concentration (MIC) values, suggesting that monomers are the main active form of lipopeptides. The introduction of β-alanine into the peptide sequence resulted in a compound with a high propensity to fibrillate, which increased the peptide stability and activity against S. epidermidis and C. albicans and reduced the cytotoxicity against human keratinocytes. The results of our study indicated that the target of action of lipopeptides is the bacterial membrane. Interestingly, the type of peptide counterion may affect the degree of penetration of the lipid bilayer. In addition, the binding of the lipopeptide to the membrane of Gram-negative bacteria may lead to the release of calcium ions necessary for stabilization of the lipopolysaccharide layer.

Human β-defensin 3, HBD-3, is a 45-residue antimicrobial and immunomodulatory peptide that plays multiple roles in the host defense system. In addition to interacting with cell membranes, HBD-3 is also a ligand for melanocortin receptors, cytokine receptors and voltage-gated potassium channels. Structural and functional studies of HBD-3 have been hampered by inefficient synthetic and recombinant expression methods. Herein, we report an optimized Fmoc solid-phase synthesis of this peptide using an orthogonal disulfide bonds formation strategy. Our results suggest that utilization of an optimized resin, coupling reagents and pseudoproline dipeptide building blocks decrease chain aggregation and largely improve the amount of the target peptide in the final crude material, making the synthesis more efficient. We also present an alternative synthesis of HBD-3 in which a replacement of a native disulfide bridge with a diselenide bond improved the oxidative folding. Our work enables further biological and pharmacological characterization of HBD-3, hence advancing our understanding of its therapeutic potential.