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Two cases of idiopathic colitis affecting the sigmoid colon in elderly patients with underlying diverticulosis are presented. Segmental resection has permitted close review of the histopathology in this syndrome which demonstrates considerable similarity to changes seen in idiopathic ulcerative colitis. The reported experience with this syndrome and its clinical features are reviewed.

A 27-year-old woman was found to have an abnormal small bowel at the time of an elective laparoscopic tubal ligation. Subsequent investigation revealed celiac disease to be the underyling cause. The changes identified are believed to reflect an increased intestinal blood flow, which has been identified in the diagnostic imaging literature to be associated with active celiac disease. Further study of this feature of celiac disease may provide additional insights into its pathophysiology.

Excitotoxicity represents a neuropathological process, describing the toxic actions of excitatory neurotransmitters, where the excessive or prolonged activation of glutamate receptors triggers a cascade of events leading to neuronal injury or death. Under conditions of reduced energy availability and increased oxidative stress neurons become particularly vulnerable to excitotoxicity and a large body of available evidence indicates that excitotoxicity represents a central mechanism in the pathogenesis of acute and degenerative diseases of the central nervous system. Astrocytes represent key elements in the regulation of glutamate homeostasis by their opposing functions of glutamate uptake and release, and microglial cells play an important role in the response to damage. Depending on the phenotype they assume when activated, microglial cells can trigger immune defense or neuroprotective processes. To perform their functions both glial cell populations monitor the extracellular space through a panel of receptors. Furthermore, a variety of signaling pathways also contribute to the modulation of the glutamatergic transmission, acting on specific cell receptors expressed by neurons, astrocytes, and microglia. In the last decades, evidence has been provided that receptors of almost all families can establish structural receptor-receptor interactions, leading to the formation of heteroreceptor complexes at the cell membrane of neurons and glial cells. The cooperativity that emerges in the actions of ligands of the monomers forming these assemblies provides the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction and allows an integration of the incoming signals already at the membrane level. Available data on possible modulatory roles played by heteroreceptor complexes in excitotoxic processes will be here reviewed and discussed. From the pharmacological standpoint, these findings may offer possibilities to explore novel therapeutic strategies targeting receptor complexes to address disorders of the central nervous system associated with dysregulation of glutamatergic signaling.

Abstract Antimicrobial resistance (AMR) is a global health threat. This randomized controlled trial evaluates the impact of experiential virtual reality (VR) versus information provision via VR or leaflet on prudent antibiotic use. A total of 249 (239 analyzed) participants were randomized into three conditions: VR Information + Experience, VR Information, or Leaflet Information. All participants received AMR information, while those in the VR Information + Experience condition additionally engaged in a game, making treatment decisions for their virtual avatar’s infection. Participants in the VR Information + Experience condition showed a significant increase in prudent use intentions from baseline (d = 1.48). This increase was significantly larger compared to the VR Information (d = 0.50) and Leaflet Information (d = 0.79) conditions. The increase in intentions from baseline remained significant at follow-up in the VR Information + Experience condition (d = 1.25). Experiential VR communication shows promise for promoting prudent antibiotics use.

Abstract Maintaining patients’ temperature during surgery is beneficial since hypothermia has been linked with perioperative complications. Laparoscopic surgery involves the insufflation of carbon dioxide (CO2) into the peritoneal cavity and has become the standard in many surgical indications since it is associated with better and faster recovery. However, the use of cold and dry CO2 insufflation can lead to perioperative hypothermia. We aimed to assess the difference between intraperitoneal and core temperatures during laparoscopic surgery and evaluate the influence of duration and CO2 insufflation volume by fitting a mixed generalized additive model. In this prospective observational single-center cohort trial, we included patients aged over 17 with American Society of Anesthesiology risk scores I to III undergoing laparoscopic surgery. Anesthesia, ventilation, and analgesia followed standard protocols, while patients received active warming using blankets and warmed fluids. Temperature data, CO2 ventilation parameters, and intraabdominal pressure were collected. We recruited 51 patients. The core temperature was maintained above 36 °C and progressively raised toward 37 °C as pneumoperitoneum time passed. In contrast, the intraperitoneal temperature decreased, thus creating a widening difference from 0.4 [25th–75th percentile: 0.2–0.8] °C at the beginning to 2.3 [2.1–2.3] °C after 240 min. Pneumoperitoneum duration and CO2 insufflation volume significantly increased this temperature difference (P

ABSTRACT: Objectives: The purpose of this work was to optimise printable polycaprolactone (PCL)/β-tricalcium phosphate (β-TCP) biomaterials with high percentages of β-TCP endowed with balanced mechanical characteristics to resemble human cancellous bone, presumably improving osteogenesis. Methods: PCL/β-TCP scaffolds were obtained from customised filaments for fused deposition modelling (FDM) 3D printing with increasing amounts of β-TCP. Samples mechanical features, surface topography and wettability were evaluated as well as cytocompatibility assays, cell adhesion and differentiation. Results: The parameters of the newly fabricated materila were optimal for PCL/β-TCP scaffold fabrication. Composite surfaces showed higher hydrophilicity compared with the controls, and their surface roughness sharply was higher, possibly due to the presence of β-TCP. The Young's modulus of the composites was significantly higher than that of pristine PCL, indicating that the intrinsic strength of β-TCP is beneficial for enhancing the elastic modulus of the composite biomaterials. All novel composite biomaterials supported greater cellular growth and stronger osteoblastic differentiation compared with the PCL control. Conclusions: This project highlights the possibility to fabricat, through an FDM solvent-free approach, PCL/β-TCP scaffolds of up to 70 % concentrations of β-TCP. overcoming the current lmit of 60 % stated in the literature. The combination of 3D printing and customised biomaterials allowed production of highly personalised scaffolds with optimal mechanical and biological features resembling the natural structure and the composition of bone. This underlines the promise of such structures for innovative approaches for bone and periodontal regeneration.

Abstract Background The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. Methods Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. Results IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). Conclusions The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

(1) Background: The aim of this review was to identify and summarize adverse cardiovascular health events associated with the simultaneous consumption of energy drinks (ED) and alcohol. Potential prevention strategies and the implementation of research toward the underlying mechanisms for these pathologies were highlighted to emphasize the need for further investigation and to encourage more attention to this field. (2) Methods: The PubMed database was searched for case reports linked with adverse cardiovascular events after simultaneous ED and alcohol consumption. Inclusion criteria were: the reported age of the patient is between 16 and 35 years and confirmed co-consumption of EDs and alcohol. All relevant articles that met the inclusion criteria were fully read and all relevant data was extracted. The extracted data was summarized and presented in this review of cases. (3) Results: In total, 10 cases were identified. The analysis showed that mainly young adults (median age = 24.5 years), in particular men (80%) were affected. The three parts of the cardiovascular system affected were heart rhythm (42%), myocardial function (33%), and coronary arteries (25%). In 3 cases the outcome was fatal. Moreover, preexisting health conditions and/or potential trigger factors were present in 60% of selected cases. (4) Conclusions: This review of case reports suggests that the simultaneous consumption of EDs and alcohol can lead to adverse cardiovascular health events and even incidents with fatal outcomes were reported. Potential trigger factors and preexisting health conditions seem to increase the probability of adverse cardiovascular health events. Consumers should be informed about the potential risks and follow responsible consumption behavior to prevent future health events. More systematic studies are needed to determine the acute effects on the cardiovascular system in young adults.

RESUMO Trata-se de uma resenha de “A Fantasia Organizada” de Celso Furtado.

BCL-2 protein overexpression, common in B-cell acute lymphoblastic leukemia (B-ALL), including the Philadelphia (Ph)-like subtype, mediates leukemic cell survival. We treated 24 patients with 14 days of BCL-2 inhibitor, venetoclax, 400 mg daily (dose level 1) during induction and consolidation cycles combined with the CALGB 10403 regimen in newly diagnosed adults with Ph-negative B-ALL. Median age was 31 (range: 18-53) years, 92% were Hispanic, and 12 (50%) patients had Ph-like ALL. No dose limiting toxicity occurred in the phase 1 part. Median times to neutrophil and platelet count recovery were 20 and 21 days from start of induction, respectively. The most common grade ≥3 treatment-related adverse events were leukopenia (96%), neutropenia (83%), anemia (83%), thrombocytopenia (79%), lymphopenia (71%), hyperbilirubinemia (38%), and elevated ALT (33%). One patient with non-Ph-like ALL died from asparaginase-associated pancreatitis, and 23 (96%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) following induction with or without extended induction phase. Of 22 patients who started consolidation, 20 (91%) achieved negative minimal residual disease status (MRD-) (

Introduction The rise of opioid-free anaesthesia (OFA) aims to reduce postoperative pain while reducing opioid-related side effects during surgery. However, the various adjuvant agents used in OFA complicate the evaluation of their effectiveness and risks. Recent reviews question the clinical benefits of OFA, highlighting the need for thorough evaluation. This protocol describes a network meta-analysis to compare the effectiveness of OFA with opioid-based anaesthesia and will identify key components for optimal postoperative outcomes.Methods and analysis We will perform a systematic search of literature published in English without time restriction in Embase, The Cochrane Library, MEDLINE (via PubMed) and CINAHL, along with Google Scholar for grey literature. The final search will be performed on 1 October 2024. We will include randomised controlled trials with adult patients undergoing surgery with general anaesthesia, excluding preclinical, observational, regional anaesthesia-only and prolonged anaesthesia outside the operating room studies. The primary outcome is postsurgical pain scores, with secondary outcomes including quality of recovery, opioid consumption, adverse effects and long-term events. We will assess bias using the Cochrane risk of bias 2 tool and conduct Bayesian network meta-analyses for pooled estimates. We will report effect estimates as ORs and standardised mean differences with 95% credible intervals and assess certainty using GRADE methodology.Ethics and dissemination Ethics approval is not required for this systematic review. Results will be published in a peer-reviewed journal and presented at national and international anaesthesia and pain management conferences.PROSPERO registration number CRD42024505853.

ABSTRACT The pathogenesis of COVID-19 is associated with a hyperinflammatory immune response. Monocytes and macrophages play a central role in this hyperinflammatory response to SARS-CoV-2. NLRP3 inflammasome activation has been observed in monocytes of patients with COVID-19, but the mechanism and consequences of inflammasome activation require further investigation. In this study, we inoculated a macrophage-like THP-1 cell line, primary differentiated human nasal epithelial cell (hNEC) cultures, and primary monocytes with SARS-CoV-2. We found that the activation of the NLRP3 inflammasome in macrophages does not rely on viral replication, receptor-mediated entry, or actin-dependent entry. SARS-CoV-2 productively infected hNEC cultures without triggering the production of inflammasome cytokines IL-18 and IL-1β. Importantly, these cytokines did not inhibit viral replication in hNEC cultures. SARS-CoV-2 inoculation of primary monocytes led to inflammasome activation and induced a macrophage phenotype in these cells. Monocytic cells from bronchoalveolar lavage (BAL) fluid, but not from peripheral blood, of patients with COVID-19, showed evidence of inflammasome activation, expressed the proinflammatory marker CD11b, and displayed oxidative burst. These findings highlight the central role of activated macrophages, as a result of direct viral sensing, in COVID-19 and support the inhibition of IL-1β and IL-18 as potential therapeutic strategies to reduce immunopathology without increasing viral replication.IMPORTANCEInflammasome activation is associated with severe COVID-19. The impact of inflammasome activation on viral replication and mechanistic details of this activation are not clarified. This study advances our understanding of the role of inflammasome activation in macrophages by identifying TLR2, NLRP3, ASC, and caspase-1 as dependent factors in this activation. Further, it highlights that SARS-CoV-2 inflammasome activation is not a feature of nasal epithelial cells but rather activation of bystander macrophages in the airway. Finally, we demonstrate that two pro inflammatory cytokines produced by inflammasome activation, IL-18 and IL-1β, do not restrict viral replication and are potential targets to ameliorate pathological inflammation in severe COVID-19.

Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event – free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 – 15.2) and OS was 40.0% (95%CI, 36.4 – 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 – 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 – 13.8], p=

Phomopsis cane and leaf spot (PCLS) disease, affecting grapevines (Vitis vinifera and Vitis spp.), has been historically associated with Diaporthe ampelina. Typical disease symptoms, comprising bleaching and black pycnidia, have also been associated with other Diaporthe spp. In this study, we conducted a molecular identification of the Diaporthe isolates isolated from grapevine canes from different geographic areas of southern Europe showing PCLS symptoms. Then, we investigated their morphological characteristics (including mycelium growth and production of pycnidia and alpha and beta conidia) in response to temperature. Finally, we artificially inoculated grapevine shoots and leaves with a subset of these isolates. Based on our results, PCLS etiology should be reconsidered. Though D. ampelina was the most crucial causal agent of PCLS, D. eres and D. foeniculina were also pathogenic when inoculated on green shoots and leaves of grapevines. However, D. rudis was not pathogenic. Compared to D. ampelina, D. eres and D. foeniculina produced both pycnidia and alpha conidia at lower temperatures. Thus, the range of environmental conditions favorable for PCLS development needs to be widened. Our findings warrant further validation by future studies aimed at ascertaining whether the differences in temperature requirements among species are also valid for conidia-mediated infection since it could have substantial practical implications in PCLS management.

Abstract Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMNHA neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries. To directly establish the impact of inactivation or activation of TMNHA neurons, we examined the effect of specific chemogenetic manipulations during the formation (acquisition/consolidation) or retrieval of recognition memories. We consistently found that acute chemogenetic silencing of TMNHA neurons disrupts the formation or retrieval of both social and object recognition memory in males and females. Conversely, acute chemogenetic activation of TMNHA neurons during training or retrieval extended social memory in both sexes and object memory in a sex-specific fashion. These results suggest that the formation or retrieval of recognition memory requires the tonic activity of histaminergic neurons and strengthen the concept that boosting the brain histaminergic system can promote the retrieval of apparently lost memories.

Abstract Background The identification and staging of Alzheimer’s Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. Methods One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. Results Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. Conclusions Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

The paper presents a comprehensive analysis of child labor in Ecuador, employing advanced statistical tools like logistic regression, neutrosophic Likert scales, and similarity measures to deepen the understanding of this social issue. The integration of these methodologies allows for a nuanced assessment of the various socio-economic factors contributing to child labor. By capturing the uncertainty in human responses, the research highlights the complex interplay between poverty, household income, education levels, and labor types on the incidence of child labor.Key findings suggest that rural location, the age of the child, and the informal nature of the head of the household'swork are the most significant predictors of child labor. Notably, parental education appears to have a less direct influence. Despite various efforts, including government monetary transfers through programs like the BDH, child labor persists, indicating the need for more targeted interventions.The paper proposes future research to extend these models to a broader demographic and geographic data set, emphasizing the potential for these methods to be applied to a variety of social issues. The development ofcomputational tools to automate neutrosophic analysis could greatly benefit large-scale studies, potentially aiding policymakers in designing more effective interventions for vulnerable populations.

This study examines the relationship between education and entrepreneur income in Ecuador, a prototypical small economy grappling with employment challenges. Utilizing quantile regression and neutrosophic statistical methods, the research uncovers varied impacts of education on earnings across different income levels. The findings reveal a decrease in indeterminacy as individuals ascend income quintiles, indicating that higher education levels yield more predictable and substantial economic returns at the upper end of the income spectrum. These insights are vital for policymakers to develop targeted educational interventions. The study’s methodological novelty lies in its adoption of neutrosophic statistics, which embraces the indeterminacy intrinsic to economic data, offering a refined lens for understanding the income-education interplay. Future research directions include longitudinal studies to trace the temporal effects of education and cross-comparative analyses across economies. The potential integration of machine learning with neutrosophic statistics promises enhanced predictive models, contributing to data-driven economic policy formulation.

The study of the maxillary sinus anatomy should consider the presence of two features of clinical importance. The arterial supply course and the presence of the so-called Underwood septa are two important factors to consider when planning surgical treatment to reduce the risk of surgical complications such as excessive bleeding and Schneiderian membrane perforations. This study aimed to investigate the above-mentioned anatomical structures to improve the management of eventual vascular and surgical complications in this area. This study included a total of 200 cone-beam computed topographies (CBCTs) divided into two groups of 100 CBCTs to evaluate the arterial supply (AAa) course through the lateral sinus wall and Underwood’s septa, respectively. The main parameters considered on 3D imaging were the presence of the AAa in the antral wall, the length of the arterial pathway, the height of the maxillary bone crest, the branch sizes of the artery in the first group, and the position of the septa, the length of the septa, and their gender associations in the second group. The CBCT analysis showed the presence of the arterial supply through the bone wall in 100% of the examined patients, with an average size of 1.07 mm. With regard to the septa, 19% of patients presented variations, and no gender difference was found to be statistically significant. The findings add to the current understanding of the clinical structure of the maxillary sinus, equipping medical professionals with vital details for surgical preparation and prevention of possible complications.

Abstract Acute myeloid leukemia (AML) is prevalent in both adult and pediatric patients. Despite advances in patient categorization, the heterogeneity of AML remains a challenge. Recent studies have explored the use of gene expression data to enhance AML diagnosis and prognosis, however, alternative approaches rooted in physics and chemistry may provide another level of insight into AML transformation. Utilizing publicly available databases, we analyze 884 human and mouse blood and bone marrow samples. We employ a personalized medicine strategy, combining state-transition theory and surprisal analysis, to assess the RNA transcriptome of individual patients. The transcriptome is transformed into physical parameters that represent each sample’s steady state and the free energy change (FEC) from that steady state, which is the state with the lowest free energy. We found the transcriptome steady state was invariant across normal and AML samples. FEC, representing active molecular processes, varied significantly between samples and was used to create patient-specific barcodes to characterize the biology of the disease. We discovered that AML samples that were in a transition state had the highest FEC. This disease state may be characterized as the most unstable and hence the most therapeutically targetable since a change in free energy is a thermodynamic requirement for disease progression. We also found that distinct sets of ongoing processes may be at the root of otherwise similar clinical phenotypes, implying that our integrated analysis of transcriptome profiles may facilitate a personalized medicine approach to cure AML and restore a steady state in each patient.

Background/Aim: Prevalence of gastroduodenal endoscopic and histological lesions may modify over time due to different factors. We assessed both macroscopic and histological lesions currently detected at upper endoscopy performed in routine practice. Patients and Methods: Clinical, endoscopic, and histological data of consecutive adult patients referred for upper endoscopy in the 28 participating centres were analysed. Only patients who underwent the first endoscopic examination were considered. Prevalence of erosive/ulcerative lesions, cancers and extensive precancerous lesions in the stomach, and Helicobacter pylori infection was computed. Results: A total of 1,431 patients underwent endoscopy for gastro-oesophageal reflux symptoms (31.5%), dyspepsia (29.4%), or alarm symptoms (18.5%). Erosive oesophagitis or Barrett’s oesophagus was detected in 210 (14.7%) cases, peptic ulcer in 49 (3.4%), and a neoplastic lesion in 17 (1.2%). H. pylori was present in 201 (22.6%) cases, and extensive precancerous lesions on gastric mucosa in 46 (5.6%) patients. Gastric lesions were more prevalent in patients aged ≥50 years (26% vs. 18%; p = 0.001), and peptic ulcers were more frequently detected in patients with H. pylori (9.4% vs. 2.3%; p = 0.001) and in males (5.8% vs. 1.6%; p = 0.001), while neoplastic lesions in patients with alarm symptoms (3.8% vs. 0.6%; p = 0.001). Conclusions: The overall endoscopic lesions were more prevalent in patients aged ≥50 years, peptic ulcer and erosions were more frequent in H. pylori-infected patients, and extensive gastric precancerous lesions were present in less than 6% of cases.

Introduction The emergence of new SARS-CoV-2 variants, capable of escaping the humoral immunity acquired by the available vaccines, together with waning immunity and vaccine hesitancy, challenges the efficacy of the vaccination strategy in fighting COVID-19. Improved therapeutic strategies are urgently needed to better intervene particularly in severe cases of the disease. They should aim at controlling the hyperinflammatory state generated on infection, reducing lung tissue pathology and inhibiting viral replication. Previous research has pointed to a possible role for the chaperone HSP90 in SARS-CoV-2 replication and COVID-19 pathogenesis. Pharmacological intervention through HSP90 inhibitors was shown to be beneficial in the treatment of inflammatory diseases, infections and reducing replication of diverse viruses.Methods In this study, we investigated the effects of the potent HSP90 inhibitor Ganetespib (STA-9090) in vitro on alveolar epithelial cells and alveolar macrophages to characterise its effects on cell activation and viral replication. Additionally, the Syrian hamster animal model was used to evaluate its efficacy in controlling systemic inflammation and viral burden after infection.Results In vitro, STA-9090 reduced viral replication on alveolar epithelial cells in a dose-dependent manner and lowered significantly the expression of proinflammatory genes, in both alveolar epithelial cells and alveolar macrophages. In vivo, although no reduction in viral load was observed, administration of STA-9090 led to an overall improvement of the clinical condition of infected animals, with reduced oedema formation and lung tissue pathology.Conclusion Altogether, we show that HSP90 inhibition could serve as a potential treatment option for moderate and severe cases of COVID-19.

The development of new and more effective cooling technologies is required for several high thermal power dissipation applications such as in electronics cooling or high concentrated photovoltaic panels. The present paper addresses an experimental study on the development of a microchannel based heat sink to cool photovoltaic panels. Experiments focus on the test of a microchannel, with geometry and dimensions optimized from previous work. The analysis performed here emphasizes the experimental characterization of flow boiling in the microchannel under different working conditions. The results include pressure drop and heat flux maps, obtained combining pressure sensors with high-speed imaging and time resolved thermography. The analysis performed was able to identify where nucleation sites were formed. Slug flow interfacial heat transfer could be observed and accurately described in the heat flux maps. Overall, results show the high potential of combining high-speed imaging with time resolved infrared thermography to characterize complex flows. These results also show that there is a good potential for this microchannel based flow cooling in removing the required heat fluxes for the application considered here, when compared to other liquid and air-cooling technologies.

Background and Aims: Painful shoulder is one of the most frequent consultation causes. Multiple treatments have been described to relieve pain, restore range of motion and improve functionality. Methods: This randomised clinical trial was conducted in 60 patients. The treatment group received combined pulsed radiofrequency (PRF) on suprascapular nerve (SN) and axillary-circumflex nerve (ACN). The control group received PRF on SN only. The primary outcome was pain intensity measured by the Numerical Rating Scale (NRS). The secondary outcomes were the Shoulder Pain and Disability Index (SPADI), the Constant–Murley range of motion scale and Disability of the Arm, Shoulder and Hand (DASH) scale. The patients were monitored at the baseline visit and at 1, 3, 6 and 9 months. A mixed ordinal regression model was estimated to evaluate the association between the study group and pain measured with NRS. Results: A global decrease in pain at the end of the study was noted. The global baseline NRS was 8.4, and the global final NRS at 9 months of follow-up was 6.2. Combined PRF on SN and ACN was not associated with lower NRS pain scores compared to single SN PRF [odds ratio (OR) =1.04, 95% confidence interval (CI) 0.91–1.20, P = 0.507]. Secondary outcomes showed no significant differences: SPADI (OR = 1.04, 95% CI 0.92–1.18), Constant–Murley (OR = 1.01, 95% CI 0.90–1.14), DASH (OR = 1.04, 95% CI 0.92–1.17). Conclusion: Combined PRF applied to SN and ACN was not superior to PRF applied to SN alone.

Plasmacytoma is a neoplastic disorder originating from plasma cells, with bone and soft tissue being common sites of manifestation. This report presents the clinical and radiological findings of a 65-year-old female patient who presented with an exophytic lesion in the upper right lateral incisor region. The lesion appeared as a unilocular radiotransparent area in imaging tests. Following an excisional biopsy, histological and immunohistochemical evaluations confirmed the presence of mature plasmacellular elements and small infiltrates of B and T lymphocytes. The patient did not exhibit systemic manifestations of multiple myeloma. Surgical intervention, in the form of enucleation of the lesion combined with root canal treatment and apicoectomy, was performed. This case underscores the rare occurrence of plasmacytoma in the jaw region and highlights the importance of surgical management in cases where structural damage or functional impairment is present. Further research on novel treatment approaches is also mentioned, including targeted therapies, immunomodulatory agents, and monoclonal antibodies. The patient is currently under the care of a hematologist for further investigation and the choice of the most appropriate therapy.

Abstract Background Cognitive impairments are prevalent across mood disorders and psychosis spectrum disorders, but there is a lack of real-life-like cognitive training programmes. Fully immersive virtual reality has the potential to ensure motivating and engaging cognitive training directly relevant to patients’ daily lives. We will examine the effect of a 4-week, intensive virtual reality-based cognitive remediation programme involving daily life challenges on cognition and daily life functioning in patients with mood disorders or psychosis spectrum disorders and explore the neuronal underpinnings of potential treatment efficacy. Methods The trial has a randomized, controlled, double-blinded, parallel-group design. We will include 66 symptomatically stable outpatients with mood disorders or psychosis spectrum disorders aged 18–55 years with objective and subjective cognitive impairment. Assessments encompassing a virtual reality test of daily life cognitive skills, neuropsychological testing, measures of daily life functioning, symptom ratings, questionnaires on subjective cognitive complaints, and quality of life are carried out at baseline, after the end of 4 weeks of treatment and at a 3-month follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and at the end of treatment. The primary outcome is a broad cognitive composite score comprising five subtasks on a novel ecologically valid virtual reality test of daily life cognitive functions. Two complete data sets for 54 patients will provide a power of 80% to detect a clinically relevant between-group difference in the primary outcome. Behavioural data will be analysed using linear mixed models in SPSS, while MRI data will be analysed with the FMRIB Expert Analysis Tool (FEAT). Treatment-related changes in neural activity from baseline to end of treatment will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest. Discussion The results will provide insight into whether virtual reality-based cognitive remediation has beneficial effects on cognition and functioning in symptomatically stable patients with mood disorders or psychosis spectrum disorders, which can aid future treatment development. Trial registration ClinicalTrials.gov NCT06038955. Registered on September 15, 2023.

RESUMO As obras de Celso Furtado marcam tanto o surgimento quanto a consolidação do pensamento econômico brasileiro. Suas principais obras (como Formação Econômica do Brasil e Desenvolvimento e Subdesenvolvimento) estabeleceram a base de referência para o debate econômico ocorrido nos últimos trinta anos no Brasil. A teoria do subdesenvolvimento, elaborada por Celso Furtado, forneceu a base teórica do desenvolvimento, a doutrina que norteou as políticas econômicas de vários governos latino-americanos e afirmou o estabelecimento da industrialização no Brasil. Este artigo busca recompor os passos para a constituição da teoria do subdesenvolvimento, explicitando as principais questões teóricas sobre esse problema e seus resultados práticos.

This article proposes a digital procedure to create the emergence profile of prosthetic crowns for teeth prepared with the Vertical Edgeless Preparation (VEP) technique. This technique extends the tooth preparation below the gingival margin on the root surface of teeth with reduced periodontal attachment. The tooth prepared according to this technique does not present a defined prosthetic margin or the relative finishing line. Still, it shows an edgeless axial wall that emerges from the gingival sulcus. The digital procedure for creating a prosthetic emergence profile, although representing a novelty in absolute terms, is based on traditional concepts, as they have been known and described in the literature for a long time. This article will explain and review the various clinical and laboratory steps necessary to produce, through an entirely digital procedure, a fixed partial denture composed of three zirconia elements, which are going to be subsequently veneered in a traditional way on the vestibular side to improve the esthetic appearance.

ABSTRACT: The present study aims to characterize the artisanal saffron ricotta cheese produced from the whey of Piacentinu Ennese protected designation of origin (PDO) cheesemaking, including via technological parameters detected during the production process and by assessment of the main physicochemical, microbial, sensory, and antioxidant characteristics. A survey on the manufacture process of saffron and control ricotta cheese was conducted on 3 farms, located in the production area of the Piacentinu Ennese PDO cheese. pH and temperature followed a specific behavior, characterized by an inverse trend where pH decreased and temperature increased, playing an important role in the production process. All the analytical parameters were affected by the presence of saffron, also showing high between-farm variability, with significantly higher total solids and fat contents in saffron ricotta cheese compared with the control cheese (28.68% vs. 23.86%, and 19.83% vs. 14.22%, respectively). Microbial analysis showed significantly lower values in saffron compared with control ricotta cheese, for coliforms (1.51 vs. 1.91 log10 cfu/g, respectively), yeasts (1.55 vs. 2.06 log10 cfu/g, respectively), and molds (1.03 vs. 1.30 log10 cfu/g, respectively), denoting potential reduction of microbial growth asserted by saffron. Escherichia coli concentration (1.26 log10 cfu/g) in saffron ricotta cheese was in accordance with EU Regulation 2073/2005 and then safe for consumption. The presence of saffron influenced all sensory attributes, particularly color and aroma. Interestingly, high total antioxidant activity was found in saffron ricotta cheese (372 µC) compared with the control cheese. Thus, this artisanal dairy production could be considered a suitable option for functional foods with antimicrobial properties, due to the presence of saffron, which may contribute to extend the shelf life of the product. Further studies need to focus on the bioactive compounds that affect the antioxidant proprieties, characterization of the microbiota of saffron ricotta cheese, and evaluation of consumers' acceptance and perception as well as market demand.

The practice of teleworking is being consistently and unprecedently used across multiple work sectors, including the research one, yet the direct and mediated links of specific telework designs with productivity are unclear, and analyses at multiple levels missing. Accordingly, this study aims at exploring the mediating role of the climate for well-being and well-being outcomes in the relationship between multiple components of teleworking and scientific productivity, both at the individual and team level. Data were collected from 358 members of 48 Spanish European Research Council (ERC)-granted teams. Analyses were conducted both at the individual and team level, after checking for the relevant aggregation indexes. Telework components of quantity, frequency, flexibility, and voluntariness were found to have direct and mediated significant relationships with scientific productivity, confirming the need to investigate telework with a closer focus on how it is designed and implemented in the different teams. Specifically, climate for well-being, eudaimonic well-being, and negative emotions were found to play a relevant role in mediating the relationship between some telework components (i.e., telework flexibility and voluntariness) and scientific productivity. Also, telework quantity and frequency were found to have, respectively, positive and negative relationship with scientific productivity. Practical and theoretical implications are further discussed in the article.

Over the recent decades, an apparent worldwide rise in Harmful Algae Blooms (HABs) has been observed due to the growing exploitation of the coastal environment, the exponential growth of monitoring programs, and growing global maritime transport. HAB species like Alexandrium catenella—responsible for paralytic shellfish poisoning (PSP)—Protoceratium reticulatum, and Lingulaulax polyedra (yessotoxin producers) are a major public concern due to their negative socioeconomic impacts. The significant northward geographical expansion of A. catenella into more oceanic-influenced waters from the fjords where it is usually observed needs to be studied. Currently, their northern boundary reaches the 36°S in the Biobio region where sparse vegetative cells were recently observed in the water column. Here, we describe the environment of the Biobio submarine canyon using sediment and water column variables and propose how toxic resting cyst abundance and excystment are coupled with deep-water turbulence (10−7 Watt/kg) and intense diapycnal eddy diffusivity (10−4 m2 s−1) processes, which could trigger a mono or multi-specific harmful event. The presence of resting cysts may not constitute an imminent risk, with these resting cysts being subject to resuspension processes, but may represent a potent indicator of the adaptation of HAB species to new environments like the anoxic Biobio canyon.

The development of artificial intelligence-based tools is having a big impact on industry. In this context, the maintenance operations of important assets and industrial resources are changing, both from a theoretical and a practical perspective. Namely, conventional maintenance reacts to faults and breakdowns as they occur or schedules the necessary inspections of systems and their parts at fixed times by using statistics on component failures, but this can be improved by a predictive maintenance based on the real component’s health status, which is inspected by appropriate sensors. In this way, maintenance time and costs are saved. Improvements can be achieved even in the marine industry, in which complex ship propulsion systems are produced for operation in many different scenarios. In more detail, data-driven models, through machine learning (ML) algorithms, generate the expected values of monitored variables for comparison with real measurements on the asset, for a diagnosis based on the difference between expectations and observations. The first step towards realization of predictive maintenance is choosing the ML algorithm. This selection is often not the consequence of an in-depth analysis of the different algorithms available in the literature. For that reason, here the authors propose a framework to support an initial implementation stage of predictive maintenance based on a benchmarking of the most suitable ML algorithms. The comparison is tested to predict failures of the oil circuit in a diesel marine engine as a case study. The algorithms are compared by considering not only the mean squared error between the algorithm predictions and the data, but also the response time, which is a crucial variable for maintenance. The results clearly indicate the framework well supports predictive maintenance and the prediction error and running time are appropriate variables to choose the most suitable ML algorithm for prediction. Moreover, the proposed framework can be used to test different algorithms, on the basis of more performance indexes, and to apply predictive maintenance to other engine components.

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

This systematic review aimed to verify whether there is evidence of an association between apical periodontitis and the presence of systemic biomarkers. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA. For this, the acronym PECO was used; population (P) of adult humans exposed (E) to the presence of apical periodontitis, compared (C) to adult humans without apical periodontitis, and the outcome (O) of the presence of biomarkers was observed. The articles were searched in PubMed, Scopus, Web of Science, LILACS, Cochrane Library, OpenGray, and Google Scholar grey databases. Subsequently, studies were excluded based on title, abstract, and full article reading, following the eligibility criteria. The methodological quality of the selected studies was evaluated using the Newcastle-Ottawa qualifier. After exclusion, 656 studies were identified, resulting in 17 final articles that were divided into case-control, cross-sectional, and cohort studies. Eight studies were considered to have a low risk of bias, one had a medium risk of bias, and eight had a high risk of bias. In addition, 12 articles evaluated biomarkers in blood plasma, four evaluated them in saliva, and only one evaluated them in gingival crevicular fluid. The results of these studies indicated an association between apical periodontitis and the systemic presence of biomarkers. These markers are mainly related to inflammation, such as interleukins IL-1, IL-2, and IL-6, oxidative markers, such as nitric oxide and superoxide anions, and immunoglobulins IgG and IgM.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier (CRD42023493959).

We have previously shown that after few seconds of adaptation by finger-tapping, the perceived numerosity of spatial arrays and temporal sequences of visual objects displayed near the tapping region is increased or decreased, implying the existence of a sensorimotor numerosity system (Anobile et al., 2016). To date, this mechanism has been evidenced only by adaptation. Here, we extend our finding by leveraging on a well-established covariance technique, used to unveil and characterize ‘channels’ for basic visual features such as colour, motion, contrast, and spatial frequency. Participants were required to press rapidly a key a specific number of times, without counting. We then correlated the precision of reproduction for various target number presses between participants. The results showed high positive correlations for nearby target numbers, scaling down with numerical distance, implying tuning selectivity. Factor analysis identified two factors, one for low and the other for higher numbers. Principal component analysis revealed two bell-shaped covariance channels, peaking at different numerical values. Two control experiments ruled out the role of non-numerical strategies based on tapping frequency and response duration. These results reinforce our previous reports based on adaptation, and further suggest the existence of at least two sensorimotor number channels responsible for translating symbolic numbers into action sequences.

Abstract Induced seismicity represents a negative drawback during subsurface exploitation for geothermal energy production. Understanding the triggering mechanisms of induced earthquakes can help implement effective seismic hazard mitigation actions. Among the triggering mechanisms, the pore fluid pressure is of primary importance. Here we provide a static picture of the excess pore fluid pressure at the hypocenters of a seismic sequence induced at the deep geothermal field in St. Gallen, Switzerland, in July 2013. We find that in addition to the Coulomb static stress change, fluids play a key role in promoting the sequence. The estimated excess pore fluid pressure for approximately half of the earthquakes is higher than the injection pressure necessary during the well control phase to fight the unexpected gas kick, that accidently occurred during field operations when a trap of overpressured gas was broken.

Background:. Patients with persistent glenohumeral osteoarthritis symptoms despite nonoperative management may pursue anatomic total shoulder arthroplasty (TSA). TSA revision rates are higher in patients with preoperative eccentric (asymmetric posterior erosion) compared with concentric (symmetric) glenoid deformity. If posterior rotator cuff deficiency demonstrated preoperatively in patients with eccentric deformity persists after TSA, it may manifest as relative weakness in external compared with internal rotation secondary to deficient activity of the shoulder external rotator muscles. Persistent posterior rotator cuff deficiency is hypothesized to contribute to TSA failures. However, it remains unknown whether rotational strength is impaired after TSA in patients with eccentric deformity. Our goal was to determine if patients with eccentric deformity exhibit relative external rotation weakness that may be explained by posterior rotator cuff deficiency after TSA. Methods:. Patients who were >1 year after TSA for primary glenohumeral osteoarthritis and had had preoperative eccentric or concentric deformity were prospectively recruited. Torque was measured and electromyography was performed during maximal isometric contractions in 26 three-dimensional direction combinations. Relative strength in opposing directions (strength balance) and muscle activity of 6 shoulder rotators were compared between groups. Results:. The internal (+) and external (−) rotation component of strength balance did not differ in patients with eccentric (mean internal-external rotation component of strength balance: −7.6% ± 7.4%) compared with concentric deformity (−10.3% ± 6.8%) (mean difference: 2.7% [95% confidence interval (CI), −1.3% to 6.7%]; p = 0.59), suggesting no relative external rotation weakness. Infraspinatus activity was reduced in patients with eccentric (43.9% ± 10.4% of maximum voluntary contraction [MVC]) compared with concentric (51.3% ± 10.4% of MVC) deformity (mean difference: −7.4% [95% CI, −13.4% to −1.4%] of MVC; p = 0.04). Conclusions:. A relative external rotation strength deficit following TSA was not found, despite evidence of reduced infraspinatus activity, in the eccentric-deformity group. Reduced infraspinatus activity suggests that posterior rotator cuff deficiencies may persist following TSA in patients with eccentric deformities. Longitudinal study is necessary to evaluate muscle imbalance as a contributor to higher TSA failure rates. Level of Evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify biomarkers that distinguish fast progression (FP) from slow progression (SP) and assess their temporal response. Methods We utilized mass spectrometry (MS)‐based proteomics to identify candidate biomarkers using longitudinal CSF from a discovery cohort of SP and FP ALS patients. Immunoassays were used to quantify and validate levels of the top biomarkers. A state‐transition mathematical model was created using the longitudinal MS data that also predicted FP versus SP. Results We identified a total of 1148 proteins in the CSF of all ALS patients. Pathway analysis determined enrichment of pathways related to complement and coagulation cascades in FPs and synaptogenesis and glucose metabolism in SPs. Longitudinal analysis revealed a panel of 59 candidate markers that could segregate FP and SP ALS. Based on multivariate analysis, we identified three biomarkers (F12, RBP4, and SERPINA4) as top candidates that segregate ALS based on rate of disease progression. These proteins were validated in the discovery and a separate validation cohort. Our state‐transition model determined that the overall variance of the proteome over time was predictive of the disease progression rate. Interpretation We identified pathways and protein biomarkers that distinguish rate of ALS disease progression. A mathematical model of the CSF proteome determined that the change in entropy of the proteome over time was predictive of FP versus SP.

In recent years, the development of Advanced Driver-Assistance Systems (ADASs) is driving the need for more reliable and precise on-vehicle sensing. Radar and lidar are crucial in this framework, since they allow sensing of vehicle’s surroundings. In such a scenario, it is necessary to master these sensing systems, and knowing their similarities and differences is important. Due to ADAS’s intrinsic real-time performance requirements, it is almost mandatory to be aware of the processing algorithms required by radar and lidar to understand what can be optimized and what actions can be taken to approach the real-time requirement. This review aims to present state-of-the-art radar and lidar technology, mainly focusing on modulation schemes and imaging systems, highlighting their weaknesses and strengths. Then, an overview of the sensor data processing algorithms is provided, with some considerations on what type of algorithms can be accelerated in hardware, pointing to some implementations from the literature. In conclusion, the basic concepts of sensor fusion are presented, and a comparison between radar and lidar is performed.

Background/purpose: Testing of dental materials when in contact with innate immune cells has been so far hindered by the lack of proper in vitro models. Human primary monocyte-derived macrophages (MDMs) would be an excellent option to this aim. However, the inability to detach them from the tissue culture plates contrast the possibility to culture them on biomaterials. The goal of the present work is to present and validate an innovative protocol to obtain MDMs from peripheral blood monocytes, and to reseed them in contact with biomaterials without altering their viability and phenotype. Materials and methods: We differentiated MDMs on ultra-low attachment tissue culture plastics and recovered them with specific detachment solution in order to be reseeded on a secondary substrate. Therefore, using biological assays (RT-PCR, Western blot, and immunofluorescence) we compared their phenotype to MDMs differentiated on standard culture plates. Results: Transferred MDMs keep their differentiated M0 resting state, as well as the ability to be polarized into M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages. Conclusion: These data provide the dental material research community the unprecedented possibility to investigate the immunomodulatory properties of biomaterials for dental application.

Abstract The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38− blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142 −/− BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142 +/+ BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142 −/− BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of “bulk” and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142 −/− BCR-ABL mice and patient-derived xenografts.

The receptor–receptor interaction (RRI) of G protein-coupled receptors (GPCRs) leads to new functional entities that are conceptually distinct from the simple addition of signals mediated by the activation of the receptors that form the heteromers. Focusing on astrocytes, there is evidence for the existence of inhibitory and facilitatory RRIs, including the heteromers formed by the adenosine A2A and the dopamine D2 receptors, by A2A and the oxytocin receptor (OTR), and the D2-OTR heteromers. The possible involvement of these receptors in mosaicism has never been investigated in striatal astrocytes. By biophysical and functional approaches, we focused our attention on the existence of an A2A-D2-OTR high-order receptor complex and its role in modulating cytosolic calcium levels and endogenous glutamate release, when striatal astrocyte processes were stimulated with 4-aminopyridine. Functional data indicate a permissive role of OTR on dopamine signaling in the regulation of the glutamatergic transmission, and an inhibitory control mediated by A2A on both the D2-mediated signaling and on the OTR-facilitating effect on D2. Imaging biochemical and bioinformatic evidence confirmed the existence of the A2A-D2-OTR complex and its ternary structure in the membrane. In conclusion, the D2 receptor appears to be a hotspot in the control of the glutamate release from the astrocytic processes and may contribute to the regulation and integration of different neurotransmitter-mediated signaling in the striatum by the A2A-D2-OTR heterotrimers. Considering the possible selectivity of allosteric interventions on GPCRs organized as receptor mosaics, A2A-D2-OTR heterotrimers may offer selective pharmacological targets in neuropsychiatric disorders and neurodegenerative diseases.

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial–nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific “TTGGGGGGTG” region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2′s novel function of regulating mitochondrial–nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis.

LVR-15 is a light-water-tank-type research reactor placed in a stainless-steel vessel under a shielding cover located in the Research Centre Rez (CVR) near Prague. It is operated at a steady-state power of up to 10 MWt under atmospheric pressure and is cooled by forced circulation. In 2011, the fuel was replaced, going from high-enriched uranium (HEU) to low-enriched uranium (LEU). After 2017, the State Office for Nuclear Safety (SUJB) asked CVR to evaluate the LVR-15 under Design Extended Conditions B (DEC-B). For this reason, a new model was developed in the MELCOR code, which allows for modelling the progression of a severe accident (SA) in light-water nuclear power plants and estimating the behaviour of the reactor under SA conditions. The model was built by collecting information about the LVR-15. Since the research reactor can have different core configurations according to the location of the core components, the core configuration with the most fuel (hottest campaign K221) was selected. Then, to create the radial nodalisation, the details of the core components were obtained and grouped in five radial rings and 27 axial levels. The simulation was run with the boundary conditions collected from campaign K221, and the results were compared with the reference values of the campaign with a negligible percentage of error. For the coolant inlet and outlet temperature, the reference values were 318.18 K and 323.5 K, respectively, while for the simulation, the steady state reached 319 K for the inlet temperature and 324 K for the outlet temperature. Additionally, the cladding temperature of the hottest assembly was compared with the reference value (353.72 K) and the steady-state simulation results (362 K). In future work, different transients leading to severe accidents will be simulated. When simulating the LVR-15 reactor with MELCOR, specific attention is required for the aluminium-cladded fuel assemblies, as the model requires some assumptions to cope with the phenomenological limitations.

Successful human pregnancy needs several highly controlled steps to guarantee an oocyte’s fertilization, the embryo’s pre-implantation development, and its subsequent implantation into the uterine wall. The subsequent placenta development ensures adequate fetal nutrition and oxygenation, with the trophoblast being the first cell lineage to differentiate during this process. The placenta sustains the growth of the fetus by providing it with oxygen and nutrients and removing waste products. It is not surprising that issues with the early development of the placenta can lead to common pregnancy disorders, such as recurrent miscarriage, fetal growth restriction, pre-eclampsia, and stillbirth. Understanding the normal development of the human placenta is essential for recognizing and contextualizing any pathological aberrations that may occur. The effects of these issues may not become apparent until later in pregnancy, during the mid or advanced stages. This review discusses the process of the embryo implantation phase, the molecular mechanisms involved, and the abnormalities in those mechanisms that are thought to contribute to the development of pre-eclampsia. The review also covers the histological hallmarks of pre-eclampsia as found during the examination of placental tissue from pre-eclampsia patients.

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis with a multifactorial pathogenesis. Historically, it has been classified as type 1 and type 2, according to its clinical and histological features. The diagnosis of AIP is challenging and relies on a combination of clinical, histopathologic, serologic, and imaging characteristics. In the available guidelines, the imaging hallmarks of AIP are based on cross-sectional imaging and cholangiopancreatography retrograde endoscopic findings. Endoscopic ultrasound (EUS) is generally used for pancreatic tissue acquisition to rule out pancreatic cancer and diagnose AIP with limited accuracy. Several papers reported the reliability of EUS for providing informative morphologic features of AIP. Nowadays, the improvement in the resolution of EUS conventional images and the development of new ancillary technologies have further increased the diagnostic yield of EUS: contrast-enhanced EUS and EUS elastography are non-invasive and real-time techniques that strongly support the diagnosis and management of pancreatic diseases. In this review article, we will present the role of conventional EUS and ancillary diagnostic techniques in the diagnosis of AIP to support clinicians and endosonographers in managing this condition.