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Multifunctional therapies have emerged as innovative strategies in cancer treatment. In this research article, we proposed a nanostructured lipid carrier (NLC) designed for the topical treatment of cutaneous melanoma, which simultaneously delivers 5-FU and Bcl-2 siRNA. The characterized nanoparticles exhibited a diameter of 259 ± 9 nm and a polydispersion index of 0.2, indicating a uniform size distribution. The NLCs were primarily localized in the epidermis, effectively minimizing the systemic release of 5-FU across skin layers. The ex vivo skin model revealed the formation of a protective lipid film, decreasing the desquamation process of the stratum corneum which can be associated to an effect of increasing permeation. In vitro assays demonstrated that A375 melanoma cells exhibited a higher sensitivity to the treatment compared to non-cancerous cells, reflecting the expected difference in their metabolic rates. The uptake of NLC by A375 cells reached approximately 90% within 4 h. The efficacy of Bcl-2 knockdown was thoroughly assessed using ELISA, Western blot, and qRT-PCR analyses, revealing a significant knockdown and synergistic action of the NLC formulation containing 5-FU and Bcl-2 siRNA (at low concentration --100 pM). Notably, the silencing of Bcl-2 mRNA also impacted other members of the Bcl-2 protein family, including Mcl-1, Bcl-xl, BAX, and BAK. The observed modulation of these proteins strongly indicated the activation of the apoptosis pathway, suggesting a successful inhibition of melanoma growth and prevention of its in vitro spread., (© 2024. Controlled Release Society.)

Abstract: Mitochondrial dysfunction is a recognized feature of sepsis, characterized by ultrastructural damage, diminished oxidative phosphorylation, and depletion of mitochondrial antioxidant capacity observed in deceased septic patients. LPS tolerance induces a controlled response to sepsis. This study aimed to evaluate the function of tolerant mitochondria after cecal ligation and puncture (CLP)-induced sepsis. Mytochondrial oxygen consumption was determined using polarography. Extraction and quantification of RNA for the expression of Tfam, Nrf-1, and Ppargc-1α, and respiratory complex activity were measured. CLP-tolerant animals presented preserved respiratory rates of S3 and S4 and a ratio of respiratory control (RCR) compared to CLP-nontolerant animals with reduced oxidative phosphorylation and increased uncoupled respiration. Complex I Vmax was reduced in septic animals; however, CLP animals sustained normal Vmax. Mitochondrial biogenesis was preserved in CLP-tolerant animals compared to the CLP-nontolerant group, likely due to increased TFAM expression. LPS tolerance protected septic animals from mitochondrial dysfunction, favoring mitochondrial biogenesis and preserving mitochondrial respiration and respiratory complex I activity., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Intrinsically disordered proteins (IDPs) exhibit molecular-level conformational dynamics that are functionally harnessed across a wide range of fascinating biological phenomena. The low sequence complexity of IDPs has led to the design and development of intrinsically-disordered protein polymers (IDPPs), a class of engineered repeat IDPs with stimuli-responsive properties. The perfect repetitive architecture of IDPPs allows for repeat-level encoding of tunable protein functionality. Designer IDPPs can be modeled on endogenous IDPs or engineered de novo as protein polymers with dual biophysical and biological functionality. Their properties can be rationally tailored to access enigmatic IDP biology and to create programmable smart biomaterials. With the goal of inspiring the bioengineering of multifunctional IDP-based materials, here we synthesize recent multidisciplinary progress in programming and exploiting the bio-functionality of IDPPs and IDPP-containing proteins. Collectively, expanding beyond the traditional sequence space of extracellular IDPs, emergent sequence-level control of IDPP functionality is fueling the bioengineering of self-assembling biomaterials, advanced drug delivery systems, tissue scaffolds, and biomolecular condensates -genetically encoded organelle-like structures. Looking forward, we emphasize open challenges and emerging opportunities, arguing that the intracellular behaviors of IDPPs represent a rich space for biomedical discovery and innovation. Combined with the intense focus on IDP biology, the growing landscape of IDPPs and their biomedical applications set the stage for the accelerated engineering of high-value biotechnologies and biomaterials., Competing Interests: Declaration of Competing Interest FGQ is an inventor on United States patents that describe phase transition IDPPs and in a patent application covering designs and uses of phase separation sensors. The remaining authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Biomolecular condensates are dynamic membraneless compartments with enigmatic roles across intracellular phenomena. Intrinsically-disordered proteins (IDPs) often function as condensate scaffolds, fueled by their liquid-liquid phase separation (LLPS) dynamics. Intracellular probing of these condensates relies on live-cell imaging of IDP-scaffolds tagged with fluorescent proteins. Conformational heterogeneity in IDPs, however, renders them uniquely sensitive to molecular-level fusions, risking distortion of the native biophysical properties of IDP-scaffolds and their assemblies. Probing epidermal condensates in mouse skin, we recently introduced genetically encoded LLPS-sensors that circumvent the need for molecular-level tagging of skin IDPs. The concept of LLPS-sensors involves a shift in focus from subcellular tracking of IDP-scaffolds to higher-level observations that report on the assembly and liquid-dynamics of their condensates. Towards advancing the repertoire of intracellular LLPS-sensors, here we demonstrate biomolecular approaches for the evolution and tunability of epidermal LLPS-sensors and assess their impact in early and late stages of intracellular LLPS dynamics. Benchmarking against scaffold-bound fluorescent reporters, we found that tunable ultraweak scaffold-sensor interactions are key to the sensitive and innocuous probing of nascent and established biomolecular condensates. Our LLPS-sensitive tools pave the way for the high-fidelity intracellular probing of IDP-governed biomolecular condensates across biological systems.

The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes.

Background: The intensity of dengue virus (DV) replication and circulating non-structural protein 1 (NS1) levels may promote changes in the human immune response and favor severe forms of infection. We investigated the correlations between NS1 with CXCL-8, CXCL-10, IFN-γ, and IL-12p40 serum levels, and IFN-γ receptor α chain (CD119) expression, and CXCL10 production by peripheral blood mononuclear cells (PBMCs) stimulated with recombinant IFN-γ in DV-infected patients with different clinical forms., Methods: Dengue virus NS1, CXCL-8, CXCL-10, IFN-γ, and IL-12p40 serum levels were measured in 152 DV-infected patients with different clinical forms and 20 non-infected individuals (NI) using enzyme-linked immunosorbent assay (ELISA). In addition, we investigated the CXCL-10 production after in vitro IFN-γ stimulation of PBMCs from 48 DV-infected individuals (with different clinical forms of dengue fever) and 20 NI individuals using ELISA, and CD119 expression on CD14+ cells with flow cytometry., Results: Patients with dengue hemorrhagic fever (DHF) had significantly higher NS1, CXCL-8, and CXCL-10 serum levels than those with classic dengue fever (DF). The response of PBMCs to IFN-γ stimulation was lower in patients with DHF than in those with DF or dengue with complications (DWC), with lower CD119 expression and reduced CXCL-10 synthesis. In addition, these alterations are associated with high NS1 serum levels., Conclusions: Patients with DHF reported high NS1 levels, low CD119 expression, and low CXCL-10 synthesis in PBMCs, which may be associated with infection progression and severity.

Introduction: esophageal replacement in children is indicated when it is impossible to maintain the native esophagus, which in the pediatric population includes patients with esophageal atresia and esophageal caustic stenosis. The objective of this communication is to report the experience of a university service with two techniques of esophageal replacement., Methods: this is a retrospective study based on the revision of hospital files. The study population consisted of patients who underwent esophageal replacement from 1995 to 2022, at the Hospital de Clínicas of the State University of Campinas. The analyzed data were age, sex, underlying disease, technical aspects, complications, and long-term results., Results: during the study period, 30 patients underwent esophageal replacement. The most common underlying diseases were esophageal atresia (73.33%) and caustic stenosis (26.67%). Twenty-one patients underwent gastric transposition (70%), and nine underwent esophagocoloplasty (30%). The most frequent postoperative complication was fistula of the proximal anastomosis, which occurred in 14 patients. Most of the patients with fistulas had a spontaneous recovery. There were three deaths. Of the 27 survivors, 24 can feed exclusively by mouth., Conclusion: esophageal replacement in children is a procedure with high morbidity and mortality. Esophagocoloplasty and gastric transposition have similar results and complications, with the exception of proximal anastomotic fistulas, which are generally self-resolving and are more common in esophagocoloplasty. The choice of the best surgical technique must be individualized according to the patients characteristics and the surgeons experience, as both techniques offer the ability to feed orally in the short or medium term.

Introduction: Distinguishing and categorizing the origin of garlic are highly significant, considering its widespread use as a flavoring agent. With billions of dollars annually in global trade, garlic is frequently susceptible to fraudulent practices., Methodology: Paper spray ionization mass spectrometry (PS-MS) was employed to quickly analyze garlic samples from distinct geographic origins: China and Brazil. The so-generated PS-MS data were treated with metabolomic multivariate approaches, and the garlic samples from these different geographic regions were easily discriminated., Results: Brazilian garlic was characterized to contain higher levels of amino acids, such as arginine, proline, and valine, and organosulfur compounds, such as allicin, alliin, and l-γ-glutamil-S-allyl-l-cysteine, compared to Chinese garlic. The PS-MS data were treated employing multivariate approaches, typically used in the metabolomics field, and this protocol was promptly able to discern among both types of samples., Conclusion: Hence, this combined strategy holds promise not only as an effective tool for the authentication of the geographical origin of garlic but also as a powerful means for biomarker discovery., (© 2024 John Wiley & Sons Ltd.)

Integrating agricultural, chemical, and technological knowledge is crucial for developing bio-nanotechnologies to improve agricultural production. This study explores the innovative use of biopolymeric coatings, based on sodium alginate and sodium alginate + Laponite® (nanoclay), containing biostimulants (tryptophol and thymol) or not, on garlic cloves. These coatings were analyzed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR-ATR), and scanning electron microscopy (SEM). Greenhouse bioassays showed improvements in garlic shoot plant biomass with both treatments: sodium alginate biopolymer and sodium alginate biopolymer plus Laponite®. In the field experiment, garlic plants treated with sodium alginate, in combination with conventional pesticide treatments, resulted in better quality garlic bulbs, where larger garlics were harvested in this treatment, reducing commercial losses. In tropical garlic crops, obtaining plants with greater initial vigor is essential. Our results highlight the potential of these bio-nanotechnological strategies to enhance garlic propagation, ensuring environmental protection and food security., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The use of dwarf plants in tomato breeding has provided several advantages. However, there are no identified dwarf plants ( dd ) containing the self-pruning habit ( spsp ). The aim of this work was to obtain future generations, characterize the germplasm, and select potential dwarf plants with a determinate growth habit to obtain Salad-type lines. The work was started by carrying out hybridization, followed by the first, second, and third backcrosses. Once F 2 BC 3 seeds became available, the introgression of the self-pruning gene ( spsp ) into dwarf plants ( dd ) began. Three strains of normal architecture and a determinate growth habit were hybridized with two strains of dwarf size and an indeterminate growth habit, thus yielding four hybrids. Additionally, donor genotype UFU MC TOM1, the commercial cultivar Santa Clara, and the wild accession Solanum pennellii were used in the experiment. Agronomic traits, fruit quality, metabolomics, and acylsugars content were evaluated, and dwarf plants with a determinate growth habit were selected. Hybrid 3 exhibited the highest yields. Visual differences between determinate and indeterminate dwarf plant seedlings were observed. It is suggested to carry out five self-pollinations of the best dwarf plant determined and subsequent hybridization with homozygous lines of normal plant architecture and determinate growth habit to obtain hybrids.

Adaptation of avian pathogenic E. coli (APEC) to changing host environments including virulence factors expression is vital for disease progression. FdeC is an autotransporter adhesin that plays a role in uropathogenic Escherichia coli (UPEC) adhesion to epithelial cells. Expression of fdeC is known to be regulated by environmental conditions in UPEC and Shiga toxin-producing E. coli (STEC). The observation in a previous study that an APEC strain IMT5155 in which the fdeC gene was disrupted by a transposon insertion resulted in elevated adhesion to chicken intestinal cells prompted us to further explore the role of fdeC in infection. We found that the fdeC gene prevalence and FdeC variant prevalence differed between APEC and nonpathogenic E. coli genomes. Expression of the fdeC gene was induced at host body temperature, an infection relevant condition. Disruption of fdeC resulted in greater adhesion to CHIC-8E11 cells and increased motility at 42 °C compared to wild type (WT) and higher expression of multiple transporter proteins that increased inorganic ion export. Increased motility may be related to increased inorganic ion export since this resulted in downregulation of YbjN, a protein known to supress motility. Inactivation of fdeC in APEC strain IMT5155 resulted in a weaker immune response in chickens compared to WT in experimental infections. Our findings suggest that FdeC is upregulated in the host and contributes to interactions with the host by down-modulating motility during colonization. A thorough understanding of the regulation and function of FdeC could provide novel insights into E. coli pathogenesis., (© 2024. The Author(s).)

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Perez-Sisques et al.)

Breast cancer stands out as one of the most prevalent malignancies worldwide, necessitating a nuanced understanding of its molecular underpinnings for effective treatment. Hormone receptors in breast cancer cells substantially influence treatment strategies, dictating therapeutic approaches in clinical settings, serving as a guide for drug development, and aiming to enhance treatment specificity and efficacy. Natural compounds, such as curcumin, offer a diverse array of chemical structures with promising therapeutic potential. Despite curcumin's benefits, challenges like poor solubility and rapid metabolism have spurred the exploration of analogs. Here, we evaluated the efficacy of the curcumin analog NC2603 to induce cell cycle arrest in MCF-7 breast cancer cells and explored its molecular mechanisms. Our findings reveal potent inhibition of cell viability (IC50 = 5.6 μM) and greater specificity than doxorubicin toward MCF-7 vs. non-cancer HaCaT cells. Transcriptome analysis identified 12,055 modulated genes, most notably upregulation of GADD45A and downregulation of ESR1 , implicating CDKN1A -mediated regulation of proliferation and cell cycle genes. We hypothesize that the curcumin analog by inducing GADD45A expression and repressing ESR1 , triggers the expression of CDKN1A , which in turn downregulates the expression of many important genes of proliferation and the cell cycle. These insights advance our understanding of curcumin analogs' therapeutic potential, highlighting not just their role in treatment, but also the molecular pathways involved in their activity toward breast cancer cells.

Background: Blood transfusion reactions may have a negative impact on organ function. It is unknown whether this association holds true for acute kidney injury (AKI). Therefore, we conducted a cohort study to assess the association between transfusion reactions and the incidence of AKI and major adverse kidney events., Methods: In this retrospective cohort study, we included patients who received transfusion of blood products during hospitalization at the Hospital Civil of Guadalajara. We analyzed them according to the development of transfusion reactions, and the aim was to assess the association between transfusion reactions and AKI during long-term follow-up., Results: From 2017 to 2021, 81,635 patients received a blood product transfusion, and 516 were included in our study. The most common transfusion was red blood cell packaging (50.4%), fresh frozen plasma (28.7%) and platelets (20.9%); of the 516 patients, 129 (25%) had transfusion reactions. Patients who had transfusion reactions were older and had more comorbidities. The most common type of transfusion reaction was allergic reaction (70.5%), followed by febrile nonhemolytic reaction (11.6%) and anaphylactoid reaction (8.5%). Most cases were considered mild. Acute kidney injury was more prevalent among those who had transfusion reactions (14.7%) than among those who did not (7.8%), p =  < 0.01; those with AKI had a higher frequency of diabetes, vasopressors, and insulin use. Transfusion reactions were independently associated with the development of AKI (RR 2.1, p =  < 0.02). Major adverse kidney events were more common in those with transfusion reactions. The mortality rate was similar between subgroups., Conclusion: In our retrospective cohort of patients who received blood product transfusions, 25% experienced transfusion reactions, and this event was associated with a twofold increase in the probability of developing AKI and some of the major adverse kidney events during long follow-up., (© 2024. The Author(s).)

Competing Interests: The authors have declared they have no conflicts of interest.

Gene therapy is one of the most advanced therapies in current medicine. In particular, interference RNA-based therapy by small interfering RNA (siRNA) has gained attention in recent years as it is a highly versatile, selective and specific therapy. In dermatological conditions, topical delivery of siRNA offers numerous therapeutic advantages, mainly by inhibiting the expression of target transcripts directly in the skin. However, crossing the stratum corneum and overcoming intracellular barriers is an inherent challenge. Substantial efforts by scientists have moved towards the use of multimodal and multifunctional nanoparticles to overcome these barriers and achieve greater bioavailability in their site of action, the cytoplasm. In this review the most innovative strategies based on nanoparticle and physical methods are presented, as well as the design principles and the main factors that contribute to the performance of these systems. This review also highlights the synergistic contributions of medicine, nanotechnology, and molecular biology to advancing translational research into siRNA-based therapeutics for skin diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breast cancer represents a critical global health issue, accounting for a substantial portion of cancer-related deaths worldwide. Metastasis, the spread of cancer cells to distant organs, is the primary cause of approximately 90% of breast cancer-related fatalities. Despite advances in cancer treatment, conventional chemotherapeutic drugs often encounter resistance and demonstrate limited efficacy against metastasis. Natural products have emerged as promising sources for innovative cancer therapies, with curcumin being one such example. However, despite its therapeutic potential, curcumin exhibits several limitations. Analogous compounds possessing enhanced bioavailability, potency, or specificity offer a promising avenue for overcoming these challenges and demonstrate potent anti-tumor activities. Our study investigates the antimetastatic potential of the curcumin analog NC2603 in breast cancer cells, utilizing BT-20 cells known for their migratory properties. Cell viability assessments were performed using the MTT reduction method, while migration inhibition was evaluated through scratch and Transwell migration assays. Transcriptome analysis via next-generation sequencing was employed to elucidate gene modulation and compound mechanisms, with subsequent validation using RT-qPCR. The IC50 of NC2603 was determined to be 3.5 μM, indicating potent inhibition of cell viability, and it exhibited greater specificity for BT-20 cells compared with non-cancerous HaCaT cells, surpassing the efficacy of doxorubicin. Notably, NC2603 demonstrated superior inhibition of cell migration in both scratch and Transwell assays compared with curcumin. Transcriptome analysis identified 10,620 modulated genes. We validated the expression of six: EGR3, ATF3, EMP1, SOCS3, ZFP36, and GADD45B, due to their association with migration inhibition properties. We hypothesize that the curcumin analog induces EGR3 expression, which subsequently triggers the expression of ATF3, EMP1, SOCS3, ZFP36, and GADD45B. In summary, this study significantly advances our comprehension of the intricate molecular pathways involved in cancer metastasis, while also examining the mechanisms of analog NC2603 and underscoring its considerable potential as a promising candidate for adjuvant therapy.

Advanced glycation end products (AGEs) prime macrophages for lipopolysaccharide (LPS)-induced inflammation. We investigated the persistence of cellular AGE-sensitization to LPS, considering the nuclear content of p50 and p65 nuclear factor kappa B (NFKB) subunits and the expression of inflammatory genes. Macrophages treated with control (C) or AGE-albumin were rested for varying intervals in medium alone before being incubated with LPS. Comparisons were made using one-way ANOVA or Student t -test ( n = 6). AGE-albumin primed macrophages for increased responsiveness to LPS, resulting in elevated levels of TNF, IL-6, and IL-1beta (1.5%, 9.4%, and 5.6%, respectively), compared to C-albumin. TNF, IL-6, and IL-1 beta secretion persisted for up to 24 h even after the removal of AGE-albumin (area under the curve greater by 1.6, 16, and 5.2 times, respectively). The expressions of Il6 and RelA were higher 8 h after albumin removal, and Il6 and Abca1 were higher 24 h after albumin removal. The nuclear content of p50 remained similar, but p65 showed a sustained increase (2.9 times) for up to 24 h in AGE-albumin-treated cells. The prolonged activation of the p65 subunit of NFKB contributes to the persistent effect of AGEs on macrophage inflammatory priming, which could be targeted for therapies to prevent complications based on the AGE-RAGE-NFKB axis.

An increasing number of countries and regions consider the bioeconomy transition a strategic policy priority. When approached through the lens of a circular economy perspective, investments in bioeconomy have the potential to enhance resource utilisation efficiency, preserve biodiversity and ecosystems, and foster sustainable development with low emissions. At the same time, if requirements and contextual factors of bioeconomy strategies are not formally analysed, bioeconomic investments might lead to unintended negative consequences. This paper proposes a decision support procedure to design, assess, prioritise, and monitor bioeconomy investments and policies. The flexibility and scalability of our decision support procedure is tested in Colombia to foster a regional and local transition to bioeconomy initiatives that consider the local capital assets and the stakeholders' views. The heterogeneous character of the Colombian environment, economy, society and culture represents an ideal condition to test the strength of the decision support procedure to promote bioeconomy in low and middle-income countries. Our empirical results highlight the benefit of adopting a formal assessment framework that includes strategic national indicators, regional features and stakeholders' views. In terms of the Colombian regional bioeconomy ambitions, we highlight the need for expanding knowledge hubs and participatory stakeholder networks and buttressing appropriate financial mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Coffee is a complex brew that contains several bioactive compounds and some of them can influence blood pressure (BP) and endothelial function (EF), such as caffeine and chlorogenic acids (CGAs)., Aim: This study aimed to evaluate the acute effects of coffee on BP and EF in individuals with hypertension on drug treatment who were habitual coffee consumers., Methods: This randomized crossover trial assigned 16 adults with hypertension to receive three test beverages one week apart: caffeinated coffee (CC; 135 mg caffeine, 61 mg CGAs), decaffeinated coffee (DC; 5 mg caffeine, 68 mg CGAs), and water. BP was continuously evaluated from 15 min before to 90 min after test beverages by digital photoplethysmography. Reactive hyperemia index (RHI) assessed by peripheral arterial tonometry evaluated EF before and at 90 min after test beverages. At the same time points, microvascular reactivity was assessed by laser speckle contrast imaging. Repeated-measures-ANOVA evaluated the effect of time, the effect of beverage, and the interaction between time and beverage (treatment effect)., Results: Although the intake of CC produced a significant increase in BP and a significant decrease in RHI, these changes were also observed after the intake of DC and were not significantly different from the modifications observed after the consumption of DC and water. Microvascular reactivity did not present significant changes after the 3 beverages., Conclusion: CC in comparison with DC and water neither promoted an acute increase in BP nor produced an improvement or deleterious effect on EF in individuals with hypertension on drug treatment who were coffee consumers., (© 2024. Italian Society of Hypertension.)

Due to the increasing interest in sorghum for human nutrition, recent literature reviews highlight its nutrient and bioactive contents, potential health benefits and its 'gluten-free' feature. Moreover, a current view of research advances on sorghum-based food products is needed to help both food scientists and industry identify current trends and forward-looking approaches. Studies on homemade processing are still scarce. Thus, this review aimed to provide the latest information regarding the use of sorghum to develop ready-to-eat products or food ingredients based on studies published in the last decade (2012-2022), which then guided discussions on recent advances and prospects. The articles were identified by searching the Elsevier Scopus database. Sorghum has great potential as a functional and sustainable food that can be used in daily meals as a substitute for common cereals like wheat, rice and corn. The studies in the review show that it is possible to process sorghum in a wide variety of ways to obtain ready-to-eat products and ingredients for food products and preparations, such as popping, lamination, extrusion and wet cooking. The studies also show promising approaches to use sorghum in acceptable and nutrient-dense bakery and pasta products, highlighting their gluten-free versions. However, more efforts to make these novel food products available to consumers should be made.

Objective: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults., Data Sources: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available., Methods: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge., Primary Endpoint: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used., Discussion: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?'Protocol version 0.4 - 06/26/2023PROSPERO registration:CRD42021278869.

Cyclodextrins are nanometric cyclic oligosaccharides with amphiphilic characteristics that increase the stability of drugs in pharmaceutical forms and bioavailability, in addition to protecting them against oxidation and UV radiation. Some of their characteristics are low toxicity, biodegradability, and biocompatibility. They are divided into α-, β-, and γ-cyclodextrins, each with its own particularities. They can undergo surface modifications to improve their performances. Furthermore, their drug inclusion complexes can be made by various methods, including lyophilization, spray drying, magnetic stirring, kneading, and others. Cyclodextrins can solve several problems in drug stability when incorporated into dosage forms (including tablets, gels, films, nanoparticles, and suppositories) and allow better topical biological effects of drugs at administration sites such as skin, eyeballs, and oral, nasal, vaginal, and rectal cavities. However, as they are nanostructured systems and some of them can cause mild toxicity depending on the application site, they must be evaluated for their nanotoxicology and nanosafety aspects. Moreover, there is evidence that they can cause severe ototoxicity, killing cells from the ear canal even when applied by other administration routes. Therefore, they should be avoided in otologic administration and should have their permeation/penetration profiles and the in vivo hearing system integrity evaluated to certify that they will be safe and will not cause hearing loss., (© 2022 John Wiley & Sons Ltd.)

Introduction: Worldwide, tetanus-diphtheria-acellular pertussis (Tdap) vaccination coverage of healthcare professionals (HCPs) is below 40%, but this data is not available for Brazil. We hypothesize that a high number of HCPs are not immune to pertussis in Brazil. Main objective was to determine the seroprevalence of anti-pertussis toxin (anti-PT IgG) among HCPs. Secondary objectives were to evaluate Tdap vaccination coverage, to assess predictive factors associated with anti-PT IgG, and to estimate the decay of anti-PT IgG and time to Tdap vaccination., Methods: Observational cross-sectional serological study in 352 HCPs who worked at São Paulo Hospital - Federal University of São Paulo (UNIFESP) in 2020, approved by UNIFESP Ethics Committee. Data collected included sociodemographics, knowledge about Tdap, and vaccination status. Anti-PT IgG were quantified by ELISA: <10 IU/mL seronegative and ≥ 10-1000 IU/mL seropositive. Titers ≥ 10-50 IU/mL were classified low positivity, indicating no recent B. pertussis infection or Tdap vaccination; >50 IU/mL high positivity, indicating recent B. pertussis infection or Tdap vaccination, and > 100 IU/mL as acute B. pertussis infection or Tdap vaccination in the previous year. Comparisons were done by Chi-square test, multivariable logistic regression, and Pearsońs correlation, at 5% p-level., Results: 331/352 HCPs were not aware the Brazilian National Immunization Program recommends Tdap for all HCPs and pregnant women. 68/339 HCPs received Tdap (mean 3.1 ± 2.0 years). 55/352 were seronegative for pertussis, all unvaccinated. 56/271 with no history of Tdap vaccination had high positivity. The probability of anti-PT IgG > 50 IU/mL was 11.5 times higher in Tdap vaccinated HCPs than in non-vaccinated (p < 0.001). There was a weak but significant correlation between anti-PT IgG and interval of Tdap vaccination (r = 0.404; p = 0.001). Anti-PT IgG dropped 5 IU/mL/year (p = 0.001)., Conclusion: Better education of HCPs on needs and benefits of Tdap vaccination is critical. Goals must be to improve HCPs vaccination coverage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

S-acylation is a reversible posttranslational protein modification consisting of attachment of a fatty acid to a cysteine via a thioester bond. Research over the last few years has shown that a variety of different fatty acids, such as palmitic acid (C16:0), stearate (C18:0), or oleate (C18:1), are used in cells to S-acylate proteins. We recently showed that GNAI proteins can be acylated on a single residue, Cys3, with either C16:0 or C18:1, and that the relative proportion of acylation with these fatty acids depends on the level of the respective fatty acid in the cell's environment. This has functional consequences for GNAI proteins, with the identity of the acylating fatty acid affecting the subcellular localization of GNAIs. Unclear is whether this competitive acylation is specific to GNAI proteins or a more general phenomenon in the proteome. We perform here a proteome screen to identify proteins acylated with different fatty acids. We identify 218 proteins acylated with C16:0 and 308 proteins acylated with C18-lipids, thereby uncovering novel targets of acylation. We find that most proteins that can be acylated by C16:0 can also be acylated with C18-fatty acids. For proteins with more than one acylation site, we find that this competitive acylation occurs on each individual cysteine residue. This raises the possibility that the function of many different proteins can be regulated by the lipid environment via differential S-acylation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The expression of inflammation-related miRs bound to high-density lipoproteins (HDLs), the anti-inflammatory activity of HDLs isolated from individuals with breast cancer, and controls were determined. Forty newly diagnosed women with breast cancer naïve of treatment and 10 control participants were included. Cholesterol-loaded bone-marrow-derived macrophages were incubated with HDL from both groups and challenged with lipopolysaccharide (LPS). Interleukin 6 (IL6) and tumor necrosis factor (TNF) in the medium were quantified. The miRs in HDLs were determined by RT-qPCR. Age, body mass index, menopausal status, plasma lipids, and HDL composition were similar between groups. The ability of HDL to inhibit IL6 and TNF production was higher in breast cancer compared to controls, especially in advanced stages of the disease. The miR-223-3p and 375-3p were higher in the HDLs of breast cancer independent of the histological type of the tumor and had a high discriminatory power between breast cancer and controls. The miR-375-3p was greater in the advanced stages of the disease and was inversely correlated with the secretion of inflammatory cytokines. Inflammation-related miRs and the anti-inflammatory role of HDLs may have a significant impact on breast cancer pathophysiology.

The evolution of medical knowledge about oral microbiota has increased awareness of its important role for the entire human body health. A wide range of microbial species colonizing the oral cavity interact both with each other and with their host through complex pathways. Usually, these interactions lead to a harmonious coexistence (i.e. eubiosis). However, several factors - including diet, poor oral hygiene, tobacco smoking, and certain medications, among others - can disrupt this weak homeostatic balance (i.e. dysbiosis) with potential implications on both oral (i.e. development of caries and periodontal disease) and systemic health. This article is thus aimed at providing an overview on the importance of oral microbiota in mediating several physiological and pathological conditions affecting human health. In this context, strategies based on oral hygiene and diet as well as the role of probiotics supplementation are discussed., Competing Interests: Declaration Of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Small interfering RNA (siRNA) molecules have limited transfection efficiency and stability, necessitating the use of delivery systems to be effective in gene knockdown therapies. In this regard, lipid-polymeric nanocarriers have emerged as a promising class of nanoparticles for siRNA delivery, particularly for topical applications. We proposed the use of solid lipid-polymer hybrid nanoparticles (SLPHNs) as topical delivery systems for siRNA. This approach was evaluated by assessing the ability of SLPHNs-siRNA complexes to internalize siRNA molecules and both to penetrate skin layers in vitro and induce gene knocking down in a skin cell line. The SLPHNs were formed by a specific composition of solid lipids, a surfactant polymer as a dispersive agent, and a cationic polymer as a complexing agent for siRNA. The optimized nanocarriers exhibited a spherical shape with a smooth surface. The average diameter of the nanoparticles was found to be 200 nm, and the zeta potential was measured to be +20 mV. Furthermore, these nanocarriers demonstrated excellent stability when stored at 4 °C over a period of 90 days. In vitro and in vivo permeation studies showed that SLPHNs increased the cutaneous penetration of fluorescent-labeled siRNA, which reached deeper skin layers. Efficacy studies were conducted on keratinocytes and fibroblasts, showing that SLPHNs maintained cell viability and high cellular uptake. Furthermore, SLPHNs complexed with siRNA against Firefly luciferase (siLuc) reduced luciferase expression, proving the efficacy of this nanocarrier in providing adequate intracellular release of siRNA for silencing specific genes. Based on these results, the developed carriers are promising siRNA delivery systems for skin disease therapy.

Purpose: This study aimed to compare ramucirumab-paclitaxel versus chemotherapy in second-line (2L) advanced gastroesophageal cancer (aGEC) based on HER2 status and analyze prognostic factors., Methods: The study includes patients from the AGAMENON-SEOM registry with aGEC and known HER2 status who received 2L between 2016 and 2021. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS) and multivariable Cox regression analysis was done to adjust for confounding variables., Results: Of the 552 patients who met the selection criteria, 149 (26.9%) had HER2-positive aGEC, 89 were treated with chemotherapy, and 60 with ramucirumab-paclitaxel, and 403 had an HER2-negative aGEC, 259 were treated with chemotherapy, and 144 with ramucirumab-paclitaxel. In the whole sample, 2L PFS was 3.0 months (95% CI 2.8-3.2), 2L OS, 5.7 months (5.2-6.3), and ramucirumab-paclitaxel versus chemotherapy was associated with increased PFS (HR 0.64, 95% CI 0.53-0.78, p < 0.0001) and OS (HR 0.68, 0.55-0.83, p = 0.0002). Median PFS of ramucirumab- paclitaxel versus chemotherapy was 3.5 vs 2.8 months (HR 0.67, 0.54-0.83, p = 0.0004) in HER2-negative, and 4.7 vs 2.7 months (HR 0.57, 0.40-0.82, p = 0.0031) in HER2-positive aGEC, respectively. Median OS for ramucirumab-paclitaxel versus chemotherapy was 6.6 vs 5 months (HR 0.67, 0.53-0.85, p = 0.0007) in HER2-negative, and 7.4 vs 5.6 months (HR 0.70, 0.53-1.04, p = 0.083) in HER2-positive aGEC, respectively. ECOG-PS, tumor burden, Lauren subtype, and neutrophil-lymphocyte ratio were prognostic factors., Conclusions: In patients with an aGEC from the AGAMENON-SEOM registry, 2L treatment with ramucirumab-paclitaxel was superior to chemotherapy in PFS, OS and response rate, independent of HER2 status., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breast cancer is responsible for 25% of all cancers that affect women. Due to its high heterogeneity pattern in clinical diagnosis and its molecular profile differences, researchers have been seeking new targets and therapies, with more specificity and fewer side effects. Thus, one compound that has garnered our attention is trans -chalcone, which is naturally occurring in various plants and possesses promising biological properties, including antitumor effects. MiRNA is an extensive class of non-coding small, endogenous, and single-stranded RNAs, and it is involved in post-translational gene regulation. Therefore, the objective of this study was to investigate the effects of TChal on miRNAs expression and its relationship with anticancer activity against MCF-7. Initially, the trans -chalcone IC50 value was established by MTT assay for MCF-7and HaCat (non-cancer cell), in which we found out that it was 53.73 and 44.18 μM, respectively. Subsequently, we treated MCF-7 cells with trans -chalcone at its IC50 concentration and performed Mi-seq analysis, which unveiled 23 differentially expressed miRNAs. From this set, we selected five miRNAs (miR-25-5p, miR-27a-3p, miR-891a, miR-449a, and miR-4485) for further validation using qRT-PCR, guided by in silico analysis and their known association with tumorigenesis. In conclusion, our research provides valuable insights into the potential use of TChal to reveal MicroRNAs molecular targets that can be applied in breast cancer therapy.

The aim of this work was to develop a novel bainitic steel that will be specifically dedicated to achieving a high degree of refinement (nano- or submicron scale) along with increased thermal stability of the structure at elevated temperatures. The material was characterized by improved in-use properties, expressed as the thermal stability of the structure, compared to nanocrystalline bainitic steels with a limited fraction of carbide precipitations. Assumed criteria for the expected low martensite start temperature, bainitic hardenability level, and thermal stability are specified. The steel design process and complete characteristics of the novel steel including continuous cooling transformation and time-temperature-transformation diagrams based on dilatometry are presented. Moreover, the influence of bainite transformation temperature on the degree of structure refinement and dimensions of austenite blocks was also determined. It was assessed whether, in medium-carbon steels, it is possible to achieve a nanoscale bainitic structure. Finally, the effectiveness of the applied strategy for enhancing thermal stability at elevated temperatures was analyzed.

The ICARUS collaboration employed the 760-ton T600 detector in a successful 3-year physics run at the underground LNGS laboratory, performing a sensitive search for LSND-like anomalous ν e appearance in the CERN Neutrino to Gran Sasso beam, which contributed to the constraints on the allowed neutrino oscillation parameters to a narrow region around 1 eV 2 . After a significant overhaul at CERN, the T600 detector has been installed at Fermilab. In 2020 the cryogenic commissioning began with detector cool down, liquid argon filling and recirculation. ICARUS then started its operations collecting the first neutrino events from the booster neutrino beam (BNB) and the Neutrinos at the Main Injector (NuMI) beam off-axis, which were used to test the ICARUS event selection, reconstruction and analysis algorithms. ICARUS successfully completed its commissioning phase in June 2022. The first goal of the ICARUS data taking will be a study to either confirm or refute the claim by Neutrino-4 short-baseline reactor experiment. ICARUS will also perform measurement of neutrino cross sections with the NuMI beam and several Beyond Standard Model searches. After the first year of operations, ICARUS will search for evidence of sterile neutrinos jointly with the Short-Baseline Near Detector, within the Short-Baseline Neutrino program. In this paper, the main activities carried out during the overhauling and installation phases are highlighted. Preliminary technical results from the ICARUS commissioning data with the BNB and NuMI beams are presented both in terms of performance of all ICARUS subsystems and of capability to select and reconstruct neutrino events., (© The Author(s) 2023.)

Mesoporous carbon (MC) derived from cassava starch was used to remove Acid Blue 113 azo dye from aqueous solutions. The influence of temperature, pH, ionic strength, and the adsorbent dose was investigated in a set of batch experiments. Experimental data showed that Acid Blue 113 adsorption was higher in the acid pH range than in the alkaline one, that dye adsorption increases when the ionic strength and temperature increase, and that adsorption results presented a good correlation with the Langmuir isotherm model. The adsorption capacity of MC was 295 mg g -1 , at pH = 7.0 and 298 K, respectively. Zeta potential (ζ) showed the compression of the diffuse double layer of adsorbent with an increase in temperature and ionic strength, promoting the decrease of electrostatic repulsion between the negatively charged surface of the carbon particles and the anionic dye. Thermodynamic results demonstrate that the adsorption process was spontaneous and endothermic. Moreover, for the first time, this work has demonstrated that the pH, temperature, and ionic strength of the aqueous medium are also able to change the surface charge of carbon-based adsorbents and surely influence the adsorption capacity. Finally, the regeneration of the adsorbent by the photo-Fenton reaction regenerated the adsorption capacity of the adsorbent without generating secondary pollution to the environment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cardiomyopathy is a well-known complication of sepsis that may deteriorate when accompanied by obesity. To test this hypothesis we fed C57black/6 male mice for 6 week with a high fat diet (60% energy) and submitted them to endotoxemic shock using E. coli LPS (10 mg/kg). Inflammatory markers (cytokines and adhesion molecules) were determined in plasma and heart tissue, as well as heart mitochondrial biogenesis and function. Obesity markedly shortened the survival rate of mouse after LPS injection and induced a persistent systemic inflammation since TNFα, IL-1β, IL-6 and resistin plasma levels were higher 24 h after LPS injection. Heart tissue inflammation was significantly higher in obese mice, as detected by elevated mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNFα). Obese animals presented reduced maximum respiratory rate after LPS injection, however fatty acid oxidation increased in both groups. LPS decreased mitochondrial DNA content and mitochondria biogenesis factors, such as PGC1α and PGC1β, in both groups, while NRF1 expression was significantly stimulated in obese mice hearts. Mitochondrial fusion/fission balance was only altered by obesity, with no influence of endotoxemia. Obesity accelerated endotoxemia death rate due to higher systemic inflammation and decreased heart mitochondrial respiratory capacity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The burnout syndrome can be avoided and/or have its signs and symptoms reduced by knowing the five associated factors that help identify the health and working conditions of the professors of graduate programs., Objective: To analyze the factors associated with burnout among faculty members of graduate stricto sensu programs., Design and Setting: A cross-sectional study was conducted among 585 faculty members of Graduate Programs in Language Teaching and Linguistics in Brazil., Methods: Data were collected through an online questionnaire. The outcomes were the dimensions of burnout and its related factors identified through multiple templates of logistic regression., Results: Faculty members with increased chances of emotional exhaustion and depersonalization mentioned the use of medications due to labor activities. The negative influence of pace and intensity of work, thoughts about quitting the program, and having to produce three or more scientific articles were associated with higher chances of emotional exhaustion, while having to achieve nine hours per week in undergraduate programs was related to reduced personal accomplishment. Having a conjugal relationship, satisfaction with health and work, post-doctoral degree, autonomy, and good interpersonal relationships with faculty members of the program reduced the chances of emotional exhaustion. Reduced chances of depersonalization occurred among those who were satisfied with work, had good interpersonal relationships with advisees and faculty members, and received productivity funding., Conclusion: Sociodemographic, health, and occupational factors related to the dimensions of burnout were identified.