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Abstract Spinal cord injury (SCI) can cause paralysis, and although multiple therapeutic proposals have been developed in murine models, results have hardly been replicated in humans. As non-human primates (NHP) are more similar to humans than rodents, the current study investigated whether it was possible to reproduce in a NHP, the previously obtained beneficial results by using a plasma-synthesized polypyrrole/iodine (PPy/I) biopolymer, which reduce glial scar formation and inflammatory response and promotes nerve tissue preservation, regenerative processes and functional recovery in rats. In NHPs (Rhesus monkey) with SCI by complete transection (SCT) and with plasma-synthesized PPy/I application (experimental) or without (control), the expression of pro-inflammatory cytokines in blood, preservation of nervous tissue through magnetic resonance imaging and histological and morphometric techniques, regeneration through immunohistochemistry study and functional recovery through clinical examination, were evaluated. Control NHP showed a markedly increased of pro-inflammatory cytokines vs. experimental NHP, which preserved more nerve tissue. At the end of the follow-up, a thinner glial scar in the injured spinal cord was observed in the experimental NHP as well as regenerative nerve processes (NeuN and β-III tubulin expression), while control NHP had a marked glial scar, large cysts and less nerve tissue at the injured zone. Plasma-synthesized PPy/I also reduced the loss of pelvic limb muscle mass and allowed the experimental NHP recovered knee-jerk, withdrawal and plantar reflexes as well as movement in the hind limbs. Since most of the beneficial effects of plasma-synthesized PPy/I previously reported in rats were also observed in the NHP, these preliminary findings make their replication in humans with SCI more likely. Graphical Abstract more...

In this work, the results of clean hydrogen production from the direct chemical reaction between aluminum–lithium compounds and distilled water under normal conditions, without additives or catalysts, are presented. The material was prepared by mechanical alloying using a high-energy Spex-type mill in an Al20Li ratio. Relatively short milling times were programmed for the preparation of AlLi phases. Through this process, two phases (AlLi and Al8.9Li1.1) were identified, which react efficiently to produce clean hydrogen. The experiments demonstrate fast and self-sustained reactions between AlLi phases and distilled water. In both the phase preparation and hydrogen generation, 100% efficiency was achieved. The hydrolysis reaction occurred quickly, and the hydrogen volume generated was 1700 mL/g of material. Under these conditions, aluminum generates 1390 mL of hydrogen, and lithium generates 310 mL/g from both AlLi phases. A single by-product (LiAl2(OH)7·2H2O) was identified. According to the results and the conditions applied in this research, the hydrogen produced does not require prior purification and can therefore be used directly in fuel cells. The AlLi–water reaction is a promising process for generating hydrogen in a simple and relatively short time compared to other hydrogen production methods. In this process, no greenhouse gas emissions were produced. more...

BackgroundMost children in Argentina received only the initial COVID-19 vaccine series, with presumed hybrid immunity after multiple Omicron waves. However, the durability of immune memory, particularly in immunocompromised (IC) children, remains poorly studied.MethodsA cohort of IC (n=45) and healthy children (HC, n=79) was assessed between 13 to 17 months after receiving two or three doses of BBIBP-CorV and/or BNT162b2. Plasma anti-spike IgG, neutralizing activity and antigen-specific CD4+ and CD8+ T cells against Wuhan and Omicron BA.5 variants were assessed.ResultsMost children remained seropositive after two vaccine doses, but compared with HC, IC exhibited lower neutralizing titers against both Wuhan and Omicron BA.5, particularly those vaccinated with BBIBP-CorV. Even after three vaccine doses, IC showed weaker neutralizing antibody response, CD8+ T cell responses and lower IFN-γ production compared with HC. Integrated analysis of neutralizing antibodies, memory CD4+, and CD8+ T cells revealed a weak immune memory among IC with an important compromise in memory CD8+ T cell responses.ConclusionsImmunity can last up to 17 months, but reduced effectiveness against new variants highlights the need for updated COVID-19 vaccines, especially for IC children. Additional efforts are essential to enhance vaccination coverage and protect this vulnerable population. more...

Abstract To withstand their internal turgor pressure and external threats, most bacteria have a protective peptidoglycan (PG) cell wall. The growth of this PG polymer relies on autolysins, enzymes that create space within the structure. Despite extensive research, the regulatory mechanisms governing these PG-degrading enzymes remain poorly understood. Here, we unveil a novel and widespread control mechanism of lytic transglycosylases (LTs), a type of autolysin responsible for breaking down PG glycan chains. Specifically, we show that LD-crosslinks within the PG sacculus act as an inhibitor of LT activity. Moreover, we demonstrate that this regulation controls the release of immunogenic PG fragments and provides resistance against predatory LTs of both bacterial and viral origin. Our findings address a critical gap in understanding the physiological role of the LD-crosslinking mode in PG homeostasis, highlighting how bacteria can enhance their resilience against environmental threats, including phage attacks, through a single structural PG modification. more...

Conflict of interest: No Introduction and Objectives: Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the fifth leading cause of cancer death. Hexachlorobenzene (HCB) is an environmental pollutant and endocrine disruptor. It plays a role in hepatocarcinogenesis by promoting angiogenesis and cell proliferation, partly by altering thyroid hormones, regulators of the cell cycle.We previously demonstrated that HCB deregulates liver growth, involving TGF-β1 and triiodothyronine (T3); and that Atorvastatin (AT) prevents these effects. Objective: To evaluate the capacity of AT to reverse the effects generated by HCB in the early stages of HCC development. Patients / Materials and Methods: We analyzed the effect of HCB (5μM) with/without AT (20μM) in Huh-7 cell line on 1-(PCNA), 2-(caspase-3 and cytochrome-c), 3-(TGF-β1), 4-(Cox-2); by western blot; 5- T3-generating enzyme (Deiodinase I); RT-PCR; 6-cell migration, wound technique; 7-number of colonies. We evaluated the reversal effect of AT on the previously mentioned parameters. Results and Discussion: HCB increased cell proliferation and migration (PCNA levels 38%, p more...

BackgroundDespite the extensive use of antibiotics and the growing challenge of antimicrobial resistance, there has been a lack of substantial initiatives aimed at diminishing the prevalence of infections in nursing homes and enhancing the detection of urinary tract infections (UTIs). ObjectiveThis study aims to systematize and enhance efforts to prevent health care–associated infections, mainly UTIs and reduce antibiotic inappropriateness by implementing a multifaceted intervention targeting health care professionals in nursing homes. MethodsA before-and-after intervention study carried out in a minimum of 10 nursing homes in each of the 8 European participating countries (Denmark, Greece, Hungary, Lithuania, Poland, Slovakia, Slovenia, and Spain). A team of 4 professionals consisting of nurses, doctors, health care assistants, or health care helpers are actively involved in each nursing home. Over the initial 3-month period, professionals in each nursing home are registering information on UTIs as well as infection and prevention control measures by means of the Audit Project Odense method. The audit will be repeated after implementing a multifaceted intervention. The intervention will consist of feedback and discussion of the results from the first registration, training on the implementation of infection and prevention control techniques provided by experts, appropriateness of the diagnostic approach and antibiotic prescribing for UTIs, and provision of information materials on infection control and antimicrobial stewardship targeted to staff, residents, and relatives. We will compare the pre- and postintervention audit results using chi-square test for prescription appropriateness and Student t test for implemented hygiene elements. ResultsA total of 109 nursing homes have participated in the pilot study and the first registration audit. The results of the first audit registration are expected to be published in autumn of 2024. The final results will be published by the end of 2025. ConclusionsThis is a European Union–funded project aimed at contributing to the battle against antimicrobial resistance through improvement of the quality of management of common infections based on evidence-based interventions tailored to the nursing home setting and a diverse range of professionals. We expect the intervention to result in a significant increase in the number of hygiene activities implemented by health care providers and residents. Additionally, we anticipate a marked reduction in the number of inappropriately managed UTIs, as well as a substantial decrease in the overall incidence of infections following the intervention. International Registered Report Identifier (IRRID)DERR1-10.2196/60099 more...

Abstract The bacterial cell-wall peptidoglycan is made of glycan strands crosslinked by short peptide stems. Crosslinks are catalyzed by DD-transpeptidases (4,3-crosslinks) and LD-transpeptidases (3,3-crosslinks). However, recent research on non-model species has revealed novel crosslink types, suggesting the existence of uncharacterized enzymes. Here, we identify an LD-transpeptidase, LDTGo, that generates 1,3-crosslinks in the acetic-acid bacterium Gluconobacter oxydans. LDTGo-like proteins are found in Alpha- and Betaproteobacteria lacking LD3,3-transpeptidases. In contrast with the strict specificity of typical LD- and DD-transpeptidases, LDTGo can use non-terminal amino acid moieties for crosslinking. A high-resolution crystal structure of LDTGo reveals unique features when compared to LD3,3-transpeptidases, including a proline-rich region that appears to limit substrate access, and a cavity accommodating both glycan chain and peptide stem from donor muropeptides. Finally, we show that DD-crosslink turnover is involved in supplying the necessary substrate for LD1,3-transpeptidation. This phenomenon underscores the interplay between distinct crosslinking mechanisms in maintaining cell wall integrity in G. oxydans. more...

Abstract Bacteria adapt to selective pressure in their immediate environment in multiple ways. One mechanism involves the acquisition of independent mutations that disable or modify a key pathway, providing a signature of adaptation via convergent evolution. Extra-intestinal pathogenic Escherichia coli (ExPEC) belonging to sequence type 95 (ST95) represent a global clone frequently associated with severe human infections including acute pyelonephritis, sepsis, and neonatal meningitis. Here, we analysed a publicly available dataset of 613 ST95 genomes and identified a series of loss-of-function mutations that disrupt cellulose production or its modification in 55.3% of strains. We show the inability to produce cellulose significantly enhances ST95 invasive infection in a rat model of neonatal meningitis, leading to the disruption of intestinal barrier integrity in newborn pups and enhanced dissemination to the liver, spleen and brain. Consistent with these observations, disruption of cellulose production in ST95 augmented innate immune signalling and tissue neutrophil infiltration in a mouse model of urinary tract infection. Mutations that disrupt cellulose production were also identified in other virulent ExPEC STs, Shigella and Salmonella, suggesting a correlative association with many Enterobacteriaceae that cause severe human infection. Together, our findings provide an explanation for the emergence of hypervirulent Enterobacteriaceae clones. more...

Background: The coronavirus, SARS-CoV-2, is the causative agent for COVID-19, first registered in Wuhan, China and responsible for more than 6 million deaths worldwide. Currently, RT-PCR is the gold-standard method for diagnosing COVID-19. However, serological tests are needed for screening acute disease diagnosis and screening large populations during the COVID-19 outbreak. Objectives: Herein, we described the development and validation of an in-house enzyme-linked immunosorbent assay (ELISA) for detecting the levels of anti-spike-1-RBD IgM antibody (CovIgM-ELISA) in well-defined serum/plasma panel for screening and identifying subjects infected with SARS-CoV-2 in a Latin population. Method: In-house CovIgM-ELISA has the format of an indirect ELISA. It was optimized by checkerboard titration using recombinant SARS-CoV-2 spike-S1-RBD protein as an antigen. Results: We found that, compared to the RT-PCR as the standard method, the in-house CovIgM-ELISA displayed sensitivities of 96.15% and 93.22% for samples collected up to 30 or 60 days after infection, respectively, as well as 95.59% specificity with 97.3% accuracy. The agreement kappa value (κ) of our CovIgM-ELISA was substantial when compared to RT-PCR (κ = 0.873) and the anti-SARS-CoV-2 IgM ELISA (InBios Int) (κ = 0.684). The IgM levels detected in the population positively correlated with the neutralizing activity against the wild-type, Alpha and Delta variants of concern, but failed to neutralize Omicron. Conclusions: These data indicate that our in-house CovIgM-ELISA is a compatible performing assay for the detection of SARS-CoV-2 infection. more...

Abstract This paper highlights the efficacy of the finite element method with embedded strong discontinuities in modeling discontinuities in porous media, specifically in the geomechanical behavior of Naturally Fractured Reservoirs (NFRs). The approach considers hydromechanical coupling and offers low computational cost. NFRs account for a significant portion of global reserves, representing approximately 60% of global oil reserves and 40% of gas reserves. Given that flow in NFRs is more complex than in conventional reservoirs due to the presence of multiple fractures, it's crucial to understand how pressure variations or effective stress during operations impact fracture closure and permeability of these reservoirs. To analyze this behavior, numerical simulation results using the proposed method were compared, under different liquid pressure depletion values, with the approach proposed by Oda, which is commonly used in commercial software for calculating fracture permeability tensors. This approach was enriched with Barton's fracture closure formulation and updates on rock matrix porosity and permeability. Four simulations were conducted: Firstly, a hypothetical scenario consistent with Oda's assumptions, where fractures are interconnected and span the entire grid cell, to validate the numerical hydromechanical model; subsequently, three representative sections of a Brazilian pre-salt carbonate reservoir were selected. The study confirms the efficacy of the technique of embedded strong discontinuities in calculating equivalent permeabilities in NFRs, considering geomechanical effects, especially in cells with high fracture frequencies and intensities. Furthermore, the relevance of analyzing the geomechanical behavior in NFRs is emphasized. more...

Neonatal meningitis is a devastating disease associated with high mortality and neurological sequelae. Escherichia coli is the second most common cause of neonatal meningitis in full-term infants (herein NMEC) and the most common cause of meningitis in preterm neonates. Here, we investigated the genomic relatedness of a collection of 58 NMEC isolates spanning 1974–2020 and isolated from seven different geographic regions. We show NMEC are comprised of diverse sequence types (STs), with ST95 (34.5%) and ST1193 (15.5%) the most common. No single virulence gene profile was conserved in all isolates; however, genes encoding fimbrial adhesins, iron acquisition systems, the K1 capsule, and O antigen types O18, O75, and O2 were most prevalent. Antibiotic resistance genes occurred infrequently in our collection. We also monitored the infection dynamics in three patients that suffered recrudescent invasive infection caused by the original infecting isolate despite appropriate antibiotic treatment based on antibiogram profile and resistance genotype. These patients exhibited severe gut dysbiosis. In one patient, the causative NMEC isolate was also detected in the fecal flora at the time of the second infection episode and after treatment. Thus, although antibiotics are the standard of care for NMEC treatment, our data suggest that failure to eliminate the causative NMEC that resides intestinally can lead to the existence of a refractory reservoir that may seed recrudescent infection. more...

Biomedicine today is experiencing a shift towards decentralized data collection, which promises enhanced reproducibility and collaboration across diverse laboratory environments. This inter-laboratory study evaluates the performance of biocytometry, a method utilizing engineered bioparticles for enumerating cells based on their surface antigen patterns. In centralized and aggregated inter-lab studies, biocytometry demonstrated significant statistical power in discriminating numbers of target cells at varying concentrations as low as 1 cell per 100,000 background cells. User skill levels varied from expert to beginner capturing a range of proficiencies. Measurement was performed in a decentralized environment without any instrument cross-calibration or advanced user training outside of a basic instruction manual. The results affirm biocytometry to be a viable solution for immunophenotyping applications demanding sensitivity as well as scalability and reproducibility and paves the way for decentralized analysis of rare cells in heterogeneous samples. more...

Summary: Background: Risk stratification for ventricular arrhythmias currently relies on static measurements that fail to adequately capture dynamic interactions between arrhythmic substrate and triggers over time. We trained and internally validated a dynamic machine learning (ML) model and neural network that extracted features from longitudinally collected electrocardiograms (ECG), and used these to predict the risk of malignant ventricular arrhythmias. Methods: A multicentre study in patients implanted with an implantable cardioverter-defibrillator (ICD) between 2007 and 2021 in two academic hospitals was performed. Variational autoencoders (VAEs), which combine neural networks with variational inference principles, and can learn patterns and structure in data without explicit labelling, were trained to encode the mean ECG waveforms from the limb leads into 16 variables. Supervised dynamic ML models using these latent ECG representations and clinical baseline information were trained to predict malignant ventricular arrhythmias treated by the ICD. Model performance was evaluated on a hold-out set, using time-dependent receiver operating characteristic (ROC) and calibration curves. Findings: 2942 patients (61.7 ± 13.9 years, 25.5% female) were included, with a total of 32,129 ECG recordings during a mean follow-up of 43.9 ± 35.9 months. The mean time-varying area under the ROC curve for the dynamic model was 0.738 ± 0.07, compared to 0.639 ± 0.03 for a static (i.e. baseline-only model). Feature analyses indicated dynamic changes in latent ECG representations, particularly those affecting the T-wave morphology, were of highest importance for model predictions. Interpretation: Dynamic ML models and neural networks effectively leverage routinely collected longitudinal ECG recordings for personalised and updated predictions of malignant ventricular arrhythmias, outperforming static models. Funding: This publication is part of the project DEEP RISK ICD (with project number 452019308) of the research programme Rubicon which is (partly) financed by the Dutch Research Council (NWO). This research is partly funded by the Amsterdam Cardiovascular Sciences (personal grant F.V.Y.T). more...

Background Litsea glaucencens Kuth is an aromatic plant used for food seasoning food and in Mexican traditional medicine. Among, L. glaucencens leaves properties, it has proven antibacterial activity which can be used against opportunistic pathogens like Listeria monocytogenes, a foodborne bacteria that is the causal agent of listeriosis, a disease that can be fatal in susceptible individuals. The aim of this work was to investigate the antibacterial activity of L. glaucescens Kuth leaf extracts against L. monocytogenes and to identify its bioactive components. Material and Methods L. glaucences leaves were macerated with four solvents of different polarity (n-hexane, dichloromethane, ethyl acetate, and methanol). To determine the capacity to inhibit bacterial proliferation in vitro, agar diffusion and microdilution methods were used. Next, we determined the minimal bactericidal concentration (MBC). Finally, we determined the ratio of MBC/MIC. Metabolites present in the active methanolic extract from L. glaucescens Kuth (LgMeOH) were purified by normal-phase open column chromatography. The structure of the antibacterial metabolite was determined using nuclear magnetic resonance (1H, 13C, COSY, HSQC) and by comparison with known compounds. Results The LgMeOH extract was used to purify the compound responsible for the observed antimicrobial activity. This compound was identified as 5,7-dihydroxyflavanone (pinocembrin) by analysis of its spectroscopic data and comparison with those described. The MIC and MBC values obtained for pinocembrin were 0.68 mg/mL, and the ratio MBC/MIC for both LgMeOH and pinocembrin was one, which indicates bactericidal activity. Conclusion L. glaucences Kuth leaves and its metabolite pinocembrin can be used to treat listeriosis due the bactericidal activity against L. monocytogenes. more...

Bursera fagaroides, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present investigation was to search for alternative sources of cytotoxic compounds in B. fagaroides prepared as leaves and in vitro callus cultures. The friable callus of B. fagaroides was established using a combination of plant growth regulators: 4 mgL−1 of 2,4-dichlorophenoxyacetic acid (2,4-D), 1 mgL−1 Naphthaleneacetic Acid (NAA) and 1 mgL−1 Zeatin. The maximum cell growth was at day 28 with a specific growth rate of μ = 0.059 days−1 and duplication time td = 11.8 days. HPLC quantification of the dichloromethane callus biomass extract showed that Scopoletin, with a concentration of 10.7 µg g−1 dry weight, was the main compound inducible as a phytoalexin by the addition of high concentrations of 2,4-D, as well as by the absence of nutrients in the culture medium. In this same extract, the compounds γ-sitosterol and stigmasterol were also identified by GC-MS analysis. Open column chromatography was used to separate and identify yatein, acetyl podophyllotoxin and 7′,8′-dehydropodophyllotoxin in the leaves of the wild plant. Cytotoxic activity on four cancer cell lines was tested, with PC-3 prostate carcinoma (IC50 of 12.6 ± 4.6 µgmL−1) being the most sensitive to the wild-type plant extract and HeLa cervical carcinoma (IC50 of 72 ± 5 µgmL−1) being the most sensitive to the callus culture extract. more...

In this study, we report on the isolation, purification, and anti-inflammatory evaluation of compounds from the plant species Ageratina pichinchensis. Using open-column chromatography, 11 known compounds were purified, which chemical structures were elucidated by nuclear magnetic resonance techniques (1D and 2D). All compounds were evaluated in an in vitro model of RAW 264.7 mouse macrophage cells, measuring the nitric oxide inhibition to determine the anti-inflammatory effect. The compound betuletol 3-O-β-glucoside (11) inhibited nitric oxide with a half-maximal inhibitory concentration (IC50) of 75.08 ± 3.07% at 75 µM; additionally, it inhibited the secretion of interleukin 6 (IL-6) and activation of the nuclear factor (NF-kβ). These results suggest that the anti-inflammatory effect attributed to A. pichinchensis species is promoted by compound 11, which could be considered a potential anti-inflammatory agent by suppressing the expression of NF-kβ target genes, such as those involved in the proinflammatory pathway and inducible nitric oxide synthase (iNOS). more...

Don DeLillo is an author who pays special attention to language, time, and space when constructing characters’ identity as well as their milieu. Considering this aspect of his fiction, the present article looks at how cinematic adaptations of his novels translate time, space, and the use of language onto the screen. Two of DeLillo’s novels have been adapted so far: Cosmopolis (DeLillo 2003) by David Cronenberg in a 2012 movie of the same name, and The Body Artist (DeLillo 2001) by Benoît Jacquot under the title À Jamais (2016). In light of the importance that the aforementioned elements play in the author’s works, this article delves into how they are represented in the two adaptations and analyzes the role that they play in the movies compared to the novels. more...

Background: Individuals at risk of suffering cardiovascular disease (CVD) present with larger increases in blood triglyceride (TG) concentration after a high-fat meal than do healthy individuals. These postprandial hypertriglyceride levels are an independent risk factor for CVD. Prescription of statins and a bout of prolonged exercise are both effective in lowering postprandial hypertriglyceride levels. We aimed to evaluate the comparative effectiveness of statins vs. a bout of aerobic exercise in reducing fasting and postprandial TG (PPTG) concentrations in individuals at high risk of developing CVD. Methods: Thirty-seven studies from a systematic literature search of the PubMed, EMBASE, and Cochrane databases were included in this review. The selected studies conducted trials involving statin therapy (n = 20) or a bout of aerobic exercise (n = 19) and measured their impact on PPTG levels as the outcome. Two studies analyzed both treatments and were included in duplicate. The meta-analysis was constructed using a random-effects model to calculate the mean difference (MD). The Student t test was used to compare the data sets for statins vs. exercise. Results: Overall, statin and exercise interventions showed similar reductions in PPTG levels, with an MD of –0.65 mmol/L for statins (95% confidence interval (95%CI): –0.54 to –0.77; p < 0.001) and –0.46 mmol/L for exercise (95%CI: –0.21 to –0.71; p < 0.01). However, statins lowered fasting TG levels more than exercise (MD = –1.54 mmol/L, 95%CI: –2.25 to –0.83; p = 0.009). Conclusion: Although aerobic exercise is effective in lowering blood TG levels, statins seem to be more efficient, especially in the fasted state. A combination of exercise and statins might reveal a valuable approach to the treatment and prevention of CVD. More studies are required to determine the underlying mechanisms and the possible additive effects of these interventions. more...

The aim of this study was to analyze the profiles of IgG subclasses in COVID-19 convalescent Puerto Rican subjects and compare these profiles with those of non-infected immunocompetent or immunocompromised subjects that received two or more doses of an mRNA vaccine. The most notable findings from this study are as follows: (1) Convalescent subjects that were not hospitalized developed high and long-lasting antibody responses. (2) Both IgG1 and IgG3 subclasses were more prevalent in the SARS-CoV-2-infected population, whereas IgG1 was more prevalent after vaccination. (3) Individuals that were infected and then later received two doses of an mRNA vaccine exhibited a more robust neutralizing capacity against Omicron than those that were never infected and received two doses of an mRNA vaccine. (4) A class switch toward the “anti-inflammatory” antibody isotype IgG4 was induced a few weeks after the third dose, which peaked abruptly and remained at high levels for a long period. Moreover, the high levels of IgG4 were concurrent with high neutralizing percentages against various VOCs including Omicron. (5) Subjects with IBD also produced IgG4 antibodies after the third dose, although these antibody levels had a limited effect on the neutralizing capacity. Knowing that the mRNA vaccines do not prevent infections, the Omicron subvariants have been shown to be less pathogenic, and IgG4 levels have been associated with immunotolerance and numerous negative effects, the recommendations for the successive administration of booster vaccinations to people should be revised. more...

IntroductionSpinal cord injury (SCI) can cause paralysis, for which effective therapeutic strategies have not been developed yet. The only accepted strategy for patients is rehabilitation (RB), although this does not allow complete recovery of lost functions, which makes it necessary to combine it with strategies such as plasma-synthesized polypyrrole/iodine (PPy/I), a biopolymer with different physicochemical properties than PPy synthesized by conventional methods. After SCI in rats, PPy/I promotes functional recovery. Therefore, the purpose of this study was to increase the beneficial effects of both strategies and identify which genes activate PPy/I when applied alone or in combination with a mixed scheme of RB by swimming and enriched environment (SW/EE) in rats with SCI.MethodsMicroarray analysis was performed to identify mechanisms of action underlying the effects of PPy/I and PPy/I+SW/EE on motor function recovery as evaluated by the BBB scale.ResultsResults showed robust upregulation by PPy/I in genes related to the developmental process, biogenesis, synapse, and synaptic vesicle trafficking. In addition, PPy/I+SW/EE increased the expression of genes related to proliferation, biogenesis, cell development, morphogenesis, cell differentiation, neurogenesis, neuron development, and synapse formation processes. Immunofluorescence analysis showed the expression of β-III tubulin in all groups, a decreased expression of caspase-3 in the PPy/I group and GFAP in the PPy/I+SW/EE group (p < 0.05). Better preservation of nerve tissue was observed in PPy/I and PPy/SW/EE groups (p < 0.05). In the BBB scale, the control group scored 1.72 ± 0.41, animals with PPy/I treatment scored 4.23 ± 0.33, and those with PPy/I+SW/EE scored 9.13 ± 0.43 1 month after follow-up.ConclusionThus, PPy/I+SW/EE could represent a therapeutic alternative for motor function recovery after SCI. more...

Introduction and Objectives: Chronic hepatitis B and exposure to persistent organic pollutants (COPs) can lead to cellular hepatocarcinoma (HCC), the most common liver tumor. HBV DNA encodes transactivator x, HBx protein. The HBx is required to initiate and maintain HBV replication. Hexachlorobenzene (HCB), COPs´member, is a promoter of hepatic preneoplastic foci. We have shown that HCB increases in rat liver PCNA, TGF-β1, VEGF and neo-angiogenesis in vivo models. This study aimed to analyze in vitro two models of HCC generation -associated with HCB or with the expression of HBx-. Materials and Methods: The HCB effect on cell number (BrdU incorporation by Immunohistochemistry), PCNA (Western blot), TGF-β1 (RT-PCR) was studied in vitro in: 1.1) Huh-7; 1.2) Huh-7 transfected with HBx; 2) HepG2.2.15 (stable expression HBV) and 3) EA-hy926 (endothelial cell). In these last, an inhibitor of TGF-β1-RII (SB431542) was used. In 1.2, 2 and 3 used, 5µM HCB, 24h; in 1, we performed time (30, 60, 90 and 120) and dose (0,005; 0,05; 0,5 and 5µM) curves. Evaluated: a) PCNA protein levels, b) TGF-β1 levels and positive cell number/total cell. Results: In Huh-7, TGF-β1 increased (20%, 69% and 78%, with 0.05, 0.5 and 5µM HCB, respectively) and PCNA (45% and 60%, with 0.5 and 5 µM HCB, respectively). In Huh-7/HBx, PCNA and TGF-β1 increased by 86% and 71%, respectively. In Huh-7/HBx and 5µM HCB, PCNA increased by 120% and TGF-β1 by 91%. In HepG2.2.15 PCNA was overexpressed by 76%. In EA-hy926, PCNA 29% and TGF-β1 by 43% increased. Both effects were prevented by pre-incubating endothelial cells with the specific inhibitor of TGF-B1 RII after HCB 5µM. Conclusions: HCB and HBx induce cell proliferation in vitro. This effect is equivalent for both agents (HCB and HBx) and is enhanced by combining them. The proliferative effect is associated with TGF-β1 increase, which mediates the proliferation generated on both HCC and endothelial cell lines. These findings could partially explain the molecular mechanism involved in human HCC cell proliferation, disease progression and neo-angiogenesis. more...

This is the first record of two non-native terrestrial slug species from Sinaloa, Mexico. Deroceras laeve and Sarasinula plebeia were collected between 2019 and 2022 in Concordia and Mazatlan Municipalities (north-western Mexico). The external morphology and anatomic features of the dissected specimens coincide with the descriptions of each species, whose identities were also confirmed by their partial COI sequences. The ample occurrence of S. plebeia suggests that this species has an established population, while D. laeve was found as isolated individuals, likely associated with plant nurseries. more...

Medicines for chronic inflammation can cause gastric ulcers and hepatic and renal issues. An alternative treatment for chronic inflammation is that of natural bioactive compounds, which present low side effects. Extracts of Jatropha cordata (Ortega) Müll. Arg. have been evaluated for their cytotoxicity and anti-inflammatory activity; however, testing pure compounds would be of greater interest. Campesteryl palmitate, n-heptyl ferulate, palmitic acid, and a mixture of sterols, i.e., brassicasterol, campesterol, β-sitosterol, and stigmasterol, were obtained from an ethyl acetate extract from J. cordata (Ortega) Müll. Arg. bark using column chromatography. The toxicity and in vitro anti-inflammatory activities were evaluated using RAW 264.7 murine macrophage cells. None of the products assessed exhibited toxicity. The sterol mixture exhibited greater anti-inflammatory activity than the positive control, and nitric oxide (NO) inhibition percentages were 37.97% and 41.68% at 22.5 μg/mL and 30 μg/mL, respectively. In addition, n-heptyl ferulate decreased NO by 30.61% at 30 μg/mL, while campesteryl palmitate did not show anti-inflammatory activity greater than the positive control. The mixture and n-heptyl ferulate showed NO inhibition; hence, we may conclude that these compounds have anti-inflammatory potential. Additionally, further research and clinical trials are needed to fully explore the therapeutic potential of these bioactive compounds and their efficacy in treating chronic inflammation. more...

Among broad-spectrum anticancer agents, paclitaxel (PTX) has proven to be one of the most effective against solid tumors for which more specific treatments are lacking. However, drawbacks such as neurotoxicity and the development of resistance reduce its therapeutic efficacy. Therefore, there is a need for compounds able to improve its activity by synergizing with it or potentiating its effect, thus reducing the doses required. We investigated the interaction between PTX and tannins, other compounds with anticancer activity known to act as repressors of several proteins involved in oncological pathways. We found that both tannic acid (TA) and ethyl gallate (EG) strongly potentiate the toxicity of PTX in Hep3B cells, suggesting their utility in combination therapy. We also found that AT and EG promote tubulin polymerization and enhance the effect of PTX on tubulin, suggesting a direct interaction with tubulin. Biochemical experiments confirmed that TA, but not EG, binds tubulin and potentiates the apparent binding affinity of PTX for the tubulin binding site. Furthermore, the molecular docking of TA to tubulin suggests that TA can bind to two different sites on tubulin, one at the PTX site and the second at the interface of α and β-tubulin (cluster 2). The binding of TA to cluster 2 could explain the overstabilization in the tubulin + PTX combinatorial assay. Finally, we found that EG can inhibit PTX-induced expression of pAkt and pERK defensive protein kinases, which are involved in resistance to PXT, by limiting cell death (apoptosis) and favoring cell proliferation and cell cycle progression. Our results support that tannic acid and ethyl gallate are potential chemotherapeutic agents due to their potentiating effect on paclitaxel. more...

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2′,4′-dihydroxychalcone (2′,4′-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure–activity relationship (QSAR) model was developed to study the chimeric compounds’ anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2′,4′-DHC (A) and the chimeric compound 2′-hydroxy,4′-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C–K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line. more...

This article identifies and further discusses key themes and insights from The Polar Journal Special Issue on Rights of Nature and the Antarctic. First, philosophical considerations in relation to RoN are examined, with a specific focus on Antarctica's intrinsic value and the question of whether RoN can be seen as an ecocentric or anthropocentric concept. Next, the possible modalities of an Antarctic RoN approach are examined, including questions on who should be rights holders and what rights are involved, distinguishing between substantive and procedural rights. The analysis then turns to the question of how an Antarctic RoN approach would relate to the Antarctic Treaty System, with special attention to the draft Antarctica Declaration and the relationship between a RoN approach and the values and principles of the Antarctic Treaty and the Environmental Protocol. It is hoped that the discussions in this Special Issue will be a valuable addition to the ongoing debate regarding RoN worldwide and will contribute to the policy discussions on how to strengthen the protection of the Antarctic environment. [ABSTRACT FROM AUTHOR] more...

Environmental hexachlorobenzene (HCB) increases blood pressure (BP) in female rats, causing alterations in arterial structure and function. Here we study the role of Angiotensin II receptor type 1 (AT1) in HCB-induced hypertension through the use of AT1 antagonist losartan.HCB-treated male rats showed a 22.7% increase in BP which was prevented by losartan. Losartan blocked HCB-induced changes in arterial morphology (decreased aorta cell number and increased wall thickness). Losartan also prevented HCB-induced alterations in artery relaxation by acetylcholine and nitroprusside but not the reduction in the maximum contraction by phenylephrine. Losartan rescued arterial molecular alterations caused by HCB (i.e. an increase in TGF-β1 and AT1 expression and a decrease in eNOS expression and nitrite levels) and reduced hydrogen sulfide plasma concentration.In conclusion: in this work we demonstrate that AT1 activity is involved in HCB effects on the vascular system leading to hypertension. more...

Active colloidal systems can serve as an enabling platform to study complex out-of-equilibrium physical phenomena. Using a magnetic control with a feedback loop, here the authors program the dynamics of active Brownian particles by updating their rotational diffusion coefficient depending on their locations. more...

ABSTRACT While many mechanisms governing bacterial envelope homeostasis have been identified, others remain poorly understood. To decipher these processes, we previously developed an assay in the Gram-negative model Escherichia coli to identify genes involved in maintenance of envelope integrity. One such gene was ElyC, which was shown to be required for envelope integrity and peptidoglycan synthesis at room temperature. ElyC is predicted to be an integral inner membrane protein with a highly conserved domain of unknown function (DUF218). In this study, and stemming from a further characterization of the role of ElyC in maintaining cell envelope integrity, we serendipitously discovered an unappreciated form of oxidative stress in the bacterial envelope. We found that cells lacking ElyC overproduce hydroxyl radicals (HO•) in their envelope compartment and that HO• overproduction is directly or indirectly responsible for the peptidoglycan synthesis arrest, cell envelope integrity defects, and cell lysis of the ΔelyC mutant. Consistent with these observations, we show that the ΔelyC mutant defect is suppressed during anaerobiosis. HO• is known to cause DNA damage but to our knowledge has not been shown to interfere with peptidoglycan synthesis. Thus, our work implicates oxidative stress as an important stressor in the bacterial cell envelope and opens the door to future studies deciphering the mechanisms that render peptidoglycan synthesis sensitive to oxidative stress. IMPORTANCE Oxidative stress is caused by the production and excessive accumulation of oxygen reactive species. In bacterial cells, oxidative stress mediated by hydroxyl radicals is typically associated with DNA damage in the cytoplasm. Here, we reveal the existence of a pathway for oxidative stress in the envelope of Gram-negative bacteria. Stemming from the characterization of a poorly characterized gene, we found that HO• overproduction specifically in the envelope compartment causes inhibition of peptidoglycan synthesis and eventually bacterial cell lysis. more...

ABSTRACT Many antibiotic resistant uropathogenic Escherichia coli (UPEC) strains belong to clones defined by their multilocus sequence type (ST), with ST131 being the most dominant. Although we have a good understanding of resistance development to fluoroquinolones and third-generation cephalosporins by ST131, our understanding of the virulence repertoire that has contributed to its global dissemination is limited. Here we show that the genes encoding Afa/Dr fimbriae, a group of adhesins strongly associated with UPEC that cause gestational pyelonephritis and recurrent cystitis, are found in approximately one third of all ST131 strains. Sequence comparison of the AfaE adhesin protein revealed a unique allelic variant carried by 82.9% of afa-positive ST131 strains. We identify the afa regulatory region as a hotspot for the integration of insertion sequence (IS) elements, all but one of which alter afa transcription. Close investigation demonstrated that the integration of an IS1 element in the afa regulatory region leads to increased expression of Afa/Dr fimbriae, promoting enhanced adhesion to kidney epithelial cells and suggesting a mechanism for altered virulence. Finally, we provide evidence for a more widespread impact of IS1 on ST131 genome evolution, suggesting that IS dynamics contribute to strain level microevolution that impacts ST131 fitness. IMPORTANCE E. coli ST131 is the most common antibiotic resistant UPEC clone associated with human urinary tract and bloodstream infections. Understanding the features of ST131 that have driven its global dissemination remains a critical priority if we are to counter its increasing antibiotic resistance. Here, we utilized a large collection of ST131 isolates to investigate the prevalence, regulation, and function of Afa/Dr fimbriae, a well-characterized UPEC colonization and virulence factor. We show that the afa genes are found frequently in ST131 and demonstrate how the integration of IS elements in the afa regulatory region modulates Afa expression, presenting an example of altered virulence capacity. We also exploit a curated set of ST131 genomes to map the integration of the antibiotic resistance-associated IS1 element in the ST131 pangenome, providing evidence for its widespread impact on ST131 genome evolution. more...

The peptidoglycan cell wall is a predominant structure of bacteria, determining cell shape and supporting survival in diverse conditions. Peptidoglycan is dynamic and requires regulated synthesis of new material, remodeling, and turnover – or autolysis – of old material. Despite exploitation of peptidoglycan synthesis as an antibiotic target, we lack a fundamental understanding of how peptidoglycan synthesis and autolysis intersect to maintain the cell wall. Here, we uncover a critical physiological role for a widely misunderstood class of autolytic enzymes, lytic transglycosylases (LTGs). We demonstrate that LTG activity is essential to survival by contributing to periplasmic processes upstream and independent of peptidoglycan recycling. Defects accumulate in Vibrio cholerae LTG mutants due to generally inadequate LTG activity, rather than absence of specific enzymes, and essential LTG activities are likely independent of protein-protein interactions, as heterologous expression of a non-native LTG rescues growth of a conditional LTG-null mutant. Lastly, we demonstrate that soluble, uncrosslinked, endopeptidase-dependent peptidoglycan chains, also detected in the wild-type, are enriched in LTG mutants, and that LTG mutants are hypersusceptible to the production of diverse periplasmic polymers. Collectively, our results suggest that LTGs prevent toxic crowding of the periplasm with synthesis-derived peptidoglycan polymers and, contrary to prevailing models, that this autolytic function can be temporally separate from peptidoglycan synthesis. more...

The inflammatory process, although beneficial, can produce tissue damage and systemic damage when uncontrolled. Effective therapeutic alternatives with little or no side effects are of great therapeutic interest. This study aimed to determine the phytochemical composition of bark extracts from J. cordata, an endemic plant from México, and evaluate their in vitro anti-inflammatory activity. Hexane, ethyl acetate, and methanol extracts were characterized by qualitative phytochemical tests, and their bioactive groups were identified by 1H NMR and gas chromatography coupled to mass spectrometry (GC–MS). The extract’s anti-inflammatory activity was evaluated as nitric oxide (NO) production and their cytotoxicity by an MTS cell proliferation assay in lipopolysaccharide (LPS)-activated RAW 264.7 cells at concentrations of 1–100 μg/mL. The hexane extract contained fatty acids, fatty esters, phytosterols, alkanes, vitamin E, and terpenoids; the ethyl acetate extract showed fatty acids, fatty esters, aromatic aldehyde, phytosterols, vitamin E, and terpenoids, while the methanolic extract showed fatty esters, fatty acid, aromatics aldehydes, and alcohol. The ethyl acetate extract showed the highest inhibition of NO production, followed by the methanolic extract and the hexane extract, without affecting the viability of RAW 264.7 macrophage cells. The results suggest that J. cordata extracts are a potential source of bioactive compounds with anti-inflammatory potential. more...

Ageratina pichinchensis (Kunth) R.King & Ho.Rob. is a plant used in traditional Mexican medicine, and some biotechnological studies have shown that its calluses and cell suspension cultures can produce important anti-inflammatory compounds. In this study, we established a cell culture of A. pichinchensis in a 2 L airlift bioreactor and evaluated the production of the anti-inflammatory compounds 2,3-dihydrobenzofuran (1) and 3-epilupeol (2). The maximum biomass production (11.90 ± 2.48 g/L) was reached at 11 days of culture and cell viability was between 80% and 90%. Among kinetic parameters, the specific growth rate (µ) was 0.2216 days−1 and doubling time (td) was 3.13 days. Gas chromatography coupled with mass spectrometry (GC-MS) analysis of extracts showed the maximum production of compound 1 (903.02 ± 41.06 µg/g extract) and compound 2 (561.63 ± 10.63 µg/g extract) at 7 and 14 days, respectively. This study stands out for the significant production of 2,3-dihydrobenzofuran and 3-epilupeol and by the significant reduction in production time compared to callus and cell suspension cultures, previously reported. To date, these compounds have not been found in the wild plant, i.e., its production has only been reported in cell cultures of A. pichinchensis. Therefore, plant cell cultured in an airlift reactor can be an alternative for the improved production of these anti-inflammatory compounds. more...

Objetivo: analizar motivos de consulta, experiencias y formas de atención de las afecciones dermatológicas de la población de un asentamiento de la Provincia de Buenos Aires, ubicado sobre un relleno sanitario con altos índices de contaminación ambiental. Materiales y métodos: investigación cualitativa, mediante entrevistas en profundidad a vecinos/as y elaboración de registros etnográficos de las recorridas. La investigación se realizó en el contexto de un dispositivo de atención dermatológica, planificado en conjunto con referentes barriales, bajo el marco teórico de la Epidemiología Sociocultural. Resultados: se identificaron múltiples barreras de accesibilidad a la atención dermatológica en el sistema público de salud, y prácticas de autoatención como el uso de cremas, medidas de higiene y uso de elementos de protección personal para trabajos que significaban un riesgo para la salud. Las consultas al dispositivo más frecuentes fueron “granos”, “manchas”, “bultitos” en zonas visibles del cuerpo, que generaban molestia, dolor y/o afectaban estética y emocionalmente a lo/as entrevistado/as. Estas consultas se relacionaban principalmente con piel extremadamente seca y patologías por alta exposición solar, coincidiendo con la escasez de sombra en el barrio. Para prevenir patologías relacionadas a la exposición solar, se impulsó una iniciativa para plantar árboles. Conclusión: a partir de la inmersión reflexiva del equipo de atención, en las experiencias de atención de lo/as habitantes del barrio, se desplegaron estrategias según las necesidades percibidas por la población. more...

Background: Most children and youth develop mild or asymptomatic disease during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, a very small number of patients suffer severe Coronavirus induced disease 2019 (COVID-19). The reasons underlying these different outcomes remain unknown. Methods: We analyzed three different cohorts: children with acute infection (n=550), convalescent children (n=138), and MIS-C (multisystem inflammatory syndrome in children, n=42). IgG and IgM antibodies to the spike protein of SARS-CoV-2, serum-neutralizing activity, plasma cytokine levels, and the frequency of circulating Follicular T helper cells (cTfh) and plasmablasts were analyzed by conventional methods. Findings: Fifty-eight percent of the children in the acute phase of infection had no detectable antibodies at the time of sampling while a seronegative status was found in 25% and 12% of convalescent and MIS-C children, respectively. When children in the acute phase of the infection were stratified according disease severity, we found that contrasting with the response of children with asymptomatic, mild and moderate disease, children with severe COVID-19 did not develop any detectable response. A defective antibody response was also observed in the convalescent cohort for children with severe disease at the time of admission. This poor antibody response was associated to both, a low frequency of cTfh and a high plasma concentration of inflammatory cytokines. Interpretation: A weak and delayed kinetic of antibody response to SARS-CoV-2 together with a systemic pro-inflammatory profile characterize pediatric severe COVID-19. Because comorbidities are highly prevalent in children with severe COVID-19, further studies are needed to clarify their contribution in the weak antibody response observed in severe disease. Funding: National Agency for Scientific and Technological Promotion from Argentina (IP-COVID-19-0277 and PMO-BID-PICT2018-2548). more...

In this work, we used Bibliometrix and Biblioshiny to perform a bibliometric qualitative and quantitative analysis on the main topic “microgels and nanogels”, and the sub-topic “microgels and nanogels at interfaces and emulsions”. Word-counting of the titles of the publications enabled a descriptive analysis of thematic trends. A more complex conceptual analysis used the co-occurrence of words in titles, clustered into research themes with links to other themes. A thematic map allowed to characterize the centrality and density of the themes within the topic. A similar clustering of co-authorship enabled the mapping of the collaborations. We identified in this way research opportunities theme- and collaboration-wise, such as the opportunity to bring more fundamental studies into biomedical applications and into Pickering emulsions stabilized with microgels. more...