Dysregulated microRNAs in type 2 diabetes and breast cancer: Potential associated molecular mechanisms.

Type 2 diabetes (T2D) is a multifaceted and heterogeneous syndrome associated with complications such as hypertension, coronary artery disease, and notably, breast cancer (BC). The connection between T2D and BC is established through processes that involve insulin resistance, inflammation and other factors. Despite this comprehension the specific cellular and molecular mechanisms linking T2D to BC, especially through microRNAs (miRNAs), remain elusive. miRNAs are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological processes. However, the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been elucidated. This review aims to identify dysregulated miRNAs in both T2D and BC, exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

Mitigation of Subsequent Ovariectomy Responses through Prior Exercise Training in Rats.

It is well known that cardiometabolic dysfunction gradually increases after menopause and the sedentary lifestyle can aggravated this condition. Therefore, we compared the effects of prior aerobic exercise training in premenopausal period and after ovariectomy (OVX) on metabolic, hemodynamic and autonomic parameters in experimental model of menopause in rats. Female rats were divided in 4 groups: control (C), sedentary OVX (SO), trained OVX (TO), and previously trained OVX (PTO). PTO trained four weeks previously+eight weeks after OVX and the TO group trained only after OVX on a motor treadmill. Autonomic modulation were evaluated and the adipose tissues (WAT) were removed, weighed and lipolysis was assessed. Citrate synthase activity was analysed in the soleus muscle. The trained groups prevented the impairment of BRS in relation to SO; however, only PTO reduced the low frequency band of pulse interval compared to SO. PTO reduced the weight of WAT compared to the other groups; the lipolysis in PTO was similar to C. PTO had preserved muscle metabolic injury in all types of fibres analysed. In conclusion, this study suggests that exercise training should be recommended in a pre-menopausal model in order to prevent cardiometabolic and autonomic menopause-induced deleterious effects.

Computer-aided drug design supporting sunscreen research: a showcase study using previously synthesized hybrid UV filter-antioxidant compounds.

CONTEXT: Although quantum mechanical calculations have proven effective in accurately predicting UV absorption and assessing the antioxidant potential of compounds, the utilization of computer-aided drug design (CADD) to support sustainable synthesis research of new sunscreen active ingredients remains an area with limited exploration. Furthermore, there are ongoing concerns about the safety and effectiveness of existing sunscreens. Therefore, it remains crucial to investigate photoprotection mechanisms and develop enhanced strategies for mitigating the harmful effects of UVR exposure, improving both the safety and efficacy of sunscreen products. A previous study conducted synthesis research on eight novel hybrid compounds (I-VIII) for use in sunscreen products by molecular hybridization of trans-resveratrol (RESV), avobenzone (AVO), and octinoxate (OMC). Herein, time-dependent density functional theory (TD-DFT) calculations performed in the gas phase on the isolated hybrid compounds (I-VIII) proved to reproduce the experimental UV absorption. Resveratrol-avobenzone structure-based hybrids (I-IV) present absorption maxima in the UVB range with slight differences between them, while resveratrol-OMC structure-based hybrids (V-VIII) showed main absorption in the UVA range. Among RESV-OMC hybrids, compounds V and VI exhibited higher UV absorption intensity, and compound VIII stood out for its broad-spectrum coverage in our simulations. Furthermore, both in silico and in vitro analyses revealed that compounds VII and VIII exhibited the highest antioxidant activity, with compound I emerging as the most reactive antioxidant within RESV-AVO hybrids. The study suggests a preference for the hydrogen atom transfer (HAT) mechanism over single-electron transfer followed by proton transfer (SET-PT) in the gas phase. With a strong focus on sustainability, this approach reduces costs and minimizes effluent production in synthesis research, promoting the eco-friendly development of new sunscreen active ingredients. METHODS: The SPARTAN'20 program was utilized for the geometry optimization and energy calculations of all compounds. Conformer distribution analysis was performed using the Merck molecular force field 94 (MMFF94), and geometry optimization was carried out using the parametric method 6 (PM6) followed by density functional theory (DFT/B3LYP/6-31G(d)). The antioxidant behavior of the hybrid compounds (I-VIII) was determined using the highest occupied molecular orbital (εHOMO) and the lowest unoccupied molecular orbital (εLUMO) energies, as well as the bond dissociation enthalpy (BDE), ionization potential (IP), and proton dissociation enthalpy (PDE) values, all calculated at the same level of structural optimization. TD-DFT study is carried out to calculate the excitation energy using the B3LYP functional with the 6-31G(d) basis set. The calculated transitions were convoluted with a Gaussian profile using the Gabedit program.

Listeria monocytogenes from Food Products and Food Associated Environments: Antimicrobial Resistance, Genetic Clustering and Biofilm Insights.

Listeria monocytogenes, a foodborne pathogen, exhibits high adaptability to adverse environmental conditions and is common in the food industry, especially in ready-to-eat foods. L. monocytogenes strains pose food safety challenges due to their ability to form biofilms, increased resistance to disinfectants, and long-term persistence in the environment. The aim of this study was to evaluate the presence and genetic diversity of L. monocytogenes in food and related environmental products collected from 2014 to 2022 and assess antibiotic susceptibility and biofilm formation abilities. L. monocytogenes was identified in 13 out of the 227 (6%) of samples, 7 from food products (meat preparation, cheeses, and raw milk) and 6 from food-processing environments (slaughterhouse-floor and catering establishments). All isolates exhibited high biofilm-forming capacity and antibiotic susceptibility testing showed resistance to several classes of antibiotics, especially trimethoprim-sulfamethoxazole and erythromycin. Genotyping and core-genome clustering identified eight sequence types and a cluster of three very closely related ST3 isolates (all from food), suggesting a common contamination source. Whole-genome sequencing (WGS) analysis revealed resistance genes conferring resistance to fosfomycin (fosX), lincosamides (lin), fluoroquinolones (norB), and tetracycline (tetM). In addition, the qacJ gene was also detected, conferring resistance to disinfecting agents and antiseptics. Virulence gene profiling revealed the presence of 92 associated genes associated with pathogenicity, adherence, and persistence. These findings underscore the presence of L. monocytogenes strains in food products and food-associated environments, demonstrating a high virulence of these strains associated with resistance genes to antibiotics, but also to disinfectants and antiseptics. Moreover, they emphasize the need for continuous surveillance, effective risk assessment, and rigorous control measures to minimize the public health risks associated to severe infections, particularly listeriosis outbreaks. A better understanding of the complex dynamics of pathogens in food products and their associated environments can help improve overall food safety and develop more effective strategies to prevent severe health consequences and economic losses.

Unveiling a Listeria monocytogenes Outbreak in a Rabbit Farm: Clinical Manifestation, Antimicrobial Resistance, Genomic Insights and Environmental Investigation.

Listeria monocytogenes poses a threat to both human and animal health. This work describes an L. monocytogenes outbreak in a Portuguese rabbit farm, detailing the isolates' clinical manifestations, necropsy findings, and phenotypic and genomic profiles. Clinical signs, exclusively observed in does, included lethargy and reproductive signs. Post-mortem examination of does revealed splenomegaly, hepatomegaly with a reticular pattern, pulmonary congestion, and haemorrhagic lesions in the uterus, with thickening of the uterine wall and purulent greyish exudates. Positive L. monocytogenes samples were identified in fattening and maternity units across different samples, encompassing does and environmental samples. Core-genome Multi Locus Sequence Typing (cgMLST) analysis confirmed the outbreak, with the 16 sequenced isolates (lineage II, CC31, and ST325) clustering within a ≤2 allelic difference (AD) threshold. Antimicrobial susceptibility testing for five antibiotics revealed that 15 out of 19 outbreak isolates were resistant to sulfamethoxazole-trimethoprim (SXT). Concordantly, all SXT-resistant sequenced isolates were found to exclusively harbour a plasmid containing a trimethoprim-resistance gene (dfrD), along with loci linked to resistance to lincosamides (lnuG), macrolides (mphB), and polyether ionophores (NarAB operon). All sequenced outbreak isolates carried the antibiotic resistance-related genes tetM, fosX, lin, norB, lmrB, sul, and mprF. The outbreak cluster comprises isolates from does and the environment, which underscores the ubiquitous presence of L. monocytogenes and emphasizes the importance of biosecurity measures. Despite limited data on listeriosis in rabbit farming, this outbreak reveals its significant impact on animal welfare and production.

Forensic psychological procedures in cases of technology-facilitated sexual abuse among adolescents: A scoping review.

Technology-facilitated sexual abuse refers to the use of information and communication technologies to facilitate both virtual and in-person sexual crimes. Research on this topic has focused on rates, risk factors, and consequences. This scoping review aims to understand whether and how forensic psychological procedures are adapted to assess adolescent victims and how Internet-based information might be useful as complementary data. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extensions for Scoping Reviews guidelines, searches were conducted in April 2023 in five electronic databases to include Portuguese, Spanish, or English quantitative, qualitative, or mixed-method peer-reviewed studies. Of the 2523 studies, six were considered eligible. Identified procedures include forensic interviews following the National Institute for Child Health and Human Development Protocol, and risk and trauma assessments. While discussing technology's role in abuse during interviews was informative, confronting adolescents with evidence of their abuse had adverse effects on their testimony and recovery. The assessment tools often had a narrow focus or overlooked the abuse unless explicitly disclosed, implied a referral, or when safeguarding concerns were raised. Clinical, forensic, and criminal implications are elaborated.

Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage.

BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).

Recurrence, Microevolution, and Spatiotemporal Dynamics of Legionella pneumophila Sequence Type 1905, Portugal, 2014-2022.

We investigated molecular evolution and spatiotemporal dynamics of atypical Legionella pneumophila serogroup 1 sequence type 1905 and determined its long-term persistence and linkage to human disease in dispersed locations, far beyond the large 2014 outbreak epicenter in Portugal. Our finding highlights the need for public health interventions to prevent further disease spread.

Olive mill wastewater treatment strategies to obtain quality water for irrigation: A review.

The olive mill industry is a relevant sector in the economy of Mediterranean countries, while it involves high consumption of water and the production of effluents with high environmental impact. The efficient treatment of olive mill wastewater (OMW) is of high relevance, particularly for these countries. Climate changes are leading to increasing periods of droughts, and water recovery from polluted streams is essential to ensure the sustainability of this scarce resource. A combination of various technologies involving physical, chemical, and biological processes has been developed for OMW treatment. However, the treatments studied have limitations such as the operation costs, difficulty of industrial scale-up, and the fact that the vast majority do not lead to suitable treated water for discharge/reuse. As such, it is urgent to develop a solution capable of efficiently treating this effluent, overcoming the disadvantages of existing processes to convert OMW from a serious environmental problem into a valuable source of water and nutrients. In this review, several studies based on the OMW treatment are critically discussed, from conventional approaches such as the physical (e.g. centrifugation, filtration, and adsorption) and biological (anaerobic digestion and anaerobic co-digestion) processes, to the most recent technologies such as advanced membrane filtration, advanced oxidation processes (AOPs) and sulfate radical based AOPs (SR-AOPs). Due to the complexity of the effluent, OMW cannot be efficiently treated by a single process, requiring a sequence of technologies before reaching the required characteristics for discharge into water courses or use in crop irrigation. Reviewing the published results in this matter, it seems that the sequence of processes encompassing ozonation, anaerobic digestion, and SR-AOPs could be the ideal combination for this purpose. However, membrane technologies may be necessary in the final stage of treatment so that the effluent meets legal discharge or irrigation limits.

Raw milk cheeses from Beira Baixa, Portugal-A contributive study for the microbiological hygiene and safety assessment.

Due to specific bacterial microbiota, raw milk cheeses have appreciated sensory properties. However, they may pose a threat to consumer safety due to potential pathogens presence. This study evaluated the microbiological contamination of 98 raw milk cheeses from Beira Baixa, Portugal. Presence and enumeration of Coagulase Positive Staphylococci (CPS), Listeria monocytogenes, Salmonella spp., pathogenic Escherichia coli, and indicator microorganisms (non-pathogenic E. coli and Listeria spp.) was attained. E. coli antimicrobial resistance (AMR) was also evaluated. PCR and/or Whole genome sequencing (WGS) was used to characterize E. coli, Salmonella spp. and L. monocytogenes isolates. Sixteen cheeses (16.3%) were classified as Satisfactory, 59 (60.2%) as Borderline and 23 (23.5%) as Unsatisfactory/Potential Injurious to Health. L. monocytogenes, CPS > 104 cfu g-1, Extraintestinal pathogenic E. coli (ExPEC) and Salmonella spp. were detected in 4.1%, 6.1%, 3.1% and 1.0% of the samples, respectively. Listeria innocua (4.1%) and E. coli > 104 cfu g-1 (16.3%) were also detected. AMR E. coli was detected in 23/98 (23.5%) of the cheese samples, of which two were multidrug resistant. WGS identified genotypes already associated to human disease and Listeria spp. cluster analysis indicated that cheese contamination might be related with noncompliance with Good Hygiene Practices during cheese production.

Preservation or removal of the lateral nasal wall in endoscopic management of maxillary sinus neoplasia: A comparison of approach related morbidity.

BACKGROUND: The endoscopic modified medial maxillectomy (MMM) and prelacrimal approach (PLA) are two routinely performed endoscopic approaches to the maxillary sinus when access via a middle meatal antrostomy is insufficient. However, there is no data in the literature that has compared outcomes and complication profile between the two procedures to determine which approach is superior. OBJECTIVE: To compare the approach related morbidity of PLA and MMM. METHODS: A retrospective cohort study of all consecutive adult patients undergoing either MMM or PLA from 2009 to 2023 were identified. The primary outcome was development of epistaxis, paraesthesia, lacrimal injury, iatrogenic sinus dysfunction within a minimum of 3 months post-operative follow up. RESULTS: 39 patients (44 sides) underwent PLA and 96 (96 sides) underwent MMM. There were no statistically significant differences between the rates of paraesthesia (9.1 % vs 14.6 %, p = 0.367) or prolonged paraesthesia (2.3 % vs 5.2 %, p = 0.426), iatrogenic maxillary sinus dysfunction (2.3 % vs 5.2 %, p = 0.426) or adhesions requiring removal (4.5 % vs 4.2 %, p = 0.918). No cases of epiphora or nasal cavity stenosis occurred in either arm in our study. CONCLUSIONS: According to our data, the endoscopic modified medial maxillectomy and prelacrimal approach are both equally safe approaches with their own benefits to access.

Effect of odontoplasty on intake, nutrient digestibility, and intake time of tifton hay in ponies.

We aimed to evaluate the effects of dental correction on voluntary nutrient intake, time of intake, apparent digestibility and fecal particle size in Brazilian ponies. Twelve mares, with no history of previous dental treatments, housed in individual pens and fed a diet based on tifton 85 were used. The study comprised two consecutive experimental phases, pre and post dental treatment. Each phase consisted of 15 days for adaptation to the pen and treatment and 5 days for data collection, totaling 20 days. To calculate nutrient intake and digestibility coefficients, samples of diets, leftovers, and feces were analyzed for dry matter (DM), crude protein (CP), neutral detergent fiber (NDF), acid detergent fiber (ADF), crude fat (CF), mineral matter (MM), organic matter (OM), and non-fiber carbohydrates (NFC). Food intake time was recorded using a digital video recorder. Fecal particles were analyzed by wet sieving. Dental correction did not influence the intake of DM, CP, NDF, CF, and OM by the animals. However, there was an increase in NFC intake from 0.12 kg to 0.14 kg and in food intake time from 654.50 ± 138.98 to 774.95 ± 167.14. There was a decrease in the digestibility of CP from 0.08 kg to 0.04 kg and an increase in the digestibility of NDF from 0.65 kg to 0.82 kg. Although odontoplasty increased the time of hay intake and the digestibility of the fibrous fractions of the feed of ponies, it did not influence the intake of nutrients and the size of the fecal particles.

INSaFLU-TELEVIR: an open web-based bioinformatics suite for viral metagenomic detection and routine genomic surveillance.

BACKGROUND: Implementation of clinical metagenomics and pathogen genomic surveillance can be particularly challenging due to the lack of bioinformatics tools and/or expertise. In order to face this challenge, we have previously developed INSaFLU, a free web-based bioinformatics platform for virus next-generation sequencing data analysis. Here, we considerably expanded its genomic surveillance component and developed a new module (TELEVIR) for metagenomic virus identification. RESULTS: The routine genomic surveillance component was strengthened with new workflows and functionalities, including (i) a reference-based genome assembly pipeline for Oxford Nanopore technologies (ONT) data; (ii) automated SARS-CoV-2 lineage classification; (iii) Nextclade analysis; (iv) Nextstrain phylogeographic and temporal analysis (SARS-CoV-2, human and avian influenza, monkeypox, respiratory syncytial virus (RSV A/B), as well as a "generic" build for other viruses); and (v) algn2pheno for screening mutations of interest. Both INSaFLU pipelines for reference-based consensus generation (Illumina and ONT) were benchmarked against commonly used command line bioinformatics workflows for SARS-CoV-2, and an INSaFLU snakemake version was released. In parallel, a new module (TELEVIR) for virus detection was developed, after extensive benchmarking of state-of-the-art metagenomics software and following up-to-date recommendations and practices in the field. TELEVIR allows running complex workflows, covering several combinations of steps (e.g., with/without viral enrichment or host depletion), classification software (e.g., Kaiju, Kraken2, Centrifuge, FastViromeExplorer), and databases (RefSeq viral genome, Virosaurus, etc.), while culminating in user- and diagnosis-oriented reports. Finally, to potentiate real-time virus detection during ONT runs, we developed findONTime, a tool aimed at reducing costs and the time between sample reception and diagnosis. CONCLUSIONS: The accessibility, versatility, and functionality of INSaFLU-TELEVIR are expected to supply public and animal health laboratories and researchers with a user-oriented and pan-viral bioinformatics framework that promotes a strengthened and timely viral metagenomic detection and routine genomics surveillance. INSaFLU-TELEVIR is compatible with Illumina, Ion Torrent, and ONT data and is freely available at https://insaflu.insa.pt/ (online tool) and https://github.com/INSaFLU (code).

Must a Knee with Anterior Cruciate Ligament Deficiency and High-grade Pivot Shift Test Present an Increase in Internal Rotation?

Objective: Rupture of the anterior cruciate ligament (ACL) is one of the most common injuries in athletes and is often associated with damage to anterolateral structures. This combination of injuries presents itself clinically as a high-grade pivot shift test. The hypothesis of this study is that patients with ACL deficiency and high-grade pivot shift test should have an increased internal knee rotation. Methods: Twenty-two patients were tested. After effective spinal anesthesia, two tests were performed with the patient in supine position. First, the bilateral pivot shift test was performed manually, and its grade was recorded. Then, with the knee flexed to 90 degrees, the examiner drew the projection of the foot in a neutral position and in maximum internal rotation, and the angle of internal rotation was measured from the axes built between the central point of the heel and the hallux. Results: In the ACL-deficient knee, it was observed that there is a statistically significant average internal rotation (IR) delta of 10.5 degrees between the groups when not adjusted for age, and 10.6 degrees when adjusted for age. Conclusions: Knees with ACL deficiency and with pivot shift test grade I do not show increased internal rotation in relation to knees with intact ACL. Knees with ACL deficiency and with pivot shift test grades II and III show increased internal rotation in comparison to healthy knees.

Optimizing photovoltaic thermal (PVT) collector selection: A multi-criteria decision-making (MCDM) approach for renewable energy systems.

In the realm of renewable energy systems, the effective selection of Photovoltaic Thermal (PVT) collectors is important. This study delves into the intricacies of choosing optimal PVT collectors available in the market, emphasizing the utility of Multiple Criteria Decision Making (MCDM) methodologies. PVT collectors are differentiated based on various aspects such as their transparent front cover presence and the medium-liquid or air-used for heat transfer. The study methodologically identifies commercially available PVT collectors and establishes key performance indicators for comparison. Using an 11-point fuzzy scale, a weight matrix is determined. Subsequently, advanced MCDM techniques, including PROMETHEE II, TOPSIS, EDAS, and VIKOR, are employed to rank the alternatives. This research not only provides a systematic approach to PVT collector selection but also extends to a MATLAB-based tool for facilitating the process. The results underscore the value of the proposed methodologies in refining the selection of PVT collectors and their potential adaptability to other applications, such as PVT collector design.

Synthesis and In Vitro and Silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives.

BACKGROUND: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. OBJECTIVE: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. METHODS: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. RESULTS: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 µM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. CONCLUSION: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis.

Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive assessment of their effects on the immune system in comparison to treatment-naïve pwRRMS. Herein, we evaluated the numbers of circulating B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naïve or treated with different DMTs. Compared to treatment-naïve pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4+ and CD8+ T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) ß have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study comprehensively evaluates the magnitude of the effect of different DMTs on blood immune cells providing a better understanding of therapy outcome. Furthermore, the lack of a discernible pattern in the effects of DMTs on blood immune cells suggests that multiple immune cells can independently modulate the disease.

The molecular basis of sugar detection by an insect taste receptor.

Animals crave sugars because of their energy potential and the pleasurable sensation of tasting sweetness. Yet all sugars are not metabolically equivalent, requiring mechanisms to detect and differentiate between chemically similar sweet substances. Insects use a family of ionotropic gustatory receptors to discriminate sugars1, each of which is selectively activated by specific sweet molecules2-6. Here, to gain insight into the molecular basis of sugar selectivity, we determined structures of Gr9, a gustatory receptor from the silkworm Bombyx mori (BmGr9), in the absence and presence of its sole activating ligand, D-fructose. These structures, along with structure-guided mutagenesis and functional assays, illustrate how D-fructose is enveloped by a ligand-binding pocket that precisely matches the overall shape and pattern of chemical groups in D-fructose. However, our computational docking and experimental binding assays revealed that other sugars also bind BmGr9, yet they are unable to activate the receptor. We determined the structure of BmGr9 in complex with one such non-activating sugar, L-sorbose. Although both sugars bind a similar position, only D-fructose is capable of engaging a bridge of two conserved aromatic residues that connects the pocket to the pore helix, inducing a conformational change that allows the ion-conducting pore to open. Thus, chemical specificity does not depend solely on the selectivity of the ligand-binding pocket, but it is an emergent property arising from a combination of receptor-ligand interactions and allosteric coupling. Our results support a model whereby coarse receptor tuning is derived from the size and chemical characteristics of the pocket, whereas fine-tuning of receptor activation is achieved through the selective engagement of an allosteric pathway that regulates ion conduction.

[Relationship between air temperature and dengue incidence: time series study in Minas Gerais, Brazil (2010-2019)]. / Relação entre temperatura do ar e incidência de dengue: estudo de séries temporais em Minas Gerais, Brasil (2010-2019).

Air temperature is a climatic factor that affects the incidence of dengue, with effects varying according to time and space. We investigated the relationship between minimum air temperature and dengue incidence in Minas Gerais, Brazil, and evaluated the influence of socioeconomic and geographic variables on this relationship. This is a time series study with analysis conducted in three distinct stages: modeling using a distributed lag non-linear model, meta-analysis of models obtained, and meta-regression with geographic and socioeconomic data. Minimum temperature was a protective factor at extreme cold temperatures (RR = 0.65; 95%CI: 0.56-0.76) and moderate cold temperatures (RR = 0.71; 95%CI: 0.64-0.79), and a risk factor at moderate hot temperatures (RR = 1.15; 95%CI: 1.07-1.24), but not at extreme hot temperatures (RR = 1.1; 95%CI: 0.99-1.22). Heterogeneity of the models was high (I2 = 60%), which was also observed in meta-regression. Moderate and extreme cold temperatures have a protective effect, while moderate hot temperatures increase the risk. However, minimum air temperature does not explain the variability in the region, not even with the other variables in meta-regression.

A temperatura do ar é um fator climático que afeta a incidência da dengue, com efeitos variando conforme o tempo e o espaço. Investigamos a relação entre a temperatura mínima do ar e a incidência da doença em Minas Gerais, Brasil, e avaliamos a influência de variáveis socioeconômicas e geográficas nessa relação, calculando-se o risco relativo (RR). Este é um estudo de série temporal com análise conduzida em três etapas distintas: modelagem por uso de distributed lag non-linear model (modelos não-lineares distributivos com defasagem), metanálise dos modelos obtidos e metarregressão com dados geográficos e socioeconômicos. A temperatura mínima foi um fator de proteção quando em temperaturas frias extremas (RR = 0,65; IC95%: 0,56-0,76) e moderadas (RR = 0,71; IC95%: 0,64-0,79) e fator de risco em temperaturas de calor moderado (RR = 1,15; IC95%: 1,07-1,24), mas não em extremo (RR = 1,1; IC95%: 0,99-1,22). A heterogeneidade dos modelos foi elevada (I2 = 60%) e essa medida não foi alterada em metarregressão. Temperaturas frias moderadas e extremas causam efeito protetivo, enquanto moderadas quentes aumentam o risco. No entanto, a temperatura mínima do ar não explica nem a variabilidade da região, nem mesmo com as outras variáveis em metarregressão.

La temperatura del aire es un factor climático que afecta la incidencia del dengue, con efectos que varían según el tiempo y el territorio. Investigamos la relación entre la temperatura mínima del aire y la incidencia de la enfermedad en Minas Gerais, Brasil, y evaluamos la influencia de variables socioeconómicas y geográficas en esta relación. Se trata de un estudio de serie temporal cuyo análisis se realiza en tres etapas distintas: modelación mediante el uso de distributed lag non-linear model (modelos distributivos no lineales con retraso), metaanálisis de los modelos obtenidos y metarregresión con datos geográficos y socioeconómicos. La temperatura mínima fue un factor de protección ante temperaturas extremadamente frías (RR = 0,65; IC95%: 0,56-0,76) y moderadas (RR = 0,71; IC95%: 0,64-0,79) y factor de riesgo en temperaturas de calor moderado (RR = 1,15; IC95%: 1,07-1,24), pero no en extremo (RR = 1,1; IC95%: 0,99-1,22). La heterogeneidad de los modelos fue alta (I2 = 60%), y esta medida no se modificó en la metarregresión. Las temperaturas frías moderadas y extremas tienen un efecto protector, mientras que las temperaturas moderadamente altas aumentan el riesgo. Sin embargo, la temperatura mínima del aire no explica la variabilidad de la región, ni siquiera con las demás variables en metarregresión.

Occurrence of arbovirus infections in two riverine populations in the municipality of Humaitá, Amazonas, Brazil.

BACKGROUND: The riverine communities of the Amazon comprise different social groups that inhabit the rural areas on the banks of rivers and lakes. Residents usually travel by river to rural and urban areas and are then exposed to urbanized diseases such as those caused by arbovirus infection. In Brazil, emerging diseases such as dengue, Zika, chikungunya, and those caused by infection with Oropouche and Mayaro viruses necessitate epidemiological surveillance. This study was aimed at determining the frequency of positivity for immunoglobulin (Ig)G and IgM antibodies against Zika, chikungunya, and dengue viruses and performing molecular analyses to detect viral RNA for the Zika, chikungunya, dengue virus, Oropouche, and Mayaro viruses, in the same serum samples obtained from riverside populations. METHODS: This cross-sectional study was conducted in a riverside population in the Humaitá municipality of the Brazilian Amazon. More than 80% of the local population participated in this study. Entomological samples were collected to identify local mosquito vectors. RESULTS: Analysis of 205 human serological samples revealed IgG antibodies against the dengue virus in 85 individuals. No molecular positivity was observed in human samples. Entomological analyses revealed 3,187 Diptera species, with Mansonia being the most frequent genus. Aedes aegypti and Aedes albopictus were not detected in the two collections. CONCLUSIONS: IgG antibodies against the dengue virus were highly prevalent, suggesting previous exposure. The absence of the arbovirus vectors Aedes aegypti and Aedes albopictus in the samples supports the hypothesis that the infections recorded likely occurred outside the riverside communities investigated.