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Conducting polymers are mixed ionic-electronic conductors that are emerging candidates for neuromorphic computing, bioelectronics and thermoelectrics. However, fundamental aspects of their many-body correlated electron-ion transport physics remain poorly understood. Here we show that in p-type organic electrochemical transistors it is possible to remove all of the electrons from the valence band and even access deeper bands without degradation. By adding a second, field-effect gate electrode, additional electrons or holes can be injected at set doping states. Under conditions where the counterions are unable to equilibrate in response to field-induced changes in the electronic carrier density, we observe surprising, non-equilibrium transport signatures that provide unique insights into the interaction-driven formation of a frozen, soft Coulomb gap in the density of states. Our work identifies new strategies for substantially enhancing the transport properties of conducting polymers by exploiting non-equilibrium states in the coupled system of electronic charges and counterions.
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Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.
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Antagonistas Adrenérgicos beta , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Humanos , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Progressão da Doença , Receptores Adrenérgicos beta/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
We propose a novel, non-discriminatory classification of monkeypox virus diversity. Together with the World Health Organization, we named three clades (I, IIa and IIb) in order of detection. Within IIb, the cause of the current global outbreak, we identified multiple lineages (A.1, A.2, A.1.1 and B.1) to support real-time genomic surveillance.
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Monkeypox virus , Mpox , Surtos de Doenças , Genômica , Humanos , Mpox/diagnóstico , Mpox/epidemiologia , Monkeypox virus/genéticaRESUMO
The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Prognóstico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologia , Progressão da DoençaRESUMO
BACKGROUND: Kidney stones and CKD are common disorders with a substantial interaction. Although observational studies have suggested a potential for enhanced CKD risk after prior kidney stones, the exact relationship remains ambiguous. METHODS: Shared comorbidities between two diseases were identified using unbiased screening. Genome-wide association study summary statistics were obtained from the UK Biobank (UKBB), FinnGen, and CKDGen, followed by genetic association analyses across various traits. Bidirectional Mendelian randomization (MR) analyses were performed to define causal links, complemented by multivariable MR that included the shared comorbidities including hypertension, diabetes, and obesity. Observational analyses were undertaken using cohorts from the Mayo Clinic and a UKBB subset. RESULTS: Despite identifying a total of 123 conditions as shared comorbidities, there was no significant genetic correlation between kidney stones and CKD. Unadjusted MR analysis revealed no significant association between kidney stones and CKD risk (UKBB [exposure]/FinnGen [outcome]: OR=0.97, 95% CI: 0.88â¼1.06; FinnGen/UKBB: OR=1.17, 95% CI:0.98â¼1.39). Kidney stones did significantly associate with a higher urinary albumin-creatinine ratio (UACR) (ß=0.014, 95% CI: 0.002â¼0.025), but this association disappeared in the multivariable MR model (ß=0.009, 95% CI: -0.003â¼0.020). Furthermore, in a cross-sectional analysis limited to the UKBB cohort, a robust regression model did not detect an independent association between kidney stones and UACR (ß=0.16, 95% CI: -0.04â¼0.35) or eGFR (ß=0.10, 95% CI: -0.07â¼0.28). Conversely, CKD associated with a diminished risk of kidney stones in multivariable MR models (UKBB/FinnGen: OR=0.77, 95% CI: 0.69â¼0.87; FinnGen/UKBB: OR=0.73, 95% CI: 0.66â¼0.81). Furthermore, in the Mayo Clinic cohort with available urinary biochemistries, lower eGFR was associated with lower urinary calcium excretion and urinary calcium oxalate/phosphate supersaturation. CONCLUSIONS: In this study, kidney stones were not independently associated with CKD. Conversely, CKD was associated with a lower risk of calcium kidney stones likely via changes in key urinary traits, including lower calcium excretion.
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Diffusion-based tractography in the optic nerve requires sampling strategies assisted by anatomical landmark information (regions of interest [ROIs]). We aimed to investigate the feasibility of expert-placed, high-resolution T1-weighted ROI-data transfer onto lower spatial resolution diffusion-weighted images. Slab volumes from 20 volunteers were acquired and preprocessed including distortion bias correction and artifact reduction. Constrained spherical deconvolution was used to generate a directional diffusion information grid (fibre orientation distribution-model [FOD]). Three neuroradiologists marked landmarks on both diffusion imaging variants and structural datasets. Structural ROI information (volumetric interpolated breath-hold sequence [VIBE]) was respectively registered (linear with 6/12 degrees of freedom [DOF]) onto single-shot EPI (ss-EPI) and readout-segmented EPI (rs-EPI) volumes, respectively. All eight ROI/FOD-combinations were compared in a targeted tractography task of the optic nerve pathway. Inter-rater reliability for placed ROIs among experts was highest in VIBE images (lower confidence interval 0.84 to 0.97, mean 0.91) and lower in both ss-EPI (0.61 to 0.95, mean 0.79) and rs-EPI (0.59 to 0.86, mean 0.70). Tractography success rate based on streamline selection performance was highest in VIBE-drawn ROIs registered (6-DOF) onto rs-EPI FOD (70.0% over 5%-threshold, capped to failed ratio 39/16) followed by both 12-DOF-registered (67.5%; 41/16) and nonregistered VIBE (67.5%; 40/23). On ss-EPI FOD, VIBE-ROI-datasets obtained fewer streamlines overall with each at 55.0% above 5%-threshold and with lower capped to failed ratio (6-DOF: 35/36; 12-DOF: 34/34, nonregistered 33/36). The combination of VIBE-placed ROIs (highest inter-rater reliability) with 6-DOF registration onto rs-EPI targets (best streamline selection performance) is most suitable for white matter template generation required in group studies.
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Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.
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Restrição Calórica , Sirtuínas , Animais , Humanos , Síndrome de COVID-19 Pós-Aguda , Envelhecimento/metabolismo , Longevidade/fisiologia , Sirtuínas/metabolismo , Mamíferos/metabolismoRESUMO
Background Deep learning (DL)-accelerated MRI can substantially reduce examination times. However, studies prospectively evaluating the diagnostic performance of DL-accelerated MRI reconstructions in acute suspected stroke are lacking. Purpose To investigate the interchangeability of DL-accelerated MRI with conventional MRI in patients with suspected acute ischemic stroke at 1.5 T. Materials and Methods In this prospective study, 211 participants with suspected acute stroke underwent clinically indicated MRI at 1.5 T between June 2022 and March 2023. For each participant, conventional MRI (including T1-weighted, T2-weighted, T2*-weighted, T2 fluid-attenuated inversion-recovery, and diffusion-weighted imaging; 14 minutes 18 seconds) and DL-accelerated MRI (same sequences; 3 minutes 4 seconds) were performed. The primary end point was the interchangeability between conventional and DL-accelerated MRI for acute ischemic infarction detection. Secondary end points were interchangeability regarding the affected vascular territory and clinically relevant secondary findings (eg, microbleeds, neoplasm). Three readers evaluated the overall occurrence of acute ischemic stroke, affected vascular territory, clinically relevant secondary findings, overall image quality, and diagnostic confidence. For acute ischemic lesions, size and signal intensities were assessed. The margin for interchangeability was chosen as 5%. For interrater agreement analysis and interrater reliability analysis, multirater Fleiss κ and the intraclass correlation coefficient, respectively, was determined. Results The study sample consisted of 211 participants (mean age, 65 years ± 16 [SD]); 123 male and 88 female). Acute ischemic stroke was confirmed in 79 participants. Interchangeability was demonstrated for all primary and secondary end points. No individual equivalence indexes (IEIs) exceeded the interchangeability margin of 5% (IEI, -0.002 [90% CI: -0.007, 0.004]). Almost perfect interrater agreement was observed (P > .91). DL-accelerated MRI provided higher overall image quality (P < .001) and diagnostic confidence (P < .001). The signal properties of acute ischemic infarctions were similar in both techniques and demonstrated good to excellent interrater reliability (intraclass correlation coefficient, ≥0.8). Conclusion Despite being four times faster, DL-accelerated brain MRI was interchangeable with conventional MRI for acute ischemic lesion detection. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Haller in this issue.
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Aprendizado Profundo , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Idoso , AVC Isquêmico/diagnóstico por imagem , Estudos Prospectivos , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats. Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined. SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group. SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.
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Hepatopatia Gordurosa não Alcoólica , Fenilpropionatos , Pirróis , Humanos , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Caspase 3 , Proteína de Ligação a Elemento Regulador de Esterol 1 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Necroptose , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Dexametasona/farmacologia , Lipídeos , AutofagiaRESUMO
This study assessed the ability of formulated curcumin-loaded chitosan nanoparticles (CU-CS-NPs) to reduce the kidney damage resulting from fenpropathrin (FPN) in rats compared to curcumin (CU) in rats. Sixty male Sprague Dawley rats were separated into six groups and orally administered 1 mL/kg b.wt corn oil, 50 mg CU/kg b.wt, 50 mg CU-CS-NPs /kg b.wt., 15 mg FPN /kg b.wt, CU+ FPN or CU-CS-NPs + FPN for 60 days. Then, serum renal damage products were assessed. Total antioxidant capacity, reactive oxygen species, interleukin 1ß (IL-1ß), malondialdehyde, NF-κB P65, cleaved-Caspase-1, and Caspase-8 were estimated in kidney homogenates. The cleaved Caspase-3 and TNF-α immunoexpression and pyroptosis-related genes were determined in renal tissues. The results showed that CU-CS-NPS significantly repressed the FPN-induced increment in kidney damage products (urea, uric acid, and creatinine). Moreover, the FPN-associated hypo-proteinemia, renal oxidative stress and apoptotic reactions, and impaired renal histology were considerably repaired by CU and CU-CS-NPs. Additionally, compared to FPN-exposed rats, CU, and CU-CS-NPs-treated rats had considerably lower immunoexpression of cleaved Caspase-3 and TNF-α in renal tissue. The pyroptosis-related genes NLRP3, GSDMD, IL-18, Caspase-3, Caspase-1, IL-1ß, Caspase-8, TNF-α, and NF-κB dramatically upregulated by FPN exposure in the renal tissues. Yet, in CU and CU-CS-NPs-treated rats, the gene above expression deviations were corrected. Notably, CU-CS-NPs were superior to CU in preventing oxidative damage and inflammation and regulating pyroptosis in the renal tissues of the FPN-exposed group. The results of the present study conclusively showed the superior favorable effect of CU-CS-NPs in counteracting renal impairment linked to environmental pollutants.
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Quitosana , Curcumina , Piretrinas , Piroptose , Animais , Masculino , Ratos , Caspase 1 , Caspase 3 , Caspase 8 , Curcumina/farmacologia , Rim , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piretrinas/toxicidade , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfaRESUMO
PURPOSE OF REVIEW: To eradicate atherosclerotic diseases, novel biomarkers, and future therapy targets must reveal the burden of early atherosclerosis (AS), which occurs before life-threatening unstable plaques form. The chemical and biological features of microRNAs (miRNAs) make them interesting biomarkers for numerous diseases. We summarized the latest research on miRNA regulatory mechanisms in AS progression studies, which may help us use miRNAs as biomarkers and treatments for difficult-to-treat diseases. RECENT FINDINGS: Recent research has demonstrated that miRNAs have a regulatory function in the observed changes in gene and protein expression during atherogenesis, the process that leads to atherosclerosis. Several miRNAs play a role in the development of atherosclerosis, and these miRNAs could potentially serve as non-invasive biomarkers for atherosclerosis in various regions of the body. These miRNAs have the potential to serve as biomarkers and targets for early treatment of atherosclerosis. The start and development of AS require different miRNAs. It reviews new research on miRNAs affecting endothelium, vascular smooth muscle, vascular inflammation, lipid retention, and cholesterol metabolism in AS. A miRNA gene expression profile circulates with AS everywhere. AS therapies include lipid metabolism, inflammation reduction, and oxidative stress inhibition. Clinical use of miRNAs requires tremendous progress. We think tiny miRNAs can enable personalized treatment.
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Aterosclerose , Biomarcadores , MicroRNAs , Humanos , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/diagnóstico , Aterosclerose/terapia , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Prognóstico , AnimaisRESUMO
PURPOSE OF REVIEW: This review is focused on diagnostic and management strategies for colonic diverticular bleeding (CDB). It aims to present the current state of the field, highlighting the available techniques, and emphasizing findings that influence the choice of therapy. RECENT FINDINGS: Recent guidelines recommend nonurgent colonoscopy (>24âh) for CDB. However, factors such as a shock index ≥1, which may warrant an urgent colonoscopy, remain under investigation.The standard approach to detecting the source of CDB requires a water-jet scope equipped with a cap. Innovative diagnostic techniques, such as the long-cap and tapered-cap, have proven effective in identifying stigmata of recent hemorrhage (SRH). Furthermore, the water or gel immersion methods may aid in managing massive hemorrhage by improving the visualization and stabilization of the bleeding site for subsequent intervention. Innovations in endoscopic hemostasis have significantly improved the management of CDB. New therapeutic methods such as endoscopic band ligation and direct clipping have substantially diminished the incidence of recurrent bleeding. Recent reports also have demonstrated the efficacy of cutting-edge techniques such as over-the-scope clips, which have significantly improved outcomes in complex cases that have historically necessitated surgical intervention. SUMMARY: Currently available endoscopic diagnostic and hemostatic methods for CDB have evolved with improved outcomes. Further research is necessary to refine the criteria for urgent colonoscopy and to confirm the effectiveness of new endoscopic hemostasis techniques.
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Colonoscopia , Hemorragia Gastrointestinal , Hemostase Endoscópica , Humanos , Hemorragia Gastrointestinal/cirurgia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/terapia , Colonoscopia/métodos , Hemostase Endoscópica/métodos , Divertículo do Colo/complicações , Divertículo do Colo/cirurgiaRESUMO
BACKGROUND: Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown. METHODS: We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently. FINDINGS: MS and MDD patients showed increased modularity (ANOVA partial-η2 = 0.3) and clustering (partial-η2 = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η2 = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η2 = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %). CONCLUSIONS: Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression.
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Encéfalo , Depressão , Transtorno Depressivo Maior , Substância Cinzenta , Inflamação , Imageamento por Ressonância Magnética , Esclerose Múltipla , Substância Branca , Humanos , Feminino , Masculino , Adulto , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla/psicologia , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologia , Pessoa de Meia-Idade , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Depressão/fisiopatologia , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Doenças Neuroinflamatórias/diagnóstico por imagemRESUMO
This study aimed to assess the influence of pollution on the quality of sediments and the risks associated with El-Qusier and Safaga Cities, Red Sea, Egypt, during 2021, divided into four sectors, using multiple pollution indices. To achieve that, we evaluated the metal pollution index (MPI), contamination factor (Cf), pollution load index (PLI), contamination security index (CSI), and anthropogenicity (Anp%). Moreover, carcinogenic and non-carcinogenic risks are used for human health hazards. Results indicated that Mn and Fe recorded the highest concentrations, whereas Cd had the lowest. El-Quseir City sediments were found the following metal ions: Fe > Mn > Ni > Zn > Cu > Co > Pb > Cd, where the order in the Safaga City was: Fe > Mn > Zn > Ni > Cu > Pb > Co > Cd. MPI > 1, this is alarming in the study area due to heavy metal pollution. In addition, Cf < 1 in all metals except Cd with contamination degree CD ranged from low to considerable contamination in El-Qusier city. In contrast, contamination ranged from significant to very high in Safaga city. PLI < 1 is lower than the reference at all monitored stations. CSI values ranged from relatively low to moderate. Besides Cd, data reflect each element's low environmental danger (EriMe40). This study's risk index (RI) is low to moderate in Sector 1 and high to extremely high in Sector 2. HQ and HI index < 1 means it is safe for human health in order: HI ingestion > HI dermal. CSR for different pathways was recorded as dermal > ingestion, in which total CSR for all paths is considered harmful, and the cancer risk is troublesome and higher than the reference ranges of 1 × 10-6-1 × 10-4. In conclusion, the examined heavy metals provide environmental hazards across the assessed locations.
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OBJECTIVES: Gender differences have been reported to influence medical training. We investigated gender differences encountered during training in interventional radiology maneuvers. METHODS: Catheter handling was analyzed under standardized conditions in 64 participants naïve to endovascular procedures (26 women, 38 men). Objective (e.g., catheter pathway, catheter movements, required time) and subjective parameters (stress level) were recorded. The NASA-Task Load Index (NASA-TLX; 1-20 points) was used to assess participants' stress levels and perceived workload. RESULTS: In the easier tasks, no significant differences between male and female participants regarding catheter handling were observed. In the most complex task, female participants took themselves more time (688 ± 363 vs. 501 ± 230 s; p = 0.02), asked for help more frequently (n = 19 vs. n = 8) and earlier than men (203 ± 94 vs. 305 ± 142 s; p = 0.049), whereas men stood out by more agitated catheter handling (6.0 ± 1.8 vs. 4.8 ± 1.6 movements/s; p = 0.005). Overall, female participants perceived tasks to be more difficult (11.5 ± 4.2 vs. 9.6 ± 3.3; p = 0.016), perceived higher stress levels (8.9 ± 4.9 vs. 6.3 ± 4.4; p = 0.037), and rated their own performance lower (9.12 ± 3.3 vs. 11.3 ± 3.3; p = 0.009). However, female participants were able to correlate self-assessed with objective parameters correctly (r between -0.555 and -0.469; p = 0.004-0.018), whereas male participants failed to correctly rate their performance (p between 0.34 and 0.73). Stress levels correlated with objective parameters in males (r between 0.4 and 0.587; p < 0.005), but not in female participants. CONCLUSION: Perceived stress levels, self-evaluation skills, and catheter handling differ greatly between untrained male and female participants trying to solve interventional radiological tasks. These gender-specific differences should be considered in interventional radiology training. CLINICAL RELEVANCE STATEMENT: As psychological aspects may influence individual working strategies gender-specific differences in self-perception while learning interventional radiology maneuvers could be essential regarding success in teaching and treatment outcomes. KEY POINTS: ⢠After performing standardized training, 38 male and 26 female volunteers showed significant differences regarding objective and self-assessed performance, as well as in perceived workload while performing simulated endovascular catheter maneuvers. ⢠After solving simulated endovascular radiological tasks, female participants were able to self-assess their objective performance much more accurately than male participants. ⢠Women took more time to solve simulated endovascular tasks and asked earlier and more frequently for help than men.
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Procedimentos Endovasculares , Radiologia Intervencionista , Humanos , Masculino , Feminino , Fatores Sexuais , Carga de Trabalho/psicologia , AprendizagemRESUMO
Active electroreception-the ability to detect objects and communicate with conspecifics via the detection and generation of electric organ discharges (EODs)-has evolved convergently in several fish lineages. South American electric fishes (Gymnotiformes) are a highly species-rich group, possibly in part due to evolution of an electric organ (EO) that can produce diverse EODs. Neofunctionalization of a voltage-gated sodium channel gene accompanied the evolution of electrogenic tissue from muscle and resulted in a novel gene (scn4aa) uniquely expressed in the EO. Here, we investigate the link between variation in scn4aa and differences in EOD waveform. We combine gymnotiform scn4aa sequences encoding the C-terminus of the Nav1.4a protein, with biogeographic data and EOD recordings to test whether physiological transitions among EOD types accompany differential selection pressures on scn4aa. We found positive selection on scn4aa coincided with shifts in EOD types. Species that evolved in the absence of predators, which likely selected for reduced EOD complexity, exhibited increased scn4aa evolutionary rates. We model mutations in the protein that may underlie changes in protein function and discuss our findings in the context of gymnotiform signalling ecology. Together, this work sheds light on the selective forces underpinning major evolutionary transitions in electric signal production.
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Peixe Elétrico , Animais , Peixe Elétrico/genética , Órgão Elétrico/fisiologia , Filogenia , Canais de Sódio/genética , América do SulRESUMO
In the current study, a series of benzimidazole-oxindole conjugates 8a-t were designed and synthesized as type II multi-kinase inhibitors. They exhibited moderate to potent inhibitory activity against BRAFWT up to 99.61 % at 10 µM. Notably, compounds 8e, 8k, 8n and 8s demonstrated the most promising activity, with 99.44 to 99.61 % inhibition. Further evaluation revealed that 8e, 8k, 8n and 8s exhibit moderate to potent inhibitory effects on the kinases BRAFV600E, VEGFR-2, and FGFR-1. Additionally, compounds 8a-t were screened for their cytotoxicity by the NCI, and several compounds showed significant growth inhibition in diverse cancer cell lines. Compound 8e stood out with a GI50 range of 1.23 - 3.38 µM on melanoma cell lines. Encouraged by its efficacy, it was further investigated for its antitumor activity and mechanism of action, using sorafenib as a reference standard. The hybrid compound 8e exhibited potent cellular-level suppression of BRAFWT, VEGFR-2, and FGFR-1 in A375 cell line, surpassing the effects of sorafenib. In vivo studies demonstrate that 8e significantly inhibits the growth of B16F10 tumors in mice, leading to increased survival rates and histopathological tumor regression. Furthermore, 8e reduces angiogenesis markers, mRNA expression levels of VEGFR-2 and FGFR-1, and production of growth factors. It also downregulated Notch1 protein expression and decreased TGF-ß1 production. Molecular docking simulations suggest that 8e binds as a promising type II kinase inhibitor in the target kinases interacting with the key regions in their kinase domain.
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Antineoplásicos , Melanoma , Animais , Camundongos , Sorafenibe/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf , Proliferação de Células , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Benzimidazóis/farmacologia , Oxindóis/farmacologia , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.
Assuntos
Isatina , Mycobacterium tuberculosis , Quinolinas , Humanos , Proteína de Transporte de Acila/farmacologia , Isatina/farmacologia , Simulação de Acoplamento Molecular , Oxirredutases/metabolismo , Antituberculosos/farmacologia , Antituberculosos/química , Testes de Sensibilidade Microbiana , Quinolinas/farmacologia , Proteínas de Bactérias/metabolismoRESUMO
Epigenetics plays a vital role in the interaction between living organisms and their environment by regulating biological functions and phenotypic plasticity. Considering that most aquaculture activities take place in open or natural habitats that are vulnerable to environmental changes. Promising findings from recent research conducted on various aquaculture species have provided preliminary evidence suggesting a link between epigenetic mechanisms and economically valuable characteristics. Environmental stressors, including climate changes (thermal stress, hypoxia, and water salinity), anthropogenic impacts such as (pesticides, crude oil pollution, nutritional impacts, and heavy metal) and abiotic factors (infectious diseases), can directly trigger epigenetic modifications in fish. While experiments have confirmed that many epigenetic alterations caused by environmental factors have plastic responses, some can be permanently integrated into the genome through genetic integration and promoting rapid transgenerational adaptation in fish. These environmental factors might cause irregular DNA methylation patterns in genes related to many biological events leading to organs dysfunction by inducing alterations in genes related to oxidative stress or apoptosis. Moreover, these environmental issues alter DNA/histone methylation leading to decreased reproductive competence. This review emphasizes the importance of understanding the effects of environmentally relevant issues on the epigenetic regulation of phenotypic variations in fish. The goal is to expand our knowledge of how epigenetics can either facilitate or hinder species' adaptation to these adverse conditions. Furthermore, this review outlines the areas that warrant further investigation in understanding epigenetic reactions to various environmental issues.
Assuntos
Epigênese Genética , Peixes , Animais , Peixes/genética , Peixes/fisiologia , Adaptação Fisiológica/genética , Fenótipo , Metilação de DNARESUMO
Microfluidic systems have fundamentally transformed the realm of adaptive laboratory evolution (ALE) for microorganisms by offering unparalleled control over environmental conditions, thereby optimizing mutant generation and desired trait selection. This review summarizes the substantial influence of microfluidic technologies and their design paradigms on microbial adaptation, with a primary focus on leveraging spatial stressor concentration gradients to enhance microbial growth in challenging environments. Specifically, microfluidic platforms tailored for scaled-down ALE processes not only enable highly autonomous and precise setups but also incorporate novel functionalities. These capabilities encompass fostering the growth of biofilms alongside planktonic cells, refining selection gradient profiles, and simulating adaptation dynamics akin to natural habitats. The integration of these aspects enables shaping phenotypes under pressure, presenting an unprecedented avenue for developing robust, stress-resistant strains, a feat not easily attainable using conventional ALE setups. The versatility of these microfluidic systems is not limited to fundamental research but also offers promising applications in various areas of stress resistance. As microfluidic technologies continue to evolve and merge with cutting-edge methodologies, they possess the potential not only to redefine the landscape of microbial adaptation studies but also to expedite advancements in various biotechnological areas. KEY POINTS: ⢠Microfluidics enable precise microbial adaptation in controlled gradients. ⢠Microfluidic ALE offers insights into stress resistance and distinguishes between resistance and persistence. ⢠Integration of adaptation-influencing factors in microfluidic setups facilitates efficient generation of stress-resistant strains.