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AIMS: Although static abnormalities of functional brain networks have been observed in patients with social anxiety disorder (SAD), the brain connectome dynamics at the macroscale network level remain obscure. We therefore used a multivariate data-driven method to search for dynamic functional network connectivity (dFNC) alterations in SAD. METHODS: We conducted spatial independent component analysis, and used a sliding-window approach with a k-means clustering algorithm, to characterize the recurring states of brain resting-state networks; then state transition metrics and FNC strength in the different states were compared between SAD patients and healthy controls (HC), and the relationship to SAD clinical characteristics was explored. RESULTS: Four distinct recurring states were identified. Compared with HC, SAD patients demonstrated higher fractional windows and mean dwelling time in the highest-frequency State 3, representing "widely weaker" FNC, but lower in States 2 and 4, representing "locally stronger" and "widely stronger" FNC, respectively. In State 1, representing "widely moderate" FNC, SAD patients showed decreased FNC mainly between the default mode network and the attention and perceptual networks. Some aberrant dFNC signatures correlated with illness duration. CONCLUSION: These aberrant patterns of brain functional synchronization dynamics among large-scale resting-state networks may provide new insights into the neuro-functional underpinnings of SAD.
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Encéfalo , Conectoma , Imagen por Resonancia Magnética , Red Nerviosa , Fobia Social , Humanos , Masculino , Femenino , Adulto , Fobia Social/fisiopatología , Fobia Social/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Adulto JovenRESUMEN
Effective fisheries management requires accurate estimates of stock biomass and trends; yet, assumptions in stock assessment models generate high levels of uncertainty and error. For 230 fisheries worldwide, we contrasted stock biomass estimates at the time of assessment with updated hindcast estimates modeled for the same year in later assessments to evaluate systematic over- or underestimation. For stocks that were overfished, low value, or located in regions with rising temperatures, historical biomass estimates were generally overstated compared with updated assessments. Moreover, rising trends reported for overfished stocks were often inaccurate. With consideration of bias identified retrospectively, 85% more stocks than currently recognized have likely collapsed below 10% of maximum historical biomass. The high uncertainty and bias in modeled stock estimates warrants much greater precaution by managers.
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Biomasa , Explotaciones Pesqueras , Animales , Peces , Incertidumbre , Conservación de los Recursos Naturales , Modelos TeóricosRESUMEN
BACKGROUND: The role of ECG in ruling out myocardial complications on cardiac magnetic resonance (CMR) is unclear. We examined the clinical utility of ECG in screening for cardiac abnormalities on CMR among post-hospitalised COVID-19 patients. METHODS: Post-hospitalised patients (n = 212) and age, sex and comorbidity-matched controls (n = 38) underwent CMR and 12lead ECG in a prospective multicenter follow-up study. Participants were screened for routinely reported ECG abnormalities, including arrhythmia, conduction and R wave abnormalities and ST-T changes (excluding repolarisation intervals). Quantitative repolarisation analyses included corrected QT (QTc), corrected QT dispersion (QTc disp), corrected JT (JTc) and corrected T peak-end (cTPe) intervals. RESULTS: At a median of 5.6 months, patients had a higher burden of ECG abnormalities (72.2% vs controls 42.1%, p = 0.001) and lower LVEF but a comparable cumulative burden of CMR abnormalities than controls. Patients with CMR abnormalities had more ECG abnormalities and longer repolarisation intervals than those with normal CMR and controls (82% vs 69% vs 42%, p < 0.001). Routinely reported ECG abnormalities had poor discriminative ability (area-under-the-receiver-operating curve: AUROC) for abnormal CMR, AUROC 0.56 (95% CI 0.47-0.65), p = 0.185; worse among female than male patients. Adding JTc and QTc disp improved the AUROC to 0.64 (95% CI 0.55-0.74), p = 0.002, the sensitivity of the ECG increased from 81.6% to 98.0%, negative predictive value from 84.7% to 96.3%, negative likelihood ratio from 0.60 to 0.13, and reduced sex-dependence variabilities of ECG diagnostic parameters. CONCLUSION: Post-hospitalised COVID-19 patients have more ECG abnormalities than controls. Normal ECGs, including normal repolarisation intervals, reliably exclude CMR abnormalities in male and female patients.
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In 2020, Denmark buried approximately four million culled, farmed mink in mass graves treated with slaked lime due to widespread SARS-CoV-2 infections. After six months, environmental concerns prompted the exhumation of these cadavers. Our analysis encompassed visual inspections, soil pH measurements, and gas emission assessments of the grave environment. Additionally, we evaluated carcasses for decay status, cadaverine content, and the presence of various pathogens, including SARS-CoV-2 and mink coronavirus. Our findings revealed minimal microbial activity and limited carcass decomposition. Although viral RNA from SARS-CoV-2 and mink coronavirus, along with DNA from Aleutian mink disease virus, were detected, the absence of infectious SARS-CoV-2 in cell culture assays suggests slow natural degradation processes. This study provides critical insights for future considerations in managing mass burial scenarios during outbreaks of livestock-associated zoonotic pathogens.
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Entierro , COVID-19 , Visón , SARS-CoV-2 , Animales , Visón/virología , COVID-19/epidemiología , COVID-19/virología , SARS-CoV-2/aislamiento & purificación , Dinamarca , Pandemias , Cadáver , Humanos , ARN Viral/genética , Coronavirus/aislamiento & purificación , Coronavirus/genéticaRESUMEN
INTRODUCTION: Robotic-assisted metabolic and bariatric surgery (MBS) is gaining popularity. Revisional MBS is associated with higher perioperative morbidity compared to primary MBS. The optimal surgical approach to minimize complications in these complex cases is unclear. The goal of this study was to assess robot utilization in revisional MBS and compare laparoscopic and robotic revisional MBS outcomes in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. METHODS: A retrospective review of the MBSAQIP database was performed identifying revisional sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) cases from 2015 to 2022. Primary MBS, open/emergent cases, cases converted to another approach, and combined cases other than esophagogastroduodenoscopy were excluded. 30-Day outcomes for laparoscopic and robotic cases were compared using multivariate logistic regression adjusting for patient demographics, comorbidities, and operative variables. RESULTS: 41,404 Cases (14,474 SG; 26,930 RYGB) were identified. From 2015 to 2022, the percentage of revisional SG and RYGB cases performed robotically increased from 6.1% and 7.3% to 24.2% and 32.0% respectively. Laparoscopic SG had similar rates of overall morbidity, leak, bleeding, readmission, reoperation, and length of stay compared to robotic. Laparoscopic RYGB had significantly higher rates of overall morbidity (6.2% vs. 4.8%, p < 0.001, AOR 0.80 [0.70-0.93]), blood transfusion (1.5% vs. 1.0%, p < 0.05, AOR 0.74 [0.55-0.99]), superficial incisional SSI (1.2% vs. 0.4%, p < 0.001, AOR 0.30 [0.19-0.47]), and longer length of stay (1.87 vs. 1.76 days, p < 0.001) compared to robotic. Laparoscopic operative times were significantly shorter than robotic (SG: 86.4 ± 45.8 vs. 113.5 ± 51.7 min; RYGB: 130.7 ± 64.7 vs. 165.5 ± 66.8 min, p < 0.001). CONCLUSION: Robot utilization in revisional bariatric surgery is increasing. Robotic surgery has lower postoperative morbidity and shorter length of stay in revisional RYGB when compared to laparoscopic. Robotic platforms may have the capacity to improve the delivery of care for patients undergoing revisional bariatric surgery.
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Difusión de la Información , Humanos , Reino Unido , COVID-19/economía , COVID-19/epidemiologíaRESUMEN
This parallel, two-arm, blinded, randomized controlled superiority trial examined whether, when added to usual care, active- electroencephalography neurofeedback (EEG NFB) was safe and more effective than sham control-EEG NFB for chronic pain. 116 participants with chronic pain were randomly assigned (1:1) to usual care plus ≥ 32 sessions of active-EEG NFB upregulating relative alpha power over C4 or usual care plus ≥ 32 sessions of sham control-EEG NFB. Per protocol analyses revealed no significant between-group differences in the primary outcome, brief pain inventory (BPI) average pain (mean difference [95% CI]: -0.04 [-0.39 to 0.31], p=0.90), or any secondary outcomes. However, 44% of participants in the active-EEG NFB group and 45% in the control-EEG NFB group reported at least a moderate (≥30%), clinically important improvement in BPI average pain. The number of treatment emergent adverse events were similar in both groups (p = 0.83), and none were serious. Post-hoc analyses revealed similar upregulated relative alpha power in both groups during training, with concordant positive rewards delivered to the active-EEG group 100% of the time and the control-EEG group ~25% of the time, suggesting a partially active sham intervention. When added to usual care, the active-EEG NFB intervention used in this study was not superior to the sham control-EEG NFB intervention. However, a large proportion of participants in both groups reported a clinically important reduction in pain intensity. A partially active sham intervention may have obscured between-group differences. The intervention was free of important side effects, with no safety concerns identified. PERSPECTIVES: This study is the first attempt at an appropriately blinded, randomized, sham-controlled trial of alpha EEG NFB for the treatment of chronic pain. The findings may interest people living with chronic pain, clinicians involved in chronic pain management, and may inform the design of future EEG NFB trials. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000667819.
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Bordetella pertussis is a Gram-negative bacterium that is the causative agent of the respiratory disease known as pertussis. Since the switch to the acellular vaccines of DTaP and Tap, pertussis cases in the US have risen and cyclically fallen. We have observed that mRNA pertussis vaccines are immunogenic and protective in mice. Here, we further evaluated the pertussis toxoid mRNA antigen and refined the formulation based on optimal pertussis toxin neutralization in vivo. We next evaluated the mRNA pertussis vaccine in Sprague-Dawley rats using an aerosol B. pertussis challenge model paired with whole-body plethysmography to monitor coughing and respiratory function. Female Sprague-Dawley rats were primed and boosted with either commercially available vaccines (DTaP or wP-DTP), an mRNA-DTP vaccine, or mock-vaccinated. The mRNA-DTP vaccine was immunogenic in rats and induced antigen-specific IgG antibodies comparable to DTaP. Rats were then aerosol challenged with a streptomycin-resistant emerging clinical isolate D420Sm1. Bacterial burden was assessed at days 1 and 9 post-challenge, and the mRNA vaccine reduced burden equal to both DTaP and wP-DTP. Whole-body plethysmography revealed that mRNA-DTP vaccinated rats were well protected against coughing which was comparable to the non-challenged group. These data suggest that an mRNA-DTP vaccine is immunogenic in rats and provides protection against aerosolized B. pertussis challenge in Sprague-Dawley rats.
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Bordetella pertussis , Ratas Sprague-Dawley , Tos Ferina , Animales , Tos Ferina/prevención & control , Tos Ferina/inmunología , Femenino , Ratas , Bordetella pertussis/inmunología , Bordetella pertussis/genética , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Inmunoglobulina G/sangre , Vacunas de ARNm , InmunizaciónRESUMEN
Bordetella pertussis, the bacterium responsible for whooping cough, remains a significant public health challenge despite the existing licensed pertussis vaccines. Current acellular pertussis vaccines, though having favorable reactogenicity and efficacy profiles, involve complex and costly production processes. In addition, acellular vaccines have functional challenges such as short-lasting duration of immunity and limited antigen coverage. Filamentous hemagglutinin (FHA) is an adhesin of B. pertussis that is included in all multivalent pertussis vaccine formulations. Antibodies to FHA have been shown to prevent bacterial attachment to respiratory epithelial cells, and T cell responses to FHA facilitate cell-mediated immunity. In this study, FHA's mature C-terminal domain (MCD) was evaluated as a novel vaccine antigen. MCD was conjugated to virus-like particles via SpyTag-SpyCatcher technology. Prime-boost vaccine studies were performed in mice to characterize immunogenicity and protection against the intranasal B. pertussis challenge. MCD-SpyVLP was more immunogenic than SpyTag-MCD antigen alone, and in Tohama I strain challenge studies, improved protection against challenge was observed in the lungs at day 3 and in the trachea and nasal wash at day 7 post-challenge. Furthermore, a B. pertussis strain encoding genetically inactivated pertussis toxin was used to evaluate MCD-SpyVLP vaccine immunity. Mice vaccinated with MCD-SpyVLP had significantly lower respiratory bacterial burden at both days 3 and 7 post-challenge compared to mock-vaccinated animals. Overall, these data support the use of SpyTag-SpyCatcher VLPs as a platform for use in vaccine development against B. pertussis and other pathogens.
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Adhesinas Bacterianas , Anticuerpos Antibacterianos , Bordetella pertussis , Vacuna contra la Tos Ferina , Vacunas de Partículas Similares a Virus , Tos Ferina , Animales , Bordetella pertussis/inmunología , Ratones , Tos Ferina/prevención & control , Tos Ferina/inmunología , Vacuna contra la Tos Ferina/inmunología , Vacuna contra la Tos Ferina/administración & dosificación , Anticuerpos Antibacterianos/inmunología , Adhesinas Bacterianas/inmunología , Adhesinas Bacterianas/genética , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Femenino , Ratones Endogámicos BALB C , Factores de Virulencia de Bordetella/inmunología , Infecciones del Sistema Respiratorio/prevención & control , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/microbiologíaRESUMEN
Reduction of hexaazatrinaphthylene (HAN) and its hexamethyl derivative with [Cp*2Sm(THF)2] or [Cp*2Yb(OEt2)] produces [(Cp*2Ln)3(R6HAN)] (Ln = Sm, Yb; R = H, Me), where the heterocyclic ligand forms as a trianion. The magnetism and electronic structure of these compounds reflect unusual multiconfigurational character within the reduced ligand but not the lanthanide ions.
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X-ray photoelectron spectroscopy (XPS) depth-profiling with an argon gas cluster ion source (GCIS) was used to characterize the spatial distribution of chlorophyll a (Chl) within a poly(cysteine methacrylate) (PCysMA) brush grown by surface-initiated atom-transfer radical polymerization (ATRP) from a planar surface. The organization of Chl is controlled by adjusting the brush grafting density and polymerization time. For dense brushes, the C, N, S elemental composition remains constant throughout the 36 nm brush layer until the underlying gold substrate is approached. However, for either reduced density brushes (mean thickness â¼20 nm) or mushrooms grown with reduced grafting densities (mean thickness 6-9 nm), elemental intensities decrease continuously throughout the brush layer, because photoelectrons are less strongly attenuated for such systems. For all brushes, the fraction of positively charged nitrogen atoms (N+/N0) decreases with increasing depth. Chl binding causes a marked reduction in N+/N0 within the brushes and produces a new feature at 398.1 eV in the N1s core-line spectrum assigned to tetrapyrrole ring nitrogen atoms coordinated to Zn2+. For all grafting densities, the N/S atomic ratio remains approximately constant as a function of brush depth, which indicates a uniform distribution of Chl throughout the brush layer. However, a larger fraction of repeat units bound to Chl is observed at lower grafting densities, reflecting a progressive reduction in steric congestion that enables more uniform distribution of the bulky Chl units throughout the brush layer. In summary, XPS depth-profiling using a GCIS is a powerful tool for characterization of these complex materials.
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The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.
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Antagonistas de Receptores de Angiotensina , Enzima Convertidora de Angiotensina 2 , Teoría Funcional de la Densidad , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Humanos , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , COVID-19/virología , Relación Estructura-Actividad , Estructura Molecular , Bencimidazoles/farmacología , Bencimidazoles/química , Tetrazoles/farmacología , Tetrazoles/química , Tetrazoles/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Tratamiento Farmacológico de COVID-19RESUMEN
Most organophosphates (OPs) are hydrophobic, and after exposure, can sequester into lipophilic regions within the body, such as adipose tissue, resulting in long term chronic effects. Consequently, there is an urgent need for therapeutic agents that can decontaminate OPs in these hydrophobic regions. Accordingly, an enzyme-polymer surfactant nanocomplex is designed and tested comprising chemically supercharged phosphotriesterase (Agrobacterium radiobacter; arPTE) electrostatically conjugated to amphiphilic polymer surfactant chains ([cat.arPTE][S-]). Experimentally-derived structural data are combined with molecular dynamics (MD) simulations to provide atomic level detail on conformational ensembles of the nanocomplex using dielectric constants relevant to aqueous and lipidic microenvironments. These show the formation of a compact admicelle pseudophase surfactant corona under aqueous conditions, which reconfigures to yield an extended conformation at a low dielectric constant, providing insight into the mechanism underpinning cell membrane binding. Significantly, it demonstrated that [cat.arPTE][S-] spontaneously binds to human mesenchymal stem cell membranes (hMSCs), resulting in on-cell OP hydrolysis. Moreover, the nanoconstruct can endocytose and partition into the intracellular fatty vacuoles of adipocytes and hydrolyze sequestered OP.
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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) not only caused the COVID-19 pandemic but also had a major impact on farmed mink production in several European countries. In Denmark, the entire population of farmed mink (over 15 million animals) was culled in late 2020. During the period of June to November 2020, mink on 290 farms (out of about 1100 in the country) were shown to be infected with SARS-CoV-2. Genome sequencing identified changes in the virus within the mink and it is estimated that about 4000 people in Denmark became infected with these mink virus variants. However, the routes of transmission of the virus to, and from, the mink have been unclear. Phylogenetic analysis revealed the generation of multiple clusters of the virus within the mink. Detailed analysis of changes in the virus during replication in mink and, in parallel, in the human population in Denmark, during the same time period, has been performed here. The majority of cases in mink involved variants with the Y453F substitution and the H69/V70 deletion within the Spike (S) protein; these changes emerged early in the outbreak. However, further introductions of the virus, by variants lacking these changes, from the human population into mink also occurred. Based on phylogenetic analysis of viral genome data, we estimate, using a conservative approach, that about 17 separate examples of mink to human transmission occurred in Denmark but up to 59 such events (90% credible interval: (39-77)) were identified using parsimony to count cross-species jumps on transmission trees inferred using Bayesian methods. Using the latter approach, 136 jumps (90% credible interval: (117-164)) from humans to mink were found, which may underlie the farm-to-farm spread. Thus, transmission of SARS-CoV-2 from humans to mink, mink to mink, from mink to humans and between humans were all observed.
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COVID-19 , Visón , Filogenia , SARS-CoV-2 , Visón/virología , COVID-19/transmisión , COVID-19/virología , COVID-19/epidemiología , COVID-19/veterinaria , SARS-CoV-2/genética , Animales , Dinamarca/epidemiología , Humanos , Pandemias , Granjas , Betacoronavirus/genética , Betacoronavirus/clasificación , Genoma Viral , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/transmisión , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to design two families of α-helical barrel proteins with central channels that bind small molecules. Computational designs are seeded by the sequences and structures of defined de novo oligomeric barrel-forming peptides, and adjacent helices are connected by loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix-turn-helix-turn-helix motifs that are packed onto the barrels. Throughout these computational pipelines, residues that define open states of the barrels are maintained. This minimizes sequence sampling, accelerating the design process. For each of six targets, just two to six synthetic genes are made for expression in Escherichia coli. On average, 70% of these genes express to give soluble monomeric proteins that are fully characterized, including high-resolution structures for most targets that match the design models with high accuracy.
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Escherichia coli , Proteínas , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas/química , Proteínas/genética , Conformación Proteica en Hélice alfa , Ingeniería de Proteínas/métodos , Modelos Moleculares , Péptidos/química , Péptidos/genética , Biología Computacional/métodos , Secuencia de Aminoácidos , Pliegue de ProteínaRESUMEN
Given the increased extraction of trace elements for use by new and emerging technologies, monitoring the environmental fate and potential effects of these compounds within the aquatic environment has never been more critical. Here, hepatic trace element concentrations were assessed in a key sentinel predator, the common dolphin (Delphinus delphis), using a long-term dataset. Variation in concentrations were assessed in relation to other elements, time period, decomposition state, sex, age, total body length, sexual maturity and nutritional status, and cause of death. Additionally, mercury toxicity thresholds for evaluating risk were reviewed and employed. Concentrations of elements which bioaccumulate, THg, MeHg, Cd, and Pb, in addition to Se and V, were strongly correlated with age, and/or body length. An association was observed between Zn concentrations and disease status, with significantly higher concentrations measured in individuals that died from infectious disease, compared to other causes. Strong inter-elemental relationships were detected, namely between Hg and Se, MeHg and Se, Cd and Se, and Cu and Zn. While THg:Se molar ratio values were observed to increase with age and body length, approaching equimolarity. THg was largely comprised of inorganic Hg in older individuals, potentially bound to Se, therefore the effects from THg toxicity may possibly be less important than originally assumed. In contrast, higher MeHg:Hg ratio values were reported in juveniles, suggesting a poorer efficiency in demethylation and a higher sensitivity. The generation of data on proportions of hepatic MeHg and inorganic Hg is highly informative to both future toxicity threshold assessments within pollutant indicator assessments, and to understanding the ultimate fate of mercury in the marine web.
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Monitoreo del Ambiente , Oligoelementos , Contaminantes Químicos del Agua , Animales , Oligoelementos/análisis , Oligoelementos/metabolismo , Contaminantes Químicos del Agua/análisis , Delfines/metabolismo , Masculino , Femenino , Estado de Salud , Hígado/metabolismo , Hígado/química , Mercurio/metabolismo , Océanos y MaresRESUMEN
BACKGROUND AND AIMS: Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. METHODS: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. RESULTS: Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (VÌO2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). CONCLUSION: Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD.
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Terapia por Ejercicio , Hígado , Humanos , Masculino , Persona de Mediana Edad , Femenino , Hígado/patología , Hígado/diagnóstico por imagen , Adulto , Terapia por Ejercicio/métodos , Imagen por Resonancia Magnética , Ejercicio Físico , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Composición Corporal , Ensayos Clínicos Controlados Aleatorios como Asunto , Biomarcadores/sangre , Índice de Masa Corporal , Cirrosis Hepática/terapia , Cirrosis Hepática/fisiopatologíaRESUMEN
Ferritin, a spherical protein shell assembled from 24 subunits, functions as an efficient iron storage and release system through its channels. Understanding how various chemicals affect the structural behavior of ferritin is crucial for unravelling the origins of iron-related diseases in living organisms including humans. In particular, the influence of chemicals on ferritin's dynamics and iron release is barely explored at the single-protein level. Here, by employing optical nanotweezers using double-nanohole (DNH) structures, we examined the effect of ascorbic acid (reducing reagent) and pH on individual ferritin's conformational dynamics. The dynamics of ferritin increased as the concentration of ascorbic acid approached saturation. At pH 2.0, ferritin exhibited significant structural fluctuations and eventually underwent a stepwise disassembly into fragments. This work demonstrated the disassembly pathway and kinetics of a single ferritin molecule in solution. We identified four critical fragments during its disassembly pathway, which are 22-mer, 12-mer, tetramer, and dimer subunits. Moreover, we present single-molecule evidence of the cooperative disassembly of ferritin. Interrogating ferritin's structural change in response to different chemicals holds importance for understanding their roles in iron metabolism, hence facilitating further development of medical treatments for its associated diseases.
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Ácido Ascórbico , Ferritinas , Pinzas Ópticas , Ferritinas/química , Ferritinas/metabolismo , Cinética , Ácido Ascórbico/química , Concentración de Iones de Hidrógeno , Conformación Proteica , Hierro/química , HumanosRESUMEN
Correction for 'Flax fibre reinforced alginate poloxamer hydrogel: assessment of mechanical and 4D printing potential' by Charles de Kergariou et al., Soft Matter, 2024, 20, 4021-4034, https://doi.org/10.1039/D4SM00135D.
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We provide a simple method that enables readily acquired experimental data to be used to predict whether or not a candidate molecular material may exhibit strong coupling. Specifically, we explore the relationship between the hybrid molecular/photonic (polaritonic) states and the bulk optical response of the molecular material. For a given material, this approach enables a prediction of the maximum extent of strong coupling (vacuum Rabi splitting), irrespective of the nature of the confined light field. We provide formulae for the upper limit of the splitting in terms of the molar absorption coefficient, the attenuation coefficient, the extinction coefficient (imaginary part of the refractive index) and the absorbance. To illustrate this approach, we provide a number of examples, and we also discuss some of the limitations of our approach.