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OBJECTIVE: Hypertension is a recognized risk factor for the development of cognitive impairment and dementia in older adults. Aortic stiffness and altered haemodynamics could promote the transmission of detrimental high pressure pulsatility into the cerebral circulation, potentially damaging brain microvasculature and leading to cognitive impairment. We determined whether reservoir-excess pressure parameters were associated with cognitive function in people with hypertension (HT) and normotension (NT). METHODS: We studied 35 middle-aged and older treatment-naïve stage II/III HT (office systolic BP 176 ±â€Š17 mmHg) and 35 age-, sex- and body mass index-matched NT (office systolic BP 127 ±â€Š8 mmHg). Parameters derived from reservoir-excess pressure analysis including reservoir pressure integral (INTPR), excess pressure integral (INTXSP), systolic rate constant (SRC), diastolic rate constant (DRC) and pulse wave velocity (PWV) were calculated from an ensemble-averaged aortic pressure waveform derived from radial artery tonometry. Cognitive function was assessed using the Addenbrooke's Cognitive Examination Revised (ACE-R), Trail Making Test Part A (TMT-A) and Part B (TMT-B). RESULTS: All reservoir-excess pressure parameters were greater in HT than NT (all P < 0.05). Greater INTXSP was associated with lower ACE-R score (rs = -0.31), longer TMT-A (r = 0.31) and TMT-B (r = 0.38). Likewise, greater DRC and PWV were also associated with lower ACE-R score (rs = -0.27 and rs = -0.33), longer TMT-A (r = 0.51 and r = 0.40) and TMT-B (r = 0.38 and r = 0.32). Greater INTXSP, DRC and PWV are consistently associated with worse cognitive function in this study. CONCLUSIONS: These observations support a potential mechanistic link between adverse haemodynamics and a heightened risk of cognitive impairment in older adults with hypertension.

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INTRODUCTION: Musculoskeletal pain typically occurs in multiple sites; however, no study has examined whether excessive visceral and subcutaneous adipose tissue are associated with musculoskeletal pain. This study therefore aimed to describe the associations between MRI-derived abdominal adipose tissue and multisite and widespread chronic musculoskeletal pain. METHODS: Data from the UK Biobank, a large prospective, population-based cohort study, were used. Abdominal MRI scans were performed at two imaging visits to quantify visceral adipose tissue and subcutaneous adipose tissue. Pain in the neck/shoulder, back, hip, knee or 'all over the body' was assessed at the corresponding visits. Mixed-effects ordinal/multinomial/logistic regression models were used for the analyses. RESULTS: A total of 32 409 participants were included (50.8% women, mean age 55.0±7.4 years). In multivariable analyses, there was a dose-response association of visceral adipose tissue, subcutaneous adipose tissue and their ratio with the number of chronic pain sites in both women (visceral adipose tissue: OR 2.04 per SD (95% CI 1.85 to 2.26); subcutaneous adipose tissue: OR 1.60 (95% CI 1.50 to 1.70); and their ratio: OR 1.60 (95% CI 1.37 to 1.87)) and men (visceral adipose tissue: OR 1.34 (95% CI 1.26 to 1.42); subcutaneous adipose tissue: OR 1.39 (95% CI 1.29 to 1.49); and their ratio: OR 1.13 (95% CI 1.07 to 1.20)). Higher levels of adipose tissue were also associated with greater odds of reporting chronic pain in both sexes. The effect estimates of these adipose measures were relatively larger in women than in men. CONCLUSION: Abdominal adipose tissue was associated with chronic musculoskeletal pain, suggesting that excessive and ectopic fat depositions may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain. The identified stronger effects in women than men may reflect sex differences in fat distribution and hormones.

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Flavonoids are secondary metabolites associated with plant seed coat and flower color. These compounds provide health benefits to humans as anti-inflammatory and antioxidant compounds. The expression of the late biosynthetic genes in the flavonoid pathway is controlled by a ternary MBW protein complex consisting of interfacing MYB, beta-helix-loop-helix (bHLH), and WD40 Repeat (WDR) proteins. P, the master regulator gene of the flavonoid expression in common bean (Phaseolus vulgaris L.), was recently determined to encode a bHLH protein. The T and Z genes control the distribution of color in bean seeds and flowers and have historically been considered regulators of the flavonoid gene expression. T and Z candidates were identified using reverse genetics based on genetic mapping, phylogenetic analysis, and mutant analysis. Domain and AlphaFold2 structure analyses determined that T encodes a seven-bladed ß-propeller WDR protein, while Z encodes a R2R3 MYB protein. Deletions and SNPs in T and Z mutants, respectively, altered the 3D structure of these proteins. Modeling of the Z MYB/P bHLH/T WDR MBW complex identified interfacing sequence domains and motifs in all three genes that are conserved in dicots. One Z MYB motif is a possible beta-molecular recognition feature (ß-MoRF) that only appears in a structured state when Z MYB is modeled as a component of a MBW complex. Complexes containing mutant T and Z proteins changed the interaction of members of the complex in ways that would alter their role in regulating the expression of genes in the flavonoid pathway.

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Background: Soft ticks (Family: Argasidae) are vectors of relapsing fever Borrelia in the United States and are potential vectors of African swine fever virus, a pathogen that could have a devastating effect on the U.S. swine industry if introduced to the U.S. mainland. Much of the tick-borne disease research in the U.S. focuses on hard ticks, and less is known about the ecology of soft ticks. Some soft tick species found in the southern U.S. have a wide host range and may feed on cattle, swine, native and exotic ungulates, small mammals, reptiles, and humans. Because the feeding habit of most soft tick species involves taking short, repeated blood meals that may include multiple host species, pathogen transmission among hosts is a concern both for human and animal health. Materials and Methods: Sampling was carried out at four locations in south Texas using dry ice traps placed in or near animal burrows and other sheltering cracks and crevasses that may provide refuge for soft ticks. Collected ticks were identified and subsequently screened for Rickettsia and Borrelia species and for host bloodmeal detection using conventional polymerase chain reaction and Sanger sequencing for pathogen and host species identification. Results: In total, 256 ticks of two Ornithodorinae species were screened. Borrelia species were identified in three samples. Bloodmeal detections were made in 22 tick specimens, representing eight vertebrate host species. Conclusions: Results demonstrate that the soft tick species detected herein feed on a range of wildlife hosts in south Texas and are associated with agents of human disease.

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AIMS: Parameters derived from reservoir-excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir-excess pressure parameters could have a detrimental effect on highly-perfused organs like the heart. We aimed to cross-sectionally determine whether reservoir-excess pressure parameters were associated with N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in older adults. METHODS: We studied 868 older adults with diverse cardiovascular risk. Reservoir-excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT-proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology. RESULTS: Multivariable linear regression analyses revealed that all reservoir-excess pressure parameters studied were associated with NT-proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [ß = 0.191 (95% confidence interval, CI: 0.099, 0.283), P < 0.001], SRC [ß = -0.080 (95% CI: -0.141, -0.019), P = 0.010] and DRC [ß = 0.138 (95% CI: 0.073, 0.202), P < 0.001] remained associated with NT-proBNP. Sensitivity analysis found that there were occasions where the association between SRC and NT-proBNP was attenuated, but both INTXSP and DRC remained consistently associated with NT-proBNP. CONCLUSIONS: The observed associations between reservoir-excess pressure parameters and NT-proBNP suggest that altered reservoir-excess pressure parameters may reflect an increased load inflicted on the left ventricular cardiomyocytes and could have a potential to be utilized in the clinical setting for cardiovascular risk stratification.

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Misophonia is commonly classified by intense emotional reactions to common everyday sounds. The condition has an impact both on the mental health of its sufferers and societally. As yet, formal models on the basis of misophonia are in their infancy. Based on developing behavioural and neuroscientific research we are gaining a growing understanding of the phenomenology and empirical findings in misophonia, such as the importance of context, types of coping strategies used and the activation of particular brain regions. In this article, we argue for a model of misophonia that includes not only the sound but also the context within which sound is perceived and the emotional reaction triggered. We review the current behavioural and neuroimaging literature, which lends support to this idea. Based on the current evidence, we propose that misophonia should be understood within the broader context of social perception and cognition, and not restricted within the narrow domain of being a disorder of auditory processing. We discuss the evidence in support of this hypothesis, as well as the implications for potential treatment approaches. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

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Emociones , Cognición Social , Humanos , Emociones/fisiología , Percepción Auditiva/fisiología , Cognición , Percepción Social

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Septoria nodorum blotch (SNB), caused by Parastagonospora nodorum, is a disease of durum and common wheat initiated by the recognition of pathogen-produced necrotrophic effectors (NEs) by specific wheat genes. The wheat gene Snn1 was previously cloned, and it encodes a wall-associated kinase that directly interacts with the NE SnTox1 leading to programmed cell death and ultimately the development of SNB. Here, sequence analysis of Snn1 from 114 accessions including diploid, tetraploid, and hexaploid wheat species revealed that some wheat lines possess two copies of Snn1 (designated Snn1-B1 and Snn1-B2) approximately 120 kb apart. Snn1-B2 evolved relatively recently as a paralog of Snn1-B1, and both genes have undergone diversifying selection. Three point mutations associated with the formation of the first SnTox1-sensitive Snn1-B1 allele from a primitive wild wheat were identified. Four subsequent and independent SNPs, three in Snn1-B1 and one in Snn1-B2, converted the sensitive alleles to insensitive forms. Protein modeling indicated these four mutations could abolish Snn1-SnTox1 compatibility either through destabilization of the Snn1 protein or direct disruption of the protein-protein interaction. A high-throughput marker was developed for the absent allele of Snn1, and it was 100% accurate at predicting SnTox1-insensitive lines in both durum and spring wheat. Results of this study increase our understanding of the evolution, diversity, and function of Snn1-B1 and Snn1-B2 genes and will be useful for marker-assisted elimination of these genes for better host resistance.

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Ascomicetos , Enfermedades de las Plantas , Proteínas de Plantas , Triticum , Triticum/genética , Triticum/microbiología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ascomicetos/fisiología , Ascomicetos/patogenicidad , Evolución Molecular , Genes de Plantas/genética , Polimorfismo de Nucleótido Simple , Susceptibilidad a Enfermedades , Alelos , Resistencia a la Enfermedad/genética

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Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31 Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18 F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18 F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

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Background: Prostate cancer ranks as the most frequently diagnosed cancer in men in the USA, with significant mortality rates. Early detection is pivotal for optimal patient outcomes, providing increased treatment options and potentially less invasive interventions. There remain significant challenges in prostate cancer histopathology, including the potential for missed diagnoses due to pathologist variability and subjective interpretations. Methods: To address these challenges, this study investigates the ability of artificial intelligence (AI) to enhance diagnostic accuracy. The Galen™ Prostate AI algorithm was validated on a cohort of Puerto Rican men to demonstrate its efficacy in cancer detection and Gleason grading. Subsequently, the AI algorithm was integrated into routine clinical practice during a 3-year period at a CLIA certified precision pathology laboratory. Results: The Galen™ Prostate AI algorithm showed a 96.7% (95% CI 95.6-97.8) specificity and a 96.6% (95% CI 93.3-98.8) sensitivity for prostate cancer detection and 82.1% specificity (95% CI 73.9-88.5) and 81.1% sensitivity (95% CI 73.7-87.2) for distinction of Gleason Grade Group 1 from Grade Group 2+. The subsequent AI integration into routine clinical use examined prostate cancer diagnoses on >122,000 slides and 9200 cases over 3 years and had an overall AI Impact ™ factor of 1.8%. Conclusions: The potential of AI to be a powerful, reliable, and effective diagnostic tool for pathologists is highlighted, while the AI Impact™ in a real-world setting demonstrates the ability of AI to standardize prostate cancer diagnosis at a high level of performance across pathologists.

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After burn injury there is considerable variation in scar outcome, partially due to genetic factors. Scar vascularity is one characteristic that varies between individuals, and this study aimed to identify genetic variants contributing to different scar vascularity outcomes. An exome-wide array association study and gene pathway analysis was performed on a prospective cohort of 665 patients of European ancestry treated for burn injury, using their scar vascularity (SV) sub-score, part of the modified Vancouver Scar Scale (mVSS), as an outcome measure. DNA was genotyped using the Infinium HumanCoreExome-24 BeadChip, imputed to the Haplotype Reference Consortium panel. Associations between genetic variants (single nucleotide polymorphisms) and SV were estimated using an additive genetic model adjusting for sex, age, % total body surface area and number of surgical procedures, utilising linear and multinomial logistic regression. No individual genetic variants achieved the cut-off threshold for significance. Gene sets were also analysed using the Functional Mapping and Annotation (FUMA) platform, in which biological processes indirectly related to angiogenesis were significantly represented. This study suggests that SNPs in genes associated with angiogenesis may influence SV, but further studies with larger datasets are essential to validate these findings.

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Quemaduras , Cicatriz , Polimorfismo de Nucleótido Simple , Población Blanca , Humanos , Quemaduras/genética , Femenino , Masculino , Estudios Prospectivos , Adulto , Cicatriz/genética , Persona de Mediana Edad , Población Blanca/genética , Adulto Joven , Modelos Logísticos , Estudios de Cohortes , Anciano , Genotipo , Exoma/genética

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Aedes albopictus, also known as the Asian tiger mosquito, is indigenous to the tropical forests of Southeast Asia. Ae. albopictus is expanding across the globe at alarming rates, raising concern over the transmission of mosquito-borne diseases, such as dengue, West Nile fever, yellow fever, and chikungunya fever. Since Ae. albopictus was reported in Houston (Harris County, Texas) in 1985, this species has rapidly expanded to at least 32 states across the United States. Public health efforts aimed at controlling Ae. albopictus, including surveillance and adulticide spraying operations, occur regularly in Harris County. Despite rotation of insecticides to mitigate the development of resistance, multiple mosquito species including Culex quinquefasciatus and Aedes aegypti in Harris County show organophosphate and pyrethroid resistance. Aedes albopictus shows relatively low resistance levels as compared to Ae. aegypti, but kdr-mutation and the expression of detoxification genes have been reported in Ae. albopictus populations elsewhere. To identify potential candidate detoxification genes contributing to metabolic resistance, we used RNA sequencing of field-collected malathion-resistant and malathion-susceptible, and laboratory-maintained susceptible colonies of Ae. albopictus by comparing the relative expression of transcripts from three major detoxification superfamilies involved in malathion resistance due to metabolic detoxification. Between these groups, we identified 12 candidate malathion resistance genes and among these, most genes correlated with metabolic detoxification of malathion, including four P450 and one alpha esterase. Our results reveal the metabolic detoxification and potential cuticular-based resistance mechanisms associated with malathion resistance in Ae. albopictus in Harris County, Texas.

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Aedes , Perfilación de la Expresión Génica , Resistencia a los Insecticidas , Insecticidas , Malatión , Animales , Malatión/farmacología , Aedes/genética , Aedes/efectos de los fármacos , Aedes/metabolismo , Resistencia a los Insecticidas/genética , Insecticidas/farmacología , Mosquitos Vectores/genética , Mosquitos Vectores/efectos de los fármacos , Mosquitos Vectores/metabolismo , Análisis de Secuencia de ARN , Transcriptoma , Texas , Femenino , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo

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OBJECTIVES: Proliferative verrucous leukoplakia (PVL) is a rare but highly aggressive variant of oral leukoplakia that almost inevitably progresses to oral squamous cell carcinoma (OSCC). The aims of this study were to perform whole exome sequencing of a cohort of patients diagnosed with PVL and identify potential mutational profiles and pathways in this disorder. STUDY DESIGN: A total of 12 oral cavity mucosal biopsies from 6 patients with oral lesions clinically compatible with PVL were used. Of these, 9 were diagnosed as dysplasia, 1 OSCC, and 2 hyperkeratosis/hyperplasia. Exome sequencing used the Ion AmpliSeq Exome platform. Ion Reporter software was used for variant calling, annotation, and filtering. Analysis and visualization of somatic mutations was carried out using the MAFtools R package. RESULTS: Following exome sequencing and mutational profiling, we analyzed the profiles for cancer associated genes and signatures. Genes previously associated with OSCC, including HYDIN, MUC16, MAML3, CDKN2A, FAT1, and CASP8, were mutated in multiple samples. Several DNA damage repair genes including PARP1 were mutated in PVL samples. NOTCH and Hippo pathways were the most frequently impacted by mutation. CONCLUSIONS: This genome wide characterization of premalignant PVL identifies both known and potentially novel oncogenic mechanisms in this disorder.

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Leucoplasia Bucal , Neoplasias de la Boca , Mutación , Humanos , Leucoplasia Bucal/genética , Leucoplasia Bucal/patología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Secuenciación del Exoma , Biopsia , Adulto , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología

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Potenciales Evocados Auditivos , Estimulación Magnética Transcraneal , Humanos , Potenciales Evocados Auditivos/fisiología , Estimulación Magnética Transcraneal/métodos , Electroencefalografía/métodos , Electrocorticografía/métodos , Masculino , Femenino , Adulto

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Brachial artery flow-mediated dilation (BAFMD) is induced by hyperemic wall shear rate (WSR) following forearm ischemia. In older adults, there appears to be a reduced brachial hyperemic WSR and altered stimulus-response relationship compared with young adults. However, it is unclear if an altered forearm microvascular response to ischemia influences brachial hyperemic WSR in older adults. We determined associations between brachial hyperemic WSR and forearm skeletal muscle oxygen saturation in young and older adults. Healthy young (n = 17, 29 ± 7 yr) and older (n = 32, 65 ± 4 yr) adults participated in the study. BAFMD by a multigate spectral Doppler system and forearm skeletal muscle oxygen saturation by near-infrared spectroscopy were concurrently measured. When compared with the young, older adults showed reduced oxygen extraction kinetics (OE, 0.15 [0.12-0.17] vs. 0.09 [0.05-0.12]%s-1) and magnitude (So2deficit, 3,810 ± 1,420 vs. 2,723 ± 1,240%s) during ischemia, as well as oxygen resaturation kinetics (So2slope, 2.5 ± 0.7 vs. 1.7 ± 0.7%s-1) upon reperfusion (all P < 0.05). When OE in the young and So2slope in older adults were stratified by their median values, young adults with OE above the median had greater hyperemic WSR parameters compared with those below the median (P < 0.05), but So2slope in older adults did not show clear differences in hyperemic WSR parameters between those above/below the median. This study demonstrates that, in addition to a reduced microvascular response to ischemia, there may be a dissociation between microvascular response to ischemia and brachial hyperemic WSR in older adults, which may result in a further impairment of BAFMD in this cohort.NEW & NOTEWORTHY Microvascular response to ischemia and subsequent reperfusion is diminished in older adults compared with the young. Furthermore, there appears to be a dissociation between the microvascular response to ischemia and brachial hyperemic WSR in older adults, which may further disturb the BAFMD process in this cohort. A reduced BAFMD in older adults may be a result of multiple alterations occurring both at macro- and microcirculation.

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Arteria Braquial , Antebrazo , Hiperemia , Microcirculación , Músculo Esquelético , Flujo Sanguíneo Regional , Vasodilatación , Humanos , Arteria Braquial/fisiopatología , Arteria Braquial/diagnóstico por imagen , Masculino , Femenino , Adulto , Anciano , Hiperemia/fisiopatología , Hiperemia/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Persona de Mediana Edad , Antebrazo/irrigación sanguínea , Adulto Joven , Isquemia/fisiopatología , Isquemia/metabolismo , Factores de Edad , Velocidad del Flujo Sanguíneo , Espectroscopía Infrarroja Corta , Envejecimiento/metabolismo , Envejecimiento/fisiología , Consumo de Oxígeno , Saturación de Oxígeno , Microvasos/fisiopatología , Microvasos/metabolismo , Microvasos/diagnóstico por imagen

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Microbes synthesize and secrete siderophores, that bind and solubilize precipitated or otherwise unavailable iron in their microenvironments. Gram (-) bacterial TonB-dependent outer membrane receptors capture the resulting ferric siderophores to begin the uptake process. From their similarity to fepA, the structural gene for the Escherichia coli ferric enterobactin (FeEnt) receptor, we identified four homologous genes in the human and animal ESKAPE pathogen Klebsiella pneumoniae (strain Kp52.145). One locus encodes IroN (locus 0027 on plasmid pII), and three other loci encode other FepA orthologs/paralogs (chromosomal loci 1658, 2380, and 4984). Based on the crystal structure of E. coli FepA (1FEP), we modeled the tertiary structures of the K. pneumoniae FepA homologs and genetically engineered individual Cys substitutions in their predicted surface loops. We subjected bacteria expressing the Cys mutant proteins to modification with extrinsic fluorescein maleimide (FM) and used the resulting fluorescently labeled cells to spectroscopically monitor the binding and transport of catecholate ferric siderophores by the four different receptors. The FM-modified FepA homologs were nanosensors that defined the ferric catecholate uptake pathways in pathogenic strains of K. pneumoniae. In Kp52.145, loci 1658 and 4984 encoded receptors that primarily recognized and transported FeEnt; locus 0027 produced a receptor that principally bound and transported FeEnt and glucosylated FeEnt (FeGEnt); locus 2380 encoded a protein that bound ferric catecholate compounds but did not detectably transport them. The sensors also characterized the uptake of iron complexes, including FeGEnt, by the hypervirulent, hypermucoviscous K. pneumoniae strain hvKp1. IMPORTANCE: Both commensal and pathogenic bacteria produce small organic chelators, called siderophores, that avidly bind iron and increase its bioavailability. Klebsiella pneumoniae variably produces four siderophores that antagonize host iron sequestration: enterobactin, glucosylated enterobactin (also termed salmochelin), aerobactin, and yersiniabactin, which promote colonization of different host tissues. Abundant evidence links bacterial iron acquisition to virulence and infectious diseases. The data we report explain the recognition and transport of ferric catecholates and other siderophores, which are crucial to iron acquisition by K. pneumoniae.

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Hierro , Klebsiella pneumoniae , Sideróforos , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/genética , Sideróforos/metabolismo , Hierro/metabolismo , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Enterobactina/metabolismo , Transporte Biológico , Proteínas Portadoras

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Cognición , Humanos , Cognición/fisiología , Corteza Cerebral/fisiología , Complicaciones Posoperatorias/prevención & control

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OBJECTIVES: Sickle cell disease (SCD) occurs in 2.8 % of our Jamaican antenatal population with homozygous HbSS being most associated with adverse maternal and perinatal outcomes. METHODS: A retrospective comparative analysis of HbSS, HbSC and HbSßThal pregnancy outcomes at the University Hospital of the West Indies (UHWI) between January 2012 and December 2022 was conducted. RESULTS: Of 120 patients (138 pregnancies), obesity occurred in 36 % (20/56) of the 'non-HbSS' group, i.e. HbSßThal (55 %, 5/9) and HbSC (32 %, 15/47) combined vs. 9.7 % of the HbSS (8/82). HbSS patients had more crises requiring transfusions, acute chest syndrome (ACS), maternal 'near-misses' (OR=10.7, 95 % 3.5-32.3; p<0.001), hospitalizations (OR 7.6, 95 % CI 3.4-16.9; p<0.001), low birth weight (LBW) neonates (OR 3.1, 1.1-8.9; p=0.037) and preterm birth (OR=2.6, 1.2-5.8; p=0.018) compared to HbSC and HbSßThal. Low dose aspirin was prescribed in 43 %. Logistic regression showed those NOT on aspirin (n=76) had more miscarriages (22 v. 2 %), were LESS likely to have a live birth (75 v. 95 % (0.2, 0.04-0.57, p=0.005)), but surprisingly had fewer painful crises (28 v. 46 % (0.5, 0.03-0.9, p=0.03)). CONCLUSIONS: HbSS women had a 10-fold excess of maternal near-misses. Additional research may further clarify the effects of aspirin on pregnancy outcomes as related to SCD genotypes.

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Anemia de Células Falciformes , Aspirina , Complicaciones Hematológicas del Embarazo , Resultado del Embarazo , Humanos , Femenino , Embarazo , Jamaica/epidemiología , Estudios Retrospectivos , Adulto , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Resultado del Embarazo/epidemiología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/epidemiología , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , Complicaciones Hematológicas del Embarazo/epidemiología , Recién Nacido , Adulto Joven

RESUMEN

We studied the Escherichia coli outer membrane protein Fiu, a presumed transporter of monomeric ferric catecholates, by introducing Cys residues in its surface loops and modifying them with fluorescein maleimide (FM). Fiu-FM bound iron complexes of the tricatecholate siderophore enterobactin (FeEnt) and glucosylated enterobactin (FeGEnt), their dicatecholate degradation product Fe(DHBS)2 (FeEnt*), the monocatecholates dihydroxybenzoic acid (FeDHBA) and dihydroxybenzoyl serine (FeDHBS), and the siderophore antibiotics cefiderocol (FDC) and MB-1. Unlike high-affinity ligand-gated porins (LGPs), Fiu-FM had only micromolar affinity for iron complexes. Its apparent KD values for FeDHBS, FeDHBA, FeEnt*, FeEnt, FeGEnt, FeFDC, and FeMB-1 were 0.1, 0.7, 0.7, 1.0, 0.3, 0.4, and 4 µM, respectively. Despite its broad binding abilities, the transport repertoires of E. coli Fiu, as well as those of Cir and FepA, were less broad. Fiu only transported FeEnt*. Cir transported FeEnt* and FeDHBS (weakly); FepA transported FeEnt, FeEnt*, and FeDHBA. Both Cir and FepA bound FeGEnt, albeit with lower affinity. Related transporters of Acinetobacter baumannii (PiuA, PirA, BauA) had similarly moderate affinity and broad specificity for di- or monomeric ferric catecholates. Both microbiological and radioisotopic experiments showed Fiu's exclusive transport of FeEnt*, rather than ferric monocatecholate compounds. Molecular docking and molecular dynamics simulations predicted three binding sites for FeEnt*in the external vestibule of Fiu, and a fourth site deeper in its interior. Alanine scanning mutagenesis in the outermost sites (1a, 1b, and 2) decreased FeEnt* binding affinity as much as 20-fold and reduced or eliminated FeEnt* uptake. Finally, the molecular dynamics simulations suggested a pathway of FeEnt* movement through Fiu that may generally describe the process of metal transport by TonB-dependent receptors.

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Burn injuries are devastating traumas, often leading to life-long consequences that extend beyond the observable burn scar. In the context of the nervous system, burn injury patients commonly develop chronic neurological disorders and have been suggested to have impaired motor cortex function, but the long-lasting impact on neurons and glia in the brain is unknown. Using a mouse model of non-severe burn injury, excitatory and inhibitory neurons in the primary motor cortex were labelled with fluorescent proteins using adeno-associated viruses (AAVs). A total of 5 weeks following the burn injury, virus labelled excitatory and inhibitory neurons were isolated using fluorescence-activated cell sorting (FACS). In addition, microglia and astrocytes from the remaining cortical tissue caudal to the motor cortex were immunolabelled and isolated with FACS. Whole transcriptome RNA-sequencing was used to identify any long-lasting changes to gene expression in the different cell types. RNA-seq analysis showed changes to the expression of a small number of genes with known functions in excitatory neurons and microglia, but not in inhibitory neurons or astrocytes. Specifically, genes related to GABA-A receptors in excitatory neurons and several cellular functions in microglia were found to be downregulated in burn injured mice. These findings suggest that non-severe burn injuries lead to long lasting transcriptomic changes in the brain, but only in specific cell types. Our findings provide a broad overview of the long-lasting impact of burn injuries on the central nervous system which may help identify potential therapeutic targets to prevent neurological dysfunction in burn patients.

RESUMEN

The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization. Reward outcome representations across wide-spread regions follow a sequential order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We further highlight the role of the anterior insula in generalizing between reward prediction error and risk prediction error codes. Together our results emphasize the importance of neural dynamics for understanding value-based decisions under uncertainty.

Asunto(s)

Encéfalo , Recompensa , Humanos , Encéfalo/diagnóstico por imagen