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1.
Ann Am Thorac Soc ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39255452

RESUMO

RATIONALE: The progression of lung changes in cystic fibrosis (CF) from infancy through adolescence remains poorly understood due to limited longitudinal imaging data. OBJECTIVES: To assess changes in lung morphology and perfusion in children with CF through the pediatric age range by longitudinal chest magnetic resonance imaging (MRI). METHODS: 1112 annual chest MRI were performed in 226 patients with CF aged 0-18yr. MRI was assessed using a validated MRI scoring system. MEASUREMENTS AND MAIN RESULTS: The MRI global score continuously increased from 5.5±4.6 at infancy (0yr) to 17.9±8.4 at adolescence (range 12-18yr), and the MRI morphology score from 5.0±3.9 to 12.4±6.0 (P<0.001). Bronchiectasis/wall thickening prevalence increased from 89.1% at infancy to approx. 100% from preschool age (1-5yr), and the subscore increased from 3.1±1.9 at infancy to 6.6±2.1 at adolescence (P<0.001). Mucus plugging prevalence increased from 55.4% at infancy to 83.5% at adolescence, and the subscore increased from 1.2±1.6 to 3.7±2.5 in the same period (P<0.001). Perfusion abnormalities were found in 44.4% at infancy, and increased to approx. 90% from preschool age (P<0.001). The MRI perfusion score increased from 1.1±1.6 at infancy to 5.6±3.0 at adolescence (P<0.001). Chronic Pseudomonas aeruginosa infection was associated with higher MRI scores from school age (6-11yr, P<0.05-0.001). CONCLUSIONS: This is the first study assessing longitudinal changes in lung morphology and perfusion in CF throughout the pediatric age range, providing percentiles as age-specific reference for lung disease severity. Our data may facilitate the use of MRI as an endpoint in clinical trials in children with CF.

2.
Genome Res ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39255977

RESUMO

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is due to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.

3.
Brain Commun ; 6(5): fcae276, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39229494

RESUMO

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-ɛ4, APOE-ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status. APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.

4.
BMC Prim Care ; 25(1): 324, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39232645

RESUMO

BACKGROUND: Telemedicine allows delivery of healthcare to occur between parties that are not in the same location. As telemedicine users are not co-present, effective communication methods are crucial to the delivery and reception of information. The aim of this study was to explore perspectives of general practitioners (GPs) and patients on the interactional components of telemedicine consultations. METHODS: Semi-structured qualitative interviews were held with telemedicine users; 15 GPs and nine patients self-selected from a larger telemedicine study. Participants were asked about their preparation for telemedicine consultations, conducting telemedicine consultations and post-consultation activities. Deidentified transcripts from the interviews were analysed thematically. RESULTS: GPs and patients discussed factors they used to decide whether a consultation would be best conducted by telemedicine or in-person; the condition to be discussed, the existing doctor-patient relationship and whether physical examination was required. Participants also described how they prepared for their telemedicine consultations, gathering relevant documents, and reading previous notes. Participants described strategies they employed to optimise the telemedicine interaction; improving conversational flow and building rapport, as well as difficulties they experienced when trying to provide and receive care via telemedicine. CONCLUSIONS: Patient factors including health literacy and familiarity with technology affect the transfer of information shared during telemedicine consultations and consideration of these factors when choosing patients for telemedicine is required. Many GPs and patients have innate communication skills to effectively deliver and receive care through telemedicine. However, they may not be aware of these subconscious techniques to use to optimise telemedicine consultations. Communication training could be delivered to increase conversational flow, build rapport, and establish safety netting.


Assuntos
Comunicação , Medicina Geral , Clínicos Gerais , Relações Médico-Paciente , Telemedicina , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Medicina Geral/organização & administração , Medicina Geral/métodos , Adulto , Pesquisa Qualitativa , Idoso , Entrevistas como Assunto , Consulta Remota , Atitude do Pessoal de Saúde
5.
Chimia (Aarau) ; 78(7-8): 499-512, 2024 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-39221845

RESUMO

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples.


Assuntos
Química Farmacêutica , Descoberta de Drogas , Endocanabinoides , Endocanabinoides/metabolismo , Endocanabinoides/química , Humanos , Indústria Farmacêutica , Monoacilglicerol Lipases/metabolismo , Monoacilglicerol Lipases/antagonistas & inibidores , Desenvolvimento de Medicamentos , Academia
6.
Front Endocrinol (Lausanne) ; 15: 1449326, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39286269

RESUMO

Background: The part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves. Methods: Here we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (OxtPVH). We then identify a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis using the cell-selective expression of channel rhodopsin. Results: OxtPVH neurons increase their expression of cFos after both physiological (fast-induced re-feeding or oral lipid) and pharmacological (systemic administration of cholecystokinin or lithium chloride) anorectic signals. Chemogenetic activation of OxtPVH neurons is sufficient to decrease free-feeding in Oxt Cre:hM3Dq mice, while inhibition in Oxt Cre:hM4Di mice attenuates the response to administration of cholecystokinin. Activation of OxtPVH neurons also increases energy expenditure and core-body temperature, without a significant effect on locomotor activity. Finally, the selective, optogenetic stimulation of a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis reduces the consumption of sucrose. Conclusion: Our results support a role for oxytocin neurons in the regulation of whole-body metabolism, including a modulatory action on food intake and energy expenditure. Furthermore, we demonstrate that the pathway from OxtPVH neurons to the bed nucleus of the stria terminalis can regulate sugar consumption.


Assuntos
Ingestão de Energia , Metabolismo Energético , Neurônios , Ocitocina , Núcleo Hipotalâmico Paraventricular , Núcleos Septais , Animais , Ocitocina/farmacologia , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleos Septais/metabolismo , Núcleos Septais/fisiologia , Camundongos , Neurônios/metabolismo , Masculino , Sacarose/farmacologia , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Ingestão de Alimentos/fisiologia
7.
Z Rheumatol ; 2024 Sep 13.
Artigo em Alemão | MEDLINE | ID: mdl-39271483

RESUMO

Large vessel vasculitis, including giant cell arteritis (GCA) and Takayasu arteritis (TAK), are autoimmune diseases primarily affecting the aorta and its branches. GCA is the most common primary vasculitis. Inflammatory changes in the vessel walls can cause serious complications such as amaurosis, stroke, and aortic dissection and rupture. Imaging techniques have become an integral part for the diagnosis and monitoring of large vessel vasculitis, allowing for effective disease monitoring. GCA and TAK exhibit similar patterns of vascular distribution. However, the temporal arteries are never involved in TAK, and axillary arteritis occurs more frequently in GCA. In most centers, ultrasound of the temporal and axillary arteries has replaced temporal artery biopsy as the primary diagnostic tool for GCA. In addition to ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), and [18F]-FDG (fluorodeoxyglucose) positron emission tomography-computed tomography (PET) are important, particularly for visualizing the aorta. Moreover, PET-CT is now also capable of assessing the temporal arteries, although it is not yet widely available. In polymyalgia rheumatica (PMR), ultrasound of the shoulder and hip regions is part of the ACR/EULAR classification criteria. MRI allows detailed visualization of additional inflammatory extraarticular manifestations, showing characteristic inflammatory lesions in entheses, tendons, and ligaments. [18F]-FDG-PET-CT also enables the visualization of musculoskeletal inflammation, especially in the shoulder and hip regions, as well as paravertebral areas. Ultrasound can detect subclinical GCA in up to 23% of patients with PMR, which should be treated like GCA. Technological innovations such as new radiotracers and improved MRI imaging could further enhance the diagnosis and monitoring of large vessel vasculitis and PMR, thus playing a crucial role in improving the prognosis through faster initiation of therapy.

8.
Mol Psychiatry ; 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271753

RESUMO

Abnormalities in cellular metabolism are seen early in Alzheimer's disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients' astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.

9.
Food Res Int ; 195: 114944, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39277222

RESUMO

The gelation of milk proteins can be achieved by various means, enabling the development of diverse products. In this study, heat-set milk protein gels (15 % protein) of diverse textures were made by pH modulation and two gels were selected for dynamic in vitro gastric digestion: a spoonable soft gel (SG, pH 6.55' G' of ∼100 Pa) and a sliceable firm gel (FG, pH 5.65; G' of ∼7000 Pa). The two gels displayed markedly different structural changes and digestion kinetics during gastric digestion. The SG underwent substantial structural compaction during the first 120 min of gastric digestion into a denser and firmer gastric chyme (26.3 % crude protein, G* of ∼8500 Pa) than the chyme of the FG (15.7 % crude protein, G* of ∼3000 Pa). These contrasting intragastric structural changes of the gels reversed their original textural differences, which led to slower digestion and gastric emptying of proteins from the SG compared with the FG. The different intragastric pH profiles during the digestion of the two gels likely played a key role by modulating the proteolytic activity and specificity (to κ-casein) of pepsin. Preferential early cleavage of κ-casein in SG stimulated coagulation and compaction of solid chyme, whereas rapid hydrolysis of αS- and ß-caseins in the FG weakened coagulation. This study provided new insights into controlling the structural development of dairy-based foods during gastric digestion and modulating digestion kinetics.


Assuntos
Digestão , Géis , Temperatura Alta , Proteínas do Leite , Géis/química , Digestão/fisiologia , Concentração de Íons de Hidrogênio , Cinética , Proteínas do Leite/química , Proteínas do Leite/metabolismo , Esvaziamento Gástrico , Caseínas/química , Caseínas/metabolismo , Pepsina A/metabolismo , Animais , Manipulação de Alimentos/métodos , Proteólise
10.
Vet Parasitol ; 332: 110306, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39265207

RESUMO

Toxoplasma gondii is a globally distributed zoonotic protist, capable of infecting all warm-blooded animals. In Australia, cats (Felis catus) are the only definitive host capable of spreading T. gondii infection via oocysts. Free-roaming cats are widespread in Australia and can play a central role in the ecology of T. gondii. Therefore, understanding the epidemiology of this parasite in stray and feral cats is essential to understanding the potential risk of infection in animals and humans. Due to a lack of easily accessible commercial kits, an in-house modified agglutination test (MAT) was established to test for IgG antibodies against T. gondii, using cell culture-derived T. gondii tachyzoites, and compared with a commercial MAT. A total of 552 serum samples collected during 2018 - 2021 from stray (n = 456) and feral cats (n = 90) (samples with missing data n = 6) from four Australian states, representing different age groups of both sexes, were screened for antibodies against T. gondii. Risk factors for T. gondii infection were assessed using multivariable logistic regression analysis. The in-house MAT had excellent agreement with the commercial MAT and provided a reliable and economical serological tool for T. gondii screening in animals. The overall observed seroprevalence for T. gondii in cats was 40.4 % (223/552). Bodyweight (as a proxy for age), geographical location, season and whether cats were feral or stray, were factors associated with T. gondii seropositivity in cats. Sex was not found to be a risk factor for T. gondii infection in feral and stray cats. This study shows that Australian stray and feral cats have a high T. gondii seroprevalence, which may translate to significant health impacts for wildlife species, livestock and the public.

11.
Cogn Emot ; : 1-15, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39330874

RESUMO

Pride has rarely been explored in the context of moral disengagement and unethical decision-making. Although some research has examined the associations between "authentic" and "hubristic" pride and unethical behaviour, little attention has been paid to potential mechanisms. Across two correlational studies (N = 379), we explore the associations between two facets of pride rooted on comparisons - social comparison-based pride, and self-based pride, moral disengagement, and unethical decision-making. Results show that social comparison-based pride consistently (positively) relates to moral disengagement, and that moral disengagement accounts for the association between social comparison-based pride and unethical decision-making. In sum, our findings contribute in novel ways to the understanding of how pride based in different comparison frames may lead to antisocial decision-making.

12.
Front Psychol ; 15: 1443707, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39295769

RESUMO

Introduction: Resolution of a child's diagnosis, the process of accepting and adjusting to the reality of a child's significant diagnosis, has been often associated with decreased parental stress. Hope, a potential buffer against psychological distress, has been suggested as a potential explanation for this relationship. However, the mediating role of hope in the relationship between resolution of diagnosis and parental stress has not been explored. Methods: This study aimed to examine whether four types of hope (child, parental, societal, denial of diagnosis) mediated the relationship between resolution to an autism diagnosis and reduced parental stress. Participants included 73 parents (Mage = 43.22, SD = 7.69, female 97.3%) of autistic children (Mage = 11.15, SD = 4.56, male = 67.1%). Results: Resolution to diagnosis was negatively and significantly correlated with resolution to diagnosis, as well as child, parental and societal hope. These three hopes were also significantly and negatively correlated with parental stress. Importantly, when controlling for level of support and autism awareness, parental hope mediated the relationship between resolution to diagnosis and parental stress. Denial of diagnosis was not correlated with resolution or parental stress but did have significant but weak associate with the other hopes. Discussion: These findings suggest that hope based on parent's abilities to support their child and be supported themselves play an important role in parental stress once parents are more resolved to their child's diagnosis. Supporting parents to manage factors associated with supporting their child's needs, may benefit parents of autistic children.

13.
ACS Nano ; 18(39): 26655-26665, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39305260

RESUMO

Despite the interest in improving the sensitivity of optical sensors using plasmonic nanoparticles (NPs) (rods, wires, and stars), the full structural characterization of complex shape nanostructures is challenging. Here, we derive from a single scanning transmission electron microscope diffraction map (4D-STEM) a detailed determination of both the 3D shape and atomic arrangement of an individual 6-branched AuAg nanostar (NS) with high-aspect-ratio legs. The NS core displays an icosahedral structure, and legs are decahedral rods attached along the 5-fold axes at the core apexes. The NS legs show an anomalous anisotropic spatial distribution (all close to a plane) due to an interplay between the icosahedral symmetry and the unzipping of the surfactant layer on the core. The results significantly improve our understanding of the star growth mechanism. This low dose diffraction mapping is promising for the atomic structure study of individual multidomain, multibranched, or multiphase NPs, even when constituted of beam-sensitive materials.

14.
Artigo em Inglês | MEDLINE | ID: mdl-39347865

RESUMO

Situational Judgement Tests (SJTs) are popular to screen for social skills during undergraduate medical admission as they have been shown to predict relevant study outcomes. Two different types of SJTs can be distinguished: Traditional SJTs, which measure general effective behavior, and construct-driven SJTs which are designed to measure specific constructs. To date, there has been no comparison of the predictive validity of these two types of SJTs in medical admission. With the present research, we examine whether the HAM-SJT, a traditional SJT, and the CD-SJT, a construct-driven SJT with an agentic and a communal scale, administered during undergraduate medical admission can predict OSCE (i.e., objective structured clinical examination) performance in a low-stakes (nLS = 159) and a high-stakes (nHS = 160) sample of medical students. Results showed a moderate positive relation between the communal scale of the CD-SJT and performance in OSCE stations with trained patients in the high-stakes sample (r =.20, p =.009). This SJT had also an incremental value in predicting the OSCE performance above and beyond GPA (i.e., grade point average), a science test (i.e., HAM-Nat), and gender (ß = 0.18, 95% CI [0.03; 0.33], p =.020). That is, individuals who chose more communal behavioral responses in the SJT were rated more favorably in interactions with trained patients in the OSCE. A comparable correlation coefficient was observed for the HAM-SJT when controlling for range restriction due to admission (rraw = 0.14 vs. rcontrolled = 0.20). Our research provides a first indication for the predictive validity of construct-driven SJTs in high-stakes undergraduate medical admission.

15.
JHEP Rep ; 6(10): 101159, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39314550

RESUMO

Background & Aims: Senescence has been reported to have differential functions in cholangiocytes and hepatic stellate cells (HSCs) during human and murine cholestatic disease, being detrimental in biliary cells and anti-fibrotic in HSCs. Cholestatic liver disease is associated with loss of intestinal barrier function and changes in the microbiome, the mechanistic cause of which is undetermined. Methods: Intestinal samples were analysed from controls and patients with primary sclerosing cholangitis, as well as wild-type (WT) and p16-3MR transgenic mice. Cholestatic liver disease was induced by bile duct ligation (BDL) and DDC diet feeding. Fexaramine was used as an intestinal-restricted FXR agonist and antibiotics were given to eliminate the intestinal microbiome. Senescent cells were eliminated in p16-3MR mice with ganciclovir and in WT mice with the senolytic drug ABT-263. In vitro studies were done in intestinal CaCo-2 cells and organoids were generated from intestinal crypts isolated from mice. Results: Herein, we show increased senescence in intestinal epithelial cells (IECs) in patients with primary sclerosing cholangitis and in mice after BDL and DDC diet feeding. Intestinal senescence was increased in response to reduced exposure to bile acids and increased presence of lipopolysaccharide in vitro and in vivo during cholestatic liver disease. Senescence of IECs was associated with lower proliferation but increased intestinal stem cell activation, as supported by increased organoid growth from intestinal stem cells. Elimination of senescent cells with genetic and pharmacological approaches exacerbated liver injury and fibrosis during cholestatic liver disease, which was associated with increased IEC apoptosis and permeability. Conclusions: Senescence occurs in IECs during cholestatic disease and the elimination of senescent cells has a detrimental impact on the gut-liver axis. Our results point to cell-specific rather than systemic targeting of senescence as a therapeutic approach to treat cholestatic liver disease. Impact and implications: Cholestatic liver disease associates with the dysregulation of intestinal barrier function, while the mechanisms mediating the disruption of the gut-liver axis remain largely undefined. Here, we demonstrate that senescence, a cellular response to stress, is activated in intestinal cells during cholestatic liver disease in humans and mice. Mechanistically, we demonstrate that the reduction of bile acids and the increased presence of bacterial products mediate the activation of intestinal senescence during cholestatic liver disease. Importantly, the elimination of these senescent cells promotes further damage to the intestine that aggravates liver disease, with increased tissue damage and fibrosis. Our results provide evidence that therapeutic strategies to treat cholestatic liver disease by eliminating senescent cells may have unwanted effects in the intestine and support the need to develop cell/organ-specific approaches.

16.
New J Chem ; 48(36): 15731-15734, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39234596

RESUMO

The self-assembly of highly functionalized phenanthrene-DNA conjugates into supramolecular nanostructures is presented. DNA oligomers modified with phenanthrene residues at the 3'-end and internal positions self-assemble into spherical nanostructures. The nanospheres exhibit light-harvesting properties. Upon irradiation of phenanthrene, the excitation energy is transferred along phenanthrene units, resulting in phenanthrene-pyrene exciplex formation.

18.
Endosc Ultrasound ; 13(3): 129-144, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39318646

RESUMO

Rare malignant pancreatic lesions are systematically reported in this review. The focus is on the imaging appearance of the rare epithelial pancreatic tumors such as the solid pseudopapillary neoplasm, acinar cell carcinoma, rare subtypes of adenocarcinoma, and pancreatoblastoma as seen on ultrasound, EUS, and contrast-enhanced ultrasound or EUS. The present overview summarizes the data and shows that not every pancreatic tumor is likely to be the most common entities of ductal adenocarcinoma or neuroendocrine tumor.

19.
Endosc Ultrasound ; 13(3): 145-153, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39318650

RESUMO

The focus of the review is on mesenchymal pancreatic tumors with intermediate biological behavior and their imaging appearance. Similar to benign and malignant mesenchymal pancreatic tumors, these tumors are extremely rare. The diagnosis is often confirmed only by postoperative histology. The very limited data on abdominal ultrasound and EUS findings including contrast-enhanced techniques of these pancreatic lesions are summarized here.

20.
Endosc Ultrasound ; 13(4): 218-231, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39318747

RESUMO

The focus of the review is on primary benign mesenchymal pancreatic tumors and their imaging appearance. These tumors are extremely rare. Usually, they are not diagnosed until postoperative histology is available, and so even benign tumors have undergone extensive pancreatic resection. The very limited data on abdominal and EUS findings including contrast-enhanced techniques of these pancreatic lesions are summarized here. Case reports will be presented for some of these rare tumors with application of modern ultrasound and endosonographic techniques.

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