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2.
Elife ; 132024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39168849

RESUMEN

Prominin-1 (Prom1) is a five-transmembrane-pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are physically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.

3.
Elife ; 132024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39136554

RESUMEN

Prominin 1 (Prom1) is a five-transmembrane pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane-bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are physically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane-bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.


Asunto(s)
Antígeno AC133 , Colesterol , Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Humanos , Antígeno AC133/metabolismo , Antígeno AC133/genética , Colesterol/metabolismo , Membrana Celular/metabolismo , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética
4.
Artículo en Inglés | MEDLINE | ID: mdl-39089334

RESUMEN

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples. RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. CONCLUSION: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.

5.
Phys Med Biol ; 69(14)2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38964312

RESUMEN

Objective.To present a new set of lithium-ion cross-sections for (i) ionization and excitation processes down to 700 eV, and (ii) charge-exchange processes down to 1 keV u-1. To evaluate the impact of the use of these cross-sections on micro a nano dosimetric quantities in the context of boron neutron capture (BNC) applications/techniques.Approach.The Classical Trajectory Monte Carlo method was used to calculate Li ion charge-exchange cross sections in the energy range of 1 keV u-1to 10 MeV u-1. Partial Li ion charge states ionization and excitation cross-sections were calculated using a detailed charge screening factor. The cross-sections were implemented in Geant4-DNA v10.07 and simulations and verified using TOPAS-nBio by calculating stopping power and continuous slowing down approximation (CSDA) range against data from ICRU and SRIM. Further microdosimetric and nanodosimetric calculations were performed to quantify differences against other simulation approaches for low energy Li ions. These calculations were: lineal energy spectra (yf(y) andyd(y)), frequency mean lineal energyyF-, dose mean lineal energyyD-and ionization cluster size distribution analysis. Microdosimetric calculations were compared against a previous MC study that neglected charge-exchange and excitation processes. Nanodosimetric results were compared against pure ionization scaled cross-sections calculations.Main results.Calculated stopping power differences between ICRU and Geant4-DNA decreased from 33.78% to 6.9%. The CSDA range difference decreased from 621% to 34% when compared against SRIM calculations. Geant4-DNA/TOPAS calculated dose mean lineal energy differed by 128% from the previous Monte Carlo. Ionization cluster size frequency distributions for Li ions differed by 76%-344.11% for 21 keV and 2 MeV respectively. With a decrease in theN1within 9% at 10 keV and agreeing after the 100 keV. With the new set of cross-sections being able to better simulate low energy behaviors of Li ions.Significance.This work shows an increase in detail gained from the use of a more complete set of low energy cross-sections which include charge exchange processes. Significant differences to previous simulation results were found at the microdosimetric and nanodosimetric scales that suggest that Li ions cause less ionizations per path length traveled but with more energy deposits. Microdosimetry results suggest that the BNC's contribution to cellular death may be mainly due to alpha particle production when boron-based drugs are distributed in the cellular membrane and beyond and by Li when it is at the cell cytoplasm regions.


Asunto(s)
Terapia por Captura de Neutrón de Boro , Litio , Método de Montecarlo , Radiometría , Litio/química , Terapia por Captura de Neutrón de Boro/métodos , Nanotecnología , Elasticidad
6.
West J Emerg Med ; 25(4): 477-482, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39028233

RESUMEN

Introduction: Methadone is a medically necessary and lifesaving medication for many patients with opioid use disorder. To adequately address these patients' needs, methadone should be offered in the hospital, but barriers exist that limit its continuation upon discharge. The code of federal regulations allows for methadone dosing as an inpatient as well as outpatient dispensing for up to three days to facilitate linkage to treatment. As a quality initiative, we created a new workflow for discharging patients on methadone to return to the emergency department (ED) for uninterrupted dosing. Methods: Our addiction medicine team changed hospital methadone policy to better allow hospitalization as a window of opportunity to start methadone. This necessitated the creation of a warm-handoff process to link patients to methadone clinics if that linkage could not happen immediately on discharge. Thus, our team created the "ED Bridge" process, which uses the "3-day rule" to dispense methadone from the ED post hospital discharge. We then followed every patient we directed through this workflow as an observational cohort for outcomes and trends. Results: Of the patients for whom ED bridge dosing was planned, 40.4% completed all bridge dosing and an additional 17.3% received at least one but not all bridge doses. Established methadone patients made up 38.1% of successful linkages, and 61.9% were patients who were newly started on methadone in the hospital. Conclusion: Improving methadone as a treatment option remains an ongoing issue for policymakers and advocates. Our ED bridge workflow allows us to expand access and continuation of methadone now using existing laws and regulations, and to better use hospitals as a point of entry into methadone treatment.


Asunto(s)
Servicio de Urgencia en Hospital , Metadona , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides , Alta del Paciente , Metadona/administración & dosificación , Metadona/uso terapéutico , Humanos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Tratamiento de Sustitución de Opiáceos/métodos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Masculino , Femenino
7.
Children (Basel) ; 11(7)2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-39062237

RESUMEN

BACKGROUND: Bullying is a global public health problem with severe adverse effects on behavioral health. Understanding the predictors of victimization by bullying is essential for public policy initiatives to respond to the problem effectively. In addition to traditional in-person bullying, electronic bullying has become more prevalent due to increasing social interaction and identity formation in virtual communities. This study aims to determine the predictors of in-school and electronic bullying. METHODS: We employed multivariable logistic regression to analyze a nationally representative sample of 17,232 high school students in the United States, the 2021 Youth Risk Behavior Surveillance System national component. The survey was conducted during the COVID-19 pandemic, from September through December 2021. The factors examined included sociodemographic characteristics (age, gender, race), appearance (obesity), physically active lifestyles (being physically active, spending a long time on digital games), and risk-taking behavior (using marijuana). RESULTS: Our results indicated that sociodemographic characteristics were strong predictors of being bullied in school and electronically. Being obese is more likely to result in bullying in school (AOR = 1.32, p = 0.003) and electronically (AOR = 1.30, p = 0.004). Adolescent students showing marijuana use had higher odds of being bullied in school (AOR = 2.15, p < 0.001) and electronically (AOR = 1.81, p < 0.001). While spending a long time on digital devices raises the risk of being electronically bullied (AOR = 1.25, p = 0.014), being physically active is not associated with being bullied. Neither of the two lifestyle factors was associated with in-school bullying. CONCLUSIONS: Interventions addressing violence among adolescents can benefit from empirical evidence of risk factors for bullying victimization in high school.

8.
Braz J Biol ; 84: e279899, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38896728

RESUMEN

It has been demonstrated that Lantana camara possesses several therapeutic properties that can be used to treat various human diseases, including dermatological and gastrointestinal conditions, tetanus, malaria, and tumours. In this investigation, every collected part of L. camara was extracted with absolute methanol to examine its antioxidant capacity using the DPPH assay and its anti-leukemia activity on two AML cell lines, MOLM-13 and MV4-11. In addition, anti-inflammatory effectiveness was evaluated. The results show that extracts from various sections of L. camara have a significant ability to neutralize free radicals, as indicated by their EC50 values. Most of the extracts had values less than 100 µg/ml, with the flower extract having an even lower value of less than 50 µg/ml. Experiments on two AML cell lines showed that the anti-leukemia effects of the extracts were remarkable, with the most potent impact belonging to the root extract (IC50 was 9.78 ± 0.61 and 12.48 ± 1.69 for MOLM-13 and MV4-11 cell lines). The antitumor effect of the extracts was determined to be time- and dose-dependent and did not correlate with antioxidant capacity. Furthermore, when BJ cells were exposed to L. camara root and leaf extracts, their migratory potential was dramatically reduced compared to untreated cells. The extracts demonstrated potential anti-inflammatory capabilities by lowering NO production in LPS-induced BJ cells.


Asunto(s)
Antiinflamatorios , Antioxidantes , Lantana , Extractos Vegetales , Humanos , Antioxidantes/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Lantana/química , Antiinflamatorios/farmacología , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología
9.
Int J Tuberc Lung Dis ; 28(6): 287-294, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38822484

RESUMEN

BACKGROUNDGiven the high prevalence of asthma-chronic obstructive pulmonary disease overlap (ACO) in Vietnam, there is an urgent need to establish a simplified strategy for categorising patients as either having asthma or chronic obstructive pulmonary disease (COPD). This classification would streamline the application of treatment recommendations outlined by the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD).METHODSPatients with obstructive lung function were classified as having COPD, asthma, or ACO based on GINA/GOLD guidelines. We hypothesised that ACO-like asthma (ACO-A) would present with positive skin prick tests (SPTs) or early onset of symptoms without a history of tuberculosis (TB), while those with ACO-like COPD (ACO-B) would exhibit negative SPTs and late onset of symptoms and/or a history of TB.RESULTSAmong 235 patients, the prevalence of asthma, ACO-A, ACO-B, and COPD was respectively 21%, 22%, 17%, and 40%. Allergic history, rhinitis, and childhood asthma were associated with ACO-A, while high cumulative smoking was correlated with ACO-B. Socio-economic and demographic parameters, medical history, clinical features, smoking habits, lung function, and para-clinical investigations significantly differed between "all asthma" (i.e., individuals with asthma combined with ACO-A) and "all COPD" (i.e., individuals with COPD combined with ACO-B).CONCLUSIONBased on SPTs, history of TB, and onset age, ACO patients may be defined as people with asthma or COPD..


Asunto(s)
Asma , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Persona de Mediana Edad , Masculino , Femenino , Prevalencia , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Adulto , Asma/epidemiología , Asma/diagnóstico , Vietnam/epidemiología , Anciano , Pruebas Cutáneas , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/epidemiología , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/diagnóstico
10.
Biofabrication ; 16(3)2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38776895

RESUMEN

Silk fibroin (SF) is a natural protein extracted fromBombyx morisilkworm thread. From its common use in the textile industry, it emerged as a biomaterial with promising biochemical and mechanical properties for applications in the field of tissue engineering and regenerative medicine. In this study, we evaluate for the first time the effects of SF on cardiac bioink formulations containing cardiac spheroids (CSs). First, we evaluate if the SF addition plays a role in the structural and elastic properties of hydrogels containing alginate (Alg) and gelatin (Gel). Then, we test the printability and durability of bioprinted SF-containing hydrogels. Finally, we evaluate whether the addition of SF controls cell viability and function of CSs in Alg-Gel hydrogels. Our findings show that the addition of 1% (w/v) SF to Alg-Gel hydrogels makes them more elastic without affecting cell viability. However, fractional shortening (FS%) of CSs in SF-Alg-Gel hydrogels increases without affecting their contraction frequency, suggesting an improvement in contractile function in the 3D cultures. Altogether, our findings support a promising pathway to bioengineer bioinks containing SF for cardiac applications, with the ability to control mechanical and cellular features in cardiac bioinks.


Asunto(s)
Alginatos , Elasticidad , Fibroínas , Gelatina , Hidrogeles , Miocitos Cardíacos , Alginatos/química , Alginatos/farmacología , Fibroínas/química , Fibroínas/farmacología , Gelatina/química , Hidrogeles/química , Hidrogeles/farmacología , Animales , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Bioimpresión , Supervivencia Celular/efectos de los fármacos , Ingeniería de Tejidos , Tinta , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Ratas , Contracción Miocárdica/efectos de los fármacos
11.
Artículo en Inglés | MEDLINE | ID: mdl-38748935

RESUMEN

OBJECTIVE: Our primary aim was to identify radiomic ultrasound features that can distinguish benign from malignant adnexal masses with solid ultrasound morphology, and primary invasive from metastatic solid ovarian masses, and to develop ultrasound-based machine learning models that include radiomics features to discriminate between benign and malignant solid adnexal masses. Our secondary aim was to compare the diagnostic performance of our radiomics models with that of the ADNEX model and subjective assessment by an experienced ultrasound examiner. METHODS: This is a retrospective observational single center study. Patients with a histological diagnosis of an adnexal tumor with solid morphology at preoperative ultrasound examination performed between 2014 and 2021 were included. The patient cohort was split into training and validation sets with a ratio of 70:30 and with the same proportion of benign and malignant (borderline, primary invasive and metastatic) tumors in the two subsets. The extracted radiomic features belonged to two different families: intensity-based statistical features and textural features. Models to predict malignancy were built based on a random forest classifier, fine-tuned using 5-fold cross-validation over the training set, and tested on the held-out validation set. The variables used in model building were patient's age, and those radiomic features that were statistically significantly different between benign and malignant adnexal masses (Wilcoxon-Mann-Whitney Test with Benjamini-Hochberg correction for multiple comparisons) and assessed as not redundant based on the Pearson correlation coefficient. We describe discriminative ability as area under the receiver operating characteristics curve (AUC) and classification performance as sensitivity and specificity. RESULTS: 326 patients were identified and 775 preoperative ultrasound images were analyzed. 68 radiomic features were extracted, 52 differed statistically significantly between benign and malignant tumors in the training set, and 18 features were selected for inclusion in model building. The same 52 radiomic features differed statistically significantly between benign, primary invasive malignant and metastatic tumors. However, the values of the features manifested overlap between primary malignant and metastatic tumors and did not differ statistically significantly between them. In the validation set, 25/98 tumors (25.5%) were benign, 73/98 (74.5%) were malignant (6 borderline, 57 primary invasive, 10 metastases). In the validation set, a model including only radiomics features had an AUC of 0.80, and 78% sensitivity and 76% specificity at its optimal risk of malignancy cutoff (68% based on Youden's index). The corresponding results for a model including age and radiomics features were 0.79, 86% and 56% (cutoff 60% based on Youden's method), while those of the ADNEX model were 0.88, 99% and 64% (at 20% malignancy cutoff). Subjective assessment had sensitivity 99% and specificity 72%. CONCLUSIONS: Even though our radiomics models had discriminative ability inferior to that of the ADNEX model, our results are promising enough to justify continued development of radiomics analysis of ultrasound images of adnexal masses. This article is protected by copyright. All rights reserved.

12.
bioRxiv ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38746426

RESUMEN

In eukaryotes, the essential process of cellular respiration takes place in the cristae of mitochondria. The protein Mic60 is known to stabilize crista junctions; however, how the C-terminal Mitofilin domain of Mic60 mediates cristae-supported respiration remains elusive. Here, we used ancestral sequence reconstruction to generate Mitofilin ancestors up to and including the last opisthokont common ancestor (LOCA). We found that yeast-lineage derived Mitofilin ancestors as far back as the LOCA rescue respiration. By comparing Mitofilin ancestors with different respiratory phenotypes, we identify four residues that explain the difference between respiration functional yeast- and non-functional animal-derived common Mitofilin ancestors. Our results imply that Mitofilin-supported respiration in yeast stems from a conserved mechanism, and provide a foundation for investigating the divergence of candidate crista junction interactions present during the emergence of eukaryotes.

13.
Pediatr Res ; 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38575694

RESUMEN

BACKGROUND: Invasive bacterial infections (IBIs) in febrile infants are rare but potentially devastating. We aimed to derive and validate a predictive model for IBI among febrile infants age 7-60 days. METHODS: Data were abstracted retrospectively from electronic records of 37 emergency departments (EDs) for infants with a measured temperature >=100.4 F who underwent an ED evaluation with blood and urine cultures. Models to predict IBI were developed and validated respectively using a random 80/20 dataset split, including 10-fold cross-validation. We used precision recall curves as the classification metric. RESULTS: Of 4411 eligible infants with a mean age of 37 days, 29% had characteristics that would likely have excluded them from existing risk stratification protocols. There were 196 patients with IBI (4.4%), including 43 (1.0%) with bacterial meningitis. Analytic approaches varied in performance characteristics (precision recall range 0.04-0.29, area under the curve range 0.5-0.84), with the XGBoost model demonstrating the best performance (0.29, 0.84). The five most important variables were serum white blood count, maximum temperature, absolute neutrophil count, absolute band count, and age in days. CONCLUSION: A machine learning model (XGBoost) demonstrated the best performance in predicting a rare outcome among febrile infants, including those excluded from existing algorithms. IMPACT: Several models for the risk stratification of febrile infants have been developed. There is a need for a preferred comprehensive model free from limitations and algorithm exclusions that accurately predicts IBIs. This is the first study to derive an all-inclusive predictive model for febrile infants aged 7-60 days in a community ED sample with IBI as a primary outcome. This machine learning model demonstrates potential for clinical utility in predicting IBI.

14.
Nat Commun ; 15(1): 250, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177118

RESUMEN

Baculoviruses are insect-infecting pathogens with wide applications as biological pesticides, in vitro protein production vehicles and gene therapy tools. Its cylindrical nucleocapsid, which encapsulates and protects the circular double-stranded viral DNA encoding proteins for viral replication and entry, is formed by the highly conserved major capsid protein VP39. The mechanism for VP39 assembly remains unknown. We use electron cryomicroscopy to determine a 3.2 Å helical reconstruction of an infectious nucleocapsid of Autographa californica multiple nucleopolyhedrovirus, revealing how dimers of VP39 assemble into a 14-stranded helical tube. We show that VP39 comprises a distinct protein fold conserved across baculoviruses, which includes a Zinc finger domain and a stabilizing intra-dimer sling. Analysis of sample polymorphism shows that VP39 assembles in several closely-related helical geometries. This VP39 reconstruction reveals general principles for baculoviral nucleocapsid assembly.


Asunto(s)
Baculoviridae , Nucleocápside , Animales , Baculoviridae/genética , Baculoviridae/metabolismo , Spodoptera , Nucleocápside/genética , Nucleocápside/metabolismo , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Proteínas de la Nucleocápside/genética , Proteínas de la Nucleocápside/metabolismo
15.
Perm J ; 28(1): 42-45, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38192218

RESUMEN

Mpox is a viral zoonotic infection endemic to countries in Central and West Africa. The outbreak that began in May 2022 is novel for its global spread and transmission through sexual encounters. Research of this outbreak shows a high rate of concurrent sexually transmitted infections (STIs) in patients with mpox, highlighting the need to consider STIs in mpox management, and to raise awareness of historically high levels of STIs caused by inadequacies in sexual health care. It is critical to prioritize sexual health and address health disparities to control current transmission of infections and prevent future outbreaks.


Asunto(s)
Mpox , Salud Sexual , Enfermedades de Transmisión Sexual , Humanos , Enfermedades de Transmisión Sexual/epidemiología
16.
J Invest Dermatol ; 144(1): 116-124.e4, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37478901

RESUMEN

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.


Asunto(s)
Acné Vulgar , Dermatitis , Animales , Ratones , Humanos , Piel/microbiología , Acné Vulgar/microbiología , Propionibacterium acnes/genética , Plásmidos/genética , Inflamación , Citocinas/genética
17.
bioRxiv ; 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-37986829

RESUMEN

Prominin-1 (Prom1) is a five-transmembrane-pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are biophysically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.

18.
Perm J ; 28(1): 81-85, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38073307

RESUMEN

Atrial fibrillation (AF) is an arrhythmia characterized by disorganized atrial activity with an associated unevenly irregular ventricular response on an electrocardiogram. It is the most common sustained arrhythmia, with a lifetime risk of 25% in patients older than 40 years old. The incidence of AF increases with age and is associated with an increased risk for heart failure, stroke, adverse cardiac events, and dementia. The 2 main aims of AF treatment include anticoagulation for thromboembolism prophylaxis as well as rate vs rhythm control. The focus of this article will be on the treatment strategies in managing AF. Rate control refers to the use of atrioventricular nodal blocking medications, including beta blockers and calcium channel blockers, to maintain a goal heart rate. Rhythm control, on the other hand, refers to a treatment strategy focused on the use of antiarrhythmic drugs (AAD), cardioversion, and ablation to restore and to maintain a patient in sinus rhythm. Currently, the ideal treatment strategy remains greatly debated. Thus, we hope to compare the risks and benefits of rate to rhythm control to highlight how patients with AF are managed here at Kaiser Permanente Northern California.


Asunto(s)
Fibrilación Atrial , Insuficiencia Cardíaca , Humanos , Adulto , Fibrilación Atrial/complicaciones , Fibrilación Atrial/terapia , Antiarrítmicos/uso terapéutico , Frecuencia Cardíaca , Cardioversión Eléctrica , Insuficiencia Cardíaca/inducido químicamente
19.
Aust Vet J ; 102(3): 67-73, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37875328

RESUMEN

Classical swine fever virus (CSFV) identification has witnessed significant advancements with the development of rapid reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assays. However, conventional RT-LAMP assays for CSFV diagnosis are hindered by a laborious RNA extraction step. Moreover, the need for thermal incubators and expensive micropipettes has limited their application in field settings. Addressing these challenges, our study presents a groundbreaking solution-an electro-free and point-of-care (POC) tool known as the field-LAMP assay-for the rapid clinical detection of CSFV. By eliminating the RNA extraction requirement, advancing the colorimetric read-out and lyophilized reaction reagents, our field-LAMP assay streamlines the diagnostic process, saving valuable time and effort. This novel approach also overcomes the dependency on electric-dependent thermal incubators and expensive micropipettes, making it practical and accessible for use in the field. The successful development of the field-LAMP assay marks a significant milestone in CSFV detection. This electro-free and POC tool offers several advantages, including its ability to deliver rapid results without compromising accuracy, facilitating prompt response and containment measures.


Asunto(s)
Virus de la Fiebre Porcina Clásica , Peste Porcina Clásica , Enfermedades de los Porcinos , Porcinos , Animales , ARN , Sensibilidad y Especificidad , Peste Porcina Clásica/diagnóstico , ARN Viral , Enfermedades de los Porcinos/diagnóstico
20.
Ann Oncol ; 35(2): 183-189, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37992871

RESUMEN

BACKGROUND: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome. PATIENTS AND METHODS: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation. RESULTS: Our results showed that patients with detectable ctDNA at baseline or after treatment and patients who did not clear ctDNA after treatment had a significantly worse clinical outcome. Integrating radiological analysis allowed the stratification in risk groups prognostic of clinical outcome as confirmed in an independent cohort of 32 patients. CONCLUSIONS: Our findings suggest ctDNA and radiological monitoring could be valuable tools for guiding follow-up care and treatment decisions for early-stage NSCLC patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , ADN Tumoral Circulante/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Carga Tumoral , Mutación , Recurrencia , Biomarcadores de Tumor/genética
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