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BACKGROUND: Metabolic syndrome (MS) has emerged as a significant global health concern. The relationship between MS and the risk of cancer doesn't seem clear, whether examining by components or in combination. The objective of this study is to examine the relationship between MS, its components, and the overall risk of cancer, including the risk of 13 specific cancer types. METHODS: We included 3,918,781 individuals aged 40 years or older sourced from the SIDIAP database between 2008 and 2017. Cox models were employed with MS components and their combinations. A subsample was created using a matched cohort (by age and sex). Incidence curves were computed to determine the time elapsed between the date of having 1-5 MS components and cancer incidence, compared to matched participants with no MS components, which showed that individuals who had one MS component experienced a greater incidence of cancer over 5 and 10 years than individuals with no MS, and the incidence rose with an increase in the number of MS components. RESULTS: Individuals exposed to MS components were diagnosed with cancer earlier than those who were not exposed to them. In the Cox model, HDL (HR 1.46, 95% CI: 1.41-1.52) and Glycemia (HR 1.40, 95% CI: 1.37-1.44) were the individual combinations with the highest risk of overall cancer. In combinations with two components, the highest HR was HDL+Glycemia (HR 1.52, 95% CI: 1.45-1.59) and Glycemia+HBP (HR 1.48, 95% CI: 1.45-1.50). In combinations with three components, the highest HR was HDL+Glycemia+HBP (HR 1.58, 95% CI: 1.55-1.62). CONCLUSION: In summary, having one or more MS components raises the risk of developing at least 11 cancer types and these risk differ according to type of component included. Some sex differences are also observed. Our findings suggest that implementing prevention measures aimed at specific MS components may lower the risk of various cancer types.
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Síndrome Metabólica , Neoplasias , Humanos , Síndrome Metabólica/epidemiologia , Masculino , Feminino , Neoplasias/epidemiologia , Incidência , Pessoa de Meia-Idade , Adulto , Idoso , Espanha/epidemiologia , Fatores de Risco , Estudos de Coortes , Modelos de Riscos ProporcionaisRESUMO
Background: Unlike tachyarrhythmias, which are common in pregnancy, there is a paucity of data regarding maternal bradycardias. Our objective was to describe the characteristics, associated conditions, and prognosis of women who develop bradycardia post-partum. Method: We conducted a retrospective chart review of patients referred to the Obstetrical Medicine service at British Columbia Women's Hospital from January 2012 to May 2020 for post-partum maternal bradycardia. Results: Twenty-four patients with post-partum bradycardia were included (age 34.2 ± 4.8 years; heart rate 40.4 ± 8.1 beats per minute; blood pressure 131/72â mm Hg). Sinus bradycardia (79.2%) was the most common rhythm. Dyspnea (29.4%) and chest pain (23.5%) were common symptoms. Mean time to resolution of bradycardia was 3.6 ± 3.8 days. Associated conditions potentially explaining the bradycardia were preeclampsia (54.1%), underlying (16.7%), medications (8.3%), and neuraxial anesthesia (8.3%). Conclusions: Maternal bradycardia is an uncommon condition complicating the post-partum period, that is generally self-limiting, with the majority only require clinical observation.
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Both homophily and heterophily are observed in humans. Homophily reinforces homogeneous social networks, and heterophily creates new experiences and collaborations. However, at the extremes, high levels of homophily can cultivate prejudice toward out-groups, whereas high levels of heterophily can weaken in-group support. Using data from 24,726 adults (M = 46 years; selected from 10,398 English neighborhoods) and the composition of their social networks based on age, ethnicity, income, and education, we tested the hypothesis that a middle ground between homophily and heterophily could be the most beneficial for individuals. We found that network homophily, mediated by perceived social cohesion, is associated with higher levels of subjective well-being but that there are diminishing returns, because at a certain point increasing network homophily is associated with lower social cohesion and, in turn, lower subjective well-being. Our results suggest that building diverse social networks provides benefits that cannot be attained by homogeneous networks.
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Apoio Social , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Satisfação Pessoal , Rede Social , Relações Interpessoais , Adulto Jovem , IdosoRESUMO
OBJECTIVES: This study investigates the psychological well-being of informal caregivers over time. It identifies the thresholds (or "tipping points") of caring intensity at which caregiving is associated with lower psychological well-being, and how this varies by care location and caregiver-care recipient relationships. It also examines how caring location and relationship are linked to informal caregivers' psychological well-being while controlling for caring intensity. METHODS: Waves 1-18 (1991-2009) of the harmonized British Household Panel Survey and Waves 1-8 (2009-2017) of the U.K. Household Longitudinal Study were analyzed. Psychological well-being was measured using the General Health Questionnaire (GHQ)-12 score. Care intensity was measured by the weekly hours of care provided. Fixed-effects estimators were applied to the GHQ-12 score of caregivers across different care intensities, caring locations, and caring relationships. RESULTS: All levels of informal care intensity are associated with lower psychological well-being among spousal caregivers. The thresholds to well-being are 5 hours per week when caring for a parent, and 50 hours per week when caring for a child (with a disability or long-term illness). Caring for "other relatives" or nonrelatives is not negatively associated with psychological well-being. The thresholds are 5 hours per week for both coresident and extraresident caregivers. Extraresident caregivers experience better psychological well-being compared to coresident caregivers, given relatively lower weekly care hours. Caring for primary kin (especially spouses) is linked to lower psychological well-being compared to other caregiving relationships, regardless of care intensity. DISCUSSION: Policy and practice responses should pay particular attention to spousal caregivers' well-being. Caregiving relationship has a stronger association with the caregiver's well-being than care location.
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Cuidadores , Bem-Estar Psicológico , Humanos , Cuidadores/psicologia , Estudos LongitudinaisRESUMO
BACKGROUND: COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organ systems, including the pulmonary vasculature. Endothelial cells (ECs) are thought to play a key role in the propagation of COVID-19, however, our understanding of the exact scale of dysregulation sustained by the pulmonary microvasculature (pMV) remains incomplete. Here we aim to identify transcriptional, phenotypic, and functional changes within the pMV induced by COVID-19. METHODS AND RESULTS: Human pulmonary microvascular endothelial cells (HPMVEC) treated with plasma acquired from patients hospitalised with severe COVID-19 were compared to HPMVEC treated with plasma from patients hospitalised without COVID-19 but with other severe illnesses. Exposure to COVID-19 plasma caused a significant functional decline in HPMVECs as seen by a decrease in both cell viability via the WST-1 cell-proliferation assay and cell-to-cell barrier function as measured by electric cell-substrate impedance sensing. High-content imaging using a Cell Painting image-based assay further quantified morphological variations within sub-cellular organelles to show phenotypic changes in the whole endothelial cell, nucleus, mitochondria, plasma membrane and nucleolus morphology. RNA-sequencing of HPMVECs treated with COVID-19 plasma suggests the observed phenotype may, in part, be regulated by genes such as SMAD7, BCOR, SFMBT1, IFIT5 and ZNF566 which are involved in transcriptional regulation, protein monoubiquitination and TGF-ß signalling. CONCLUSION AND IMPACT: During COVID-19, the pMV undergoes significant remodelling, which is evident based on the functional, phenotypic, and transcriptional changes seen following exposure to COVID-19 plasma. The observed morphological variation may be responsible for downstream complications, such as a decline in overall cellular function and cell-to-cell barrier integrity. Moreover, genes identified through bulk RNA sequencing may contribute to our understanding of the observed phenotype and assist in developing strategies that can inform the rescue of the dysregulated endothelium.
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COVID-19 , Células Endoteliais , Humanos , Células Endoteliais/metabolismo , SARS-CoV-2 , Pulmão , EndotélioRESUMO
BACKGROUND AND AIMS: Atrial fibrillation (AF) is a chronic progressive disorder. Persistent forms of AF are associated with increased rates of thromboembolism, heart failure, and death. Catheter ablation modifies the pathogenic mechanism of AF progression. No randomized studies have evaluated the impact of the ablation energy on progression to persistent atrial tachyarrhythmia. METHODS: Three hundred forty-six patients with drug-refractory paroxysmal AF were enrolled and randomly assigned to contact-force-guided RF ablation (CF-RF ablation, 115), 4 min cryoballoon ablation (CRYO-4, 115), or 2 min cryoballoon ablation (CRYO-2, 116). Implantable cardiac monitors placed at study entry were used for follow-up. The main outcome was the first episode of persistent atrial tachyarrhythmia. Secondary outcomes included atrial tachyarrhythmia recurrence and arrhythmia burden on the implantable monitor. RESULTS: At a median of 944.0 (interquartile range [IQR], 612.5-1104) days, 0 of 115 patients (0.0%) randomly assigned to CF-RF, 8 of 115 patients (7.0%) assigned to CRYO-4, and 5 of 116 patients (4.3%) assigned to CRYO-2 experienced an episode of persistent atrial tachyarrhythmia (P = .03). A documented recurrence of any atrial tachyarrhythmia ≥30 s occurred in 56.5%, 53.9%, and 62.9% of those randomized to CF-RF, CRYO-4, and CRYO-2, respectively; P = .65. Compared with that of the pre-ablation monitoring period, AF burden was reduced by a median of 99.5% (IQR 94.0%, 100.0%) with CF-RF, 99.9% (IQR 93.3%-100.0%) with CRYO-4, and 99.1%% (IQR 87.0%-100.0%) with CRYO-2 (P = .38). CONCLUSIONS: Catheter ablation of paroxysmal AF using radiofrequency energy was associated with fewer patients developing persistent AF on follow-up.
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Fibrilação Atrial , Ablação por Cateter , Criocirurgia , Veias Pulmonares , Humanos , Fibrilação Atrial/cirurgia , Criocirurgia/efeitos adversos , Resultado do Tratamento , Ablação por Cateter/efeitos adversos , Taquicardia , Recidiva , Veias Pulmonares/cirurgiaRESUMO
Extracellular vesicles (EVs) released from healthy endothelial cells (ECs) have shown potential for promoting angiogenesis, but their therapeutic efficacy remains poorly understood. We have previously shown that transplantation of a human embryonic stem cell-derived endothelial cell product (hESC-ECP), promotes new vessel formation in acute ischemic disease in mice, likely via paracrine mechanism(s). Here, we demonstrated that EVs from hESC-ECPs (hESC-eEVs) significantly increased EC tube formation and wound closure in vitro at ultralow doses, whereas higher doses were ineffective. More important, EVs isolated from the mesodermal stage of the differentiation (hESC-mEVs) had no effect. Small RNA sequencing revealed that hESC-eEVs have a unique transcriptomic profile and are enriched in known proangiogenic microRNAs (miRNAs, miRs). Moreover, an in silico analysis identified three novel hESC-eEV-miRNAs with potential proangiogenic function. Differential expression analysis suggested that two of those, miR-4496 and miR-4691-5p, are highly enriched in hESC-eEVs. Overexpression of miR-4496 or miR-4691-5p resulted in increased EC tube formation and wound closure in vitro, validating the novel proangiogenic function of these miRNAs. In summary, we demonstrated that hESC-eEVs are potent inducers of EC angiogenic response at ultralow doses and contain a unique EV-associated miRNA repertoire, including miR-4496 and miR-4691-5p, with novel proangiogenic function.
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Vesículas Extracelulares , MicroRNAs , Humanos , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Endoteliais/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Diferenciação Celular/genética , Células-Tronco/metabolismoRESUMO
One challenge in synthetic biology is the tuning of regulatory components within gene circuits to elicit a specific behavior. This challenge becomes more difficult in synthetic microbial consortia since each strain's circuit must function at the intracellular level and their combination must operate at the population level. Here we demonstrate that circuit dynamics can be tuned in synthetic consortia through the manipulation of strain fractions within the community. To do this, we construct a microbial consortium comprised of three strains of engineered Escherichia coli that, when cocultured, use homoserine lactone-mediated intercellular signaling to create a multistrain incoherent type-1 feedforward loop (I1-FFL). Like naturally occurring I1-FFL motifs in gene networks, this engineered microbial consortium acts as a pulse generator of gene expression. We demonstrate that the amplitude of the pulse can be easily tuned by adjusting the relative population fractions of the strains. We also develop a mathematical model for the temporal dynamics of the microbial consortium. This model allows us to identify population fractions that produced desired pulse characteristics, predictions that were confirmed for all but extreme fractions. Our work demonstrates that intercellular gene circuits can be effectively tuned simply by adjusting the starting fractions of each strain in the consortium.
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Escherichia coli , Consórcios Microbianos , Consórcios Microbianos/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Transdução de Sinais , Modelos Teóricos , Redes Reguladoras de Genes/genética , Biologia SintéticaRESUMO
Human footprints at White Sands National Park, New Mexico, USA, reportedly date to between ~23,000 and 21,000 years ago according to radiocarbon dating of seeds from the aquatic plant Ruppia cirrhosa. These ages remain controversial because of potential old carbon reservoir effects that could compromise their accuracy. We present new calibrated 14C ages of terrestrial pollen collected from the same stratigraphic horizons as those of the Ruppia seeds, along with optically stimulated luminescence ages of sediments from within the human footprint-bearing sequence, to evaluate the veracity of the seed ages. The results show that the chronologic framework originally established for the White Sands footprints is robust and reaffirm that humans were present in North America during the Last Glacial Maximum.
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Evolução Biológica , Hominidae , Animais , Humanos , Luminescência , América do Norte , Datação Radiométrica/métodos , New Mexico , Parques Recreativos , Pólen , Alismatales , Radioisótopos de Carbono , SementesRESUMO
Reef-building crustose coralline algae (CCA) are known to facilitate the settlement and metamorphosis of scleractinian coral larvae. In recent decades, CCA coverage has fallen globally and degrading environmental conditions continue to reduce coral survivorship, spurring new restoration interventions to rebuild coral reef health. In this study, naturally produced chemical compounds (metabolites) were collected from two pantropical CCA genera to isolate and classify those that induce coral settlement. In experiments using four ecologically important Caribbean coral species, we demonstrate the applicability of extracted, CCA-derived metabolites to improve larval settlement success in coral breeding and restoration efforts. Tissue-associated CCA metabolites induced settlement of one coral species, Orbicella faveolata, while metabolites exuded by CCA (exometabolites) induced settlement of three species: Acropora palmata, Colpophyllia natans and Orbicella faveolata. In a follow-up experiment, CCA exometabolites fractionated and preserved using two different extraction resins induced the same level of larval settlement as the unfractionated positive control exometabolites. The fractionated CCA exometabolite pools were characterized using liquid chromatography tandem mass spectrometry, yielding 145 distinct molecular subnetworks that were statistically defined as CCA-derived and could be classified into 10 broad chemical classes. Identifying these compounds can reveal their natural prevalence in coral reef habitats and facilitate the development of new applications to enhance larval settlement and the survival of coral juveniles.
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Antozoários , Animais , Larva , Sinais (Psicologia) , Recifes de Corais , EcossistemaRESUMO
Background Self-administration of investigational intranasal L-type calcium channel blocker etripamil during paroxysmal supraventricular tachycardia (PSVT) appeared safe and well-tolerated in the phase 3 NODE-301 (Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia) trial of adults with sustained atrioventricular nodal-dependent PSVT. The NODE-302 open-label extension further characterized etripamil safety and efficacy. Methods and Results Eligible patients were monitored via self-applied cardiac monitoring system for 5 hours after etripamil self-administration. The primary end point was time-to-conversion of positively adjudicated PSVT to sinus rhythm after etripamil treatment. Probability of conversion to sinus rhythm was reported via Kaplan-Meier plot. Adverse events were based on self-reported symptoms and clinical evaluations. Among 169 patients enrolled, 105 self-administered etripamil ≥1 time for perceived PSVT (median [range], 232 [8-584] days' follow-up). Probability of conversion within 30 minutes of etripamil was 60.2% (median time to conversion, 15.5 minutes) among 188 PSVT episodes (92 patients) positively adjudicated as atrioventricular nodal dependent by independent ECG analysis. Among 40 patients who self-treated 2 episodes, 75% had a significantly consistent response by 30 minutes; 9 did not convert on either episode, and 21 converted on both episodes (χ2=8.09; P=0.0045). Forty-five of 105 patients (42.9%) had ≥1 treatment-emergent adverse event, generally transient and mild-to-moderate, including nasal congestion (14.3%), nasal discomfort (14.3%), or rhinorrhea (12.4%). No serious cardiac safety events were observed within 24 hours of etripamil. Conclusions In this extension study, investigational etripamil nasal spray was well tolerated for self-treating recurrent episodes of PSVT without medical supervision. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03635996.
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Taquicardia Paroxística , Taquicardia Supraventricular , Taquicardia Ventricular , Adulto , Humanos , Nó Atrioventricular , Sprays Nasais , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/tratamento farmacológico , Ensaios Clínicos Fase III como AssuntoRESUMO
BACKGROUND: Maori are the Indigenous people of Aotearoa (New Zealand). Despite global acceptance that cervical cancer is almost entirely preventable through vaccination and screening, wahine Maori (Maori women) are more likely to have cervical cancer and 2.5 times more likely to die from it than non-Maori women. Rural Maori residents diagnosed with cervical cancer have worse outcomes than urban residents. Living in rural Aotearoa means experiencing barriers to appropriate and timely health care, resulting from distance, the lack of community resourcing, and low prioritization of rural needs by the health system and government. These barriers are compounded by the current screening processes and referral pathways that create delays at each step. Screening for high-risk human papillomavirus (hrHPV) and point-of-care (POC) testing are scientific advances used globally to prevent cervical cancer. OBJECTIVE: This study aims to compare acceptability, feasibility, timeliness, referral to, and attendance for colposcopy following hrHPV detection between a community-controlled pathway and standard care. METHODS: This is a cluster randomized crossover trial, with 2 primary care practices (study sites) as clusters. Each site was randomized to implement either pathway 1 or 2, with crossover occurring at 15 months. Pathway 1 (community-controlled pathway) comprises HPV self-testing, 1-hour POC results, face-to-face information, support, and immediate referral to colposcopy for women with a positive test result. Pathway 2 (standard care) comprises HPV self-testing, laboratory analysis, usual results giving, information, support, and standard referral pathways for women with a positive test result. The primary outcome is the proportion of women with hrHPV-positive results having a colposcopy within 20 working days of the HPV test (national performance indicator). Qualitative research will analyze successes and challenges of both pathways from the perspectives of governance groups, clinical staff, women, and their family. This information will directly inform the new National Cervical Screening Program. RESULTS: In the first 15-month period, 743 eligible HPV self-tests were performed: 370 in pathway 1 with POC testing and 373 in pathway 2 with laboratory testing. The positivity rate for hrHPV was 7.3% (54/743). Data collection for the second period, qualitative interviews, and analyses are ongoing. CONCLUSIONS: This Maori-centered study combines quantitative and qualitative research to compare 2 clinical pathways from detection of hrHPV to colposcopy. This protocol draws on rural community practices strengths, successfully engaging Maori from a whanau ora (family wellness) approach including kanohi ki te kanohi (face-to-face), kaiawhina (nonclinical community health workers), and multiple venues for interventions. It will inform the theory and practice of rural models of the use of innovative technology, addressing Maori cervical cancer inequities and facilitating Maori wellness. The findings are anticipated to be applicable to other Indigenous and rural people in high-income countries. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000553875; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621000553875. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51643.
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BACKGROUND: Current inferences about the site of origin (SOO) of premature ventricular complexes (PVC) from the surface ECG have not been subjected to newer data analytic techniques that identify signals that are not recognized by visual inspection. AIMS: The objective of this study was to apply data analytics to PVC characteristics. METHODS: PVCs from 12-lead ECGs of a consecutive series of 338 individuals were examined by unsupervised machine learning cluster analysis, and indexes were compared to a composite criterion for SOO. RESULTS: Data analytics found that V1S plus V2S ≤ 9.25 of the PVC had a LVOT origin (sensitivity 95.4%; specificity 97.5%). V1R + V2R + V3R > 15.0 (a RBBB configuration) likely had a LVOT origin. PVCs with V1S plus V2S > 12.75 (LBBB configuration) likely had a RVOT origin. PVC with V1S plus V2S > 14.25 (LBBB configuration) and all inferior leads positive likely had a RVOT origin. CONCLUSION: Newer data analytic techniques provide a non-invasive approach to identifying PVC SOO, which should be useful for the clinician evaluating a 12-lead ECG.
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AIMS: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN). METHODS: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding. RESULTS: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection. CONCLUSIONS: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN. TRIAL REGISTRATION: ClincalTrials.gov Identifier, NCT03228420.
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Diabetes Mellitus , Neuropatias Diabéticas , Estimulação da Medula Espinal , Humanos , Estimulação da Medula Espinal/métodos , Neuropatias Diabéticas/terapia , Qualidade de Vida , Estudos Prospectivos , Dor , Resultado do TratamentoRESUMO
A lack of composable and tunable gene regulators has hindered efforts to engineer non-model bacteria and consortia. Toward addressing this, we explore the broad-host potential of small transcription activating RNA (STAR) and propose a design strategy to achieve tunable gene control. First, we demonstrate that STARs optimized for E. coli function across different Gram-negative species and can actuate using phage RNA polymerase, suggesting that RNA systems acting at the level of transcription are portable. Second, we explore an RNA design strategy that uses arrays of tandem and transcriptionally fused RNA regulators to precisely alter regulator concentration from 1 to 8 copies. This provides a simple means to predictably tune output gain across species and does not require access to large regulatory part libraries. Finally, we show RNA arrays can be used to achieve tunable cascading and multiplexing circuits across species, analogous to the motifs used in artificial neural networks.
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Bacteriófagos , Escherichia coli , Escherichia coli/genética , Bactérias/genética , Bacteriófagos/genética , Engenharia , RNARESUMO
Microbial communities such as swarms or biofilms often form at the interfaces of solid substrates and open fluid flows. At the same time, in laboratory environments these communities are commonly studied using microfluidic devices with media flows and open boundaries. Extracellular signaling within these communities is therefore subject to different constraints than signaling within classic, closed-boundary systems such as developing embryos or tissues, yet is understudied by comparison. Here, we use mathematical modeling to show how advective-diffusive boundary flows and population geometry impact cell-cell signaling in monolayer microbial communities. We reveal conditions where the intercellular signaling lengthscale depends solely on the population geometry and not on diffusion or degradation, as commonly expected. We further demonstrate that diffusive coupling with the boundary flow can produce signal gradients within an isogenic population, even when there is no flow within the population. We use our theory to provide new insights into the signaling mechanisms of published experimental results, and we make several experimentally verifiable predictions. Our research highlights the importance of carefully evaluating boundary dynamics and environmental geometry when modeling microbial cell-cell signaling and informs the study of cell behaviors in both natural and synthetic systems.
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Microbiota , Modelos Teóricos , Biofilmes , Transdução de Sinais , Comunicação CelularRESUMO
Controlled continuous crystallization of the active pharmaceutical ingredient (API) telmisartan (TEL) has been conducted from TEL/DMSO solutions by antisolvent crystallization in deionized water using membrane micromixing contactors. The purpose of this work was to test stainless-steel membranes with ordered 10 µm pores spaced at 200 µm in a stirred-cell (batch, LDC-1) and crossflow (continuous, AXF-1) system for TEL formation. By controlling the feed flow rate of the API and solvent, through the membrane pores as well as the antisolvent flow, it was possible to tightly control the micromixing and with that to control the crystal nucleation and growth. Batch crystallization without the membrane resulted in an inhomogeneous crystallization process, giving a mixture of crystalline and amorphous TEL materials. The rate of crystallization was controlled with a higher DMSO content (4:1 DMSO/DI water), resulting in slower crystallization of the TEL material. Both membrane setups, stirred batch and the crossflow, yielded the amorphous TEL particles when deionized water was used, while a crystalline material was produced when a mixture of DI water and DMSO was used.
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BACKGROUND: Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood. METHODS: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA (INKILN). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA-protein and protein-protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKILN expression and function in ligation injury-induced neointimal formation. RESULTS: INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks interleukin-1ß-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, INKILN knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in bacterial artificial chromosome transgenic mice. CONCLUSIONS: These findings elucidate an important pathway of VSMC inflammation involving an INKILN/MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.