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Purpose: Changes in meibum composition and quantity in meibomian gland dysfunction (MGD) result in tear film instability and dry eye. This exploratory study aimed to identify changes in (O-acyl)-ω-hydroxy fatty acid (OAHFA) and hydrocarbon chain (HC) unsaturation levels in meibum related to the presence and severity of MGD. Methods: Meibum samples were collected from 3 cohorts of adults with no MGD, mild-to-moderate MGD, and severe MGD in a noninterventional clinical trial (NCT01979887). OAHFAs, cholesterol esters (CE), HC unsaturation, and HC length in the meibum samples were quantified with 1H-nuclear magnetic resonance spectroscopy using 2 methods of normalization. Results: Meibum samples from 62 subjects were analyzed: 21 non-MGD, 21 mild-to-moderate MGD, and 20 severe MGD. Meibum OAHFA and CE levels and HC unsaturation were reduced with increasing severity of MGD, with most pairwise comparisons significant (P < 0.05, t-tests), following the order non-MGD > mild-to-moderate MGD > severe MGD. Regardless of the resonances used for normalization, each pairwise comparison of OAHFA, CE, and HC unsaturation levels in MGD (combined severities) versus non-MGD samples was significant (P < 0.01, t-test). Analysis using various normalization equations showed reductions of 20%-22% for OAHFAs, 51%-57% for CE, and 36%-66% for HC unsaturation in MGD (combined severities) compared with non-MGD. HC length was not altered in MGD (combined severities) compared with non-MGD samples (t-test). Conclusions: Meibum OAHFA, CE, and HC unsaturation levels were reduced in MGD and were lowest in the severe MGD cohort. These findings may contribute to the understanding of the pathophysiology of MGD.
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Objective: Treatment of obesity has been transformed by the recent approval of incretin-based therapies for weight loss (e.g., glucagon-like peptide 1 agonist semaglutide), but little is known about patient perspectives on these medications. Methods: Between December 2023 and March 2024, healthcare patients from an academic medical center in the Southeast United States with Body Mass Index ≥30 kg/m2 completed a cross-sectional online survey on attitudes toward incretin-based medications. Results: Compared to patients with a bachelor's degree, those without a degree were less likely to be aware of incretin-based pharmacotherapies (96% vs. 78%) and to have discussed pharmacotherapies with a doctor (43% vs. 27%) but had greater interest in using these pharmacotherapies (4.3 vs. 4.7). These pharmacotherapy-related variables did not differ significantly according to gender, race, or financial security. Concerns about side effects, long-term health risks, and potential for weight regain were highly endorsed and were associated with lower interest in using incretin-based therapies and with some demographic factors. Patients reported high interest in lifestyle programs designed for individuals taking anti-obesity medications. Conclusion: Demographic considerations, notably education level, should be factored into the strategy to promote equitable utilization of incretin-based therapies, particularly as their accessibility expands.
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The field of ability-related emotional intelligence (ability EI) could benefit from new perspectives concerning dynamic operations. According to a recent perspective, variations in ability EI are likely to be linked to variations in skills related to evaluation. This perspective contends, perhaps counterintuitively, that higher levels of ability EI are likely to be linked to higher levels of emotional reactivity, defined in terms of stronger event-emotion relationships. Two studies (total N = 245) pursue such ideas in the context of multilevel models involving event valence and emotional experience. Variations in ability EI modulated event-emotion relationships in the context of laboratory inductions involving hypothetical events (Study 1), affective images varying in valence (Study 1), and with respect to naturally occurring variations in positive and negative daily events (Study 2), such that higher levels of ability EI were linked to stronger event-emotion relationships, regardless of whether events and emotions were positive or negative in valence. These results provide new evidence for recent theorizing concerning ability EI while speaking to functional versus dysfunctional perspectives on emotional reactivity.
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MPS IIIC is a lysosomal storage disease caused by mutations in heparan-α-glucosaminide N-acetyltransferase (HGSNAT), for which no treatment is available. Because HGSNAT is a trans-lysosomal-membrane protein, gene therapy for MPS IIIC needs to transduce as many cells as possible for maximal benefits. All cells continuously release extracellular vesicles (EVs) and communicate by exchanging biomolecules via EV trafficking. To address the unmet need, we developed a rAAV-hHGSNATEV vector with an EV-mRNA-packaging signal in the 3'UTR to facilitate bystander effects, and tested it in an in vitro MPS IIIC model. In human MPS IIIC cells, rAAV-hHGSNATEV enhanced HGSNAT mRNA and protein expression, EV-hHGSNAT-mRNA packaging, and cleared GAG storage. Importantly, incubation with EVs led to hHGSNAT protein expression and GAG contents clearance in recipient MPS IIIC cells. Further, rAAV-hHGSNATEV transduction led to the reduction of pathological EVs in MPS IIIC cells to normal levels, suggesting broader therapeutic benefits. These data demonstrate that incorporating the EV-mRNA-packaging signal into a rAAV-hHGSNAT vector enhances EV packaging of hHGSNAT-mRNA, which can be transported to non-transduced cells and translated into functional rHGSNAT protein, facilitating cross-correction of disease pathology. This study supports the therapeutic potential of rAAVEV for MPS IIIC, and broad diseases, without having to transduce every cell.
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Efeito Espectador , Dependovirus , Vesículas Extracelulares , Terapia Genética , RNA Mensageiro , Humanos , Terapia Genética/métodos , Dependovirus/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Vesículas Extracelulares/metabolismo , Mucopolissacaridose III/terapia , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/genética , Vetores Genéticos , Acetiltransferases/metabolismo , Acetiltransferases/genéticaRESUMO
Adding 50% vitreous humor to the media surrounding lens explants induces fiber cell differentiation and a significant immune/inflammatory response. While Fgfr loss blocks differentiation in lens epithelial explants, this blockage is partially reversed by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of ß-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrate that many of the vitreous-induced gene-expression changes in Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten.
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Diferenciação Celular , Cristalino , PTEN Fosfo-Hidrolase , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Diferenciação Celular/genética , Animais , Cristalino/citologia , Cristalino/metabolismo , Camundongos , Transdução de Sinais , Perfilação da Expressão Gênica , Transcriptoma/genéticaRESUMO
Astrocytes play an essential role in regulating synaptic transmission. This study describes a novel form of modulation of excitatory synaptic transmission in the mouse hippocampus by astrocytic G-protein-coupled receptors (GPCRs). We have previously described astrocytic glutamate release via protease-activated receptor-1 (PAR1) activation, although the regulatory mechanisms for this are complex. Through electrophysiological analysis and modeling, we discovered that PAR1 activation consistently increases the concentration and duration of glutamate in the synaptic cleft. This effect was not due to changes in the presynaptic glutamate release or alteration in glutamate transporter expression. However, blocking group II metabotropic glutamate receptors (mGluR2/3) abolished PAR1-mediated regulation of synaptic glutamate concentration, suggesting a role for this GPCR in mediating the effects of PAR1 activation on glutamate release. Furthermore, activation of mGluR2/3 causes glutamate release through the TREK-1 channel in hippocampal astrocytes. These data show that astrocytic GPCRs engage in a novel regulatory mechanism to shape the time course of synaptically-released glutamate in excitatory synapses of the hippocampus.
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Astrócitos , Região CA1 Hipocampal , Ácido Glutâmico , Camundongos Endogâmicos C57BL , Receptor PAR-1 , Receptores de Glutamato Metabotrópico , Sinapses , Animais , Receptores de Glutamato Metabotrópico/metabolismo , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Sinapses/metabolismo , Região CA1 Hipocampal/metabolismo , Receptor PAR-1/metabolismo , Camundongos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Transmissão Sináptica/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Canais de Potássio de Domínios Poros em Tandem/metabolismoRESUMO
Emotionally intelligent people are thought to be more skilled in recognizing, thinking about, using, and regulating emotions. This construct has garnered considerable interest, but initial enthusiasm has faded and it is time to take stock. There is consensus that ability-related measures of emotional intelligence (EI) can be favored to self-report tests, in part because the resulting scores cannot be equated with personality traits. However, there are questions surrounding measurement as well as predictive value. Experts in the field were encouraged to chart new directions, with the idea that these new directions could reinvigorate EI scholarship. Special Issue papers speak to theory, mechanism, measurement, and training. In addition, these papers seek to forge links with research traditions focused on interpersonal perception, emotional awareness, and emotion regulation. As a result of these efforts, new insights into what EI is and how it works can be anticipated in upcoming years.
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OBJECTIVE AND BACKGROUND: The personality trait of agreeableness is linked to a number of core tendencies (e.g., empathy, warmth) that operate in a feeling-based manner. Following considerations of this type, it is proposed that the motivations and characteristics of agreeable individuals, relative to disagreeable individuals, should render them more receptive to emotional events and more responsive to them for this reason. METHOD: Potential links between agreeableness and emotional reactivity were assessed in two studies involving four samples (total N = 517) in which participants continuously rated their feeling states in response to a variety of affective images. RESULTS: Agreeableness did not predict the speed with which emotional reactions began, but agreeable individuals exhibited higher-magnitude peak intensities, regardless of whether stimuli were appetitive (pleasant) or aversive (unpleasant) in nature. CONCLUSIONS: The findings provide novel insights into the personality trait of agreeableness, emotional reactivity phenomena, and the dynamic processes that link agreeableness to emotion.
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Purpose: Despite strong evidence demonstrating that normal lens development requires regulation governed by microRNAs (miRNAs), the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods: A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance, was conducted by miRNA sequencing. Mouse lenses lacking each of three abundantly expressed lens miRNAs (miR-184, miR-26, and miR-1) were analyzed to explore the role of these miRNAs in lens development. Results: Mice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4 to 6 weeks of age. RNA sequencing analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens enriched and linked to cataract (e.g., Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes) and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). Conclusions: miR-1, miR-184, and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.
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Catarata , Cristalino , MicroRNAs , Transcriptoma , Animais , MicroRNAs/genética , Cristalino/metabolismo , Cristalino/patologia , Catarata/genética , Catarata/metabolismo , Camundongos , Camundongos Knockout , Animais Recém-Nascidos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Evolutionary theorizing has given rise to the idea that responding to any particular threat may be more mandatory than responding to any particular reward. The present three experiments (total N = 375) sought to provide support for this perspective in an emotion dynamics task in which participants continuously rated their affective state in response to appetitive (reward-related) versus aversive (threat-related) images. Even when equating images for arousal and extremity, several negativity effects (e.g., steeper reactivity slopes in response to aversive images) were found. These negativity effects can serve as an experimental model of threat sensitivity, which should predispose some individuals, more than others, to symptoms related to fear and anxiety. This point was made with respect to sex differences, given that women (relative to men) are diagnosed with anxiety disorders at higher rates. Sex differences were pronounced and extensions of this work, both basic and applied, are proposed.
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Emoções , Medo , Humanos , Masculino , Feminino , Adulto Jovem , Medo/psicologia , Medo/fisiologia , Emoções/fisiologia , Adulto , Caracteres Sexuais , Ansiedade/psicologia , Adolescente , Fatores Sexuais , Nível de Alerta/fisiologia , RecompensaRESUMO
Purpose: To investigate gel stent implantation with and without intraoperative sustained-release mitomycin C (MMC SR) in a rabbit model for gel stent implantation, and to examine aqueous humor outflow (AHO) postimplantation. Methods: Four groups of rabbits were included. Group 1 was untreated (control). Groups 2, 3, and 4 received the gel stent without MMC, with MMC solution (subconjunctival injection), and with MMC SR (subconjunctival injection), respectively. Intraocular pressure (IOP) and AHO were assessed via tonometry and indocyanine green-based angiography, respectively. The main efficacy measure was change in IOP from baseline. Results: Following gel stent implantation, Groups 2, 3, and 4 maintained ≥20% IOP reduction (response) for a median duration of 1 week, 6.5 weeks, and 30 weeks, respectively. Angiography showed normal aqueous humor drainage (Group 1) beginning at the perilimbal trabecular plexus and continuing posteriorly to episcleral outflow vessels. Following implantation, drainage occurred preferentially and directly into the subconjunctival bleb. Conclusions: Gel stent implantation with MMC SR was most effective in achieving sustained, long-term IOP reduction in the rabbit model, compared with implantation with or without MMC solution. Bleb presence and the postimplantation aqueous angiography results indicated redirection of the AHO to the subconjunctival vasculature and presumed lymphatics, suggesting efficient glaucoma filtration to lower IOP in this model. This rabbit model and aqueous angiography may help refine understanding of the mechanism of action of minimally invasive glaucoma surgeries and ultimately translate to improved surgical devices and procedures for patients with glaucoma.
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Humor Aquoso , Preparações de Ação Retardada , Cirurgia Filtrante , Pressão Intraocular , Mitomicina , Animais , Coelhos , Mitomicina/administração & dosagem , Mitomicina/farmacologia , Cirurgia Filtrante/métodos , Pressão Intraocular/efeitos dos fármacos , Humor Aquoso/metabolismo , Humor Aquoso/efeitos dos fármacos , Stents , Géis , Glaucoma/cirurgia , Glaucoma/tratamento farmacológico , Túnica Conjuntiva/cirurgia , Modelos Animais de DoençasRESUMO
River networks are composed of a mainstem and tributaries. These tributaries dissect landscapes, regulate water and habitat availability, and transport sediment and nutrients. Despite the importance of tributaries, we currently lack theory and data describing whether and how tributary length and spacing varies within watersheds, thereby limiting our ability to accurately describe river network geometry. We address this knowledge gap by analyzing 4,696 tributaries across six landscapes with varying climate, tectonic setting, and lithology. Our results show that both tributary length and spacing systematically increase with downstream distance along the mainstem river, following a power-law scaling. This power-law scaling can be modulated by basin shape, with tributaries becoming shorter and, in some cases, more closely spaced as basin elongate. Furthermore, the power-law scaling may break down in cases where river networks have been disturbed by pervasive faulting, raising the possibility that the scaling we observe is not unique to all branching networks, and instead may be universal across undisturbed fluvial networks. These findings can be used to improve predictions of river network geometry and potentially to distinguish fluvial river networks from other branching networks.
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This article provides a comparative analysis of the treatment of disabled First World War veterans in 1920s Britain and the simultaneous care of Imperial Pensioners residing in Australia and South Africa via the detailed administrative reports of a British civil servant, G.F. Gilbert. Imperial Pensioners were disabled veteran migrants of the British Army residing overseas. A study of these veteran populations in Australia and South Africa provides two primary insights into the broader historiography of disabled veterans. Firstly, a comparative case study helps to show the way in which cultural notions of disability were part of broader ideas of nation-building overseas. Secondly, the specific disability diagnosis category chosen as a more in-depth case study can further complicate and contradict broader assessments of national responses. This article attempts to build upon recent transnational histories of veterans by transcending national boundaries and homogenous veteran profiles with an extension in methodological scope by providing an intra-national case study via the Imperial Pensioner.
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Purpose: Despite strong evidence demonstrating that normal lens development requires regulation governed by miRNAs, the functional role of specific miRNAs in mammalian lens development remains largely unexplored. Methods: A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance was conducted by miRNA-seq. Mouse lenses lacking each of three abundantly expressed lens miRNAs: miR-184, miR-26 and miR-1 were analyzed to explore the role of these miRNAs in lens development. Results: Mice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4-6 weeks of age. RNA-seq analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens-enriched and linked to cataract (e.g. Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes), and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3 ), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). Conclusion: miR-1, miR-184 and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.
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New efforts to understand the processes involved in ability-related emotional intelligence (ability EI) could reinvigorate this area of scholarship and research. It is proposed that participants with higher levels of ability EI are evaluation experts, which should be evident in the attitude domain. Study 1 (n = 148) probed for affective, cognitive, and behavioral reactions to a diverse set of attitude objects. In addition, attitude certainty ratings were collected. Higher levels of ability EI, but not self-reports of EI, were linked to attitudes that were more extreme, certain, and structurally integrated. In Study 2 (n = 602), participant employees completed standard personality and job satisfaction assessments. Higher levels of ability EI were predictive of greater polarization (as assessed in extremity-related terms) in both domains. The individual differences assessed by ability EI, these results suggest, also tend to support attitudes and opinions with stronger features. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Atitude , Inteligência Emocional , Humanos , Inteligência Emocional/fisiologia , Masculino , Feminino , Adulto , Adulto Jovem , Personalidade/fisiologia , Satisfação no Emprego , Aptidão/fisiologiaRESUMO
Ocular lens development entails epithelial to fiber cell differentiation, defects in which cause congenital cataracts. We report the first single-cell multiomic atlas of lens development, leveraging snRNA-seq, snATAC-seq and CUT&RUN-seq to discover previously unreported mechanisms of cell fate determination and cataract-linked regulatory networks. A comprehensive profile of cis- and trans-regulatory interactions, including for the cataract-linked transcription factor MAF, is established across a temporal trajectory of fiber cell differentiation. Furthermore, we identify an epigenetic paradigm of cellular differentiation, defined by progressive loss of the H3K27 methylation writer Polycomb repressive complex 2 (PRC2). PRC2 localizes to heterochromatin domains across master-regulator transcription factor gene bodies, suggesting it safeguards epithelial cell fate. Moreover, we demonstrate that FGF hyper-stimulation in vivo leads to MAF network activation and the emergence of novel lens cell states. Collectively, these data depict a comprehensive portrait of lens fiber cell differentiation, while defining regulatory effectors of cell identity and cataract formation.
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Catarata , Cristalino , Humanos , Multiômica , Catarata/genética , Diferenciação Celular/genética , OlhoRESUMO
Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.
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Encéfalo , Metabolismo Energético , Animais , Humanos , Encéfalo/metabolismoRESUMO
Polypharmacy, commonly defined as ≥5 medications, is a rising public health concern due to its many risks of harm. One commonly recommended strategy to address polypharmacy is medication reviews, with subsequent deprescription of inappropriate medications. In this review, we explore the intersection of older age, polypharmacy, and deprescribing in a contemporary context by appraising the published literature (2012-2022) to identify articles that included new primary data on deprescribing medications in patients aged ≥65 years currently taking ≥5 medications. We found 31 articles were found which describe the current perceptions of clinicians towards deprescribing, the identified barriers, key enabling factors, and future directions in approaching deprescribing. Currently, clinicians believe that deprescribing is a complex process, and despite the majority of clinicians reporting feeling comfortable in deprescribing, fewer engage with this process regularly. Common barriers cited include a lack of knowledge and training around the deprescribing process, a lack of time, a breakdown in communication, perceived 'abandonment of care', fear of adverse consequences, and resistance from patients and/or their carers. Common enabling factors of deprescribing include recognition of key opportunities to instigate this process, regular medication reviews, improving lines of communication, education of both patients and clinicians and a multidisciplinary approach towards patient care. Addressing polypharmacy requires a nuanced approach in a generally complex group of patients. Key strategies to reducing the risks of polypharmacy include education of patients and clinicians, in addition to improving communication between healthcare providers in a multidisciplinary approach.