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1.
Am Psychol ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38815063

RESUMO

Natural language processing (NLP)-previously the domain of a select few language and computer scientists-is undergoing an unprecedented surge in popularity across disciplines. The ubiquity of language data, alongside extremely rapid methodological innovations, has magnetized the field, attracting researchers with the promise of measuring, forecasting, and understanding the most central questions in business, psychology, biology, sociology, the humanities, and beyond. The power of language analysis to reveal insights into human thought, feeling, and behavior has become a core interest emerging from recent technological advances, which are being probed to unearth deeply embedded truths about the human condition. However, NLP research has reached a critical juncture, sitting at the cusp of societal transformation in many aspects of daily life. The details of how NLP research develops over the next 3-5 years will define this transformation. In this emerging, near-infinite space of NLP-driven research, we provide a critical frame of reference for how, when, and why these technologies should evolve in a particularly transdisciplinary manner. Specifically, we discuss (a) the urgency of pairing existing and emerging NLP research with existing scientific knowledge, theory, and principles from the behavioral sciences; (b) the coevolution of NLP technologies; and (c) the practical implications and ethical consequences of expanding language analysis using broader psychosocial theories of the human condition. While our discussion focuses principally on using language as a window in the individual mind, this topic holds substantial implications for other disciplines and lines of inquiry, including the dynamics of social interaction and beyond. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

2.
Vet Ophthalmol ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700998

RESUMO

Subretinal injections are not commonly performed during clinical treatment of animals but are frequently used in laboratory animal models to assess therapeutic efficacy and safety of gene and cell therapy products. Veterinary ophthalmologists are often employed to perform the injections in the laboratory animal setting, due to knowledge of comparative ocular anatomy between species and familiarity with operating on non-human eyes. Understanding the different approaches used for subretinal injection in each species and potential complications that may be encountered is vital to achieving successful and reproducible results. This manuscript provides a summary of different approaches to subretinal injections in the most common animal model species, along with information from published literature and experience of the authors to educate novice or experienced surgeons tasked with performing these injections for the first time.

3.
Proc Natl Acad Sci U S A ; 121(12): e2314600121, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38470920

RESUMO

Global atmospheric methane concentrations rose by 10 to 15 ppb/y in the 1980s before abruptly slowing to 2 to 8 ppb/y in the early 1990s. This period in the 1990s is known as the "methane slowdown" and has been attributed in part to the collapse of the former Soviet Union (USSR) in December 1991, which may have decreased the methane emissions from oil and gas operations. Here, we develop a methane plume detection system based on probabilistic deep learning and human-labeled training data. We use this method to detect methane plumes from Landsat 5 satellite observations over Turkmenistan from 1986 to 2011. We focus on Turkmenistan because economic data suggest it could account for half of the decline in oil and gas emissions from the former USSR. We find an increase in both the frequency of methane plume detections and the magnitude of methane emissions following the collapse of the USSR. We estimate a national loss rate from oil and gas infrastructure in Turkmenistan of more than 10% at times, which suggests the socioeconomic turmoil led to a lack of oversight and widespread infrastructure failure in the oil and gas sector. Our finding of increased oil and gas methane emissions from Turkmenistan following the USSR's collapse casts doubt on the long-standing hypothesis regarding the methane slowdown, begging the question: "what drove the 1992 methane slowdown?"

4.
PLoS One ; 19(2): e0293963, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38381724

RESUMO

Health-related quality of life (HRQoL) assesses the perceived impact of health status across life domains. Although research has explored the relationship between specific conditions, including HIV, and HRQoL in low-resource settings, less attention has been paid to the association between multimorbidity and HRQoL. In a secondary analysis of cross-sectional data from the Vukuzazi ("Wake up and know ourselves" in isiZulu) study, which identified the prevalence and overlap of non-communicable and infectious diseases in the uMkhanyakunde district of KwaZulu-Natal, we (1) evaluated the impact of multimorbidity on HRQoL; (2) determined the relative associations among infectious diseases, non-communicable diseases (NCDs), and HRQoL; and (3) examined the effects of controlled versus non-controlled disease on HRQoL. HRQoL was measured using the EQ-5D-3L, which assesses overall perceived health, five specific domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and three levels of problems (no problems, some problems, and extreme problems). Six diseases and disease states were included in this analysis: HIV, diabetes, stroke, heart attack, high blood pressure, and TB. After examining the degree to which number of conditions affects HRQoL, we estimated the effect of joint associations among combinations of diseases, each HRQoL domain, and overall health. Then, in one set of ridge regression models, we assessed the relative impact of HIV, diabetes, stroke, heart attack, high blood pressure, and tuberculosis on the HRQoL domains; in a second set of models, the contribution of treatment (controlled vs. uncontrolled disease) was added. A total of 14,008 individuals were included in this analysis. Having more conditions adversely affected perceived health (r = -0.060, p<0.001, 95% CI: -0.073 to -0.046) and all HRQoL domains. Infectious conditions were related to better perceived health (r = 0.051, p<0.001, 95% CI: 0.037 to 0.064) and better HRQoL, whereas non-communicable diseases (NCDs) were associated with worse perceived health (r = -0.124, p<0.001, -95% CI: 0.137 to -0.110) and lower HRQoL. Particular combinations of NCDs were detrimental to perceived health, whereas HIV, which was characterized by access to care and suppressed viral load in the large majority of those affected, was counterintuitively associated with better perceived health. With respect to disease control, unique combinations of uncontrolled NCDs were significantly related to worse perceived health, and controlled HIV was associated with better perceived health. The presence of controlled and uncontrolled NCDs was associated with poor perceived health and worse HRQoL, whereas the presence of controlled HIV was associated with improved HRQoL. HIV disease control may be critical for HRQoL among people with HIV, and incorporating NCD prevention and attention to multimorbidity into healthcare strategies may improve HRQoL.


Assuntos
Doenças Transmissíveis , Diabetes Mellitus , Infecções por HIV , Hipertensão , Infarto do Miocárdio , Doenças não Transmissíveis , Acidente Vascular Cerebral , Humanos , Multimorbidade , Qualidade de Vida , África do Sul/epidemiologia , Doenças não Transmissíveis/epidemiologia , Estudos Transversais , Infecções por HIV/epidemiologia , Infecções por HIV/complicações , Diabetes Mellitus/epidemiologia , Doenças Transmissíveis/complicações , Hipertensão/epidemiologia , Infarto do Miocárdio/complicações , Acidente Vascular Cerebral/complicações
5.
Sci Rep ; 14(1): 1708, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38242954

RESUMO

The COVID-19 pandemic posed a global threat to nearly every society around the world. Individuals turned to their political leaders to safely guide them through this crisis. The most direct way political leaders communicated with their citizens was through official speeches and press conferences. In this report, we compare psychological language markers of four different heads of state during the early stage of the pandemic. Specifically, we collected all pandemic-related speeches and press conferences delivered by political leaders in the USA (Trump), UK (Johnson), Germany (Merkel), and Switzerland (Swiss Federal Council) between February 27th and August 31st, 2020. We used natural language analysis to examine language markers of expressed positive and negative emotions, references to the community (we-talk), analytical thinking, and authenticity and compare these language markers across the four nations. Level differences in the language markers between the leaders can be detected: Trump's language was characterized by a high expression of positive emotion, Merkel's by a strong communal focus, and Johnson's and the Swiss Federal Council by a high level of analytical thinking. Overall, these findings mirror different strategies used by political leaders to deal with the COVID-19 pandemic.


Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , Suíça/epidemiologia , Pandemias , Política , Idioma , Alemanha/epidemiologia , Reino Unido/epidemiologia
6.
J Pers Disord ; 37(4): 444-455, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37721778

RESUMO

Borderline personality disorder (BPD) is characterized by severe interpersonal dysfunction, yet the underlying nature of such dysfunction remains poorly understood. The present study adopted a behavioral approach to more objectively describe the social-cognitive contributors to interpersonal dysfunction in BPD. Participants (N = 530) completed an online survey comprising validated measures of BPD features and other problematic interpersonal traits (e.g., narcissism), as well as a writing prompt where they were asked to share their personal thoughts about relationships. Computerized language analysis methods were used to quantify various psychosocial dimensions of participants' writing, which were incorporated into a principal component analysis. Analyses revealed four core social dimensions of thought: (1) Connectedness/Intimacy; (2) Immediacy; (3) Social Rumination; (4) Negative Affect. All four dimensions correlated with BPD features in intuitive ways, some of which were specific to BPD. This study highlights the value of natural language analysis to explore fundamental dimensions of personality disorder.


Assuntos
Transtorno da Personalidade Borderline , Humanos , Transtornos da Personalidade , Idioma , Narcisismo , Cognição
7.
PLoS One ; 18(9): e0291369, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37747891

RESUMO

BACKGROUND: Mental health (MH) peer online forums offer robust support where internet access is common, but healthcare is not, e.g., in countries with under-resourced MH support, rural areas, and during pandemics. Despite their widespread use, little is known about who posts in such forums, and in what mood states. The discussion platform Reddit is ideally suited to study this as it hosts forums (subreddits) for MH and non-MH topics. In bipolar disorder (BD), where extreme mood states are core defining features, mood influences are particularly relevant. OBJECTIVES: This exploratory study investigated posting patterns of Reddit users with a self-reported BD diagnosis and the associations between posting and emotions, specifically: 1) What proportion of the identified users posts in MH versus non-MH subreddits? 2) What differences exist in the emotions that they express in MH or non-MH subreddit posts? 3) How does mood differ between those users who post in MH subreddits compared to those who only post in non-MH subreddits? METHODS: Reddit users were automatically identified via self-reported BD diagnosis statements and all their 2005-2019 posts were downloaded. First, the percentages of users who posted only in MH (non-MH) subreddits were calculated. Second, affective vocabulary use was compared in MH versus non-MH subreddits by measuring the frequency of words associated with positive emotions, anxiety, sadness, anger, and first-person singular pronouns via the LIWC text analysis tool. Third, a logistic regression distinguished users who did versus did not post in MH subreddits, using the same LIWC variables (measured from users' non-MH subreddit posts) as predictors, controlling for age, gender, active days, and mean posts/day. RESULTS: 1) Two thirds of the identified 19,685 users with a self-reported BD diagnosis posted in both MH and non-MH subreddits. 2) Users who posted in both MH and non-MH subreddits exhibited less positive emotion but more anxiety and sadness and used more first-person singular pronouns in their MH subreddit posts. 3) Feminine gender, higher positive emotion, anxiety, and sadness were significantly associated with posting in MH subreddits. CONCLUSIONS: Many Reddit users who disclose a BD diagnosis use a single account to discuss MH and other concerns. Future work should determine whether users exhibit more anxiety and sadness in their MH subreddit posts because they more readily post in MH subreddits when experiencing lower mood or because they feel more able to express negative emotions in these spaces. MH forums may reflect the views of people who experience more extreme mood (outside of MH subreddits) compared to people who do not post in MH subreddits. These findings can be useful for MH professionals to discuss online forums with their clients. For example, they may caution them that forums may underrepresent people living well with BD.


Assuntos
Transtorno Bipolar , Humanos , Transtorno Bipolar/diagnóstico , Emoções , Afeto , Ansiedade , Tristeza
8.
Affect Sci ; 4(2): 291-306, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37304562

RESUMO

Emotional granularity is the ability to create differentiated and nuanced emotional experiences and is associated with positive health outcomes. Individual differences in granularity are hypothesized to reflect differences in emotion concepts, which are informed by prior experience and impact current and future experience. Greater variation in experience, then, should be related to the rich and diverse emotion concepts that support higher granularity. Using natural language processing methods, we analyzed descriptions of everyday events to estimate the diversity of contexts and activities encountered by participants. Across three studies varying in language (English, Dutch) and modality (written, spoken), we found that participants who referred to a more varied and balanced set of contexts and activities reported more differentiated and nuanced negative emotions. Experiential diversity was not consistently associated with granularity for positive emotions. We discuss the contents of daily life as a potential source and outcome of individual differences in emotion. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-023-00185-2.

9.
Sex Med ; 11(3): qfad020, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37273891

RESUMO

Background: Despite its growing prevalence, BDSM practice (bondage, discipline, dominance, submission, and sadomasochism) is still stigmatized, and little is known about the physical marks and injuries that individuals sustain from consensual BDSM-related activities. Aim: In this exploratory study, we examined BDSM sexual experiences and the physical marks and injuries resulting from these experiences in a convenience sample of 513 US adults. Methods: We examined the extent to which individuals at various stages of BDSM exploration engage with different types of BDSM and kink behaviors, along with the frequency with which they communicate about, inflict, and receive physical marks from these activities. Outcomes: Our main outcome measures were intentional and unintentional marks sustained from BDSM-related activities, BDSM experiences, and the use of safe words. Results: Results revealed that BDSM marks and injuries are common and quite varied (from small scratches to very large bruises) and unintentional and intentional marks differ in terms of typical size, place on body, and severity of injury. Additionally, BDSM experience is positively associated with the use of safe words and marking behaviors. Clinical Translation: Disclosure of marks and injuries, intentional and unintentional, may be improved if health care providers are aware of, and make efforts to reduce stigma surrounding, BDSM and rough sex activity. Strengths and Limitations: The findings of this study must be interpreted with acknowledgment of the limitations that it was a survey study with a convenience sample. However, as one of the few studies exploring the marks and injuries sustained from BDSM activities, the exploration of intentional and unintentional marks sustained provides a critical starting point for future examination of BDSM consequences that intersect with health care and the law. Conclusion: Marks and injuries from BDSM-related activities are common, and despite the greater use of safe words, practitioners with more BDSM experience inflict more marks than those with less BDSM experience.

10.
New Phytol ; 239(2): 506-517, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37194956

RESUMO

Volume and surface area of chloroplasts and surface area of plasmodesmata pit fields are presented for two C4 species, maize and sugarcane, with respect to cell surface area and cell volume. Serial block face scanning electron microscopy (SBF-SEM) and confocal laser scanning microscopy with the Airyscan system (LSM) were used. Chloroplast size estimates were much faster and easier using LSM than with SBF-SEM; however, the results were more variable than SBF-SEM. Mesophyll cells were lobed where chloroplasts were located, facilitating cell-to-cell connections while allowing for greater intercellular airspace exposure. Bundle sheath cells were cylindrical with chloroplasts arranged centrifugally. Chloroplasts occupied c. 30-50% of mesophyll cell volume, and 60-70% of bundle sheath cell volume. Roughly 2-3% of each cell surface area was covered by plasmodesmata pit fields for both bundle sheath and mesophyll cells. This work will aid future research to develop SBF-SEM methodologies with the aim to better understand the effect of cell structure on C4 photosynthesis.


Assuntos
Saccharum , Zea mays , Zea mays/metabolismo , Plasmodesmos/metabolismo , Cloroplastos/metabolismo , Folhas de Planta/metabolismo , Fotossíntese , Células do Mesofilo/metabolismo , Grão Comestível
11.
Methods Mol Biol ; 2597: 251-259, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36374426

RESUMO

Structural discovery of viral chemokine binding proteins can provide valuable information on the binding domains and protein-protein interfaces (PPI) of these immunologically relevant proteins. Protein expression in mammalian cells produces high-quality protein compared to other expression methods; however, because structural discovery methods such as cryo-EM-based single particle analysis (SPA) and x-ray crystallography use methods which combine data from many individual proteins, these demand a highly monodispersed sample composed of protein with ordered structure. These techniques are often incompatible with flexible glycosyl groups commonly present on proteins produced by mammalian cells and require deglycosylation to enable observation of the conserved tertiary structure beneath these variable, flexible, glycans. Using the Myxoma viral protein M-T7 as a test case, we discuss considerations and preliminary bioinformatic analysis for approaching structural discovery using freely accessible sequence and structure databases to maximize success and guide experiments. We describe a simple deglycosylation optimization protocol utilizing Endo H followed by size exclusion chromatography (SEC) based purification to produce and validate protein suitable for structural discovery. Considerations such as protein concentration and volumes required for crystallography and negative stain electron microscopy are discussed as well as grid blotting techniques for negative stain experiments to validate protein quality.


Assuntos
Quimiocinas , Proteínas Virais , Animais , Microscopia Crioeletrônica/métodos , Cristalografia por Raios X , Cromatografia em Gel , Mamíferos
12.
Artigo em Inglês | MEDLINE | ID: mdl-36497774

RESUMO

While experiencing the unpredictable events of the COVID-19 pandemic, we are likely to turn to people in order to regulate our emotions. In this research, we investigate how this interpersonal emotion regulation is connected to affective symptoms, above and beyond intrapersonal emotion regulation. Furthermore, we explore whether perceived psychosocial resources moderate these associations, i.e., if individuals reporting healthier social connections benefit differently from interpersonal emotion regulation. N = 1401 participants from the USA, UK, Germany, and Switzerland completed an online survey that included text samples. Affective symptoms (depression, adjustment disorder, fear of COVID-19) were examined based on self-reported as well as language-based indicators. As psychosocial resources, we examined social support, loneliness, attachment style, and trust. We defined latent variables for adaptive and maladaptive interpersonal emotion regulation and analyzed how they were associated with affective symptoms controlling for intrapersonal emotion regulation. Further, we analyzed how they interacted with psychosocial resources. Maladaptive interpersonal emotion regulation strategies were associated with affective symptoms. With lower psychosocial resources, the associations between interpersonal emotion regulation and depressive symptoms were more pronounced. The results highlight that maladaptive interpersonal emotion regulation is associated with worse mental health. These effects are not buffered by more psychosocial resources and are stronger for people with low psychosocial resources.


Assuntos
COVID-19 , Regulação Emocional , Humanos , Relações Interpessoais , Pandemias , COVID-19/epidemiologia , Emoções/fisiologia
13.
New Phytol ; 236(5): 1661-1675, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36098668

RESUMO

Use of a complete dynamic model of NADP-malic enzyme C4 photosynthesis indicated that, during transitions from dark or shade to high light, induction of the C4 pathway was more rapid than that of C3 , resulting in a predicted transient increase in bundle-sheath CO2 leakiness (ϕ). Previously, ϕ has been measured at steady state; here we developed a new method, coupling a tunable diode laser absorption spectroscope with a gas-exchange system to track ϕ in sorghum and maize through the nonsteady-state condition of photosynthetic induction. In both species, ϕ showed a transient increase to > 0.35 before declining to a steady state of 0.2 by 1500 s after illumination. Average ϕ was 60% higher than at steady state over the first 600 s of induction and 30% higher over the first 1500 s. The transient increase in ϕ, which was consistent with model prediction, indicated that capacity to assimilate CO2 into the C3 cycle in the bundle sheath failed to keep pace with the rate of dicarboxylate delivery by the C4 cycle. Because nonsteady-state light conditions are the norm in field canopies, the results suggest that ϕ in these major crops in the field is significantly higher and energy conversion efficiency lower than previous measured values under steady-state conditions.


Assuntos
Dióxido de Carbono , Fotossíntese , Dióxido de Carbono/metabolismo , Zea mays/metabolismo , Produtos Agrícolas/metabolismo , Ataxia , Folhas de Planta/metabolismo
14.
Am J Vet Res ; 83(11): 1-8, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36170212

RESUMO

OBJECTIVE: To identify genetic associations with primary glaucoma (PG) in American Cocker Spaniels using a genome-wide association study (GWAS). ANIMALS: A nationwide ambidirectional case-control cohort study was performed in American Cocker Spaniels that had an ophthalmic examination performed by a veterinarian. Ninety-four dogs with PG (cases) and 111 dogs without glaucoma (controls) met phenotypic criteria and had a blood sample collected after receiving informed owner consent. PROCEDURES: Genomic DNA was extracted from whole blood samples and genotyped (CanineHD BeadChip, Illumina Inc). A case-control GWAS using a linear mixed model was performed, and 3 significance thresholds were calculated (1) using a Bonferroni correction on all single nucleotide polymorphisms (SNPs) included in the GWAS, (2) using a Bonferroni correction on only the unlinked SNPs from a pruned data set, and (3) using 10,000 random phenotype permutations. RESULTS: Following genotype data quality control, 89 cases and 93 controls were included in the GWAS. We identified an association on canine chromosome (CFA10); however, it did not reach statistical significance. Potential candidate genes within the surrounding linkage disequilibrium interval include coiled-coil domain containing 85A (CCDC85A) and extracellular growth factor containing fibulin extracellular matrix protein 1 (EFEMP1). CLINICAL RELEVANCE: Primary glaucoma in the American Cocker Spaniel is a complex heterogeneous disease that may be influenced by a locus on CFA10. The candidate genes CCDC85A and EFEMP1 within the identified linkage disequilibrium interval have been shown to be involved in human open-angle glaucoma.


Assuntos
Doenças do Cão , Glaucoma de Ângulo Aberto , Glaucoma , Animais , Cães , Estudos de Casos e Controles , Doenças do Cão/genética , Proteínas da Matriz Extracelular/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/veterinária , Genótipo , Glaucoma/genética , Glaucoma/veterinária , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/veterinária , Polimorfismo de Nucleotídeo Único
15.
Appetite ; 178: 106143, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35787403

RESUMO

Despite the established health and ecological benefits of a plant-based diet, the decision to eschew meat and other animal-derived food products remains controversial. So polarising is this topic that anti-vegan communities - groups of individuals who stand vehemently against veganism - have sprung up across the internet. Much scholarship on veganism characterizes anti-vegans in passing, painting them as ill-informed, uneducated, or simply obstinate. However, little empirical work has investigated these communities and the individuals within them. Accordingly, we conducted a study using social media data from the popular platform, Reddit. Specifically, we collected all available submissions (∼3523) and comments (∼45,528) from r/AntiVegan subreddit users (N = 3819) over a five-year period. Using a battery of computerized text analytic tools, we examined the psychosocial characteristics of Reddit users who publicly identify as anti-vegan, how r/AntiVegan users discuss their beliefs, and how the individual user changes as a function of community membership. Results from our analyses suggest several individual differences that align r/AntiVegan users with the community, including dark entertainment, ex-veganism and science denial. Several topics were extensively discussed by r/AntiVegan members, including nuanced discourse on the ethicality and health implications of vegan diets, and the naturalness of animal death, which ran counter to our expectations and lay stereotypes of r/AntiVegan users. Finally, several longitudinal changes in language use were observed within the community, reflecting enhanced group commitment over time, including an increase in group-focused language and a decrease in cognitive processing. Implications for vegan-nonvegan relations are discussed.


Assuntos
Dieta Vegana , Mídias Sociais , Dieta , Dieta Vegana/psicologia , Humanos , Psicologia Social , Veganos/psicologia
16.
Pathogens ; 11(5)2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35631109

RESUMO

Immune cell invasion after the transplantation of solid organs is directed by chemokines binding to glycosaminoglycans (GAGs), creating gradients that guide immune cell infiltration. Renal transplant is the preferred treatment for end stage renal failure, but organ supply is limited and allografts are often injured during transport, surgery or by cytokine storm in deceased donors. While treatment for adaptive immune responses during rejection is excellent, treatment for early inflammatory damage is less effective. Viruses have developed highly active chemokine inhibitors as a means to evade host responses. The myxoma virus-derived M-T7 protein blocks chemokine: GAG binding. We have investigated M-T7 and also antisense (ASO) as pre-treatments to modify chemokine: GAG interactions to reduce donor organ damage. Immediate pre-treatment of donor kidneys with M-T7 to block chemokine: GAG binding significantly reduced the inflammation and scarring in subcapsular and subcutaneous allografts. Antisense to N-deacetylase N-sulfotransferase1 (ASONdst1) that modifies heparan sulfate, was less effective with immediate pre-treatment, but reduced scarring and C4d staining with donor pre-treatment for 7 days before transplantation. Grafts with conditional Ndst1 deficiency had reduced inflammation. Local inhibition of chemokine: GAG binding in donor organs immediately prior to transplant provides a new approach to reduce transplant damage and graft loss.

17.
FASEB J ; 36(7): e22378, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35639414

RESUMO

Structural discovery of guanine nucleotide exchange factor (GEF) protein complexes is likely to become increasingly relevant with the development of new therapeutics targeting small GTPases and development of new classes of small molecules that inhibit protein-protein interactions. Syx (also known as PLEKHG5 in humans) is a RhoA GEF implicated in the pathology of glioblastoma (GBM). Here we investigated protein expression and purification of ten different human Syx constructs and performed biophysical characterizations and computational studies that provide insights into why expression of this protein was previously intractable. We show that human Syx can be expressed and isolated and Syx is folded as observed by circular dichroism (CD) spectroscopy and actively binds to RhoA as determined by co-elution during size exclusion chromatography (SEC). This characterization may provide critical insights into the expression and purification of other recalcitrant members of the large class of oncogenic-Diffuse B-cell lymphoma (Dbl) homology GEF proteins. In addition, we performed detailed homology modeling and molecular dynamics simulations on the surface of a physiologically realistic membrane. These simulations reveal novel insights into GEF activity and allosteric modulation by the plekstrin homology (PH) domain. These newly revealed interactions between the GEF PH domain and the membrane embedded region of RhoA support previously unexplained experimental findings regarding the allosteric effects of the PH domain from numerous activity studies of Dbl homology GEF proteins. This work establishes new hypotheses for structural interactivity and allosteric signal modulation in Dbl homology RhoGEFs.


Assuntos
Glioblastoma , Fatores de Troca de Nucleotídeo Guanina Rho , Glioblastoma/genética , Fatores de Troca do Nucleotídeo Guanina , Humanos , Proteínas , Fatores de Troca de Nucleotídeo Guanina Rho/genética
18.
BMC Vet Res ; 18(1): 182, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35578341

RESUMO

BACKGROUND: A number of etiologies for different canine chorioretinal lesions have been proved or suggested but some fundic lesions remain unclear in terms of an etiologic diagnosis, treatment options and prognosis. The purpose of this case series is to describe atypical chorioretinal lesions observed in dogs with primary angle-closure glaucoma (PACG). CASE PRESENTATION: Two spayed-female Siberian Huskies (3- and 4-year-old) and one Siberian Husky/Australian Shepherd mixed breed dog (11-month-old) that had multifocal depigmented retinal lesions and PACG were included. PROCEDURES: Ophthalmic examination, gross, and histopathologic examination findings are described. One of the dogs underwent further clinical diagnostics. Advanced clinical diagnostics on the fellow, presumed to be non-glaucomatous eye of a dog revealed: pectinate ligament dysplasia by gonioscopy, retinal thinning in the depigmented area and wedge shaped retinal thinning with delayed choroidal vascular perfusion by optical coherence tomography, confocal scanning laser ophthalmoscopy, fluorescein and indocyanine green angiography. Quantifiable maze testing for the same eye revealed mild nyctalopia but the full-field electroretinogram showed no generalized decrease of retinal function. Genetic testing for mutations within the retinitis pigmentosa GTPase regulator gene causing X-linked progressive retinal atrophy in Siberian Huskies was negative. Histopathologic evaluations on enucleated eyes in two dogs confirmed goniodysgenesis, PACG with optic nerve head cupping, and diffuse inner retinal atrophy. In addition, segmental profound retinal atrophy, loss of retinal pigment epithelium, and adhesion of the retina to Bruch's membrane was observed and coincided with multifocal depigmented lesions noted on fundic examination. CONCLUSIONS: To our knowledge, this is the first case series with clinical and histopathologic data of chorioretinal lesions, most likely caused by severely impaired choroidal perfusion. Further studies are warranted to elucidate the etiology and pathophysiology, including its possible association with PACG.


Assuntos
Doenças do Cão , Glaucoma de Ângulo Fechado , Disco Óptico , Animais , Atrofia/complicações , Atrofia/patologia , Atrofia/veterinária , Austrália , Corioide/patologia , Doenças do Cão/diagnóstico , Doenças do Cão/genética , Doenças do Cão/patologia , Cães , Feminino , Glaucoma de Ângulo Fechado/diagnóstico , Glaucoma de Ângulo Fechado/genética , Glaucoma de Ângulo Fechado/veterinária , Disco Óptico/patologia
19.
Proc Natl Acad Sci U S A ; 119(13): e2117038119, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35316139

RESUMO

SignificanceCanine models of inherited retinal diseases have helped advance adeno-associated virus (AAV)-based gene therapies targeting specific cells in the outer retina for treating blinding diseases in patients. However, therapeutic targeting of diseases such as congenital stationary night blindness (CSNB) that exhibit defects in ON-bipolar cells (ON-BCs) of the midretina remains underdeveloped. Using a leucine-rich repeat, immunoglobulin-like and transmembrane domain 3 (LRIT3) mutant canine model of CSNB exhibiting ON-BC dysfunction, we tested the ability of cell-specific AAV capsids and promotors to specifically target ON-BCs for gene delivery. Subretinal injection of one vector demonstrated safety and efficacy with robust and stable rescue of electroretinography signals and night vision up to 1 y, paving the way for clinical trials in patients.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Cegueira Noturna , Animais , Dependovirus/genética , Cães , Eletrorretinografia , Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Humanos , Proteínas de Membrana/genética , Miopia , Cegueira Noturna/genética , Cegueira Noturna/terapia
20.
Am J Audiol ; 31(3S): 993-1002, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-35130042

RESUMO

BACKGROUND: This study was aimed at identifying key topics in online discussions about tinnitus by examining a large data set extracted from Reddit social media using a natural language processing technique. METHOD: A corpus of 113,215 posts about tinnitus was extracted from Reddit's application programming interface. After cleaning the data for duplications and posts without any text information, the sample was reduced to 101,905 posts, which was subjected to cluster analysis using the open-source IRaMuTeQ software to identify main topics based on the co-occurrence of texts. These clusters were named by a panel of tinnitus experts (n = 9) by reading typical text segments within each cluster. RESULTS: The cluster analysis identified 16 unique clusters that belong to two topics, which were named "tinnitus causes and consequences" and "tinnitus management and coping." Based on their characteristics, the clusters were named: tinnitus timeline (10%), tinnitus perception (9.7%), medical triggers and modulators (8.8%), hearing research (8.8%), attention and silence (8.6%), social media posts about tinnitus (7.4%), hearing protection (7.3%), interaction with hearing health care providers (6.7%), mental health and coping (5.8%), music listening (5.7%), hope for a cure (5.6%), interactions with people without tinnitus (5.4%), dietary supplements and alternative therapies (3.2%), sleep (3.9%), dietary effects (1.7%), and writing about tinnitus and being thankful to online community (1.4%). CONCLUSIONS: Despite some limitations, tinnitus posts on Reddit provide rich real-world data to identify various issues and complaints that tinnitus patients and their significant others discuss in online communities. Some of the clusters identified here are novel (e.g., tinnitus timeline, interactions with people without tinnitus) and have not been much discussed in the tinnitus literature. The results suggest that individuals with tinnitus relay on social media for support and highlight the service delivery needs in providing social support through other means (e.g., support groups).


Assuntos
Mídias Sociais , Zumbido , Humanos , Processamento de Linguagem Natural , Grupos de Autoajuda , Apoio Social
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