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The phenomenon of lithic miniaturization during the Late Pleistocene at times coincided with increased artifact standardization and cutting edge efficiency-likely reflecting the use of small, sharp artifacts as interchangeable inserts for composite cutting tools and hunting weapons. During Marine Isotope Stage 2, Upper Paleolithic toolmakers in northern East Asia specifically used pressure techniques to make small, highly standardized lithic artifacts called microblades. However, little is currently known about how microblades affected the cutting edge efficiency of the toolkits they were a part of. We applied three methods of analyzing cutting edge efficiency to two Upper Paleolithic assemblages recently excavated from Tolbor-17, Mongolia, that document the periods before and after the introduction of microblade technology to the Tolbor Valley. A model incorporating allometric relationships between blank cutting edge length and mass suggests no difference in efficiency between the two periods, while two more conventional approaches both indicate a significant increase. The potential for improved cutting edge efficiency is only observed when the microblade sample is artificially inflated via simulation. Our results highlight challenges related to detecting and interpreting archaeological differences in cutting edge efficiency at the assemblage level.
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Arqueologia , Tecnologia , Mongólia , Arqueologia/métodos , Fósseis , Humanos , História AntigaRESUMO
The mosquito midgut functions as a key interface between pathogen and vector. However, studies of midgut physiology and associated virus infection dynamics are scarce, and in Culex tarsalis - an extremely efficient vector of West Nile virus (WNV) - nonexistent. We performed single-cell RNA sequencing on Cx. tarsalis midguts, defined multiple cell types, and determined whether specific cell types are more permissive to WNV infection. We identified 20 cell states comprised of 8 distinct cell types, consistent with existing descriptions of Drosophila and Aedes aegypti midgut physiology. Most midgut cell populations were permissive to WNV infection. However, there were higher levels of WNV RNA (vRNA) in enteroendocrine cells and cells enriched for mitochondrial genes, suggesting enhanced replication in these populations. In contrast, proliferating intestinal stem cell (ISC) populations had the lowest levels of vRNA, a finding consistent with studies suggesting ISC proliferation in the midgut is involved in viral control. Notably, we did not detect significant WNV-infection induced upregulation of canonical mosquito antiviral immune genes (e.g., AGO2, R2D2, etc.) at the whole-midgut level. Rather, we observed a significant positive correlation between immune gene expression levels and vRNA in individual cells, suggesting that within midgut cells, high levels of vRNA may trigger antiviral responses. Our findings establish a Cx. tarsalis midgut cell atlas, and provide insight into midgut infection dynamics of WNV by characterizing cell-type specific enhancement/restriction of, and immune response to, infection at the single-cell level.
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Introduction: Control of the mosquito Aedes albopictus is confounded by its behavior due to females preferring to oviposition in small natural and artificial containers that are often difficult to remove or treat with insecticides. Autodissemination strategies utilizing highly potent insect growth regulators (IGRs) have emerged as promising tools for the control of this container-inhabiting species. The intended goal of autodissemination approaches is to use mosquitoes to self-deliver an IGR to these cryptic oviposition locations. Previous studies have focused on the efficacy of these approaches to impact natural populations, but little focus has been placed on the impacts on mosquitoes when exposed to non-lethal doses of IGRs similar to the levels they would be exposed to with autodissemination approaches. Methods: In this study, the impact of non-lethal doses of pyriproxyfen (PPF) on the reproductive fitness of Ae. albopictus was investigated. Female and male Ae. albopictus mosquitoes were exposed to non-lethal doses of PPF and their fecundity and fertility were measured. To examine the impact of non-lethal doses of PPF, the expression of the ecdysone-regulated genes USP, HR3, and Vg, which are involved in vitellogenesis, was determined. Results: Our results demonstrated a significant reduction in female fecundity and in the blood feeding and egg hatching rates upon exposure to non-lethal doses of PPF. Oocyte development was also delayed in PPF-treated females. Furthermore, exposure to non-lethal doses of PPF altered the expression of the genes involved in vitellogenesis, indicating disruption of hormonal regulation. Interestingly, PPF exposure also reduced the sperm production in males, suggesting a potential semi-sterilization effect. Discussion: These findings suggest that non-lethal doses of PPF could enhance the efficacy of autodissemination approaches by impacting the reproductive fitness of both males and females. However, further research is needed to validate these laboratory findings in field settings and to assess their practical implications for vector control strategies.
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BACKGROUND: To understand the prevalence and types of publications addressing darker skin types within the existing evidence base for sunscreen use. Evidence Review: PubMed was searched from 1988, the time point at which the first skin of color (SOC) article was identified, through December 2022 using PubMed's Medical Subject Headings terms and keyword searches in title and abstract, with and without terms for SOC and ethnicity. Identified articles were reviewed for relevance, de-duplicated, and categorized; results are summarized. FINDINGS: Of the 5927 articles on sunscreen overall, only 314 (5.3%) articles addressed SOC, with the majority published since 2007 and representing only 4% to 7% of total publications annually except in 2022 when the proportion of SOC articles was 23.5%. Of the articles on SOC, many reported sunscreen knowledge and patient behaviors (29%), but very few reported clinical trials (5%). The 3 conditions most often discussed were melasma, post-inflammatory hyperpigmentation, and dyschromia. South Asian ethnicities (India, Pakistan, Bangladesh) had the highest representation within the literature, followed by Hispanics. CONCLUSIONS AND RELEVANCE: Although it was assumed there would be fewer papers discussing the use of sunscreen in darker skin types, the scale of the disparity revealed by this study is stark. The increase in a number of articles in 2022 suggests an increasing focus on SOC, but further discussion of the issues presented here will help the SOC community address gaps in the evidence base and better inform discussions on sunscreen and photoprotection between clinicians and patients.J Drugs Dermatol. 2024;23(7):575-577. doi:10.36849/JDD.8250.
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Pigmentação da Pele , Protetores Solares , Humanos , Protetores Solares/administração & dosagem , Pigmentação da Pele/efeitos dos fármacos , Conhecimentos, Atitudes e Prática em Saúde , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODS: We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In the tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTS: Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala, and tau binding in these regions was associated with mood symptoms. Across amygdalar divisions, amyloid-positive individuals had relatively higher regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex, but medial amygdala to retrosplenial cortex was lower. Medial amygdala to retrosplenial connectivity was negatively associated with anxiety symptoms, as was retrosplenial tau. CONCLUSIONS: Our findings suggest that preclinical tau deposition in the amygdala and associated changes in functional connectivity may relate to early mood symptoms in AD.
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BACKGROUND: Older adults with varying patterns of multimorbidity may require distinct types of care and rely on informal caregiving to meet their care needs. This study aims to identify groups of older adults with distinct, empirically-determined multimorbidity patterns and compare characteristics of informal care received among estimated classes. METHODS: Data are from the 2011 National Health and Aging Trends Study (NHATS). Ten chronic conditions were included to estimate multimorbidity patterns among 7532 individuals using latent class analysis. Multinomial logistic regression model was estimated to examine the association between sociodemographic characteristics, health status and lifestyle variables, care-receiving characteristics and latent class membership. RESULTS: A four-class solution identified the following multimorbidity groups: some somatic conditions with moderate cognitive impairment (30%), cardiometabolic (25%), musculoskeletal (24%), and multisystem (21%). Compared with those who reported receiving no help, care recipients who received help with household activities only (OR = 1.44, 95% CI 1.05-1.98), mobility but not self-care (OR = 1.63, 95% CI 1.05-2.53), or self-care but not mobility (OR = 2.07, 95% CI 1.29-3.31) had greater likelihood of being in the multisystem group versus the some-somatic group. Having more caregivers was associated with higher odds of being in the multisystem group compared with the some-somatic group (OR = 1.09, 95% CI 1.00-1.18), whereas receiving help from paid helpers was associated with lower odds of being in the multisystem group (OR = 0.36, 95% CI 0.19-0.77). CONCLUSIONS: Results highlighted different care needs among persons with distinct combinations of multimorbidity, in particular the wide range of informal needs among older adults with multisystem multimorbidity. Policies and interventions should recognize the differential care needs associated with multimorbidity patterns to better provide person-centered care.
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Análise de Classes Latentes , Multimorbidade , Humanos , Masculino , Idoso , Feminino , Estados Unidos/epidemiologia , Idoso de 80 Anos ou mais , Cuidadores , Doença Crônica/epidemiologia , Assistência ao Paciente/métodos , Assistência ao Paciente/tendênciasRESUMO
BACKGROUND: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODS: We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTS: Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala (F(4,442)=14.61, p=0.00045; F(4,442)=5.83, p=0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (rs=-0.103, p=0.015). CONCLUSIONS: Our findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms.
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Background: In some hidradenitis suppurativa (HS) clinical trial study arms, there is an unexpected decline in efficacy between the penultimate visit and the prespecified primary endpoint week, which we have termed a "wobble." Objective: We aimed to establish how often study arms in HS programs wobble. Methods: In a retrospective review, we identified HS clinical trials listed on ClinicalTrials.gov testing systemic, nonantibiotic medications that utilized Hidradenitis Suppurativa Clinical Response (HiSCR) as an outcome measure. We identified study arms demonstrating greater improvement in a visit prior to the primary endpoint week. Baseline subject characteristics were compared between studies with HiSCR wobble and no HiSCR wobble. Results: A total of 21 studies (randomized control trial [RCT], n = 14; open-label, n = 7) with 35 study drug arms (RCT, n = 27; open-label, n = 8) and 14 placebo arms were identified. HiSCR wobble occurred significantly more often in RCT compared to open-label study drug arms (11/27 [40.7%] vs 0/8 [0%]). In RCT study arms with HiSCR wobble, baseline draining fistula counts were significantly lower (2.3 vs 3.2), and numerically fewer Hurley stage 3 patients (33.2% vs 42.5%), lower weighted total abscess and nodule counts (12.1 vs 12.6), lower weighted dermatology life quality index scores (12.5 vs 14.5), and a higher proportion of female patients (63.9% vs 58.3%) were observed. Limitations: Include low number of HS clinical trials and insufficient data reported in many studies to assess for wobble, degree of wobble, and to compare all baseline characteristics. Conclusion: Nonlinear improvement in study arm response occurs in some HS RCTs. Potential contributing factors include a higher proportion of less severe patients at baseline and more female patients.
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Microplastics (MPs) and nanoplastics (NPs) are pervasive environmental pollutants that are commonly ingested by organisms at different trophic levels. While the effects of MPs on aquatic organisms have been extensively studied, the impacts of MP ingestion on the host fitness of terrestrial organisms, mainly insects, have been relatively unexplored. This study investigates the effects of MP and NP ingestion on the survivorship and reproduction of 2 medically important mosquito species, Aedes aegypti Linnaeus (Diptera: Culicidae) and Aedes albopictus Skuse (Diptera: Culicidae). Larval and pupal survivorship of Ae. albopictus were not significantly affected by particle size or concentration, but there was a reduction of Ae. aegypti pupal survivorship associated with the ingestion of 0.03 µm NPs. In addition, there was little observed impact of 0.03 µm NP and 1.0 µm MP ingestion on adult survivorship, fecundity, and longevity. To further investigate the effects of MP ingestion on mosquito fitness, we also examined the effects of MPs of varying shape, size, and plastic polymer type on Ae. aegypti immature and adult survivorship. The data suggest that the polymer type and shape did not impact Ae. aegypti immature or adult survivorship. These findings highlight that understanding the effects of microplastic ingestion by mosquitoes may be complicated by the size, composition, and amount ingested.
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Aedes , Larva , Microplásticos , Pupa , Reprodução , Animais , Aedes/efeitos dos fármacos , Aedes/crescimento & desenvolvimento , Microplásticos/toxicidade , Reprodução/efeitos dos fármacos , Pupa/crescimento & desenvolvimento , Pupa/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Feminino , Masculino , Nanopartículas , Longevidade/efeitos dos fármacosRESUMO
Lamin A/C (LMNA) is an important component of nuclear lamina. Mutations cause arrhythmia, heart failure, and sudden cardiac death. While LMNA-associated cardiomyopathy typically has an aggressive course that responds poorly to conventional heart failure therapies, there is variability in severity and age of penetrance between and even within specific mutations, which is poorly understood at the cellular level. Further, this heterogeneity has not previously been captured to mimic the heterozygous state, nor have the hundreds of clinical LMNA mutations been represented. Herein, we have overexpressed cardiopathic LMNA variants in HEK cells and utilized state-of-the-art quantitative proteomics to compare the global proteomic profiles of (1) aggregating Q353 K alone, (2) Q353 K coexpressed with WT, (3) aggregating N195 K coexpressed with WT, and (4) nonaggregating E317 K coexpressed with WT to help capture some of the heterogeneity between mutations. We analyzed each data set to obtain the differentially expressed proteins (DEPs) and applied gene ontology (GO) and KEGG pathway analyses. We found a range of 162 to 324 DEPs from over 6000 total protein IDs with differences in GO terms, KEGG pathways, and DEPs important in cardiac function, further highlighting the complexity of cardiac laminopathies. Pathways disrupted by LMNA mutations were validated with redox, autophagy, and apoptosis functional assays in both HEK 293 cells and in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) for LMNA N195 K. These proteomic profiles expand our repertoire for mutation-specific downstream cellular effects that may become useful as druggable targets for personalized medicine approach for cardiac laminopathies.
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Lamina Tipo A , Mutação , Proteômica , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Humanos , Proteômica/métodos , Células HEK293 , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Proteoma/genética , Proteoma/metabolismo , Ontologia GenéticaRESUMO
INTRODUCTION: Multimorbidity may confer higher risk for cognitive decline than any single constituent disease. This study aims to identify distinct trajectories of cognitive impairment probability among middle-aged and older adults, and to assess the effect of changes in mental-somatic multimorbidity on these distinct trajectories. METHODS: Data from the Health and Retirement Study (1998-2016) were employed to estimate group-based trajectory models identifying distinct trajectories of cognitive impairment probability. Four time-varying mental-somatic multimorbidity combinations (somatic, stroke, depressive, stroke and depressive) were examined for their association with observed trajectories of cognitive impairment probability with age. Multinomial logistic regression analysis was conducted to quantify the association of sociodemographic and health-related factors with trajectory group membership. RESULTS: Respondents (N = 20,070) had a mean age of 61.0 years (SD = 8.7) at baseline. Three distinct cognitive trajectories were identified using group-based trajectory modelling: (1) Low risk with late-life increase (62.6%), (2) Low initial risk with rapid increase (25.7%), and (3) High risk (11.7%). For adults following along Low risk with late-life increase, the odds of cognitive impairment for stroke and depressive multimorbidity (OR:3.92, 95%CI:2.91,5.28) were nearly two times higher than either stroke multimorbidity (OR:2.06, 95%CI:1.75,2.43) or depressive multimorbidity (OR:2.03, 95%CI:1.71,2.41). The odds of cognitive impairment for stroke and depressive multimorbidity in Low initial risk with rapid increase or High risk (OR:4.31, 95%CI:3.50,5.31; OR:3.43, 95%CI:2.07,5.66, respectively) were moderately higher than stroke multimorbidity (OR:2.71, 95%CI:2.35, 3.13; OR: 3.23, 95%CI:2.16, 4.81, respectively). In the multinomial logistic regression model, non-Hispanic Black and Hispanic respondents had higher odds of being in Low initial risk with rapid increase and High risk relative to non-Hispanic White adults. CONCLUSIONS: These findings show that depressive and stroke multimorbidity combinations have the greatest association with rapid cognitive declines and their prevention may postpone these declines, especially in socially disadvantaged and minoritized groups.
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Disfunção Cognitiva , Multimorbidade , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Disfunção Cognitiva/epidemiologia , Cognição/fisiologia , Depressão/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: The rapidly growing field of multimorbidity research demonstrates that changes in multimorbidity in mid- and late-life have far reaching effects on important person-centered outcomes, such as health-related quality of life. However, there are few organizing frameworks and comparatively little work weighing the merits and limitations of various quantitative methods applied to the longitudinal study of multimorbidity. METHODS: We identify and discuss methods aligned to specific research objectives with the goals of (i) establishing a common language for assessing longitudinal changes in multimorbidity, (ii) illuminating gaps in our knowledge regarding multimorbidity progression and critical periods of change, and (iii) informing research to identify groups that experience different rates and divergent etiological pathways of disease progression linked to deterioration in important health-related outcomes. RESULTS: We review practical issues in the measurement of multimorbidity, longitudinal analysis of health-related data, operationalizing change over time, and discuss methods that align with 4 general typologies for research objectives in the longitudinal study of multimorbidity: (i) examine individual change in multimorbidity, (ii) identify subgroups that follow similar trajectories of multimorbidity progression, (iii) understand when, how, and why individuals or groups shift to more advanced stages of multimorbidity, and (iv) examine the coprogression of multimorbidity with key health domains. CONCLUSIONS: This work encourages a systematic approach to the quantitative study of change in multimorbidity and provides a valuable resource for researchers working to measure and minimize the deleterious effects of multimorbidity on aging populations.
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Multimorbidade , Humanos , Estudos Longitudinais , Qualidade de Vida , Progressão da Doença , IdosoRESUMO
Objective: There are clinical differences in healthy skin requirements and skin-aging features by race and ethnicity. However, individuals of color are underrepresented in dermatology-related medical information. We sought to gather information from women of color regarding their attitudes about the importance of the prevention of skin aging, available information, and perception of representation in skin-aging prevention information. Methods: This study involved an observational, cross-sectional, online survey of women aged 18 to 70 years residing in the United States. Participants were placed into one of seven cohorts based on self-reported race/ethnicity. Relative frequencies of responses were compared across cohorts; adjusted logistic regression was used to assess perception of representation in skin-aging prevention information. Results: The mean age of the 1,646 participants was 44.4 years. The mean (standard deviation) rating (from 0, "not at all important" to 10, "extremely important") of the importance of the prevention of skin aging ranged from 7.3 to 8.2 across the seven cohorts. All cohorts reported the most trusted source of information for skin-aging prevention products and treatments was a skin-care professional, but not all cohorts believed they are well represented in available sources of information. Older age, lower median household income, and a race/ethnicity of Black, Asian, "Other," and "More Than One Race" were less likely to report being well represented. Limitations: People without internet access could not participate, potentially excluding some older and lower-income groups. Conclusion: Women of color are less likely to feel represented in available information on the prevention of skin aging.
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The kidney, parathyroid gland, and choroid plexus express the aging-related transmembrane protein α-Klotho, a coreceptor of the fibroblast growth factor 23 (FGF23) receptor complex. Reduced α-Klotho levels are correlated with chronic kidney disease and other age-related diseases, wherein they are released from membranes into circulation. Klotho's potential physiological action as a hormone is of current scientific interest. Part of the challenges associated with advancing these studies, however, has been the long-standing difficulty in detecting soluble α-Klotho in biofluids. Here, we describe the discovery of peptides that recognize α-Klotho with high affinity and selectivity by applying in-solution size-exclusion-based affinity selection-mass spectrometry (AS-MS). After two rounds of AS-MS and subsequent N-terminal modifications, the peptides improved their binding affinity to α-Klotho by approximately 2300-fold compared to the reported starting peptide Pep-10, previously designed based on the C-terminal region of FGF23. The lead peptide binders were shown to enrich α-Klotho from cell lysates and to label α-Klotho in kidney cells. Our results further support the utility of in-solution, label-free AS-MS protocols to discover peptide-based binders to target proteins of interest with high affinity and selectivity, resulting in functional probes for biological studies.
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To determine whether relationship status moderates sexual prejudice, we compared heterosexual men and women's self-reported social distancing toward gay and lesbian targets who varied in relationship status (coupled, single, no information). Relationship status of gay male targets did not affect responses (Study 1): heterosexual men reported increased social distancing toward gay compared to heterosexual male targets, whereas women did not. Similarly, in Study 2, heterosexual men reported increased social distancing toward lesbian compared to heterosexual female targets, but women did not, and men reported decreased social distancing toward single lesbian women. Working from an affordance management approach, Study 3 replicated Studies 1 and 2, testing potential mediators of effects. In particular, heterosexual men reported increased social distancing toward gay male targets, compared to responses from heterosexual women. Moreover, heterosexual women reported increased social distancing toward single, compared to coupled, lesbian targets, mediated through perceptions of undesired sexual interest from the target. This work demonstrates the nuanced nature of sexual prejudice and provides further evidence of the role of perceptions of undesired sexual interest in prejudiced responses toward lesbian and gay individuals.
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BACKGROUND: Modified Kligman's formula (mKF) is the gold standard treatment for melasma; however, its prolonged use is not recommended due to side effects. Cysteamine is a potent, safe, and effective depigmenting agent. Here, we conducted a double-blind, randomized, and placebo-controlled clinical trial to assess the efficacy of cysteamine isobionic-amide -- a complex with enhanced depigmenting efficacy -- and compared it to mKF for the treatment of melasma. METHODS: This study involved a total of 80 patients divided into 3 groups: cysteamine-isobionic amide, placebo, or mKF. The modified Melasma Area Severity Index (mMASI) score and spectrophotometric evaluation were conducted at baseline, week 4, week 8, and week 16. Dermatological assessment, patients’ feedback, and satisfaction including quality-of-life scores were also collected. RESULTS: At week 4, cysteamine isobionic-amide and mKF groups showed an equivalent onset of action in terms of mMASI and skin pigmentation contrast reduction. The 2 groups significantly reduced melasma severity and improved the overall skin condition with a comparable efficacy at week 16. Quality of life of melasma patients was significantly improved in the cysteamine isobionic-amide group at week 8 and further at week 16 (P<0.001) compared to the mKF group. Patients’ feedback and satisfaction were higher with the cysteamine isobionic-amide product compared to mKF. CONCLUSION: Cysteamine isobionic-amide provided a rapid onset of action and was as effective as the mKF for the treatment of melasma. The data suggest that cysteamine isobionic-amide could potentially be an acceptable alternative to mKF for the long-term treatment of melasma. J Drugs Dermatol. 2024;23(2):9-16. doi:10.36849/JDD.7428.
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Cisteamina , Melanose , Humanos , Cisteamina/efeitos adversos , Resultado do Tratamento , Qualidade de Vida , Melanose/diagnóstico , Melanose/tratamento farmacológico , Método Duplo-CegoRESUMO
Protein-protein interactions (PPIs) are intriguing targets in drug discovery and development. Peptides are well suited to target PPIs, which typically present with large surface areas lacking distinct features and deep binding pockets. To improve binding interactions with these topologies and advance the development of PPI-focused therapeutics, potential ligands can be equipped with electrophilic groups to enable binding through covalent mechanisms of action. We report a strategy termed electrophile scanning to identify reactivity hotspots in a known peptide ligand and demonstrate its application in a model PPI. Cysteine mutants of a known ligand are used to install protein-reactive modifiers via a palladium oxidative addition complex (Pd-OAC). Reactivity hotspots are revealed by cross-linking reactions with the target protein under physiological conditions. In a model PPI with the 9-mer peptide antigen VL9 and major histocompatibility complex (MHC) class I protein HLA-E, we identify two reactivity hotspots that afford up to 87% conversion to the protein-peptide conjugate within 4 h. The reactions are specific to the target protein in vitro and dependent on the peptide sequence. Moreover, the cross-linked peptide successfully inhibits molecular recognition of HLA-E by CD94-NKG2A possibly due to structural changes enacted at the PPI interface. The results illustrate the potential application of electrophile scanning as a tool for rapid discovery and development of covalent peptide binders.
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Antígenos HLA-E , Antígenos de Histocompatibilidade Classe I , Ligantes , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptídeos/química , Ligação ProteicaRESUMO
BACKGROUND: Treatment of infraorbital dark circles and under-eye puffiness is challenging due to its multifactorial nature and lack of broadly applicable, effective treatments. A daily skincare treatment option that is multimodal, effective, and tolerable across a broad patient population is an unmet need. AIM: A multicorrective topical eye cream (MTEC) formulated with Tetrahexyldecyl (THD) ascorbate (vitamin C), prebiotic Inula Helenium, bioavailable peptides, botanical extracts, chrysin, and caffeine is hypothesized to improve the appearance of infraorbital dark circles and under-eye puffiness by targeting microvasculature congestion and permeability, melanin accumulation and hemoglobin degradation-related pigmentation, and skin health. METHODS: An IRB approved, open-label, 12-week clinical study set out to evaluate the efficacy and tolerability of the MTEC across a broad patient population including varying ethnicities and Fitzpatrick Skin Types (FST). Female subjects (n = 40) ages 35-60 years old, with moderate-to-severe under-eye dark circles, moderate under-eye puffiness, and mild-to-moderate fine lines were enrolled into the study. Objective (Chromameter, VISIA® imaging, and Laser Doppler) and subjective assessments (clinical grading and self-assessment questionnaire) were conducted at baseline and post-baseline timepoints. RESULTS: Thirty-seven subjects completed the study, and the MTEC efficaciously demonstrated short-term and long-term improvements in objective and subjective assessments across a broad patient population. Specifically, the MTEC demonstrated significant improvement of infraorbital dark circles, mainly by the reduction in microvasculature congestion and permeability, melanin, and hemoglobin degradation-related pigmentation. CONCLUSION: Topical application of the MTEC may offer an effective and tolerable treatment option for infraorbital dark circles and puffiness.
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Hiperpigmentação , Transtornos da Pigmentação , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Melaninas , Olho , Pele , Resultado do Tratamento , HemoglobinasRESUMO
BACKGROUND: Retinoids and alpha- and beta hydroxy acids are common components utilized in regimens for blemish-prone skin. However, balancing efficacy and tolerability is often challenging. PATIENTS/METHODS: This pilot study evaluated a double-conjugated retinoid serum specifically formulated for blemish-prone skin (AHARet-SA) in combination with exfoliating peel pads (double-conjugated retinoid, glycolic, lactic, and salicylic acids), a cleanser, mineral-based sunscreen, and a lightweight moisturizer in female participants with mild-to-moderate blemish-prone skin. Fifty-five percent of participants were Fitzpatrick Skin Type (FST) IV and 27% were FST V. Participants used the exfoliating peel pads (3x/week for 8 weeks; 2x/week for 4 weeks) followed by nightly AHARet-SA and a moisturizer (as needed). Improvements in skin were assessed using the 5-point Investigator Global Assessment Scale, and participant satisfaction and tolerability were assessed over 12 weeks. RESULTS: Significant mean improvement from baseline in skin clarity occurred after 4 weeks (14%; p = 0.04) with progressive improvements through week 12 (52%; p = 0.004). Eighty-eight percent of participants reported improvements in the appearance and texture of their skin and fewer blemishes/breakouts. Mild, transient adverse events were reported. CONCLUSIONS: A regimen comprised of a double-conjugated serum and exfoliating peel pads formulated for blemish-prone skin led to significant improvements from baseline in skin clarity after 12 weeks in participants with predominately darker skin tones and mild-to-moderate blemish-prone skin.