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1.
Methods Enzymol ; 697: 113-150, 2024.
Article in English | MEDLINE | ID: mdl-38816120

ABSTRACT

The self-assembly of proteins and peptides into ordered structures called amyloid fibrils is a hallmark of numerous diseases, impacting the brain, heart, and other organs. The structure of amyloid aggregates is central to their function and thus has been extensively studied. However, the structural heterogeneities between aggregates as they evolve throughout the aggregation pathway are still not well understood. Conventional biophysical spectroscopic methods are bulk techniques and only report on the average structural parameters. Understanding the structure of individual aggregate species in a heterogeneous ensemble necessitates spatial resolution on the length scale of the aggregates. Recent technological advances have led to augmentation of infrared (IR) spectroscopy with imaging modalities, wherein the photothermal response of the sample upon vibrational excitation is leveraged to provide spatial resolution beyond the diffraction limit. These combined approaches are ideally suited to map out the structural heterogeneity of amyloid ensembles. AFM-IR, which integrates IR spectroscopy with atomic force microscopy enables identification of the structural facets the oligomers and fibrils at individual aggregate level with nanoscale resolution. These capabilities can be extended to chemical mapping in diseased tissue specimens with submicron resolution using optical photothermal microscopy, which combines IR spectroscopy with optical imaging. This book chapter provides the basic premise of these novel techniques and provides the typical methodology for using these approaches for amyloid structure determination. Detailed procedures pertaining to sample preparation and data acquisition and analysis are discussed and the aggregation of the amyloid ß peptide is provided as a case study to provide the reader the experimental parameters necessary to use these techniques to complement their research efforts.


Subject(s)
Amyloid , Microscopy, Atomic Force , Spectrophotometry, Infrared , Humans , Spectrophotometry, Infrared/methods , Microscopy, Atomic Force/methods , Amyloid/chemistry , Protein Aggregates , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Spectroscopy, Fourier Transform Infrared/methods , Animals
2.
J Phys Chem B ; 128(1): 33-44, 2024 Jan 11.
Article in English | MEDLINE | ID: mdl-38124262

ABSTRACT

The aggregation of amyloid ß(Aß) peptides is at the heart of Alzheimer's disease development and progression. As a result, amyloid aggregates have been studied extensively in vitro, and detailed structural information on fibrillar amyloid aggregates is available. However, forwarding these structural models to amyloid plaques in the human brain is still a major challenge. The chemistry of amyloid plaques, particularly in terms of the protein secondary structure and associated chemical moieties, remains poorly understood. In this report, we use Raman microspectroscopy to identify the presence of carotenoids in amyloid plaques and demonstrate that the abundance of carotenoids is correlated with the overall protein secondary structure of plaques, specifically to the population of ß-sheets. While the association of carotenoids with plaques has been previously identified, their correlation with the ß structure has never been identified. To further validate these findings, we have used optical photothermal infrared (O-PTIR) spectroscopy, which is a spatially resolved technique that yields complementary infrared contrast to Raman. O-PTIR unequivocally demonstrates the presence of elevated ß-sheets in carotenoid-containing plaques and the lack of ß structure in noncarotenoid plaques. Our findings underscore the potential link between anti-inflammatory species as carotenoids to specific secondary structural motifs within Aß plaques and highlight the possible role of chemically distinct plaques in neuroinflammation, which can uncover new mechanistic insights and lead to new therapeutic strategies for AD.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Humans , Amyloid beta-Peptides/chemistry , Protein Conformation, beta-Strand , Plaque, Amyloid/metabolism , Alzheimer Disease/metabolism , Spectrum Analysis
3.
J Med Case Rep ; 17(1): 451, 2023 Oct 30.
Article in English | MEDLINE | ID: mdl-37899461

ABSTRACT

BACKGROUND: We present an unusual case of a left axillary lymph node metastasis from a primary dedifferentiated endometrial carcinoma. This pattern of metastasis is likely the result of circulating tumor cells reaching the node through its arterial blood supply. CASE PRESENTATION: In this report, a 68-year-old white woman with a dedifferentiated endometrial carcinoma underwent a hysterectomy. She later developed an enlarged axillary lymph node due to metastatic dedifferentiated endometrial carcinoma, treated with chemotherapy and anti-programmed cell death protein 1 immunotherapy resulting in a complete clinical and radiological response. CONCLUSION: A review of the literature reveals the rarity of blood-borne lymph node metastasis, especially with uterine carcinoma. Immunotherapy has shown promising results in the treatment of some subtypes of metastatic uterine carcinoma.


Subject(s)
Carcinoma , Endometrial Neoplasms , Female , Humans , Aged , Lymphatic Metastasis/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Carcinoma/pathology , Endometrial Neoplasms/therapy , Endometrial Neoplasms/pathology , Hysterectomy
4.
BMC Pulm Med ; 21(1): 19, 2021 Jan 07.
Article in English | MEDLINE | ID: mdl-33413293

ABSTRACT

BACKGROUND: While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment. METHODS: In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment and constructed logistic regression models to identify characteristics associated with pulmonary impairment. RESULTS: Among 134 participants with a median CD4 count of 110 cells/µl, 112 (83%) completed baseline spirometry at which time 32 (29%) had restriction, 13 (12%) had obstruction, and 9 (7%) had a mixed pattern. Lung function was dynamic over time and 30 (33%) participants had impaired lung function at 12 months. Baseline restriction was associated with greater symptoms and with long-term pulmonary impairment (adjusted odds ratio 5.44, 95% confidence interval 1.16-25.45), while baseline obstruction was not (adjusted odds ratio 1.95, 95% confidence interval 0.28-13.78). CONCLUSIONS: In this cohort of people with HIV and tuberculosis, restriction was the most common, symptomatic, and persistent pattern of pulmonary impairment. These data can help to raise awareness among clinicians about the heterogeneity of post-tuberculosis pulmonary impairment, and highlight the need for further research into mediators of lung injury in this vulnerable population.


Subject(s)
HIV Infections/physiopathology , Lung/physiopathology , Tuberculosis, Pulmonary/physiopathology , Adult , Anti-HIV Agents/therapeutic use , Antitubercular Agents/therapeutic use , CD4 Lymphocyte Count , Cohort Studies , Female , Forced Expiratory Volume/physiology , HIV Infections/complications , HIV Infections/drug therapy , Humans , Lung Diseases, Obstructive/physiopathology , Male , Prospective Studies , South Africa , Spirometry , Tuberculosis, Pulmonary/complications , Tuberculosis, Pulmonary/drug therapy , Vital Capacity/physiology
5.
New Phytol ; 226(3): 921-938, 2020 05.
Article in English | MEDLINE | ID: mdl-31930503

ABSTRACT

Plants must rearrange the network of complex carbohydrates in their cell walls during normal growth and development. To accomplish this, all plants depend on proteins called expansins that nonenzymatically loosen noncovalent bonding between cellulose microfibrils. Surprisingly, expansin genes have more recently been found in some bacteria and microbial eukaryotes, where their biological functions are largely unknown. Here, we reconstruct a comprehensive phylogeny of microbial expansin genes. We find these genes in all eukaryotic microorganisms that have structural cell wall cellulose, suggesting expansins evolved in ancient marine microorganisms long before the evolution of land plants. We also find expansins in an unexpectedly high diversity of bacteria and fungi that do not have cellulosic cell walls. These bacteria and fungi inhabit varied ecological contexts, mirroring the diversity of terrestrial and aquatic niches where plant and/or algal cellulosic cell walls are present. The microbial expansin phylogeny shows evidence of multiple horizontal gene transfer events within and between bacterial and eukaryotic microbial lineages, which may in part underlie their unusually broad phylogenetic distribution. Overall, expansins are unexpectedly widespread in bacteria and eukaryotes, and the contribution of these genes to microbial ecological interactions with plants and algae has probbaly been underappreciated.


Subject(s)
Cellulose , Gene Transfer, Horizontal , Biomass , Cell Wall , Phylogeny , Plant Proteins/genetics
6.
Clin Infect Dis ; 70(8): 1750-1753, 2020 04 10.
Article in English | MEDLINE | ID: mdl-31552412

ABSTRACT

End-organ impairment has received relatively little research attention as a possible manifestation of tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS). In this prospective cohort study, one-half of adults with human immunodeficiency virus and pulmonary tuberculosis experienced meaningful declines in lung function on antiretroviral therapy, suggesting a role for lung function in TB-IRIS definitions.


Subject(s)
HIV Infections , Immune Reconstitution Inflammatory Syndrome , Tuberculosis , Adult , HIV , HIV Infections/complications , HIV Infections/drug therapy , Humans , Lung , Prospective Studies
7.
Clin Infect Dis ; 71(4): 924-932, 2020 08 14.
Article in English | MEDLINE | ID: mdl-31751447

ABSTRACT

BACKGROUND: Inflammasomes mediate inflammation in adults living with both human immunodeficiency virus (HIV) and tuberculosis (TB), but the relevance of inflammasome gene polymorphisms in TB-associated pulmonary damage is unknown. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in inflammasome pathway genes modify systemic and pulmonary inflammation, contributing to respiratory impairment in adults living with HIV/pulmonary TB. METHODS: This was a prospective cohort study set in South Africa following individuals living with HIV/TB up to 48 weeks post-antiretroviral therapy (ART) initiation. Ten functional SNPs in 5 inflammasome pathway genes were related to circulating inflammatory biomarkers and lung function assessed by spirometry pre- and post-ART initiation. Analyses used 2-sided t tests, Wilcoxon rank sum tests, Spearman correlation coefficients, linear regression, and generalized estimating equation models. RESULTS: Among 102 patients with baseline samples, the minor allele (T) in NLRC4 rs385076 was independently associated with lower levels of interleukin (IL)-18 and IL-6 before and up to 12 weeks post-ART initiation (Benjamini-Hochberg corrected P values < .02). Patients with the CT/TT genotypes also had improved lung function vs CC patients up to 48 weeks post-ART initiation (forced vital capacity, 206 mL higher; 95% confidence interval [CI], 67-345 mL; P = .004 and forced expiratory volume in 1 second, 143 mL higher; 95% CI, 11-274 mL; P = .034). CONCLUSIONS: A common SNP in the NLRC4 inflammasome may modify TB-associated inflammation in clinically relevant ways. This SNP may identify high-risk groups for lung damage in TB. Inhibition of NLRC4 activity may be an important approach for TB host-directed therapy.


Subject(s)
HIV Infections , Tuberculosis , Adult , CARD Signaling Adaptor Proteins , Calcium-Binding Proteins/genetics , HIV , HIV Infections/complications , HIV Infections/drug therapy , Humans , Inflammation/genetics , Lung , Prospective Studies , South Africa , Tuberculosis/genetics
9.
Dent Assist ; 79(1): 16, 18, 20, 2010.
Article in English | MEDLINE | ID: mdl-21033046
10.
Todays FDA ; 19(4): 28-9, 31, 33, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17708053
11.
J Okla Dent Assoc ; 99(3): 20-3, 2007.
Article in English | MEDLINE | ID: mdl-18274383
13.
J Mich Dent Assoc ; 88(1): 40-3; 70, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16479795
14.
Psychoneuroendocrinology ; 29(4): 501-15, 2004 May.
Article in English | MEDLINE | ID: mdl-14749095

ABSTRACT

Individually housed rhesus monkeys sometimes spontaneously develop self-injurious behavior (SIB) in the form of self-directed biting that, on occasion, results in severe tissue damage and mutilation. We previously demonstrated lower levels of plasma cortisol in rhesus monkeys with a history of self-wounding (SW) when compared to non-wounders (NW). Furthermore, cortisol levels were negatively correlated with rates of self-directed biting. The present study was designed to further characterize the relationships between hypothalamic-pituitary-adrenocortical (HPA) activity, self-wounding, and self-directed biting. Basal 24-h urinary free cortisol excretion, the urinary free cortisol response to a low dose of dexamethasone, and the plasma cortisol response to ACTH were examined in 24 individually housed rhesus monkeys, based on wounding history, i.e. the presence/absence of a veterinary record of self-wounding, and current rates of self-directed biting, i.e. the median split of self-directed biting frequency (independent of wounding status). There were no reliable group differences on any of the physiological measures when analyzed by wounding history. However, the plasma cortisol response 30 min post-ACTH stimulation was significantly correlated with wounding recency, such that lower responsivity was associated with more recent wounding episodes. When the results were analyzed on the basis of biting frequency, high frequency biters (HFB) compared to low frequency biters (LFB) showed decreased HPA negative feedback sensitivity to dexamethasone and a trend towards an attenuated plasma cortisol response to ACTH stimulation. These findings suggest that SIB in socially reared monkeys is associated with complex changes in HPA axis function that are related to the expression of the pathology, i.e. self-directed biting, and to the recency of a wounding episode. It remains to be determined whether humans who exhibit SIB show similar alterations in HPA function.


Subject(s)
Hydrocortisone/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Macaca mulatta/psychology , Pituitary-Adrenal System/physiopathology , Self-Injurious Behavior/physiopathology , Adrenocorticotropic Hormone/pharmacology , Analysis of Variance , Animals , Catecholamines/urine , Dexamethasone/pharmacology , Female , Glucocorticoids/pharmacology , Hydrocortisone/blood , Hydrocortisone/urine , Hypothalamo-Hypophyseal System/drug effects , Macaca mulatta/blood , Macaca mulatta/urine , Pituitary-Adrenal System/drug effects
16.
Physiol Behav ; 78(1): 33-9, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12536008

ABSTRACT

Self-injurious behaviors (SIB), such as self-biting and self-wounding, have been observed in a small percentage of captive nonhuman primates. Because rhesus monkeys that exhibit SIB also tend to be more aggressive, it was hypothesized that SIB is related to externally directed aggression and is associated with contexts in which physical contact between participants is prevented. The purpose of this study was to test the hypothesized relationship between SIB and outward aggression. Subjects were first presented with videotapes of conspecifics, scenery and a blank screen, and their behavior was recorded. Levels of salivary cortisol, an indicator of stress, were also measured before and after presentation of the videos. Although aggression increased when subjects viewed tapes containing conspecifics, neither cortisol levels nor self-biting behavior varied as a function of tape content. The subjects were then placed in two additional test situations: an empty room and the same room containing an unfamiliar conspecific. Aggression was significantly higher in the stranger condition compared to the empty room condition. The two situations yielded parallel increases in cortisol, suggesting that being alone was just as stressful as being paired with an unfamiliar conspecific. Self-biting rates were also similar in these two conditions. Thus, contrary to our prediction, increases in aggression did not correlate with increases in SIB. These results suggest that under similarly stressful conditions, SIB and externally directed aggression are unrelated.


Subject(s)
Aggression/psychology , Self-Injurious Behavior/psychology , Animals , Environment , Hydrocortisone/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Macaca mulatta , Male , Pituitary-Adrenal System/physiopathology , Saliva/chemistry , Saliva/metabolism , Social Behavior , Social Environment
17.
West Indian med. j ; 43(3): 93-6, Sept. 1994.
Article in English | MedCarib | ID: med-7757

ABSTRACT

Among 200 mothers interviewed in St. Lucia, 82 percent described their pregnancy as unintended and 44 percent as unwanted; 80 percent of women having an intended pregnancy and 94.6 percent having an unintended pregnancy were unmarried and 18.5 percent were teenagers. Mothers of unintended pregnancies were significantly younger, were significantly higher parity and had begun sexual relations at a significantly earlier age than mothers of intended pregnancies; and unlike mothers of plannerd pregnancies, their desired interpregnancy interval was significantly longer than the actual interval. These results and the sporadic and ineffective use of contraception in St. Lucia emphasize the need for improvements in fertility regulation in that country (AU)


Subject(s)
Humans , Adolescent , Adult , Female , Pregnancy, Unwanted , Socioeconomic Factors , Health Knowledge, Attitudes, Practice , Saint Lucia , Family Planning Services
18.
West Indian med. j ; 43(3): 93-6, Sept. 1994.
Article in English | LILACS | ID: lil-140349

ABSTRACT

Among 200 mothers interviewed in St. Lucia, 82//described their pregnancy as unintended and 44//as unwanted; 80//of women having an intended pregnancy and 94.6//having an unintended pregnancy were unmarried and 18.5//were teenagers. Mothers of unintended pregnancies were significantly younger, were significantly higher parity and had begun sexual relations at a significantly earlier age than mothers of intended pregnancies; and unlike mothers of plannerd pregnancies, their desired interpregnancy interval was significantly longer than the actual interval. These results and the sporadic and ineffective use of contraception in St. Lucia emphasize the need for improvements in fertility regulation in that country


Subject(s)
Humans , Adolescent , Adult , Female , Pregnancy, Unwanted , Socioeconomic Factors , Health Knowledge, Attitudes, Practice , Contraception , Saint Lucia
19.
Am J Clin Nutr ; 53(5): 1197-204, May 1991.
Article in English | MedCarib | ID: med-12566

ABSTRACT

Triglycerides, cholesterol, fatty acid composition, and tocopherols were determined in colustrum, transitional milk, and mature milk in St. Lucia. With progress of lactation, triglycerides and percentage medium-chain fatty acids increased whereas tocopherols, cholesterol and percentage long-chain polyunsaturated fatty acids decreased. These changes reflect augmented de novo synthesis of fatty acids (8:0, 10:0, 12:0, and 14:0) in the mammary gland and a tendency of increasing fat-globule size as milk matures. Transitional and mature milks, but particularly colustrum, contained higher concentrations of components considered to be derived from the fat-globule membrane (cholesterol, tocopherols, percentage long-chain polyunsaturated fatty acids) compared with those reported for Western countries. Percentage medium-chain fatty acids in mature milk was two to three times higher than in developed countries. Differences from data from studies in Western countries are discussed in relation to analytical methods and possible consequences for lipid digestion, lipid absorption, growth, and brain development.(AU)


Subject(s)
Humans , Female , Fatty Acids/analysis , Lipids/analysis , Milk, Human/chemistry , Vitamin E/analysis , Colostrum/chemistry , Cholesterol/analysis , Developing Countries , Fatty Acids, Monounsaturated/analysis , Fatty Acids, Omega-3/analysis , Fatty Acids, Unsaturated/analysis , Lactation/metabolism , Longitudinal Studies , Triglycerides/analysis , Saint Lucia
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