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1.
Ther Adv Vaccines Immunother ; 12: 25151355241278852, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39314902

RESUMO

Background: Two monovalent mRNA vaccines, available in December 2020, were demonstrated to have high efficacy against both the original SARS-CoV-2 strain and variants circulating through the summer and into the fall of 2021. In the context of the Omicron/BA.1 variant, which was predominant from late fall 2021 into winter of 2022 in the United States, and subsequent Omicron subvariants that have been predominant thereafter, vaccine effectiveness of the monovalent mRNA vaccine option is attenuated. Objectives: We aim to investigate the relative effectiveness of the bivalent booster compared to the monovalent booster against SARS-CoV-2 infection in the 60 days following administration in Shelby County, TN. Design: This observational population-based cohort study utilizes COVID-19 surveillance data to identify adults who were vaccinated with a monovalent booster dose between August 1, 2022 and August 30, 2022 or a bivalent booster dose between September 1, 2022 and September 30, 2022. Both groups were followed for COVID-19 status for 60 days from their administration date. Methods: We calculated incidence rates with 95% confidence intervals and propensity-adjusted hazard ratios with 95% confidence intervals of COVID-19 diagnosis in the 60 days following administration of the booster dose between the bivalent group and the monovalent group. Stratified analysis was conducted by age group (18-34, 35-64, and 65+ years old). Results: The incidence of reported SARS-CoV-2 infection was substantially higher for those who received the monovalent booster, across age groups. Overall, we observed a 51% lower hazard of infection during the study period among those who received the bivalent booster, compared to the monovalent booster. Conclusion: These results support and extend prior findings that the bivalent booster dose may be more effective in preventing infection against the Omicron sub-variants of SARS-CoV-2.

2.
Ann Fam Med ; 22(5): 400-409, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39313348

RESUMO

PURPOSE: Meeting scholarly activity requirements continues to be a challenge in many family medicine (FM) residency programs. Studies comprehensively describing FM resident scholarship have been limited. We sought to identify institutional factors associated with increased scholarly output and meeting requirements of the Accreditation Council for Graduate Medical Education (ACGME). OBJECTIVES: Our goals were to: (1) describe scholarly activity experiences among FM residents compared with ACGME requirements; (2) classify experiences by Boyer's domains of scholarship; and (3) associate experiences with residency program characteristics and scholarly activity infrastructure. METHODS: This was a cross-sectional survey. The survey questions were part of an omnibus survey to FM residency program directors conducted by the Council of Academic Family Medicine Educational Research Alliance (CERA). All ACGME-accredited US FM residency program directors, identified by the Association of Family Medicine Residency Directors, were sampled. RESULTS: Of the 691 eligible program directors, 298 (43%) completed the survey. The respondents reported that 25% or more residents exceeded ACGME minimum output, 17% reported that 25% or more residents published their work, and 50% reported that 25% or more residents delivered conference presentations. Programs exceeding ACGME scholarship requirements exhibit robust infrastructure characterized by access to faculty mentorship, scholarly activity curricula, Institutional Review Board, medical librarian, and statistician. CONCLUSIONS: These findings suggest the need for codified ACGME requirements for scholarly activity infrastructure to ensure access to resources in FM residency programs. By fostering FM resident engagement in scholarly activity, programs help to create a culture of inquiry, and address discrepancies in funding and output among FM residency programs.


Assuntos
Acreditação , Educação de Pós-Graduação em Medicina , Medicina de Família e Comunidade , Internato e Residência , Medicina de Família e Comunidade/educação , Humanos , Estudos Transversais , Inquéritos e Questionários , Estados Unidos , Masculino , Feminino
3.
Molecules ; 29(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38999095

RESUMO

Propolis is a bee product mainly consisting of plant resins and is used by bees to maintain the structural integrity of the colony. Propolis is known to contribute to bee health via its antimicrobial activity and is a valued product for human use owing to its nutritional and medicinal properties. Propolis is often characterised into seven categories depending on the resin source. New Zealand propolis is typically assumed as being poplar-type propolis, but few studies have chemically characterised New Zealand propolis to confirm or reject this assumption. Here, for the first time, we characterise propolis originating from different regions in New Zealand based on its volatile organic compounds, using gas chromatography coupled with mass spectrometry (GC-MS). To support this characterisation, we also collected and analysed resin samples from a variety of resin-producing plants (both native to New Zealand and introduced). Our findings suggest that bees mainly use poplar as a resin source, but also utilize native plant species to produce propolis. While regional variation did not allow for clear separation between samples, some patterns emerged, with samples from some regions having more chemical complexity and a higher contribution from native species (as suggested by a higher number of compounds unique to native species resin). Further studies are needed to accurately identify the botanical sources contributing to these samples. It may be also of interest to explore the biological activity of regional propolis samples and their potential nutritional or medicinal benefits.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Própole , Compostos Orgânicos Voláteis , Própole/química , Nova Zelândia , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/análise , Abelhas/química , Animais , Resinas Vegetais/química
5.
J Parasitol ; 110(2): 150-154, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38613824

RESUMO

Freshwater snails are commonly studied within the context of their role as intermediate hosts for digenetic trematodes. However, there are fundamental data deficiencies related to our understanding of directly transmitted parasites, such as coccidia, for freshwater snails. Because variation in coccidia pathogenicity and transmission among snail species likely has major impacts on snail community structure, we aimed to investigate the spatial distribution and prevalence of coccidia in several freshwater snail species throughout the Ozark and Ouachita Mountains ecoregions in Arkansas. We opportunistically collected 220 freshwater snails from 24 Ozark sites in summer 2022 and scanned fecal slides for the presence of coccidia. In summer 2023, we surveyed an additional 146 snails from 19 Ouachita sites. To test for apparent interactions among coccidia and trematodes, we scanned feces from a subset of snails (Physa and Planorbella in the Ozarks) that did not have concurrent trematode infections and from those that did. We observed oocysts that morphologically conformed to Pfeifferinella ellipsoides in 2 of the 9 snail taxa from 7 of the 43 sites. Planorbella trivolvis was infected at 2 of 6 sites in the Ozarks and 0 of 5 sites in the Ouachitas. Physa species were infected at 6 of 14 sites in the Ozarks and 0 of 12 sites in the Ouachitas. In the Ozarks, Pl. trivolvis had an overall prevalence of 0.13 (6 of 47), whereas individuals in the genus Physa had an overall prevalence of 0.08 (8 of 97). Our chi-square and Fisher exact tests revealed no significant evidence for trematode-coccidia competition or synergism within the two snail species. There were no other species infected, and we did not observe any coccidia in the snails from the Ouachitas. Our survey of 366 snails among 9 taxa and 43 sites represents the largest survey for freshwater snail coccidia to date and indicates that both Pl. trivolvis and Physa spp. may be primary hosts and/or reservoir hosts for Pf. ellipsoides in freshwater snail communities. The highly aggregated distribution of Pf. ellipsoides in northwestern Arkansas requires further investigation. Our results led to proposal of several hypotheses for additional research, including questions regarding the variation of coccidia host specificity and virulence.


Assuntos
Coccídios , Caramujos , Humanos , Prevalência , Arkansas , Água Doce
6.
Front Neurosci ; 18: 1380009, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38655111

RESUMO

Introduction: Dopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for in vitro binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the in vitro binding properties of a new radioiodinated ligand, [125I]HY-3-24. Methods: In vitro binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand. Results: HY-3-24 showed high potency at D3R (Ki = 0.67 ± 0.11 nM, IC50 = 1.5 ± 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R Ki = 86.7 ± 11.9 nM and D4R Ki > 1,000). The Kd (0.34 ± 0.22 nM) and Bmax (38.91 ± 2.39 fmol/mg) values of [125I]HY-3-24 were determined. In vitro binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [125I]HY-3-24. Autoradiography results demonstrated that [125I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections. Conclusion: These results suggest that [125I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [125I]HY-3-24 can be used as the specific D3R radioligand.

7.
Int J Mol Sci ; 24(23)2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38069435

RESUMO

The need for prehospital hemostatic dressings that exert an antibacterial effect is of interest for prolonged field care. Here, we consider a series of antibacterial and zeolite formulary treatment approaches applied to a cotton-based dressing. The design of the fabric formulations was based on the hemostatic dressing TACGauze with zeolite Y incorporated as a procoagulant with calcium and pectin to facilitate fiber adherence utilizing silver nanoparticles, and cellulose-crosslinked ascorbic acid to confer antibacterial activity. Infra-red spectra were employed to characterize the chemical modifications on the dressings. Contact angle measurements were employed to document the surface hydrophobicity of the cotton fabric which plays a role in the contact activation of the coagulation cascade. Ammonium Y zeolite-treated dressings initiated fibrin equal to the accepted standard hemorrhage control dressing and showed similar improvement with antibacterial finishes. The antibacterial activity of cotton-based technology utilizing both citrate-linked ascorbate-cellulose conjugate analogs and silver nanoparticle-embedded cotton fibers was observed against Staphylococcus aureus and Klebsiella pneumoniae at a level of 99.99 percent in the AATCC 100 assay. The hydrogen peroxide levels of the ascorbic acid-based fabrics, measured over a time period from zero up to forty-eight hours, were in line with the antibacterial activities.


Assuntos
Hemostáticos , Nanopartículas Metálicas , Zeolitas , Prata/farmacologia , Prata/química , Nanopartículas Metálicas/química , Zeolitas/farmacologia , Hemostáticos/farmacologia , Ácido Ascórbico/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Fibra de Algodão , Bandagens , Celulose/química
8.
AJPM Focus ; 2(4): 100150, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37941824

RESUMO

Introduction: COVID-19 mRNA vaccine protection against the Omicron variant of SARS-CoV-2 has been shown to be attenuated. Previous research in Shelby County, Tennessee found that vaccine effectiveness might differ by age in the Omicron surge, a finding not reported for other variants. To assess whether patterns in vaccine effectiveness by age group differed on the basis of the predominant strain of SARS-CoV2, we evaluated vaccine effectiveness in Shelby County, Tennessee by age group in the Delta wave and Omicron BA.1 (Omicron) wave. Methods: Case and vaccination statuses of residents were assessed using COVID-19 surveillance data. Age was stratified as 18-34, 35-64, and ≥65 years. Vaccination groups included unvaccinated, fully vaccinated, and fully vaccinated + booster. Person time was counted in each wave by vaccination status until the time of a positive reported COVID-19 test or until the end of the study period. Results: Incidence of COVID-19 was much higher during the Omicron wave than during the Delta wave across all vaccination groups. During the Delta wave, among adults, 79.2% fewer cases were identified in those fully vaccinated and 94.8% fewer in those fully vaccinated + booster, compared with 40.2% and 66.7%, respectively, in the Omicron wave, compared with those who were unvaccinated. Conclusions: This study found evidence that vaccine effectiveness differed by age group during the Omicron wave, where the same pattern was not prominent in the Delta wave. Further analysis investigating the influence of behavior patterns and other potential confounders on vaccine effectiveness would be useful in further understanding the relationship between age and vaccine effectiveness.

9.
PeerJ ; 11: e16024, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37846312

RESUMO

Management of deep-sea fisheries in areas beyond national jurisdiction by Regional Fisheries Management Organizations/Arrangements (RFMO/As) requires identification of areas with Vulnerable Marine Ecosystems (VMEs). Currently, fisheries data, including trawl and longline bycatch data, are used by many RFMO/As to inform the identification of VMEs. However, the collection of such data creates impacts and there is a need to collect non-invasive data for VME identification and monitoring purposes. Imagery data from scientific surveys satisfies this requirement, but there currently is no established framework for identifying VMEs from images. Thus, the goal of this study was to bring together a large international team to determine current VME assessment protocols and establish preliminary global consensus guidelines for identifying VMEs from images. An initial assessment showed a lack of consistency among RFMO/A regions regarding what is considered a VME indicator taxon, and hence variability in how VMEs might be defined. In certain cases, experts agreed that a VME could be identified from a single image, most often in areas of scleractinian reefs, dense octocoral gardens, multiple VME species' co-occurrence, and chemosynthetic ecosystems. A decision flow chart is presented that gives practical interpretation of the FAO criteria for single images. To further evaluate steps of the flow chart related to density, data were compiled to assess whether scientists perceived similar density thresholds across regions. The range of observed densities and the density values considered to be VMEs varied considerably by taxon, but in many cases, there was a statistical difference in what experts considered to be a VME compared to images not considered a VME. Further work is required to develop an areal extent index, to include a measure of confidence, and to increase our understanding of what levels of density and diversity correspond to key ecosystem functions for VME indicator taxa. Based on our results, the following recommendations are made: 1. There is a need to establish a global consensus on which taxa are VME indicators. 2. RFMO/As should consider adopting guidelines that use imagery surveys as an alternative (or complement) to using bycatch and trawl surveys for designating VMEs. 3. Imagery surveys should also be included in Impact Assessments. And 4. All industries that impact the seafloor, not just fisheries, should use imagery surveys to detect and identify VMEs.


Assuntos
Conservação dos Recursos Naturais , Ecossistema , Conservação dos Recursos Naturais/métodos , Pesqueiros
10.
Eur J Med Chem ; 261: 115751, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37688938

RESUMO

The difference in the secondary binding site (SBS) between the dopamine 2 receptor (D2R) and dopamine 3 receptor (D3R) has been used in the design of compounds displaying selectivity for the D3R versus D2R. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for D3R versus D2R. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in D3R versus D2R selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing D3R affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for D3R versus D2R and a high potency in the ß-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the D3R. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for D3R versus D2R.


Assuntos
Dopamina , Receptores de Dopamina D3 , Receptores de Dopamina D3/química , Benzamidas/farmacologia , Ligantes
11.
Mol Phylogenet Evol ; 188: 107910, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37640170

RESUMO

Keratoisididae is a globally distributed, and exclusively deep-sea, family of octocorals that contains species and genera that are polyphyletic. An alphanumeric system, based on a three-gene-region phylogeny, is widely used to describe the biodiversity within this family. That phylogeny identified 12 major groups although it did not have enough signal to explore the relationships among groups. Using increased phylogenomic resolution generated from Ultraconserved Elements and exons (i.e. conserved elements), we aim to resolve deeper nodes within the family and investigate the relationships among those predefined groups. In total, 109 libraries of conserved elements were generated from individuals representing both the genetic and morphological diversity of our keratoisidids. In addition, the conserved element data of 12 individuals from previous studies were included. Our taxon sampling included 11 of the 12 keratoisidid groups. We present two phylogenies, constructed from a 75% (231 loci) and 50% (1729 loci) taxon occupancy matrix respectively, using both Maximum Likelihood and Multiple Species Coalescence methods. These trees were congruent at deep nodes. As expected, S1 keratoisidids were recovered as a well-supported sister clade to the rest of the bamboo corals. S1 corals do not share the same mitochondrial gene arrangement found in other members of Keratoisididae. All other bamboo corals were recovered within two major clades. Clade I comprises individuals assigned to alphanumeric groups B1, C1, D1&D2, F1, H1, I4, and J3 while Clade II contains representatives from A1, I1, and M1. By combining genomics with already published morphological data, we provide evidence that group H1 is not monophyletic, and that the division between other groups - D1 and D2, and A1 and M1 - needs to be reconsidered. Overall, there is a lack of robust morphological markers within Keratoisididae, but subtle characters such as sclerite microstructure and ornamentation seem to be shared within groups and warrant further investigation as taxonomically diagnostic characters.


Assuntos
Antozoários , Animais , Filogenia , Antozoários/genética , Evolução Biológica , Biodiversidade , Éxons
12.
Dela J Public Health ; 9(2): 96-99, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37622135

RESUMO

The number of individuals and families facing homelessness in Delaware far outstrips the available stock of subsidized or low-income units. This article reviews facts and figures that paint a grim picture of the plight of persons experiencing homelessness or unstable housing conditions. It discusses low-income, rent-stressed families who do not earn enough to meet basic needs such as food, transportation, childcare and health care. It further explains why the housing crisis has an impact on all of us, whether or not we, ourselves, ever have been without a home. Finally, it provides several possible steps to take to address this seemingly unsolvable puzzle.

13.
J Sch Psychol ; 99: 101213, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37507193

RESUMO

The teaching career, and especially the transition from pre-service to in-service teaching, is uniquely characterized by change. Adaptability is an internal characteristic that has been shown to benefit teachers and may be especially relevant as they begin developing initial perceptions of themselves as educators, of their relationships with students, and of the teaching career at large. Importantly though, it is likely that the impacts of adaptability depend in part on the broader context. One such contextual factor that is highly relevant to teachers is their school's climate. The present study explored direct and indirect (moderated) relations among first-year teachers' (N = 133) adaptability and perceived school climate and their teaching self-efficacy, perceptions of the classroom relational climate, and career optimism. Path analysis revealed positive main effects of adaptability on self-efficacy and perceptions of classroom relational climate, as well as positive main effects of school climate on self-efficacy and career optimism. In addition, an interaction effect was detected whereby relations among adaptability and self-efficacy were strongest among participants who reported high and average levels of school climate. Results can inform future research on teacher adaptability and can also be used to inform interventions and supports provided to new teachers by school psychologists and other school personnel.


Assuntos
Pessoal de Educação , Instituições Acadêmicas , Humanos , Estudantes , Autoeficácia , Professores Escolares
14.
Neurotherapeutics ; 20(4): 1229-1240, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37296356

RESUMO

Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2+PDGFRa-) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2+CC1+ cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the mice with NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelination of the corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Remielinização , Camundongos , Animais , Cuprizona/toxicidade , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Bainha de Mielina , Esclerose Múltipla/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
16.
Epilepsy Behav Rep ; 21: 100590, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36818645

RESUMO

Young adulthood is a critical developmental period which having epilepsy tends to complicate, suggesting support could be useful. This study aimed to examine the experiences and perspectives of peer support among young adults with epilepsy (YAWE). An online survey was completed by 144 YAWE. Most YAWE reported not having access to peer support but perceived several potential benefits which could support their mental health including mutual understanding, fostering friendships and reducing loneliness, and promoting self-management and coping strategies. Reported barriers to accessing peer support included practical barriers such as travel and time constraints, emotional barriers (e.g., anxiety), and peers not feeling confident or skilled enough to support others. The need for epilepsy peer support groups specifically designed for young adults, university students, and individuals with co-occurring conditions such as autism and attention deficit hyperactivity disorder were also recognised as well as online delivery to address some of the identified barriers. Appropriate training for facilitators and group moderation were noted as important. Overall, these preliminary findings support the acceptability of peer support among YAWE, indicating peer support could be a worthy focus of policy and care pathway development. However, future research is needed to evaluate the effectiveness of peer support for epilepsy populations.

17.
ACS Chem Neurosci ; 14(5): 947-957, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36780706

RESUMO

Reduced haloperidol (1) was previously reported to act as a potent sigma-1 receptor (S1R) ligand with substantially lower affinity to the dopamine D2 receptor (D2R) compared to haloperidol. It was also found to facilitate brain-derived neurotrophic factor (BDNF) secretion from astrocytic glial cell lines in a sigma-1 receptor (S1R)-dependent manner. Although an increase in BDNF secretion may have beneficial effects in some neurological conditions, the therapeutic utility of reduced haloperidol (1) is limited because it can be oxidized back to haloperidol in the body, a potent dopamine D2 receptor antagonist associated with well-documented adverse effects. A difluorinated analogue of reduced haloperidol, (±)-4-(4-chlorophenyl)-1-(3,3-difluoro-4-(4-fluorophenyl)-4-hydroxybutyl)piperidin-4-ol (2), was synthesized in an attempt to minimize the oxidation. Compound (±)-2 was found to exhibit high affinity to S1R and facilitate BDNF release from mouse brain astrocytes. It was also confirmed that compound 2 cannot be oxidized back to the corresponding haloperidol analogue in liver microsomes. Furthermore, compound 2 was distributed to the brain following intraperitoneal administration in mice and reversed the learning deficits in active avoidance tasks. These findings suggest that compound 2 could serve as a promising S1R ligand with therapeutic potential for the treatment of cognitive impairments.


Assuntos
Haloperidol , Receptores sigma , Camundongos , Animais , Haloperidol/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ligantes , Receptor Sigma-1
18.
Diabetes Care ; 46(4): 714-721, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36701208

RESUMO

OBJECTIVE: Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts. RESEARCH DESIGN AND METHODS: A broad, multiplex analysis of 4,068 proteins in serum samples from MZ twins concordant (n = 43) and discordant (n = 27) for type 1 diabetes identified major differences that were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n = 39) and discordant (n = 42) for type 1 diabetes, individuals at risk for (n = 195) and with (n = 990) type 1 diabetes, as well as individuals with non-insulin-requiring adult-onset diabetes diagnosed as either autoimmune (n = 96) or type 2 (n = 291). RESULTS: Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite a strong correlation between twins, whether concordant or discordant for type 1 diabetes (P < 0.01 for both). In validation experiments, trypsin(ogen) levels were lower in twins with diabetes than in the co-twin without diabetes (P < 0.0001) and healthy control participants (P < 0.0001). In recently diagnosed participants, trypsin(ogen) levels were lower than in control participants across a broad age range. In at-risk relatives, levels <15 ng/mL were associated with an increased risk of progression (uncorrected P = 0.009). Multiple linear regression in recently diagnosed participants showed that trypsin(ogen) levels were associated with insulin dose and diabetic ketoacidosis, while age and BMI were confounders. CONCLUSIONS: Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and nongenetically determined factors. Exocrine/endocrine interactions are important underinvestigated factors in type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Adulto , Humanos , Diabetes Mellitus Tipo 1/genética , Tripsina , Proteômica , Biomarcadores
19.
Molecules ; 29(1)2023 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-38202706

RESUMO

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound. The effect of the flexible linker ((R,S)-trans-2a-d), SBFs ((R,S)-trans-2h-j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP1103.32 of the D3R, thereby reducing the D3R affinity to a suboptimal level.


Assuntos
Química Computacional , Nitrogênio , Ligantes , Projetos de Pesquisa
20.
Biology (Basel) ; 11(12)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36552215

RESUMO

Ice shelves cover ~1.6 million km2 of the Antarctic continental shelf and are sensitive indicators of climate change. With ice-shelf retreat, aphotic marine environments transform into new open-water spaces of photo-induced primary production and associated organic matter export to the benthos. Predicting how Antarctic seafloor assemblages may develop following ice-shelf loss requires knowledge of assemblages bordering the ice-shelf margins, which are relatively undocumented. This study investigated seafloor assemblages, by taxa and functional groups, in a coastal polynya adjacent to the Larsen C Ice Shelf front, western Weddell Sea. The study area is rarely accessed, at the frontline of climate change, and located within a CCAMLR-proposed international marine protected area. Four sites, ~1 to 16 km from the ice-shelf front, were explored for megabenthic assemblages, and potential environmental drivers of assemblage structures were assessed. Faunal density increased with distance from the ice shelf, with epifaunal deposit-feeders a surrogate for overall density trends. Faunal richness did not exhibit a significant pattern with distance from the ice shelf and was most variable at sites closest to the ice-shelf front. Faunal assemblages significantly differed in composition among sites, and those nearest to the ice shelf were the most dissimilar; however, ice-shelf proximity did not emerge as a significant driver of assemblage structure. Overall, the study found a biologically-diverse and complex seafloor environment close to an ice-shelf front and provides ecological baselines for monitoring benthic ecosystem responses to environmental change, supporting marine management.

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