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1.
Cell ; 183(3): 786-801.e19, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33125893

RESUMO

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Nanotecnologia , Acetilmuramil-Alanil-Isoglutamina/metabolismo , Animais , Comportamento Animal , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Colesterol/metabolismo , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade/efeitos dos fármacos , Imunoterapia , Lipoproteínas HDL/metabolismo , Camundongos Endogâmicos C57BL , Primatas , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
2.
Immunity ; 57(1): 171-187.e14, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38198850

RESUMO

Immune responses are tightly regulated yet highly variable between individuals. To investigate human population variation of trained immunity, we immunized healthy individuals with Bacillus Calmette-Guérin (BCG). This live-attenuated vaccine induces not only an adaptive immune response against tuberculosis but also triggers innate immune activation and memory that are indicative of trained immunity. We established personal immune profiles and chromatin accessibility maps over a 90-day time course of BCG vaccination in 323 individuals. Our analysis uncovered genetic and epigenetic predictors of baseline immunity and immune response. BCG vaccination enhanced the innate immune response specifically in individuals with a dormant immune state at baseline, rather than providing a general boost of innate immunity. This study advances our understanding of BCG's heterologous immune-stimulatory effects and trained immunity in humans. Furthermore, it highlights the value of epigenetic cell states for connecting immune function with genotype and the environment.


Assuntos
Vacina BCG , Imunidade Treinada , Humanos , Multiômica , Vacinação , Epigênese Genética
3.
PLoS Biol ; 20(9): e3001765, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36094960

RESUMO

The antituberculosis vaccine Bacillus Calmette-Guérin (BCG) induces nonspecific protection against heterologous infections, at least partly through induction of innate immune memory (trained immunity). The amplitude of the response to BCG is variable, but the factors that influence this response are poorly understood. Metabolites, either released by cells or absorbed from the gut, are known to influence immune responses, but whether they impact BCG responses is not known. We vaccinated 325 healthy individuals with BCG, and collected blood before, 2 weeks and 3 months after vaccination, to assess the influence of circulating metabolites on the immune responses induced by BCG. Circulating metabolite concentrations after BCG vaccination were found to have a more pronounced impact on trained immunity responses, such as the increase in IL-1ß and TNF-α production upon Staphylococcus aureus stimulation, than on specific adaptive immune memory, assessed as IFN-γ production in response to Mycobacterium tuberculosis. Circulating metabolites at baseline were able to predict trained immunity responses at 3 months after vaccination and enrichment analysis based on the metabolites positively associated with trained immunity revealed enrichment of the tricarboxylic acid (TCA) cycle and glutamine metabolism, both of which were previously found to be important for trained immunity. Several new metabolic pathways that influence trained immunity were identified, among which taurine metabolism associated with BCG-induced trained immunity, a finding validated in functional experiments. In conclusion, circulating metabolites are important factors influencing BCG-induced trained immunity in humans. Modulation of metabolic pathways may be a novel strategy to improve vaccine and trained immunity responses.


Assuntos
Vacina BCG , Mycobacterium bovis , Antituberculosos , Glutamina , Humanos , Imunidade Inata , Metaboloma , Taurina , Ácidos Tricarboxílicos , Fator de Necrose Tumoral alfa , Vacinação
4.
Artigo em Inglês | MEDLINE | ID: mdl-39297206

RESUMO

BACKGROUND: Realistic reconstruction of the in vivo human atherosclerotic environment requires the coculture of different cell types arranged in atherosclerotic vessel-like structures with exposure to flow and circulating cells, presenting challenges for disease modeling. This study aimed to develop a 3-dimensional tubular microfluidic model with quadruple coculture of human aortic smooth muscle cells, human umbilical cord vein endothelial cells, and foam cells to recreate a complex human atherosclerotic vessel in vitro to study the effects of flow and circulating immune cells. METHODS: We developed a coculture protocol utilizing BFP (blue fluorescent protein)-labeled human aortic smooth muscle cells, GFP (green fluorescent protein)-labeled human umbilical cord vein endothelial cells, and THP-1 macrophage-derived, Dil-labeled oxidized LDL (low-density lipoprotein) foam cells within a fibrinogen/collagen I-based 3-dimensional ECM (extracellular matrix). Perfusion experiments were conducted for 24 hours on both atherosclerotic vessels and healthy vessels (BFP-labeled human aortic smooth muscle cells and GFP-labeled human umbilical cord vein endothelial cells without foam cells). Additionally, perfusion with circulating THP-1 monocytes was performed to observe cell extravasation and recruitment. RESULTS: The resulting vessels displayed early lesion morphology, with a layered composition including an endothelium and media, and foam cells accumulating in the subendothelial space. The layered wall composition of both atherosclerotic and healthy vessels remained stable under perfusion. Circulating THP-1 monocytes demonstrated cell extravasation into the atherosclerotic vessel wall and recruitment to the foam cell core. The qPCR analysis indicated increased expression of atherosclerosis markers in the atherosclerotic vessels and adaptation of vascular smooth muscle cell migration in response to flow and the plaque microenvironment, compared with control vessels. CONCLUSIONS: The human 3-dimensional atherosclerosis model demonstrated stability under perfusion and allowed for the observation of immune cell behavior, providing a valuable tool for the atherosclerosis research field.

5.
J Infect Dis ; 229(3): 630-634, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38309709

RESUMO

The 2023 United States infectious diseases (ID) fellowship match resulted in a large percentage of programs with unfilled positions. A survey was sent to ID program directors nationwide to better understand their perceptions on the match. Program directors perceived geography, a small applicant pool, and low specialty pay as contributing factors to the match results. Developing specialized fellowship tracks, increasing funding for the ID trainee pipeline, and national advocacy for higher compensation were identified as areas to focus on to increase the applicant pool. Areas of controversy, such as decreasing the number or size of fellowship programs, require further discussion.


Assuntos
Bolsas de Estudo , Medicina , Estados Unidos , Inquéritos e Questionários
6.
Cell Immunol ; 403-404: 104862, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39159505

RESUMO

Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette-Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking lactate dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.


Assuntos
Vacina BCG , Imunidade Inata , Leucócitos Mononucleares , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares , Humanos , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Vacina BCG/imunologia , Imunidade Inata/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Citocinas/metabolismo , Adulto , Masculino , Feminino , Vacinação , Células Cultivadas , Mycobacterium bovis/imunologia , Glicólise/imunologia , Imunidade Treinada
7.
Org Biomol Chem ; 22(41): 8293-8299, 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39302224

RESUMO

The Knoevenagel condensation constitutes one of the most well-studied and crucial transformations in organic chemistry, since it facilitates the synthesis of numerous valuable compounds. With the advent of green chemistry, several alternative protocols for the Knoevenagel reaction have been introduced and catalyst-free approaches to the Knoevenagel condensation have also been mentioned, however the harsh temperatures employed and the limited substrate scope restricted their application. Herein, we have performed an extensive study on the catalyst-free and water-mediated Knoevenagel reaction, with specific focus on optimising the green parameters and metrics of our methodology. Additionally, we directly compared our approach with previous catalyst-free methods, while providing a fast assembly of multiple compounds in parallel.

8.
Phys Chem Chem Phys ; 26(6): 5693-5703, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38289341

RESUMO

For the first time, the two factors (the number of sites in the transition state and the nature of the catalytically active species) that affect the energy barriers (Ea and ΔG‡) in atmospheric aldehyde reactions are proposed. The contribution of each factor to the energy barriers of the ammonization and amination stages, dehydration, and intramolecular hydrogen transfer is studied using the example of the acetaldehyde and glyoxal interactions with ammonia in aqueous solution. A regular decrease in energy barriers is observed in a series of 4-, 6-, and 8-membered transition states (TSs) regardless of the nature of the catalytically active species and their numbers. The 8-membered TSs of ammonization, amination, and dehydration reactions are the most efficient catalytic systems. The role of the nature of catalytically active species is secondary and is expressed in different cases through the influence of entropy and different acidity/basicity of catalytically active species and their structures. The regularities for the stage of intramolecular hydrogen transfer stand out from those for the ammonization, amination, and dehydration stages. The intramolecular hydrogen transfer is organized by three atoms in TSs without the participation of catalytically active species, while the 5- and 7-membered TSs are formed with the participation of such species. A proportional decrease in energy barrier with a sequential increase in the number of TS sites (3-, 5-, and 7-) is not observed. A sharp decrease in the barriers occurs only during the formation of the 7-membered TSs, while the 5-membered structures lie above the 3-membered catalytically inactive structures on the potential energy surface (PES) regardless of the nature of the species forming these structures.

9.
Arch Phys Med Rehabil ; 105(2): 352-358, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37690740

RESUMO

OBJECTIVE: To assess effects of the CARE4Carer blended care intervention on caregiver mastery and psychosocial functioning compared with usual care in partners of patients with acquired brain injury (ABI). DESIGN: Multicenter randomized controlled trial. SETTING: Nine sites for rehabilitation medicine. PARTICIPANTS: 120 partners of outpatients with ABI were randomly allocated to blended care (N=59) or usual care (N=61). INTERVENTION: The blended care intervention (20 weeks) was aimed at improving caregiving skills and consisted of 9 online sessions, combined with 2 face-to-face consultations with a social worker. MAIN OUTCOME MEASURES: Mastery was assessed with the Caregiver Mastery Scale, secondary outcome measures were caregiver strain (Caregiver Strain Index), family functioning (Family Assessment Device), anxiety and depression (Hospital Anxiety and Depression Scale), burden (self-rated), and quality of life (CarerQol). Assessments were performed at baseline, 24, and 40 weeks. RESULTS: The adjusted mean difference in caregiver mastery between intervention and control group at week 24 was 1.31 (SD3.48, 95% confidence interval (CI) -0.12 to 2.74, P=.072) and at week 40 was 1.31 (SD3.69, 95% CI -0.26 to 2.88, P=.100). In the per protocol analysis, the adjusted mean difference in caregiver mastery at week 24 was 1.53 (SD3.38, 95% CI 0.10 to 2.96, P=.036) and at week 40 was 1.57 (SD3.63, 95% CI 0.01 to 3.14, P=.049). Regarding secondary outcomes, caregiver strain was lower in the intervention group in the per protocol analysis at week 40. Family functioning was higher in the intervention group in week 24, whereas anxiety was lower at both timepoints. CONCLUSIONS: In the subset of participants who were able to complete the intervention, caregiver mastery and psychosocial functioning improved. Future work should focus on improving adherence as this will optimize beneficial effects of blended care.


Assuntos
Lesões Encefálicas , Qualidade de Vida , Humanos , Ansiedade , Cuidadores/psicologia
10.
Molecules ; 29(4)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38398603

RESUMO

Due to traumatic injuries, including those from surgical procedures, adhesions occur in over 50% of cases, necessitating exclusive surgical intervention for treatment. However, preventive measures can be implemented during abdominal organ surgeries. These measures involve creating a barrier around internal organs to forestall adhesion formation in the postoperative phase. Yet, the effectiveness of the artificial barrier relies on considerations of its biocompatibility and the avoidance of adverse effects on the body. This study explores the biocompatibility aspects, encompassing hemocompatibility, cytotoxicity, and antibacterial and antioxidant activities, as well as the adhesion of blood serum proteins and macrophages to the surface of new composite film materials. The materials, derived from the sodium salt of carboxymethylcellulose modified by glycoluril and allantoin, were investigated. The research reveals that film materials with a heterocyclic fragment exhibit biocompatibility comparable to commercially used samples in surgery. Notably, film samples developed with glycoluril outperform the effects of commercial samples in certain aspects.


Assuntos
Ácido Hialurônico , Ureia , Humanos , Aderências Teciduais/prevenção & controle , Carboximetilcelulose Sódica
11.
Clin Infect Dis ; 77(9): 1265-1272, 2023 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-37310036

RESUMO

BACKGROUND: Antimicrobial stewardship (AS) is an important topic in infectious diseases (ID) training, yet many ID fellowships lack formal training, and little is known about fellows' learning preferences. METHODS: We conducted 24 in-depth interviews with ID fellows across the United States during 2018 and 2019 to explore their experiences with and preferences for AS education during fellowship. Interviews were transcribed, deidentified, and analyzed to identify themes. RESULTS: Fellows had variable exposure to AS before and during fellowship, which impacted their knowledge about and attitude toward stewardship as a career; however, all fellows expressed the importance of learning general stewardship principles during fellowship. Some fellows' training included mandatory stewardship lectures and/or rotations, but most fellows felt their primary stewardship learning occurred through informal experiences in the clinical setting, such as holding the antimicrobial approval pager. Fellows expressed a preference for a standardized, structured curriculum that included in-person practical, interactive discussions with multidisciplinary faculty along with the opportunity to practice and apply their skills; however, they emphasized that time needed to be set aside for those educational activities. Although they wanted to learn the evidence and rationale for stewardship recommendations, they especially wanted training in and feedback on how to communicate stewardship recommendations to other health professionals, particularly in the setting of conflict. CONCLUSIONS: ID fellows believe that standardized AS curricula should be included in their fellowship training, and they prefer structured, practical, and interactive learning experiences.


Assuntos
Gestão de Antimicrobianos , Doenças Transmissíveis , Treinamento por Simulação , Humanos , Estados Unidos , Currículo , Educação de Pós-Graduação em Medicina , Bolsas de Estudo , Inquéritos e Questionários
12.
Eur J Immunol ; 52(3): 431-446, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34821391

RESUMO

Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.


Assuntos
Vacina BCG , Imunidade Inata , Genômica , Humanos , Fosfatidilinositol 3-Quinases/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico
13.
Cell ; 135(7): 1237-50, 2008 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-19109895

RESUMO

Eukaryotic protein synthesis begins with assembly of 48S initiation complexes at the initiation codon of mRNA, which requires at least seven initiation factors (eIFs). First, 43S preinitiation complexes comprising 40S ribosomal subunits, eIFs 3, 2, 1, and 1A, and tRNA(Met)(i) attach to the 5'-proximal region of mRNA and then scan along the 5' untranslated region (5'UTR) to the initiation codon. Attachment of 43S complexes is mediated by three other eIFs, 4F, 4A, and 4B, which cooperatively unwind the cap-proximal region of mRNA and later also assist 43S complexes during scanning. We now report that these seven eIFs are not sufficient for efficient 48S complex formation on mRNAs with highly structured 5'UTRs, and that this process requires the DExH-box protein DHX29. DHX29 binds 40S subunits and hydrolyzes ATP, GTP, UTP, and CTP. NTP hydrolysis by DHX29 is strongly stimulated by 43S complexes and is required for DHX29's activity in promoting 48S complex formation.


Assuntos
Regiões 5' não Traduzidas , Biossíntese de Proteínas , RNA Helicases/metabolismo , RNA Mensageiro/genética , Animais , Células HeLa , Humanos , Coelhos , Reticulócitos/metabolismo
14.
J Endocrinol Invest ; 46(4): 805-814, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36323983

RESUMO

PURPOSE: To compare the intraoperative and surgical outcomes of normotensive pheochromocytomas and sympathetic paragangliomas (PPGLs), hypertensive PPGLs and non-PPGL adrenal lesions. METHODS: This a retrospective multicenter cohort study of patients with PPGLs from 18 tertiary hospitals. A control group of histologically confirmed adrenocortical adenomas (non-PPGL group) was selected to compare intraoperative and surgical outcomes with of the normotensive PPGLs. RESULTS: Two hundred and ninety-six surgeries performed in 289 patients with PPGLs were included. Before surgery, 209 patients were classified as hypertensive PPGLs (70.6%) and 87 as normotensive PPGLs. A higher proportion of normotensive PPGLs than hypertensive PPGLs did not receive alpha presurgical blockade (P = 0.009). When we only considered those patients who received presurgical alpha blockers (200 hypertensive PPGLs and 76 normotensive PPGLs), hypertensive PPGLs had a threefold higher risk of intraoperative hypertensive crisis (OR 3.0 [95% 1.3-7.0]) and of hypotensive episodes (OR 2.9 [95% CI 1.2-6.7]) than normotensive PPGLs. When we compared normotensive PPGLs (n = 76) and non-PPGLs (n = 58), normotensive PPGLs had a fivefold higher risk of intraoperative complications (OR 5.3 [95% CI 1.9-14.9]) and a six times higher risk of postoperative complications (OR 6.1 [95% CI 1.7-21.6]) than non-PPGLs. CONCLUSION: Although the risk of intraoperative hypertensive and hypotensive episodes in normotensive PPGLs is significantly lower than in hypertensive PPGLs, normotensive PPGLs have a greater risk of intraoperative and postoperative complications than non-PPGL adrenal lesions. Therefore, it is recommended to follow the standard of care for presurgical and anesthetic management of PPGLs also in normotensive PPGLs.


Assuntos
Neoplasias das Glândulas Suprarrenais , Hipertensão , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/cirurgia , Feocromocitoma/patologia , Estudos de Coortes , Paraganglioma/cirurgia , Paraganglioma/patologia , Hipertensão/epidemiologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Resultado do Tratamento
15.
Int J Mol Sci ; 24(23)2023 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-38069405

RESUMO

This work presents the synthesis of a new compound, 1-[aryl-(diphenylphosphono)methyl]-3,4,6-trimethylglycolurils, via the interaction of benzaldehyde and its mononitro- and monohydroxyderivatives with 1,3,4-trimethylglycoluril and triphenylphosphite. By varying the reaction conditions and the catalysts, the obtained product yields ranged from satisfactory to good. The diastereomers formed during the reaction were separated by semipreparative HPLC on the C18 stationary phase. The isolated diastereomers were characterized by 1H, 13C, and 31P NMR, and the structures of the diastereomers were confirmed using a single-crystal X-ray crystal structure analysis and quantum chemical calculations.

16.
Int J Mol Sci ; 24(23)2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38069426

RESUMO

Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation-inhibition balance in the brain, and it can serve as a mouse model of epilepsy.


Assuntos
Epilepsia Reflexa , Criança , Animais , Humanos , Camundongos , Epilepsia Reflexa/genética , Epilepsia Reflexa/metabolismo , Etilnitrosoureia/toxicidade , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Anticonvulsivantes/farmacologia , Encéfalo/metabolismo , Modelos Animais de Doenças
17.
J Environ Manage ; 326(Pt B): 116838, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36435138

RESUMO

Multifunctional lignin bio-based adsorbent, b-LMS, was obtained via inverse copolymerization in the suspension of acryloyl modified kraft lignin (KfL-AA) and bio-based trimethylolpropane triacrylate (bio-TMPTA). Morphological and structural characterization of KfL-AA and b-LMS was performed using BET, FTIR, Raman, NMR, TGA, SEM, and XPS techniques. The b-LMS microspheres with 253 ± 42 µm diameters, 69.4 m2 g-1 surface area, and 59% porosity efficiently adsorb Malachite Green (MG), Tartrazine (T), and Methyl Red (MR) dye. The influence of pH, pollutant concentration, temperature, and time on the removal efficiency was studied in a batch mode. Favorable and spontaneous processes with high adsorption capacities e.g. 116.8 mg g-1 for MG, 86.8 mg g-1 for T, and 68.6 mg g-1 for MR indicate the significant adsorptive potential of b-LMS. Results from diffusional and single mass transfer resistance studies indicate that pore diffusion is a rate-limiting step. Theoretical calculations confirmed a higher affinity of b-LMS to cationic dye MG compared with an anionic and neutral one, i.e. T and MR, respectively. The data fitting from a flow system, using semi-empirical equations and Pore Surface Diffusion Modelling (PSDM) provided breakthrough point determination. The results from the desorption and competitive adsorption study proved the exceptional performance of b-LMS. Moreover, sulfation of b-LMS, i.e.production of b-LMS-OSO3H, introduced high-affinity sulfate groups with respect to cationic dye and cations. Developed methodology implements the principle of sustainable development and offers concept whose results contribute to the minimization of environmental pollution.


Assuntos
Corantes , Poluentes Químicos da Água , Corantes/química , Adsorção , Microesferas , Lignina , Poluentes Químicos da Água/química , Cinética , Cátions/química , Modelos Teóricos
18.
Molecules ; 28(20)2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37894520

RESUMO

The influence of the reaction medium on the surface structure and properties of a Ni-based catalyst used for the reductive transformations of O-, N-, and S-containing aromatic substrates under hydrogen transfer conditions has been studied. The catalysts were characterized by XRD, XPS, and IR spectroscopy and TEM methods before and after the reductive reaction. It has been shown that the conversion of 1-benzothiophene causes irreversible poisoning of the catalyst surface with the formation of the Ni2S3 phase, whereas the conversion of naphthalene, 1-benzofuran, and indole does not cause any phase change of the catalyst at 250 °C. However, after the indole conversion, the catalyst surface remains enriched with N-containing compounds, which are evenly distributed over the surface.

19.
Clin Infect Dis ; 74(6): 965-972, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-34192322

RESUMO

BACKGROUND: Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here we study its impact. METHODS: ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows' knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation ("pre-curriculum") and compared to first-year fellows who complete the curriculum the following year ("post-curriculum"). RESULTS: Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a "formal" curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows' confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P = .028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning. CONCLUSIONS: Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors.


Assuntos
Gestão de Antimicrobianos , Doenças Transmissíveis , Idoso , Doenças Transmissíveis/tratamento farmacológico , Currículo , Educação de Pós-Graduação em Medicina , Bolsas de Estudo , Humanos , Medicare , Inquéritos e Questionários , Estados Unidos
20.
Phys Chem Chem Phys ; 24(16): 9394-9402, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35384955

RESUMO

The most thermodynamically and kinetically favorable pathways for the formation of 2-methylimidazole (2MI) in the reaction of glyoxal and acetaldehyde with ammonia in aqueous solution have been determined. The formation of 2MI proceeds through a number of successive intermediates of acyclic and cyclic structures, and the most favorable route (thermodynamically and kinetically) for the formation of the imidazole ring is the condensation of amine intermediates, in contrast to the existing concepts of imine structures. The limiting stage is the stage of cyclization involving the intramolecular attack by the amino group of the precyclic intermediate on the carbon atom bound to the hydroxyl group with the simultaneous release of a water molecule according to the SN2 mechanism. Further stages of stepwise dehydration lead to the formation of a cyclic diazine, the intramolecular migration of the proton of the tertiary carbon atom to the nitrogen atom of which completes the formation of 2MI. Experimental studies on the effect of the order of mixing of initial reagents on the 2MI yield confirmed the quantum-chemically substantiated favorable pathway for the formation of 2MI during the interaction of amine intermediates, and also revealed that the selectivity of the 2MI formation is achieved by successive mixing of acetaldehyde with ammonia until the formation of hydroxyamine products and their further interaction with glyoxal.


Assuntos
Acetaldeído , Glioxal , Acetaldeído/química , Aminas , Amônia , Carbono , Glioxal/química , Imidazóis , Termodinâmica
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