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1.
Cureus ; 16(9): e69185, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39282484

RESUMO

INTRODUCTION: In Romania, the latest official report indicates that more than half of the births (80,890 cases, representing 52.88% of the total) are performed by cesarean, a rate significantly higher than the World Health Organization (WHO) recommendation of 15-20%. This study aims to identify the predictors associated with women's decisions to opt for cesarean in Romania. MATERIALS AND METHODS:  An analytical cross-sectional observational study was conducted in the general population of Romania. The study was carried out over the course of 2023, with a total duration of four months. During this period, researchers targeted pregnant women from various regions of the country, regardless of their place of residence, age, or education level. The primary data collection tool was a self-administered online questionnaire, distributed via Google Forms, an accessible and efficient platform that allows for automatic response collection. The questionnaire was distributed online, particularly on social media platforms frequented by pregnant women, such as Facebook, Instagram, and TikTok. RESULTS: A total of 1,301 participants were validated. Socio-demographic and clinical factors significantly influence women's decisions to give birth by cesarean. Among these participants, 435 expressed a preference for cesarean delivery. Key predictors include fear of pain and concern for the child's health. Fear of pain at birth is the first predictor in Romanian women to choose cesarean (OR=2.09; 95% CI: 1.62-2.68). Concerns about the child's health do not increase the likelihood of opting for a cesarean. CONCLUSION:  By utilizing valuable resources such as midwives and implementing strategies like birth plans, significant contributions can be made toward reducing the cesarean rate and improving the childbirth experience for women worldwide.

2.
bioRxiv ; 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39253514

RESUMO

The interplay between transcription factors and chromatin accessibility regulates cell type diversification during vertebrate embryogenesis. To systematically decipher the gene regulatory logic guiding this process, we generated a single-cell multi-omics atlas of RNA expression and chromatin accessibility during early zebrafish embryogenesis. We developed a deep learning model to predict chromatin accessibility based on DNA sequence and found that a small number of transcription factors underlie cell-type-specific chromatin landscapes. While Nanog is well-established in promoting pluripotency, we discovered a new function in priming the enhancer accessibility of mesendodermal genes. In addition to the classical stepwise mode of differentiation, we describe instant differentiation, where pluripotent cells skip intermediate fate transitions and terminally differentiate. Reconstruction of gene regulatory interactions reveals that this process is driven by a shallow network in which maternally deposited regulators activate a small set of transcription factors that co-regulate hundreds of differentiation genes. Notably, misexpression of these transcription factors in pluripotent cells is sufficient to ectopically activate their targets. This study provides a rich resource for analyzing embryonic gene regulation and reveals the regulatory logic of instant differentiation.

3.
Clin Transl Radiat Oncol ; 48: 100838, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39224662

RESUMO

Aims: Multidisciplinary tumor boards (MDTs) are an integral part of ensuring high-quality, evidence-based and personalized cancer care. In this study, we aimed to evaluate the adherence to and implementation of MDT recommendations in patients with oligometastatic disease (OMD). Methods: We screened all oncologic positron emission tomography (PET) scans conducted at a single comprehensive cancer center in 2020. Patients were included if they had evidence of imaging-based OMD from a solid organ malignancy on the index scans, had their OMD case discussed at an MDT, and were treated and followed up at the same center. A switch away from the MDT-recommended treatment modalities was classified as a major deviation; non-MDT-mandated adjustments to a recommended treatment modality were coded as minor deviation. Clinical data was obtained via chart review; statistical calculations were computed using the R software. Results: After review of PET and/or concurrent brain scans, 787 cases of OMD were identified. Thereof, 347 (44.1 %) cases were discussed at MDT, of which 331 (42.1 %) were therapeutically managed and subsequently followed. The three most commonly recommended therapies were systemic therapy (35.6 %), multimodality treatment including definitive local therapy (17.8 %), and radiotherapy (13.9 %). A major deviation was recorded in 16.3 % of cases (most commonly: none of the MDT-recommended treatment modalities were performed: 19 (35.2 %); not all MDT-planned treatment modalities were performed: 12 (22.2 %); and additional treatment modality was performed: 11 (20.3 %). A minor deviation was found in 1.5 % of cases. On multivariable regression, number of distant metastases (n > 1) was associated with a major deviation (OR: 1.85; 95 % CI, 1.0-3.52). Major deviations were associated with a significantly worse OS (p = 0.0034). Conclusions: Adherence to and implementation of MDT recommendations in OMD patients was generally high (83.7%). Major deviations might be further reduced by more careful and elaborate discussions of OMD patient characteristics s and patient preferences.

4.
J Couns Psychol ; 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39250277

RESUMO

Transgender and nonbinary (TNB) people experience elevated rates of posttraumatic stress (PTS) due to transphobic violence, discrimination, microaggressions, and minority stress. Nonbinary people in particular experience unique chronic minority stressors (e.g., misgendering, interpersonal invalidation) because of the assumption that gender is inherently binary. Such examples of oppression against TNB people could contribute to complex PTS (c-PTS) symptoms, which arise due to exposure to chronic, cumulative, and interpersonal trauma. This study aimed to examine how misgendering and invalidation may be associated with PTS and c-PTS symptoms among nonbinary people and whether this association is moderated by pride and community connectedness. Cross-sectional data from 610 nonbinary people living in the United States and Canada were analyzed using hierarchical linear regressions. Misgendering and invalidation had significant positive associations with PTS and c-PTS symptoms. However, pride and community connectedness were not significant moderators of these associations. Findings from this study contribute to the conceptualizations of traumatic stress among nonbinary people and provide considerations for more affirming trauma-informed care. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

5.
BJA Educ ; 24(8): 288-295, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39099752
6.
Artigo em Inglês | MEDLINE | ID: mdl-39042016

RESUMO

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combination with Streptococcus pneumoniae infection further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage and pulmonary inflammation in mice infected with Streptococcus pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier during Streptococcus pneumoniae infection. Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, and epithelial barrier function and integrity. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

7.
J Am Chem Soc ; 146(31): 21476-21489, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39042706

RESUMO

The dynamics of electron and spin transfer in the radical cation and photogenerated triplet states of a tetramethylbiphenyl-linked zinc-porphyrin dimer were investigated, so as to test the relevant parameters for the design of a single-molecule spin valve and the creation of a novel platform for the photogeneration of high-multiplicity spin states. We used a combination of multiple techniques, including variable-temperature continuous wave EPR, pulsed proton electron-nuclear double resonance (ENDOR), transient EPR, and optical spectroscopy. The conclusions are further supported by density functional theory (DFT) calculations and comparison to reference compounds. The low-temperature cw-EPR and room-temperature near-IR spectra of the dimer monocation demonstrate that the radical cation is spatially localized on one side of the dimer at any point in time, not coherently delocalized over both porphyrin units. The EPR spectra at 298 K reveal rapid hopping of the radical spin density between both sites of the dimer via reversible intramolecular electron transfer. The hyperfine interactions are modulated by electron transfer and can be quantified using ENDOR spectroscopy. This allowed simulation of the variable-temperature cw-EPR spectra with a two-site exchange model and provided information on the temperature-dependence of the electron transfer rate. The electron transfer rates range from about 10.0 MHz at 200 K to about 53.9 MHz at 298 K. The activation enthalpies Δ‡H of the electron transfer were determined as Δ‡H = 9.55 kJ mol-1 and Δ‡H = 5.67 kJ mol-1 in a 1:1:1 solvent mixture of CD2Cl2/toluene-d8/THF-d8 and in 2-methyltetrahydrofuran, respectively, consistent with a Robin-Day class II mixed valence compound. These results indicate that the interporphyrin electronic coupling in a tetramethylbiphenyl-linked porphyrin dimer is suitable for the backbone of a single-molecule spin valve. Investigation of the spin density distribution of the photogenerated triplet state of the Zn-porphyrin dimer reveals localization of the triplet spin density on a nanosecond time scale on one-half of the dimer at 20 K in 2-methyltetrahydrofuran and at 250 K in a polyvinylcarbazole film. This establishes the porphyrin dimer as a molecular platform for the formation of a localized, photogenerated triplet state on one porphyrin unit that is coupled to a second redox-active, ground-state porphyrin unit, which can be explored for the formation of high-multiplicity spin states.

8.
J Infect ; 89(2): 106220, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38960103

RESUMO

OBJECTIVES: Efficacy and safety of letermovir as prophylaxis for clinically significant cytomegalovirus infections (csCVMi) was evaluated in randomised controlled trials while most of the real-world studies are single-centre experiences. METHODS: We performed a retrospective, multi-centre case-control study at six German university hospitals to evaluate clinical experiences in patients receiving CMV prophylaxis with letermovir (n = 200) compared to controls without CMV prophylaxis (n = 200) during a 48-week follow-up period after allogeneic hematopoietic cell transplantation (aHCT). RESULTS: The incidence of csCMVi after aHCT was significantly reduced in the letermovir (34%, n = 68) compared to the control group (56%, n = 112; p < 0.001). Letermovir as CMV prophylaxis (OR 0.362) was found to be the only independent variable associated with the prevention of csCMVi. Patients receiving letermovir showed significantly better survival compared to the control group (HR = 1.735, 95% CI: 1.111-2.712; p = 0.014). Of all csCMVi, 46% (n = 31) occurred after discontinuation of letermovir prophylaxis. Severe neutropenia (<500 neutrophils/µL) on the day of the stem cell infusion was the only independent variable for an increased risk of csCMVi after the end of letermovir prophylaxis. CONCLUSIONS: Our study highlights the preventive effects of letermovir on csCMVi after aHCT. A substantial proportion of patients developed a csCMVi after discontinuation of letermovir. In particular, patients with severe neutropenia require specific attention after drug discontinuation.


Assuntos
Acetatos , Antivirais , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Infecções por Citomegalovirus/prevenção & controle , Feminino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Estudos Retrospectivos , Antivirais/uso terapêutico , Adulto , Acetatos/uso terapêutico , Acetatos/administração & dosagem , Estudos de Casos e Controles , Idoso , Transplante Homólogo/efeitos adversos , Adulto Jovem , Citomegalovirus , Adolescente , Alemanha/epidemiologia , Incidência
9.
J Biol Chem ; 300(8): 107573, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39009340

RESUMO

Galectins (Gals), a family of multifunctional glycan-binding proteins, have been traditionally defined as ß-galactoside binding lectins. However, certain members of this family have shown selective affinity toward specific glycan structures including human milk oligosaccharides (HMOs) and blood group antigens. In this work, we explored the affinity of human galectins (particularly Gal-1, -3, -4, -7, and -12) toward a panel of oligosaccharides including HMOs and blood group antigens using a complementary approach based on both experimental and computational techniques. While prototype Gal-1 and Gal-7 exhibited differential affinity for type I versus type II Lac/LacNAc residues and recognized fucosylated neutral glycans, chimera-type Gal-3 showed high binding affinity toward poly-LacNAc structures including LNnH and LNnO. Notably, the tandem-repeat human Gal-12 showed preferential recognition of 3-fucosylated glycans, a unique feature among members of the galectin family. Finally, Gal-4 presented a distinctive glycan-binding activity characterized by preferential recognition of specific blood group antigens, also validated by saturation transfer difference nuclear magnetic resonance experiments. Particularly, we identified oligosaccharide blood group A antigen tetraose 6 (BGA6) as a biologically relevant Gal-4 ligand, which specifically inhibited interleukin-6 secretion induced by this lectin on human peripheral blood mononuclear cells. These findings highlight unique determinants underlying specific recognition of HMOs and blood group antigens by human galectins, emphasizing the biological relevance of Gal-4-BGA6 interactions, with critical implications in the development and regulation of inflammatory responses.


Assuntos
Antígenos de Grupos Sanguíneos , Galectina 4 , Galectinas , Leite Humano , Oligossacarídeos , Humanos , Leite Humano/metabolismo , Leite Humano/química , Oligossacarídeos/metabolismo , Oligossacarídeos/química , Antígenos de Grupos Sanguíneos/metabolismo , Antígenos de Grupos Sanguíneos/química , Galectinas/metabolismo , Galectinas/química , Ligantes , Galectina 4/metabolismo , Galectina 4/química , Ligação Proteica , Interleucina-6/metabolismo
10.
Nat Commun ; 15(1): 5745, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987239

RESUMO

Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.


Assuntos
Neuropatias Diabéticas , Glioxal , Ácido Pirúvico , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Animais , Camundongos , Glioxal/análogos & derivados , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Glucose/metabolismo , Ácido Pirúvico/metabolismo , Acetolactato Sintase/metabolismo , Encéfalo/metabolismo , Carbono-Carbono Liases/metabolismo , Humanos , Camundongos Endogâmicos C57BL
11.
Mol Syst Biol ; 20(9): 1006-1024, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39026103

RESUMO

Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.


Assuntos
Ilhas de CpG , Reparo de Erro de Pareamento de DNA , Mutação , Neoplasias , Humanos , Reparo de Erro de Pareamento de DNA/genética , Neoplasias/genética , Neoplasias/imunologia , Ilhas de CpG/genética , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteínas de Ligação a DNA/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Proteína Supressora de Tumor p53/genética
12.
Cardiooncology ; 10(1): 43, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014463

RESUMO

AIMS: Cancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy. CTRCD most frequently appears in patients with cardiovascular risk factors (CVR) or known cardiovascular disease. However, limited data exist on incidence and course of anthracycline-induced CTRCD in patients without preexisting risk factors. We therefore aimed to longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease (NCT03940625). METHODS AND RESULTS: We enrolled 59 women with primary breast cancer and scheduled anthracycline-based therapy, but without CVR or preexisting cardiovascular disease. We conducted a longitudinal assessment before, immediately and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping. Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3% immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation, two of them were symptomatic. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired. CONCLUSION: In every single patient anthracyclines induce a decline of myocardial contractility, even among patients without pre-existing risk factors for CTRCD. Our data suggest to thoroughly evaluate whether this may lead to an increased risk of future cardiovascular events.

13.
JCO Precis Oncol ; 8: e2400106, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39013133

RESUMO

PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.


Assuntos
Predisposição Genética para Doença , Humanos , Feminino , Pessoa de Meia-Idade , Adulto , Masculino , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Sequenciamento do Exoma , Guias de Prática Clínica como Assunto , Idoso , Testes Genéticos/métodos , Adulto Jovem , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Heterozigoto
14.
Anesthesiol Clin ; 42(3): 491-502, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39054022

RESUMO

Anesthesia clinicians often navigate a delicate balance between maternal and fetal safety. Interventions for at fetal well-being may introduce risks of harm to the mother and raise ethical dilemmas. Emergency procedures often focus on direct fetal safety, sidelining maternal physical and mental well-being. The clash between ethical principles, particularly nonmaleficence and beneficence, often arises, with maternal autonomy guiding decisions. Fetal surgery exemplifies risking maternal health for fetal benefit, whereas emergent cesarean deliveries pose physical and psychological challenges for both the mother and child.


Assuntos
Anestesia , Humanos , Gravidez , Feminino , Anestesia/métodos , Feto/cirurgia , Anestesia Obstétrica/métodos
15.
J Extracell Vesicles ; 13(7): e12476, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38978287

RESUMO

The current study analyzed the intersecting biophysical, biochemical, and functional properties of extracellular particles (EPs) with the human immunodeficiency virus type-1 (HIV-1) beyond the currently accepted size range for HIV-1. We isolated five fractions (Frac-A through Frac-E) from HIV-infected cells by sequential differential ultracentrifugation (DUC). All fractions showed a heterogeneous size distribution with median particle sizes greater than 100 nm for Frac-A through Frac-D but not for Frac-E, which contained small EPs with an average size well below 50 nm. Synchronized and released cultures contained large infectious EPs in Frac-A, with markers of amphisomes and viral components. Additionally, Frac-E uniquely contained EPs positive for CD63, HSP70, and HIV-1 proteins. Despite its small average size, Frac-E contained membrane-protected viral integrase, detectable only after SDS treatment, indicating that it is enclosed in vesicles. Single particle analysis with dSTORM further supported these findings as CD63, HIV-1 integrase, and the viral surface envelope (Env) glycoprotein (gp) colocalized on the same Frac-E particles. Surprisingly, Frac-E EPs were infectious, and infectivity was significantly reduced by immunodepleting Frac-E with anti-CD63, indicating the presence of this protein on the surface of infectious small EPs in Frac-E. To our knowledge, this is the first time that extracellular vesicle (EV) isolation methods have identified infectious small HIV-1 particles (smHIV-1) that are under 50 nm. Collectively, our data indicate that the crossroads between EPs and HIV-1 potentially extend beyond the currently accepted biophysical properties of HIV-1, which may have further implications for viral pathogenesis.


Assuntos
Vesículas Extracelulares , Infecções por HIV , HIV-1 , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/virologia , Infecções por HIV/virologia , Infecções por HIV/metabolismo , Vírion/metabolismo , Ultracentrifugação/métodos , Linfócitos T/virologia , Linfócitos T/metabolismo , Tetraspanina 30/metabolismo , Tamanho da Partícula
16.
ACS Cent Sci ; 10(6): 1276-1282, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38947197

RESUMO

Directing groups guide substitution patterns in organic synthetic schemes, but little is known about pathways to control reactivity patterns, such as regioselectivity, in complex inorganic systems such as bioinorganic cofactors or extended surfaces. Interadsorbate effects are known to encode surface reactivity patterns in inorganic materials, modulating the location and binding strength of ligands. However, owing to limited experimental resolution into complex inorganic structures, there is little opportunity to resolve these effects on the atomic scale. Here, we utilize an atomically precise Fe/Co/Se nanocluster platform, [Fe3(L)2Co6Se8L'6]+ ([1(L)2]+; L = CN t Bu, THF; L' = Ph2PN(-)Tol), in which allosteric interadsorbate effects give rise to pronounced site-differentiation. Using a combination of spectroscopic techniques and single-crystal X-ray diffractometry, we discover that coordination of THF at the ligand-free Fe site in [1(CN t Bu)2]+ sets off a domino effect wherein allosteric through-cluster interactions promote the regioselective dissociation of CN t Bu at a neighboring Fe site. Computational analysis reveals that this active site correlation is a result of delocalized Fe···Se···Co···Se covalent interactions that intertwine edge sites on the same cluster face. This study provides an unprecedented atom-scale glimpse into how interfacial metal-support interactions mediate a collective and regiospecific path for substrate exchange across multiple active sites.

17.
Br J Haematol ; 2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-38973132

RESUMO

Management of immune thrombocytopenia (ITP) beyond initial glucocorticoid therapy is challenging. In this retrospective single-centre cohort study, we compared all ITP patients relapsed or non-responsive to glucocorticoid therapy treated with either continuous TPO-RAs (n = 35) or rituximab induction (n = 20) between 2015 and 2022. While both groups showed high initial complete response rates (CR, 68.6 vs. 80.0%, ns), the overall rate of progression to the next therapy was higher after time-limited rituximab (75.0 vs. 42.9%), resulting in a lower relapse-free survival (median 16.6 vs. 25.8 months, log-rank; p < 0.05). We conclude that both treatments show similar initial efficacy and their ideal duration of therapy warrants further investigation.

18.
Mol Biol Evol ; 41(7)2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38913681

RESUMO

Natural proteins are frequently marginally stable, and an increase in environmental temperature can easily lead to unfolding. As a result, protein engineering to improve protein stability is an area of intensive research. Nonetheless, since there is usually a high degree of structural homology between proteins from thermophilic organisms and their mesophilic counterparts, the identification of structural determinants for thermoadaptation is challenging. Moreover, in many cases, it has become clear that the success of stabilization strategies is often dependent on the evolutionary history of a protein family. In the last few years, the use of ancestral sequence reconstruction (ASR) as a tool for elucidation of the evolutionary history of functional traits of a protein family has gained strength. Here, we used ASR to trace the evolutionary pathways between mesophilic and thermophilic kinases that participate in the biosynthetic pathway of vitamin B1 in bacteria. By combining biophysics approaches, X-ray crystallography, and molecular dynamics simulations, we found that the thermal stability of these enzymes correlates with their kinetic stability, where the highest thermal/kinetic stability is given by an increase in small hydrophobic amino acids that allow a higher number of interatomic hydrophobic contacts, making this type of interaction the main support for stability in this protein architecture. The results highlight the potential benefits of using ASR to explore the evolutionary history of protein sequence and structure to identify traits responsible for the kinetic and thermal stability of any protein architecture.


Assuntos
Evolução Molecular , Simulação de Dinâmica Molecular , Estabilidade Proteica , Cristalografia por Raios X , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Cinética , Estabilidade Enzimática
19.
J Am Chem Soc ; 146(25): 17318-17324, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38869185

RESUMO

Covalent organic frameworks (COFs) containing well-defined redox-active groups have become competitive materials for next-generation batteries. Although high potentials and rate performance can be expected, only a few examples of p-type COFs have been reported for charge storage to date with even fewer examples on the use of COFs in multivalent ion batteries. Herein, we report the synthesis of a p-type highly porous and crystalline azatruxene-based COF and its application as a positive electrode material in Li- and Mg-based batteries. When this material is used in Li-based half cells as a COF/carbon nanotube (CNT) electrode, a discharge potential of 3.9 V is obtained with discharge capacities of up to 70 mAh g-1 at a 2 C rate. In Mg batteries using a tetrakis(hexafluoroisopropyloxy)borate electrolyte, cycling proceeds with an average discharge voltage of 2.9 V. Even at a fast current rate of 5 C, the capacity retention amounts to 84% over 1000 cycles.

20.
Artigo em Inglês | MEDLINE | ID: mdl-38847208

RESUMO

Sea squirts (Tunicata) are chordates and develop a swimming larva with a small and defined number of individually identifiable cells. This offers the prospect of connecting specific stimuli to behavioral output and characterizing the neural activity that links these together. Here, we describe the development of a microfluidic chip that allows live larvae of the sea squirt Ciona intestinalis to be immobilized and recorded. By generating transgenic larvae expressing GCaAMP6m in defined cells, we show that calcium ion levels can be recorded from immobilized larvae, while microfluidic control allows larvae to be exposed to specific waterborne stimuli. We trial this on sea water carrying increased levels of carbon dioxide, providing evidence that larvae can sense this gas.

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