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1.
Physiol Rep ; 12(13): e16129, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38955668

RESUMO

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT-1 also has a protective role in immune-mediated glomerular disease. Using immunohistochemistry and analysis of single-cell RNA-sequencing data of isolated glomeruli, we demonstrate that CT-1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT-1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT-1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT-1 treatment also reduced fibrosis in the kidney cortex, peri-glomerular macrophage accumulation and the kidney levels of the pro-inflammatory mediator complement component 5a. In conclusion, CT-1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.


Assuntos
Citocinas , Glomérulos Renais , Camundongos Endogâmicos C57BL , Animais , Masculino , Citocinas/metabolismo , Citocinas/genética , Camundongos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Modelos Animais de Doenças , Humanos , Fibrose , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glomerulonefrite/tratamento farmacológico
2.
Phys Rev Lett ; 132(21): 215201, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38856280

RESUMO

We investigate the propagation of Alfvén waves in the solar chromosphere, distinguishing between upward and downward propagating waves. We find clear evidence for the reflection of waves in the chromosphere and differences in propagation between cases with waves interpreted to be resonant or nonresonant with the overlying coronal structures. This establishes the wave connection to coronal element abundance anomalies through the action of the wave ponderomotive force on the chromospheric plasma, which interacts with chromospheric ions but not neutrals, thereby providing a novel mechanism of ion-neutral separation. This is seen as a "first ionization potential effect" when this plasma is lifted into the corona, with implications elsewhere on the Sun for the origin of the slow speed solar wind and its elemental composition.

3.
bioRxiv ; 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38352443

RESUMO

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse. MYC, an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the fallopian tube epithelium.

4.
Nat Commun ; 15(1): 1452, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365780

RESUMO

The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids, tumoroids, or tissue explants. Despite rapid advancement in microvascular network systems and organoid technologies, vascularizing organoids-on-chips remains a challenge in tissue engineering. Most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical set-ups. Considering these constraints, we develop a platform to establish and monitor the formation of endothelial networks around mesenchymal and pancreatic islet spheroids, as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 30 days on-chip. We show that these networks establish functional connections with the endothelium-rich spheroids and vascular organoids, as they successfully provide intravascular perfusion to these structures. We find that organoid growth, maturation, and function are enhanced when cultured on-chip using our vascularization method. This microphysiological system represents a viable organ-on-chip model to vascularize diverse biological 3D tissues and sets the stage to establish organoid perfusions using advanced microfluidics.


Assuntos
Ilhotas Pancreáticas , Microfluídica , Organoides , Engenharia Tecidual/métodos , Endotélio , Ilhotas Pancreáticas/irrigação sanguínea
5.
bioRxiv ; 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38370789

RESUMO

Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.

6.
Child Abuse Negl ; : 106640, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38278687

RESUMO

BACKGROUND: While adverse childhood experiences (ACEs) predict poorer mental health across the life course, positive childhood experiences (PCEs) predict better mental health. It is unclear whether PCEs protect against poor mental health outcomes and promote mental well-being in pandemic-era adolescents with ACEs. METHODS: We examined the individual and joint contributions of ACEs and PCEs to mental health and well-being (MHW) in eleventh-grade British Columbian adolescents (N = 8864) during the fifth wave of COVID-19. We used a novel measure of ACEs that included community- and societal-level ACEs in addition to ACEs experienced at home to investigate the role of social and structural determinants of mental health in supporting the MHW of pandemic-era adolescents. A series of two-way ANCOVAs were conducted comparing MHW outcomes between adolescents with and without ACEs. Interaction effects were examined to investigate whether PCEs moderated the association between ACEs and MHW. RESULTS: Adolescents with no ACEs had significantly better MHW than those with one or more ACE. Having six or more PCEs was associated with better MHW in adolescents with and without ACEs. PCEs significantly moderated the association between ACEs and depression. Effect sizes were larger for PCEs than ACEs in relation to depression, mental well-being, and life satisfaction. CONCLUSIONS: PCEs may protect against depression among adolescents with ACEs and promote MHW among all pandemic-era adolescents. These findings emphasize the importance of addressing social determinants of mental health to mitigate the impact of ACEs and promote PCEs as part of a public health approach to MHW.

7.
Am J Bot ; 110(11): e16249, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37792319

RESUMO

PREMISE: Bryophytes form a major component of terrestrial plant biomass, structuring ecological communities in all biomes. Our understanding of the evolutionary history of hornworts, liverworts, and mosses has been significantly reshaped by inferences from molecular data, which have highlighted extensive homoplasy in various traits and repeated bursts of diversification. However, the timing of key events in the phylogeny, patterns, and processes of diversification across bryophytes remain unclear. METHODS: Using the GoFlag probe set, we sequenced 405 exons representing 228 nuclear genes for 531 species from 52 of the 54 orders of bryophytes. We inferred the species phylogeny from gene tree analyses using concatenated and coalescence approaches, assessed gene conflict, and estimated the timing of divergences based on 29 fossil calibrations. RESULTS: The phylogeny resolves many relationships across the bryophytes, enabling us to resurrect five liverwort orders and recognize three more and propose 10 new orders of mosses. Most orders originated in the Jurassic and diversified in the Cretaceous or later. The phylogenomic data also highlight topological conflict in parts of the tree, suggesting complex processes of diversification that cannot be adequately captured in a single gene-tree topology. CONCLUSIONS: We sampled hundreds of loci across a broad phylogenetic spectrum spanning at least 450 Ma of evolution; these data resolved many of the critical nodes of the diversification of bryophytes. The data also highlight the need to explore the mechanisms underlying the phylogenetic ambiguity at specific nodes. The phylogenomic data provide an expandable framework toward reconstructing a comprehensive phylogeny of this important group of plants.


Assuntos
Briófitas , Hepatófitas , Filogenia , Briófitas/genética , Plantas/genética , Hepatófitas/genética
8.
Phys Rev Lett ; 131(10): 106301, 2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37739351

RESUMO

The dynamical phase diagram of interacting disordered systems has seen substantial revision over the past few years. Theory must now account for a large prethermal many-body localized regime in which thermalization is extremely slow, but not completely arrested. We derive a quantitative description of these dynamics in short-ranged one-dimensional systems using a model of successive many-body resonances. The model explains the decay timescale of mean autocorrelators, the functional form of the decay-a stretched exponential-and relates the value of the stretch exponent to the broad distribution of resonance timescales. The Jacobi method of matrix diagonalization provides numerical access to this distribution, as well as a conceptual framework for our analysis. The resonance model correctly predicts the stretch exponents for several models in the literature. Successive resonances may also underlie slow thermalization in strongly disordered systems in higher dimensions, or with long-range interactions.

9.
Redox Biol ; 65: 102841, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37566945

RESUMO

Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9 MDa mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary human monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB, which impairs both glutathione- and thioredoxin-based reductase systems, elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, LPS and MitoCDNB together are highly synergistic for PDCE2 glutathionylation, ROS production, and cell death. Surprisingly, the two treatments together had differential effects on cytokine production; pro-inflammatory IL-1ß production was enhanced by the co-treatment, while IL-10, an important anti-inflammatory cytokine, dropped precipitously compared to LPS treatment alone. This new information may expand opportunities to understand and modulate PDC redox status and activity and improve the outcomes of pathological inflammation.


Assuntos
Lipopolissacarídeos , Estresse Oxidativo , Humanos , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/genética , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Inflamação , Piruvatos , Citocinas/metabolismo
10.
Int J Ment Health Nurs ; 32(6): 1473-1483, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37605318

RESUMO

Emerging terms in the literature such as climate anxiety describe heightened concern, fear, and anxiety related to the climate crisis. Recent efforts have attempted to develop and validate scales to measure climate anxiety; however, extant research is largely focused on adults. Consequently, it is unclear whether developed measures are appropriate for adolescent populations, despite disproportionate impacts of the climate crisis experienced by this age group. The purpose of this study was two-fold; first, we aimed to assess levels of climate concern among Canadian adolescents using the Youth Development Instrument (YDI), a population-level youth well-being survey administered in schools with students (ages 15-18). Secondly, we collaborated with adolescents to adapt an existing climate anxiety scale to be included in the YDI survey. We used survey results to validate the adapted scale for use with adolescents and assessed levels of climate anxiety within our sample. In consultation with adolescents, the 13-item Climate Change Anxiety Scale (CCAS) was adapted to create the Climate Change Anxiety Scale - Short-form (CCAS-S) which consists of four-items adapted from the original CCAS. A total of 2306 respondents were included in analyses. Most adolescents reported feeling climate change concern (75.8%). A smaller proportion reported experiences of climate anxiety (48.7%). Confirmatory factor analysis supported a one-factor structure for the CCAS-S, with high internal consistency (Cronbach's alpha = 0.95) and good model fit with error co-variance. Findings from this study provide construct validity evidence and reliability for the use of the CCAS-S in adolescent populations.


Assuntos
Transtornos de Ansiedade , Ansiedade , Adulto , Humanos , Adolescente , Reprodutibilidade dos Testes , Canadá , Inquéritos e Questionários , Ansiedade/diagnóstico , Psicometria
11.
Plants (Basel) ; 12(12)2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37375890

RESUMO

Former mine sites can provide habitat for many rare specialised bryophyte species that have adapted to metal-rich soil conditions that are toxic to most other plant species. Some of the bryophyte species found in this habitat are facultative metallophytes, and others are regarded as strict metallophytes, the so-called 'copper mosses'. It is a general assumption in the literature that Cephaloziella nicholsonii and C. massalongoi, both categorised as Endangered in the IUCN Red List for Europe, are also strict metallophytes and obligate copper bryophytes. This in vitro experiment investigated the growth and gemma production of these two species from different sites in Ireland and Britain on treatment plates of 0 ppm, 3 ppm, 6 ppm, 12 ppm, 24 ppm, 48 ppm and 96 ppm copper. Results show that elevated copper is not an obligate requirement for optimum growth. Differences in response to the copper treatment levels among populations evident within both species could possibly be due to ecotypic variation. A case is also made for the taxonomic revision of the Cephaloziella genus. Implications for the species' conservation are discussed.

12.
bioRxiv ; 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37034801

RESUMO

Background: The kidney vasculature is exquisitely structured to orchestrate renal function. Structural profiling of the vasculature in intact rodent kidneys, has provided insights into renal haemodynamics and oxygenation, but has never been extended to the human kidney beyond a few vascular generations. We hypothesised that synchrotron-based imaging of a human kidney would enable assessment of vasculature across the whole organ. Methods: An intact kidney from a 63-year-old male was scanned using hierarchical phase-contrast tomography (HiP-CT), followed by semi-automated vessel segmentation and quantitative analysis. These data were compared to published micro-CT data of whole rat kidney. Results: The intact human kidney vascular network was imaged with HiP-CT at 25 µm voxels, representing a 20-fold increase in resolution compared to clinical CT scanners. Our comparative quantitative analysis revealed the number of vessel generations, vascular asymmetry and a structural organisation optimised for minimal resistance to flow, are conserved between species, whereas the normalised radii are not. We further demonstrate regional heterogeneity in vessel geometry between renal cortex, medulla, and hilum, showing how the distance between vessels provides a structural basis for renal oxygenation and hypoxia. Conclusions: Through the application of HiP-CT, we have provided the first quantification of the human renal arterial network, with a resolution comparable to that of light microscopy yet at a scale several orders of magnitude larger than that of a renal punch biopsy. Our findings bridge anatomical scales, profiling blood vessels across the intact human kidney, with implications for renal physiology, biophysical modelling, and tissue engineering.

14.
bioRxiv ; 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-36747682

RESUMO

Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9 megadalton mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary human monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB, which impairs both glutathione- and thioredoxin-based reductase systems, elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, LPS and MitoCDNB together are highly synergistic for PDCE2 glutathionylation, ROS production, and cell death. Surprisingly, the two treatments together had differential effects on cytokine production; pro-inflammatory IL-1ß production was enhanced by the co-treatment, while IL-10, an important anti-inflammatory cytokine, dropped precipitously compared to LPS treatment alone. This new information may expand opportunities to understand and modulate PDC redox status and activity and improve the outcomes of pathological inflammation.

15.
Health Promot Chronic Dis Prev Can ; 43(4): 182-190, 2023 04 12.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-36651881

RESUMO

INTRODUCTION: The COVID-19 pandemic has had widespread effects on adolescent mental health. However, little is known about support-seeking, unmet need and preferences for mental health care among adolescents. METHODS: The Youth Development Instrument (YDI) is a school-administered survey of adolescents (N = 1928, mean age = 17.1, SD = 0.3) across British Columbia, Canada. In this cohort, we assessed the characteristics of accessed mental health supports, prevalence of unmet need and preferences for in-person versus internet-based services. RESULTS: Overall, 40% of adolescents obtained support for mental health, while 41% experienced unmet need. The most commonly accessed supports were family doctors or pediatricians (23.1%) and adults at school (20.6%). The most preferred mode of mental health care was in-person counselling (72.4%), followed by chat-based services (15.0%), phone call (8.1%) and video call (4.4%). The adjusted prevalence of accessing support was elevated among adolescents with anxiety (adjusted prevalence ratio [aPR] = 1.29, 95% CI: 1.10-1.51), those who used alcohol (1.14, 1.01-1.29), gender minorities (1.28, 1.03-1.58) and sexual minorities (1.28, 1.03-1.45). The adjusted prevalence of unmet need was elevated among adolescents with depression (1.90, 1.67-2.18), those with anxiety (1.78, 1.56-2.03), females (1.43, 1.31-1.58), gender minorities (1.45, 1.23-1.70) and sexual minorities (1.15, 1.07-1.23). CONCLUSION: Adolescents of gender or sexual minority status and those with anxiety were more likely than others to have discussed mental health concerns and also to have reported unmet need. The most common sources of support were primary health care providers and adults at school, while the most and least preferred modes of support were in-person and video call services, respectively.


Assuntos
COVID-19 , Serviços de Saúde Mental , Adulto , Feminino , Humanos , Adolescente , Saúde Mental , Pandemias , COVID-19/epidemiologia , COVID-19/terapia , Colúmbia Britânica/epidemiologia
16.
Prehosp Emerg Care ; 27(5): 669-686, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35579544

RESUMO

INTRODUCTION: There is limited research available on safe medication management practices in emergency medical services (EMS) practice, with most evidence-based medication safety guidelines based on research in nursing, operating theater and pharmacy settings. Prevention of errors requires recognition of contributing factors across the spectrum from the organizational level to procedural elements and patient characteristics. Evidence is inconsistent regarding the incidence of medication errors and multiple sources also state that errors are under-reported, making the true magnitude of the problem difficult to quantify. Definitions of error also vary, with the specific context of medication errors in prehospital practice yet to be established. The objective of this review is to identify the factors influencing the occurrence of medication errors by EMS personnel in the prehospital environment. METHODS AND ANALYSIS: The review included both qualitative and quantitative research involving interventions or phenomena related to medication safety or medication error by EMS personnel in the prehospital environment. A search of multiple databases was conducted to identify studies meeting these inclusion criteria. All studies selected were assessed for methodological quality; however, this was not used as a basis for exclusion. Each stage of study selection, appraisal and data extraction was conducted by two independent reviewers, with a third reviewer deciding any unresolved conflicts. The review follows a convergent integrated approach, conducting a single qualitative synthesis of qualitative and "qualitized" quantitative data. RESULTS: Fifty-six articles were included in the review, with case reports and qualitative studies being the most frequent study types. Qualitative analysis revealed seven major themes: organizational factors (with reporting as a sub-theme), equipment/medications, environmental factors, procedure-related factors, communication, patient-related factors (with pediatrics as a sub-theme) and cognitive factors. Both contributing factors and protective factors were identified. DISCUSSION: The body of evidence regarding medication errors is heterogenous and limited in both quantity and quality. Multiple factors influence medication error occurrence; knowledge of these is necessary to mitigate the risk of errors. Medication error incidence is difficult to quantify due to inconsistent measure, definitions and contexts of research conducted to date. Further research is required to quantify the prevalence of identified factors in specific practice settings.


Assuntos
Serviços Médicos de Emergência , Auxiliares de Emergência , Humanos , Criança , Paramédico , Erros de Medicação/prevenção & controle , Pesquisa Qualitativa
17.
Sci Adv ; 8(49): eadd8928, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36475791

RESUMO

BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4 functions on transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interacts with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 recruitment to acetylated histones/chromatin. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 and highlight targeting PRMT2/4 for better antitumor effect of BET inhibitors and DNA damaging agents.


Assuntos
Neoplasias , Proteínas Nucleares , Humanos , Proteínas Nucleares/genética , Arginina , Fatores de Transcrição/genética , Reparo do DNA , DNA , Cromatina , Proteína-Arginina N-Metiltransferases/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Ciclo Celular/genética
18.
J Biol Chem ; 298(11): 102578, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36220390

RESUMO

Modification of histones provides a dynamic mechanism to regulate chromatin structure and access to DNA. Histone acetylation, in particular, plays a prominent role in controlling the interaction between DNA, histones, and other chromatin-associated proteins. Defects in histone acetylation patterns interfere with normal gene expression and underlie a wide range of human diseases. Here, we utilize Xenopus egg extracts to investigate how changes in histone acetylation influence transcription of a defined gene construct. We show that inhibition of histone deacetylase 1 and 2 (HDAC1/2) specifically counteracts transcription suppression by preventing chromatin compaction and deacetylation of histone residues H4K5 and H4K8. Acetylation of these sites supports binding of the chromatin reader and transcription regulator BRD4. We also identify HDAC1 as the primary driver of transcription suppression and show that this activity is mediated through the Sin3 histone deacetylase complex. These findings highlight functional differences between HDAC1 and HDAC2, which are often considered to be functionally redundant, and provide additional molecular context for their activity.


Assuntos
Histonas , Proteínas Nucleares , Animais , Humanos , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo , Histonas/metabolismo , Xenopus laevis/metabolismo , Proteínas Nucleares/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Cromatina , Acetilação , DNA/metabolismo , Proteínas de Ciclo Celular/metabolismo
19.
Opt Express ; 30(11): 19510-19523, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-36221725

RESUMO

We demonstrate a microfabricated optomechanical accelerometer that is capable of percent-level accuracy without external calibration. To achieve this capability, we use a mechanical model of the device behavior that can be characterized by the thermal noise response along with an optical frequency comb readout method that enables high sensitivity, high bandwidth, high dynamic range, and SI-traceable displacement measurements. The resulting intrinsic accuracy was evaluated over a wide frequency range by comparing to a primary vibration calibration system and local gravity. The average agreement was found to be 2.1 % for the calibration system between 0.1 kHz and 15 kHz and better than 0.2 % for the static acceleration. This capability has the potential to replace costly external calibrations and improve the accuracy of inertial guidance systems and remotely deployed accelerometers. Due to the fundamental nature of the intrinsic accuracy approach, it could be extended to other optomechanical transducers, including force and pressure sensors.

20.
Sensors (Basel) ; 22(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36298277

RESUMO

Ocean Acidification (OA) is negatively affecting the physiological processes of marine organisms, altering biogeochemical cycles, and changing chemical equilibria throughout the world's oceans. It is difficult to measure pH broadly, in large part because accurate pH measurement technology is expensive, bulky, and requires technical training. Here, we present the development and evaluation of a hand-held, affordable, field-durable, and easy-to-use pH instrument, named the pHyter, which is controlled through a smartphone app. We determine the accuracy of pH measurements using the pHyter by comparison with benchtop spectrophotometric seawater pH measurements, measurement of a certified pH standard, and comparison with a proven in situ instrument, the iSAMI-pH. These results show a pHyter pH measurement accuracy of ±0.046 pH or better, which is on par with interlaboratory seawater pH measurement comparison experiments. We also demonstrate the pHyter's ability to conduct both temporal and spatial studies of coastal ecosystems by presenting data from a coral reef and a bay, in which the pHyter was used from a kayak. These studies showcase the instrument's portability, applicability, and potential to be used for community science, STEM education, and outreach, with the goal of empowering people around the world to measure pH in their own backyards.


Assuntos
Ecossistema , Água do Mar , Água do Mar/química , Prótons , Concentração de Íons de Hidrogênio , Fótons , Oceanos e Mares , Dióxido de Carbono/análise
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