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The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.
Assuntos
Doença de Alzheimer , Amiloide , Encéfalo , Líquido Cefalorraquidiano , Líquido Extracelular , Ritmo Gama , Sistema Glinfático , Animais , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Amiloide/metabolismo , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Líquido Cefalorraquidiano/metabolismo , Modelos Animais de Doenças , Líquido Extracelular/metabolismo , Sistema Glinfático/fisiologia , Interneurônios/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Estimulação ElétricaRESUMO
Communication between neurons and glia has an important role in establishing and maintaining higher-order brain function1. Astrocytes are endowed with complex morphologies, placing their peripheral processes in close proximity to neuronal synapses and directly contributing to their regulation of brain circuits2-4. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation5-7; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unclear. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABAB receptor (GABABR) and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABABR in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together, our studies identify input from inhibitory neurons and astrocytic GABABR as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes.
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Astrócitos , Forma Celular , Inibição Neural , Neurônios , Receptores de GABA-B , Astrócitos/citologia , Astrócitos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Neurônios/metabolismo , Sinapses/metabolismo , Receptores de GABA-B/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição NFI/metabolismo , Regulação da Expressão GênicaRESUMO
The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.
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Neoplasias Encefálicas , Carcinogênese , Glioma , Neurônios , Microambiente Tumoral , Humanos , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Glioma/patologia , Glioma/fisiopatologia , Neurônios/patologia , Proliferação de Células , Sinapses , Progressão da Doença , Animais , Camundongos , Axônios , Corpo Caloso/patologia , Vias NeuraisRESUMO
Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.
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Dioxigenases , Intolerância à Glucose , Hiperglicemia , Oócitos , Adulto , Animais , Dioxigenases/metabolismo , Feminino , Glucose/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Herança Materna , Camundongos , Oócitos/metabolismoRESUMO
Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment1,2. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma3,4. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.
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Neoplasias Encefálicas/enzimologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Glioblastoma/enzimologia , Animais , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/genética , Modelos Animais de Doenças , Glioblastoma/patologia , Glipicanas/metabolismo , CamundongosRESUMO
The ParABS system, composed of ParA (an ATPase), ParB (a DNA binding protein), and parS (a centromere-like DNA), regulates bacterial chromosome partition. The ParB-parS partition complex interacts with the nucleoid-bound ParA to form the nucleoid-adaptor complex (NAC). In Helicobacter pylori, ParA and ParB homologs are encoded as HpSoj and HpSpo0J (HpParA and HpParB), respectively. We determined the crystal structures of the ATP hydrolysis deficient mutant, HpParAD41A, and the HpParAD41A-DNA complex. We assayed the CTPase activity of HpParB and identified two potential DNA binding modes of HpParB regulated by CTP, one is the specific DNA binding by the DNA binding domain and the other is the non-specific DNA binding through the C-terminal domain under the regulation of CTP. We observed an interaction between HpParAD41A and the N-terminus fragment of HpParB (residue 1-10, HpParBN10) and determined the crystal structure of the ternary complex, HpParAD41A-DNA-HpParBN10 complex which mimics the NAC formation. HpParBN10 binds near the HpParAD41A dimer interface and is clamped by flexible loops, L23 and L34, through a specific cation-π interaction between Arg9 of HpParBN10 and Phe52 of HpParAD41A. We propose a molecular mechanism model of the ParABS system providing insight into chromosome partition in bacteria.
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Proteínas de Bactérias , Cromossomos Bacterianos , Proteínas de Ligação a DNA , Helicobacter pylori , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Cromossomos Bacterianos/metabolismo , Cromossomos Bacterianos/química , Cromossomos Bacterianos/genética , Modelos Moleculares , Cristalografia por Raios X , Ligação Proteica , DNA Bacteriano/metabolismo , DNA Bacteriano/química , DNA Bacteriano/genética , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Segregação de Cromossomos , Trifosfato de Adenosina/metabolismo , Sítios de LigaçãoRESUMO
Genome segregation is a fundamental process that preserves the genetic integrity of all organisms, but the mechanisms driving genome segregation in archaea remain enigmatic. This study delved into the unknown function of SegC (SSO0033), a novel protein thought to be involved in chromosome segregation in archaea. Using fluorescence polarization DNA binding assays, we discovered the ability of SegC to bind DNA without any sequence preference. Furthermore, we determined the crystal structure of SegC at 2.8 Å resolution, revealing the multimeric configuration and forming a large positively charged surface that can bind DNA. SegC has a tertiary structure folding similar to those of the ThDP-binding fold superfamily, but SegC shares only 5-15% sequence identity with those proteins. Unexpectedly, we found that SegC has nucleotide triphosphatase (NTPase) activity. We also determined the SegC-ADP complex structure, identifying the NTP binding pocket and relative SegC residues involved in the interaction. Interestingly, images from negative-stain electron microscopy revealed that SegC forms filamentous structures in the presence of DNA and NTPs. Further, more uniform and larger SegC-filaments are observed, when SegA-ATP was added. Notably, the introduction of SegB disrupts these oligomers, with ATP being essential for regulating filament formation. These findings provide insights into the functional and structural role of SegC in archaeal chromosome segregation.
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Whereas previous research has described motherhood penalties in US survey data, we leverage administrative data on 811,000 quarterly earnings histories from the US Unemployment Insurance program. We analyze contexts where smaller motherhood penalties might be expected: couples where the woman outearns her male partner prior to childbearing, at firms that are headed by women, and at firms that are predominantly women. Our startling result is that none of these propitious contexts appear to diminish the motherhood penalty, and indeed, the gap often increases in magnitude over time following childbearing. We estimate one of the largest motherhood penalties in "female-breadwinner" families, where higher-earning women experience a 60% drop from their prechildbirth earnings relative to their male partners. Turning to proximate mechanisms, women are less likely to switch to a higher-paying firm postchildbearing than men and are substantially more likely to quit the labor force. On the whole, our findings are discouraging relative even to existing research on motherhood penalties.
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Emprego , Renda , Humanos , Masculino , Feminino , Salários e BenefíciosRESUMO
Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.
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After Epstein-Barr virus (EBV) genome replication and encapsidation in the nucleus, nucleocapsids are translocated into the cytoplasm for subsequent tegumentation and maturation. The EBV BGLF4 kinase, which induces partial disassembly of the nuclear lamina, and the nuclear egress complex BFRF1/BFLF2 coordinately facilitate the nuclear egress of nucleocapsids. Here, we demonstrate that within EBV reactivated epithelial cells, viral capsids, tegument proteins, and glycoproteins are clustered in the juxtanuclear concave region, accompanied by redistributed cytoplasmic organelles and the cytoskeleton regulator IQ-domain GTPase-activation protein 1 (IQGAP1), close to the microtubule-organizing center (MTOC). The assembly compartment (AC) structure was diminished in BGLF4-knockdown TW01-EBV cells and BGLF4-knockout bacmid-carrying TW01 cells, suggesting that the formation of AC structure is BGLF4-dependent. Notably, glycoprotein gp350/220 was observed by confocal imaging to be distributed in the perinuclear concave region and surrounded by the endoplasmic reticulum (ER) membrane marker calnexin, indicating that the AC may be located within a globular structure derived from ER membranes, adjacent to the outer nuclear membrane. Moreover, the viral capsid protein BcLF1 and tegument protein BBLF1 were co-localized with IQGAP1 near the cytoplasmic membrane in the late stage of replication. Knockdown of IQGAP1 did not affect the AC formation but decreased virion release from both TW01-EBV and Akata+ cells, suggesting IQGAP1-mediated trafficking regulates EBV virion release. The data presented here show that BGLF4 is required for cytoskeletal rearrangement, coordination with the redistribution of cytoplasmic organelles and IQGAP1 for virus maturation, and subsequent IQGAP1-dependent virion release.IMPORTANCEEBV genome is replicated and encapsidated in the nucleus, and the resultant nucleocapsids are translocated to the cytoplasm for subsequent virion maturation. We show that a cytoplasmic AC, containing viral proteins, markers of the endoplasmic reticulum, Golgi, and endosomes, is formed in the juxtanuclear region of epithelial and B cells during EBV reactivation. The viral BGLF4 kinase contributes to the formation of the AC. The cellular protein IQGAP1 is also recruited to the AC and partially co-localizes with the virus capsid protein BcLF1 and tegument protein BBLF1 in EBV-reactivated cells, dependent on the BGLF4-induced cytoskeletal rearrangement. In addition, virion release was attenuated in IQGAP1-knockdown epithelial and B cells after reactivation, suggesting that IQGAP1-mediated trafficking may regulate the efficiency of virus maturation and release.
Assuntos
Citoplasma , Herpesvirus Humano 4 , Proteínas Serina-Treonina Quinases , Proteínas Virais , Vírion , Montagem de Vírus , Liberação de Vírus , Proteínas Ativadoras de ras GTPase , Humanos , Proteínas do Capsídeo/metabolismo , Citoplasma/metabolismo , Citoplasma/virologia , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/química , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas Virais/metabolismo , Vírion/química , Vírion/crescimento & desenvolvimento , Vírion/metabolismo , Montagem de Vírus/fisiologia , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Complexo de Golgi/metabolismoRESUMO
The quantum behaviour of electrons in materials is the foundation of modern electronics and information technology1-11, and quantum materials with topological electronic and optical properties are essential for realizing quantized electronic responses that can be used for next generation technology. Here we report the first observation of topological quantum properties of chiral crystals6,7 in the RhSi family. We find that this material class hosts a quantum phase of matter that exhibits nearly ideal topological surface properties originating from the crystals' structural chirality. Electrons on the surface of these crystals show a highly unusual helicoid fermionic structure that spirals around two high-symmetry momenta, indicating electronic topological chirality. The existence of bulk multiply degenerate band fermions is guaranteed by the crystal symmetries; however, to determine the topological invariant or charge in these chiral crystals, it is essential to identify and study the helicoid topology of the arc states. The helicoid arcs that we observe on the surface characterize the topological charges of ±2, which arise from bulk higher-spin chiral fermions. These topological conductors exhibit giant Fermi arcs of maximum length (π), which are orders of magnitude larger than those found in known chiral Weyl fermion semimetals5,8-11. Our results demonstrate an electronic topological state of matter on structurally chiral crystals featuring helicoid-arc quantum states. Such exotic multifold chiral fermion semimetal states could be used to detect a quantized photogalvanic optical response, the chiral magnetic effect and other optoelectronic phenomena predicted for this class of materials6.
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Pulmonary hypertension (PH) is a chronic progressive vascular disease characterized by abnormal pulmonary vascular resistance and pulmonary artery pressure. The major structural alteration during PH is pulmonary vascular remodelling, which is mainly caused by the imbalance between proliferation and apoptosis of pulmonary vascular cells. Previously, it was thought that apoptosis was the only type of programmed cell death (PCD). Soon afterward, other types of PCD have been identified, including autophagy, pyroptosis, ferroptosis and necroptosis. In this review, we summarize the role of the above five forms of PCD in mediating pulmonary vascular remodelling, and discuss their guiding significance for PH treatment. The current review could provide a better understanding of the correlation between PCD and pulmonary vascular remodelling, contributing to identify new PCD-associated drug targets for PH.
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Apoptose , Hipertensão Pulmonar , Remodelação Vascular , Humanos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Animais , Necroptose , Transdução de Sinais , Autofagia , Ferroptose , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , PiroptoseRESUMO
Taiwan provided several COVID-19 vaccine platforms: mRNA (BNT162b2, mRNA-1273), adenoviral vector-based (AZD1222), and protein subunit (MVC-COV1901). After Taiwan shifted from its zero-COVID strategy in April 2022, population-based evaluation of vaccine effectiveness (VE) became possible. We conducted an observational cohort study of 21,416,151 persons to examine VE against SARS-CoV-2 infection, moderate and severe illness, and death during March 22, 2021-September 30, 2022. After adjusting for age and sex, we found that persons who completed 3 vaccine doses (2 primary, 1 booster) or received MVC-COV1901 as the primary series had the lowest hospitalization incidence (0.04-0.20 cases/100,000 person-days). We also found 95.8% VE against hospitalization for 3 doses of BNT162b2, 91.0% for MVC-COV1901, 81.8% for mRNA-1273, and 65.7% for AZD1222, which had the lowest overall VE. Our findings indicated that protein subunit vaccines provide similar protection against SARS-CoV-2---associated hospitalization as mRNA vaccines and can inform mix-and-match vaccine selection in other countries.
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COVID-19 , Humanos , Vacina de mRNA-1273 contra 2019-nCoV , Vacina BNT162 , ChAdOx1 nCoV-19 , Estudos de Coortes , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , SARS-CoV-2/genética , Taiwan/epidemiologia , Eficácia de Vacinas , Masculino , FemininoRESUMO
Data from 200 children with high-risk acute myeloid leukaemia who underwent their first haploidentical haematopoietic stem cell transplantation (haplo-HSCT) between 2015 and 2021 at our institution were analysed. The 4-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 71.9%, 62.3% and 32.4% respectively. The 100-day cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 41.1% and 9.5% respectively. The 4-year cumulative incidence of chronic GVHD (cGVHD) was 56.1%, and that of moderate-to-severe cGVHD was 27.3%. Minimal residual disease (MRD)-positive (MRD+) status pre-HSCT was significantly associated with lower survival and a higher risk of relapse. The 4-year OS, EFS and CIR differed significantly between patients with MRD+ pre-HSCT (n = 97; 63.4%, 51.4% and 41.0% respectively) and those with MRD-negative (MRD-) pre-HSCT (n = 103; 80.5%, 73.3% and 23.8% respectively). Multivariate analysis also revealed that acute megakaryoblastic leukaemia without Down syndrome (non-DS-AMKL) was associated with extremely poor outcomes (hazard ratios and 95% CIs for OS, EFS and CIR: 3.110 (1.430-6.763), 3.145 (1.628-6.074) and 3.250 (1.529-6.910) respectively; p-values were 0.004, 0.001 and 0.002 respectively). Thus, haplo-HSCT can be a therapy option for these patients, and MRD status pre-HSCT significantly affects the outcomes. As patients with non-DS-AMKL have extremely poor outcomes, even with haplo-HSCT, a combination of novel therapies is urgently needed.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Megacarioblástica Aguda , Leucemia Mieloide Aguda , Criança , Humanos , Seguimentos , Recidiva Local de Neoplasia/etiologia , Leucemia Mieloide Aguda/terapia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Megacarioblástica Aguda/complicações , Recidiva , Estudos RetrospectivosRESUMO
Landfilling is long the most common method of disposal for municipal solid waste (MSW). However, many countries seek to implement different methods of MSW treatment due to the high global warming potential associated with landfilling. Other methods such as recycling and incineration are either limited to only a fraction of generated MSW or still produce large greenhouse gas emissions, thereby providing an unsustainable disposal method. Here, the production of graphene from treated MSW is reported that including treated wood waste, using flash Joule heating. Results indicated a 71%-83% reduction in global warming potential compared to traditional disposal methods at a net cost of -$282 of MSW, presuming the graphene is sold at just 5% of its current market value to offset the cost of the flash Joule heating process.
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Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI3) perovskite is investigated. Abundant {111}c intragrain planar defects in pure FAPbI3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111}c intragrain planar defects.
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Defects can introduce atomic structural modulation and tailor performance of materials. Herein, it demonstrates that semiconductor WO3 with inert electrocatalytic behavior can be activated through defect-induced tensile strains. Structural characterizations reveal that when simply treated in Ar/H2 atmosphere, oxygen vacancies will generate in WO3 and cause defective structures. Stacking faults are found in defects, thus modulating electronic structure and transforming electrocatalytic-inert WO3 into highly active electrocatalysts. Density functional theory (DFT) calculations are performed to calculate *H adsorption energies on various WOx surfaces, revealing the oxygen vacancy composition and strain predicted to optimize the catalytic activity of hydrogen evolution reaction (HER). Such defective tungsten oxides can be integrated into commercial proton exchange membrane (PEM) electrolyser with comparable performance toward Pt-based PEM. This work demonstrates defective metal oxides as promising non-noble metal catalysts for commercial PEM green-hydrogen generation.
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OBJECTIVES: We aimed to develop a computer-aided detection (CAD) system to localize and detect the malposition of endotracheal tubes (ETTs) on portable supine chest radiographs (CXRs). DESIGN: This was a retrospective diagnostic study. DeepLabv3+ with ResNeSt50 backbone and DenseNet121 served as the model architecture for segmentation and classification tasks, respectively. SETTING: Multicenter study. PATIENTS: For the training dataset, images meeting the following inclusion criteria were included: 1) patient age greater than or equal to 20 years; 2) portable supine CXR; 3) examination in emergency departments or ICUs; and 4) examination between 2015 and 2019 at National Taiwan University Hospital (NTUH) (NTUH-1519 dataset: 5,767 images). The derived CAD system was tested on images from chronologically (examination during 2020 at NTUH, NTUH-20 dataset: 955 images) or geographically (examination between 2015 and 2020 at NTUH Yunlin Branch [YB], NTUH-YB dataset: 656 images) different datasets. All CXRs were annotated with pixel-level labels of ETT and with image-level labels of ETT presence and malposition. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For the segmentation model, the Dice coefficients indicated that ETT would be delineated accurately (NTUH-20: 0.854; 95% CI, 0.824-0.881 and NTUH-YB: 0.839; 95% CI, 0.820-0.857). For the classification model, the presence of ETT could be accurately detected with high accuracy (area under the receiver operating characteristic curve [AUC]: NTUH-20, 1.000; 95% CI, 0.999-1.000 and NTUH-YB: 0.994; 95% CI, 0.984-1.000). Furthermore, among those images with ETT, ETT malposition could be detected with high accuracy (AUC: NTUH-20, 0.847; 95% CI, 0.671-0.980 and NTUH-YB, 0.734; 95% CI, 0.630-0.833), especially for endobronchial intubation (AUC: NTUH-20, 0.991; 95% CI, 0.969-1.000 and NTUH-YB, 0.966; 95% CI, 0.933-0.991). CONCLUSIONS: The derived CAD system could localize ETT and detect ETT malposition with excellent performance, especially for endobronchial intubation, and with favorable potential for external generalizability.
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Aprendizado Profundo , Medicina de Emergência , Humanos , Estudos Retrospectivos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Hospitais UniversitáriosRESUMO
Multistrand RNA complexes play a critical role in RNA-related biological processes. The understanding of RNA functions and the rational design of RNA nanostructures require accurate prediction of the structure and folding stability of the complexes, including those containing pseudoknots. Here, we present VfoldMCPX, a new model for predicting two-dimensional (2D) structures and folding stabilities of multistrand RNA complexes. Based on a partition function-based algorithm combined with physical loop free energy parameters, the VfoldMCPX model predicts not only the native structure but also the folding stability of the complex. An important advantage of the model is the ability to treat pseudoknotted structures. Extensive tests on structure predictions show the VfoldMCPX model provides improved accuracy for multistranded RNA complexes, especially for RNA complexes with three or more strands and/or containing pseudoknots. We have developed a freely accessible VfoldMCPX web server at http://rna.physics.missouri.edu/vfoldMCPX2.
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Nanoestruturas , RNA , Algoritmos , Conformação de Ácido Nucleico , RNA/genéticaRESUMO
PURPOSE OF REVIEW: Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS). RECENT FINDINGS: Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype. SUMMARY: Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.