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1.
Nature ; 599(7886): 594-598, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34819678

RESUMO

Light-emitting diodes (LEDs) based on perovskite quantum dots have shown external quantum efficiencies (EQEs) of over 23% and narrowband emission, but suffer from limited operating stability1. Reduced-dimensional perovskites (RDPs) consisting of quantum wells (QWs) separated by organic intercalating cations show high exciton binding energies and have the potential to increase the stability and the photoluminescence quantum yield2,3. However, until now, RDP-based LEDs have exhibited lower EQEs and inferior colour purities4-6. We posit that the presence of variably confined QWs may contribute to non-radiative recombination losses and broadened emission. Here we report bright RDPs with a more monodispersed QW thickness distribution, achieved through the use of a bifunctional molecular additive that simultaneously controls the RDP polydispersity while passivating the perovskite QW surfaces. We synthesize a fluorinated triphenylphosphine oxide additive that hydrogen bonds with the organic cations, controlling their diffusion during RDP film deposition and suppressing the formation of low-thickness QWs. The phosphine oxide moiety passivates the perovskite grain boundaries via coordination bonding with unsaturated sites, which suppresses defect formation. This results in compact, smooth and uniform RDP thin films with narrowband emission and high photoluminescence quantum yield. This enables LEDs with an EQE of 25.6% with an average of 22.1 ±1.2% over 40 devices, and an operating half-life of two hours at an initial luminance of 7,200 candela per metre squared, indicating tenfold-enhanced operating stability relative to the best-known perovskite LEDs with an EQE exceeding 20%1,4-6.

2.
Nucleic Acids Res ; 51(10): 5040-5055, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37114996

RESUMO

A large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, the mitotic behaviors of TFs from the same DBD family may vary. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is somewhat decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes to the same degree, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF DBDs can coat mitotic chromosomes, and that HSF2 DBD is able to establish site-specific binding. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.


Assuntos
Cromossomos , Proteínas de Choque Térmico , Mitose , Fatores de Transcrição , Animais , Camundongos , Cromossomos/genética , Cromossomos/metabolismo , DNA/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Fatores de Transcrição/metabolismo
3.
Proc Natl Acad Sci U S A ; 119(43): e2200215119, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36252004

RESUMO

Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.


Assuntos
Caquexia , Cadeias Pesadas de Miosina , Neoplasias , Ubiquitina-Proteína Ligases , Animais , Camundongos , Actinas/metabolismo , Caquexia/genética , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neoplasias/complicações , Neoplasias/genética , Neoplasias/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Tropomodulina/metabolismo , Tropomiosina/metabolismo , Troponina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
4.
RNA Biol ; 21(1): 42-51, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38958280

RESUMO

The TATA-box binding protein (TBP) is the sole transcription factor common in the initiation complexes of the three major eukaryotic RNA Polymerases (Pol I, II and III). Although TBP is central to transcription by the three RNA Pols in various species, the emergence of TBP paralogs throughout evolution has expanded the complexity in transcription initiation. Furthermore, recent studies have emerged that questioned the centrality of TBP in mammalian cells, particularly in Pol II transcription, but the role of TBP and its paralogs in Pol I transcription remains to be re-evaluated. In this report, we show that in murine embryonic stem cells TBP localizes onto Pol I promoters, whereas the TBP paralog TRF2 only weakly associates to the Spacer Promoter of rDNA, suggesting that it may not be able to replace TBP for Pol I transcription. Importantly, acute TBP depletion does not fully disrupt Pol I occupancy or activity on ribosomal RNA genes, but TBP binding in mitosis leads to efficient Pol I reactivation following cell division. These findings provide a more nuanced role for TBP in Pol I transcription in murine embryonic stem cells.


Assuntos
Mitose , Regiões Promotoras Genéticas , RNA Polimerase I , Proteína de Ligação a TATA-Box , Transcrição Gênica , Animais , RNA Polimerase I/metabolismo , RNA Polimerase I/genética , Proteína de Ligação a TATA-Box/metabolismo , Proteína de Ligação a TATA-Box/genética , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Ligação Proteica , DNA Ribossômico/genética , DNA Ribossômico/metabolismo
5.
Neuroimage ; 273: 120075, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37054828

RESUMO

Developmental reading disability is a prevalent and often enduring problem with varied mechanisms that contribute to its phenotypic heterogeneity. This mechanistic and phenotypic variation, as well as relatively modest sample sizes, may have limited the development of accurate neuroimaging-based classifiers for reading disability, including because of the large feature space of neuroimaging datasets. An unsupervised learning model was used to reduce deformation-based data to a lower-dimensional manifold and then supervised learning models were used to classify these latent representations in a dataset of 96 reading disability cases and 96 controls (mean age: 9.86 ± 1.56 years). A combined unsupervised autoencoder and supervised convolutional neural network approach provided an effective classification of cases and controls (accuracy: 77%; precision: 0.75; recall: 0.78). Brain regions that contributed to this classification accuracy were identified by adding noise to the voxel-level image data, which showed that reading disability classification accuracy was most influenced by the superior temporal sulcus, dorsal cingulate, and lateral occipital cortex. Regions that were most important for the accurate classification of controls included the supramarginal gyrus, orbitofrontal, and medial occipital cortex. The contribution of these regions reflected individual differences in reading-related abilities, such as non-word decoding or verbal comprehension. Together, the results demonstrate an optimal deep learning solution for classification using neuroimaging data. In contrast with standard mass-univariate test results, results from the deep learning model also provided evidence for regions that may be specifically affected in reading disability cases.


Assuntos
Aprendizado Profundo , Dislexia , Humanos , Criança , Dislexia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Neuroimagem/métodos , Compreensão
6.
Glycoconj J ; 40(5): 565-573, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37402017

RESUMO

Streptococcus pneumoniae is a highly invasive bacterial pathogen that can cause a range of illnesses. Pneumococcal capsular polysaccharides (CPS) are the main virulence factors that causes invasive pneumococcal disease (IPD). Pneumococcal CPS serotype 7F along with a few other serotypes is more invasive and likely to cause IPD. Therefore, 7F is a target for pneumococcal vaccine development, and is included in the two recently approved multi-valent pneumococcal conjugated vaccines, i.e. VAXNEUVANCE and PREVNAR 20.To support process and development of our 15-valent pneumococcal conjugated vaccine (PCV15), chromatographic methods have been developed for 7F polysaccharide and conjugate characterization. A size-exclusion chromatography (SEC) method with UV, light scattering and refractive index detections was employed for concentration, size and conformation analysis. A reversed-phase ultra-performance liquid chromatography (RP-UPLC) method was used for analysis of conjugate monosaccharide composition and degree of conjugation. The collective information obtained by these chromatographic analysis provided insights into the pneumococcal conjugate and conjugation process.


Assuntos
Infecções Pneumocócicas , Humanos , Sorogrupo , Sorotipagem , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae , Vacinas Pneumocócicas , Vacinas Conjugadas , Antígenos de Bactérias
7.
J Med Primatol ; 52(5): 290-293, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37658590

RESUMO

HIV-2 Group F virus with an origin in NHPs was isolated from only two individuals. Two serial passages in hu-mice showed increased viral loads, CD4+ T cell decline and nonsynonymous genetic changes showing its capacity for further evolution, and spread in the human.


Assuntos
HIV-2 , Humanos , Animais , Camundongos , HIV-2/genética , Inoculações Seriadas , Carga Viral
8.
J Med Primatol ; 52(5): 294-297, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37658595

RESUMO

HIV-1 emerged from SIVcpz evolving in humans. Humanized mice are an effective tool for assessing viral evolution via measuring viral loads, CD4+ T cell decline, and analyzing genetic changes. Four serial passages showed many non-synonymous mutations important for the adaptation and evolution of SIVcpz to human immune cells.


Assuntos
HIV-1 , Pan troglodytes , Humanos , Animais , Camundongos , HIV-1/genética , Inoculações Seriadas , Carga Viral
9.
Environ Sci Technol ; 57(41): 15627-15634, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37805932

RESUMO

Rivers are often assumed to be the main source of nutrients triggering eutrophication in the Great Barrier Reef (GBR). However, existing nutrient budgets suggest a major missing source of nitrogen and phosphorus sustaining primary production. Here, we used radium isotopes to resolve submarine groundwater discharge (SGD)-derived, shelf-scale nutrient inputs to the GBR. The total SGD was ∼10-15 times greater than average river inputs, with nearshore groundwater discharge accounting for ∼30% of this. Total SGD accounted for >30% of all known dissolved inorganic N and >60% of inorganic P inputs and exceeded regional river inputs. However, SGD was only a small proportion of the nutrients necessary to sustain primary productivity, suggesting that internal recycling processes still dominate the nutrient budget. With millions of dollars spent managing surface water nutrient inputs to reef systems globally, we argue for a shift in the focus of management to safeguard reefs from the impacts of excess nutrients.


Assuntos
Água Subterrânea , Rios , Monitoramento Ambiental , Eutrofização , Nutrientes
10.
Proc IEEE Inst Electr Electron Eng ; 111(10): 1236-1286, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37859667

RESUMO

The emergence of artificial emotional intelligence technology is revolutionizing the fields of computers and robotics, allowing for a new level of communication and understanding of human behavior that was once thought impossible. While recent advancements in deep learning have transformed the field of computer vision, automated understanding of evoked or expressed emotions in visual media remains in its infancy. This foundering stems from the absence of a universally accepted definition of "emotion," coupled with the inherently subjective nature of emotions and their intricate nuances. In this article, we provide a comprehensive, multidisciplinary overview of the field of emotion analysis in visual media, drawing on insights from psychology, engineering, and the arts. We begin by exploring the psychological foundations of emotion and the computational principles that underpin the understanding of emotions from images and videos. We then review the latest research and systems within the field, accentuating the most promising approaches. We also discuss the current technological challenges and limitations of emotion analysis, underscoring the necessity for continued investigation and innovation. We contend that this represents a "Holy Grail" research problem in computing and delineate pivotal directions for future inquiry. Finally, we examine the ethical ramifications of emotion-understanding technologies and contemplate their potential societal impacts. Overall, this article endeavors to equip readers with a deeper understanding of the domain of emotion analysis in visual media and to inspire further research and development in this captivating and rapidly evolving field.

11.
Platelets ; 34(1): 2264978, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37933490

RESUMO

Platelets contribute to COVID-19 clinical manifestations, of which microclotting in the pulmonary vasculature has been a prominent symptom. To investigate the potential diagnostic contributions of overall platelet morphology and their α-granules and mitochondria to the understanding of platelet hyperactivation and micro-clotting, we undertook a 3D ultrastructural approach. Because differences might be small, we used the high-contrast, high-resolution technique of focused ion beam scanning EM (FIB-SEM) and employed deep learning computational methods to evaluate nearly 600 individual platelets and 30 000 included organelles within three healthy controls and three severely ill COVID-19 patients. Statistical analysis reveals that the α-granule/mitochondrion-to-plateletvolume ratio is significantly greater in COVID-19 patient platelets indicating a denser packing of organelles, and a more compact platelet. The COVID-19 patient platelets were significantly smaller -by 35% in volume - with most of the difference in organelle packing density being due to decreased platelet size. There was little to no 3D ultrastructural evidence for differential activation of the platelets from COVID-19 patients. Though limited by sample size, our studies suggest that factors outside of the platelets themselves are likely responsible for COVID-19 complications. Our studies show how deep learning 3D methodology can become the gold standard for 3D ultrastructural studies of platelets.


COVID-19 patients exhibit a range of symptoms including microclotting. Clotting is a complex process involving both circulating proteins and platelets, a cell within the blood. Increased clotting is suggestive of an increased level of platelet activation. If this were true, we reasoned that parts of the platelet involved in the release of platelet contents during clotting would have lost their content and appear as expanded, empty "ghosts." To test this, we drew blood from severely ill COVID-19 patients and compared the platelets within the blood draws to those from healthy volunteers. All procedures were done under careful attention to biosafety and approved by health authorities. We looked within the platelets for empty ghosts by the high magnification technique of electron microscopy. To count the ghosts, we developed new computer software. In the end, we found little difference between the COVID patient platelets and the healthy donor platelets. The results suggest that circulating proteins outside of the platelet are more important to the strong clotting response. The software developed will be used to analyze other disease states.


Assuntos
COVID-19 , Aprendizado Profundo , Humanos , RNA Viral , SARS-CoV-2 , Plaquetas/ultraestrutura , Organelas
12.
J Surg Res ; 273: 85-92, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35033821

RESUMO

BACKGROUND: Anastomotic leakage (AL) is an infrequent but life-threatening surgical complication following colorectal surgery. Early diagnosis remains clinically difficult but is a necessity to reduce associated morbidity and mortality. Clinical review and radiological modalities for the diagnosis of leakage remain non-specific and often only detect AL once it is well developed. Inflammatory biomarkers however have shown promise in early pre-clinical detection of leakage following colorectal surgery. METHODS: A multi-center, prospective observational study was conducted across four public hospitals in Auckland and Christchurch, New Zealand. Consecutive adults undergoing elective colectomy were initially recruited over a 3-y period. Perioperative blood samples were collected to measure interleukin (IL)-6, IL-1ß, tumor necrosis factor α, IL-10, C-reactive protein (CRP), leukocyte and neutrophil counts. Statistical analysis was performed to compare patients with an uncomplicated recovery with patients with AL. RESULTS: Sixteen patients developed AL (5.7%), diagnosed at a median post-operative (POD) day 7. CRP and IL-6 were consistently elevated in the early post-operative period in patients with AL, and had the best diagnostic accuracy on POD 3 (area under the curve 0.70; P = 0.02) and POD 1 (area under the curve 0.69; P = 0.02), respectively. IL-10, once adjusted for body mass index and surgical approach, was the sole biomarker significantly elevated in patients with AL on POD 4. CONCLUSIONS: Early post-operative elevations of CRP and IL-6 provide utility for early detection of AL after elective colectomy. Application of these inflammatory biomarkers and their combinations in daily practice warrants further investigation.


Assuntos
Fístula Anastomótica , Interleucina-10 , Adulto , Fístula Anastomótica/diagnóstico , Fístula Anastomótica/etiologia , Biomarcadores , Proteína C-Reativa/metabolismo , Colectomia/efeitos adversos , Colectomia/métodos , Humanos , Interleucina-6
13.
J Med Primatol ; 51(5): 284-287, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36030392

RESUMO

Serial passage of SIVmac239 allows for greater understanding of the genetic changes necessary for cross-species transmission of primate lentiviruses into humans. Using humanized mice, we show that adaptive mutations continue to accumulate in SIVmac239 during four serial passages, with persistent CD4+ T cell decline and increases in plasma viral loads.


Assuntos
Doenças dos Roedores , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Humanos , Macaca mulatta , Camundongos , Inoculações Seriadas , Vírus da Imunodeficiência Símia/genética , Carga Viral
14.
Int J Colorectal Dis ; 37(1): 1-15, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34608561

RESUMO

BACKGROUND: Anal fissure is a common condition that can be treated medically or surgically. Chemical sphincterotomy is often used before surgical intervention. This study aims to evaluate the effectiveness of topical agents for chemical sphincterotomy on healing of anal fissures and side-effects. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant systematic review was performed using MEDLINE, EMBASE, Scopus, and CENTRAL databases. Eligible studies included randomized controlled trials which compared topical sphincterotomy agents with topical placebo agents or each other. Studies that included surgical treatments were excluded. Overall evidence was synthesized according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: Thirty-seven studies met the study selection criteria. Seventeen studies show that glyceryl trinitrate (GTN) was significantly more likely to heal anal fissure than placebo (relative risk (RR) = 1.96, 95% confidence interval (95%CI) = 1.35-2.84, I2 = 80%). Eleven studies showed a marginally significant difference between healing rates for diltiazem vs GTN, RR = 1.16, (1.01-1.33) I2 = 48%. There was no significant difference in healing between diltiazem and placebo, RR = 1.65, (0.64-4.23), I2 = 92%. GTN significantly reduced pain on the visual analog scale compared to the placebo group, MD-0.97 (-1.64 to -0.29) I2 = 92%. There was high certainty of evidence that GTN was significantly more likely to cause headache than placebo (RR = 2.73 (1.82-4.10) I2 = 58%) and diltiazem RR = 6.88 (2.19-21.63) I2 = 17%. CONCLUSION: There is low certainty evidence topical nitrates are an effective treatment for anal fissure healing and pain reduction compared to placebo. Despite widespread use of topical diltiazem, more evidence is required to establish the effectiveness of calcium channel blockers compared to placebo.


Assuntos
Fissura Anal , Esfincterotomia , Administração Tópica , Doença Crônica , Diltiazem/uso terapêutico , Fissura Anal/tratamento farmacológico , Fissura Anal/cirurgia , Humanos , Nitroglicerina/uso terapêutico , Resultado do Tratamento , Vasodilatadores/uso terapêutico
15.
Gastroenterology ; 158(8): 2093-2103, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32092310

RESUMO

BACKGROUND & AIMS: Refractory gastroesophageal reflux disease (GERD) reduces quality of life and creates significant financial burden on the health care system. Approximately 30% of patients with GERD who receive label-dose proton pump inhibitors (PPIs) still have symptoms. We performed a trial to evaluate the efficacy and safety of IW-3718, a bile acid sequestrant, as an adjunct to PPI therapy. METHODS: We performed a multicenter, double-blind, placebo-controlled trial, from March 2016 through April 2017, of 280 patients with confirmed GERD. The patients, stratified by esophagitis status, were randomly assigned (1:1:1:1) to groups given placebo or IW-3718 (500, 1000, or 1500 mg) twice daily, with ongoing label-dose PPI. The primary endpoint was percent change from baseline to week 8 in weekly heartburn severity score. We also analyzed percent change from baseline to week 8 in weekly regurgitation frequency score. RESULTS: Mean changes from baseline to week 8 in weekly heartburn severity scores were reductions of 46.0% in the placebo group, 49.0% in the 500 mg group, 55.1% in the 1000 mg group, and 58.0% in the 1500 mg IW-3718 group (dose-response P = .02). The treatment difference was 11.9% between the 1500 mg IW-3718 and placebo groups (P = .04, analysis of covariance). The mean change in weekly regurgitation frequency score from baseline to week 8 in the 1500 mg IW-3718 vs placebo groups was a reduction of 17.5% (95% confidence interval, reductions of 31.4% to 3.6%). The most common adverse event was constipation (in 8.1% of patients receiving IW-3718 and 7.1% of patients receiving placebo). There were no drug-related serious adverse events. CONCLUSIONS: In a randomized trial of patients with refractory GERD, adding 1500 mg IW-3718 to label-dose PPIs significantly reduced heartburn symptoms compared with adding placebo. Regurgitation symptoms also decreased. IW-3718 was well tolerated. (ClinicalTrials.gov, Number: NCT02637557).


Assuntos
Ácidos e Sais Biliares/metabolismo , Cloridrato de Colesevelam/administração & dosagem , Esofagite/tratamento farmacológico , Refluxo Gastroesofágico/tratamento farmacológico , Azia/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Colesevelam/efeitos adversos , Cloridrato de Colesevelam/metabolismo , Preparações de Ação Retardada , Método Duplo-Cego , Quimioterapia Combinada , Esofagite/diagnóstico , Esofagite/metabolismo , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/metabolismo , Azia/diagnóstico , Azia/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/efeitos adversos , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
16.
Adv Exp Med Biol ; 1332: 51-66, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251638

RESUMO

Autophagy is a dynamic process in which the eukaryotic cells break down intracellular components by lysosomal degradation. Under the normal condition, the basal level of autophagy removes damaged organelles, misfolded proteins, or protein aggregates to keep cells in a homeostatic condition. Deprivation of nutrients (e.g., removal of amino acids) stimulates autophagy activity, promoting lysosomal degradation and the recycling of cellular components for cell survival. Importantly, insulin and amino acids are two main inhibitors of autophagy. They both activate the mTOR complex 1 (mTORC1) signaling pathway to inhibit the autophagy upstream of the uncoordinated-51 like kinase 1/2 (ULK1/2) complex that triggers autophagosome formation. In particular, insulin activates mTORC1 via the PI3K class I-AKT pathway; while amino acids activate mTORC1 either through the PI3K class III (hVps34) pathway or through a variety of amino acid sensors located in the cytosol or lysosomal membrane. These amino acid sensors control the translocation of mTORC1 from the cytosol to the lysosomal surface where mTORC1 is activated by Rheb GTPase, therefore regulating autophagy and the lysosomal protein degradation.


Assuntos
Aminoácidos , Serina-Treonina Quinases TOR , Autofagia , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
17.
Nano Lett ; 20(7): 5284-5291, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32543860

RESUMO

Shortwave infrared colloidal quantum dots (SWIR-CQDs) are semiconductors capable of harvesting across the AM1.5G solar spectrum. Today's SWIR-CQD solar cells rely on spin-coating; however, these films exhibit cracking once thickness exceeds ∼500 nm. We posited that a blade-coating strategy could enable thick QD films. We developed a ligand exchange with an additional resolvation step that enabled the dispersion of SWIR-CQDs. We then engineered a quaternary ink that combined high-viscosity solvents with short QD stabilizing ligands. This ink, blade-coated over a mild heating bed, formed micron-thick SWIR-CQD films. These SWIR-CQD solar cells achieved short-circuit current densities (Jsc) that reach 39 mA cm-2, corresponding to the harvest of 60% of total photons incident under AM1.5G illumination. External quantum efficiency measurements reveal both the first exciton peak and the closest Fabry-Perot resonance peak reaching approximately 80%-this is the highest unbiased EQE reported beyond 1400 nm in a solution-processed semiconductor.

18.
J Am Chem Soc ; 142(14): 6554-6568, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32191035

RESUMO

Universal immune receptors represent a rapidly emerging form of adoptive T-cell therapy with the potential to overcome safety and antigen escape challenges faced by conventional chimeric antigen receptor (CAR) T-cell therapy. By decoupling antigen recognition and T-cell signaling domains via bifunctional antigen-specific targeting ligands, universal immune receptors can regulate T-cell effector function and target multiple antigens with a single receptor. Here, we describe the development of the SpyCatcher immune receptor, the first universal immune receptor that allows for the post-translational covalent attachment of targeting ligands at the T-cell surface through the application of SpyCatcher-SpyTag chemistry. The SpyCatcher immune receptor redirected primary human T cells against a variety of tumor antigens via the addition of SpyTag-labeled targeting ligands, both in vitro and in vivo. SpyCatcher T-cell activity relied upon the presence of both target antigen and SpyTag-labeled targeting ligand, allowing for dose-dependent control of function. The mutational disruption of covalent bond formation between the receptor and the targeting ligand still permitted redirected T-cell function but significantly compromised antitumor function. Thus, the SpyCatcher immune receptor allows for rapid antigen-specific receptor assembly, multiantigen targeting, and controllable T-cell activity.


Assuntos
Engenharia Genética/métodos , Linfócitos T/imunologia , Humanos , Ligantes
19.
J Am Chem Soc ; 142(11): 5126-5134, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32150404

RESUMO

Metal halide perovskites show promise for light-emitting diodes (LEDs) owing to their facile manufacture and excellent optoelectronic performance, including high color purity and spectral stability, especially in the green region. However, for blue perovskite LEDs, the emission spectrum line width is broadened to over 25 nm by the coexistence of multiple reduced-dimensional perovskite domains, and the spectral stability is poor, with an undesirable shift (over 7 nm) toward longer wavelengths under operating conditions, degradation that occurs due to phase separation when mixed halides are employed. Here we demonstrate chloride insertion-immobilization, a strategy that enables blue perovskite LEDs, the first to exhibit narrowband (line width of 18 nm) and spectrally stable (no wavelength shift) performance. We prepare bromide-based perovskites and then employ organic chlorides for dynamic treatment, inserting and in situ immobilizing chlorides to blue-shift and stabilize the emission. We achieve sky-blue LEDs with a record luminance over 5100 cd/m2 at 489 nm, and an operating half-life of 51 min at 1500 cd/m2. By device structure optimization, we further realize an improved EQE of 5.2% at 479 nm and an operating half-life of 90 min at 100 cd/m2.

20.
Plant Cell ; 29(10): 2413-2432, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28974550

RESUMO

Plant cell separation and expansion require pectin degradation by endogenous pectinases such as polygalacturonases, few of which have been functionally characterized. Stomata are a unique system to study both processes because stomatal maturation involves limited separation between sister guard cells and stomatal responses require reversible guard cell elongation and contraction. However, the molecular mechanisms for how stomatal pores form and how guard cell walls facilitate dynamic stomatal responses remain poorly understood. We characterized POLYGALACTURONASE INVOLVED IN EXPANSION3 (PGX3), which is expressed in expanding tissues and guard cells. PGX3-GFP localizes to the cell wall and is enriched at sites of stomatal pore initiation in cotyledons. In seedlings, ablating or overexpressing PGX3 affects both cotyledon shape and the spacing and pore dimensions of developing stomata. In adult plants, PGX3 affects rosette size. Although stomata in true leaves display normal density and morphology when PGX3 expression is altered, loss of PGX3 prevents smooth stomatal closure, and overexpression of PGX3 accelerates stomatal opening. These phenotypes correspond with changes in pectin molecular mass and abundance that can affect wall mechanics. Together, these results demonstrate that PGX3-mediated pectin degradation affects stomatal development in cotyledons, promotes rosette expansion, and modulates guard cell mechanics in adult plants.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Estômatos de Plantas/metabolismo , Plântula/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Estômatos de Plantas/genética , Plântula/genética
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