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Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug resistance. Nitrogen-containing heterocycles have compatible structures and properties with exceptional biological activity for the drug design of antiviral agents. They provided a broad spectrum of interference against viral infection at various stages, from blocking early viral entry to disrupting the viral genome replication process by targeting different enzymes and proteins of viruses. This review focused on the synthesis and application of antiviral agents derived from various nitrogen-containing heterocycles, such as indole, pyrrole, pyrimidine, pyrazole, and quinoline, within the last ten years. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19, and influenza viruses.
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Antivirais , Tratamento Farmacológico da COVID-19 , Antivirais/química , Humanos , Nitrogênio/farmacologia , SARS-CoV-2 , Replicação ViralRESUMO
In this paper, the classical least-squares (CLS) method with molecular absorption spectrophotometric measurement was used to determine simultaneously paracetamol (PAR), ibuprofen (IBU), and caffeine (CAF) in tablets. The absorbance spectra of the standard solutions and samples were measured over a wavelength from 220 to 300 nm with a 0.5 nm step. The concentration of PAR, IBU, and CAF in the sample solutions was calculated by using Visual Basic for Applications (VBA) and a program called CLS-Excel written in Microsoft Excel 2016. The method and the CLS-Excel program were tested on mixed standard laboratory samples with different PAR, IBU, and CAF concentration ratios, and they showed only small errors and a satisfying repeatability. An analytical procedure for tablets containing PAR, IBU, and CAF was developed. The reliability of the procedure was proved via the recovery and repeatability of the analysis results with an actual tablet sample and by comparing the mean contents of active substances in the tablets obtained from the analytical procedure with the HPLC method. The procedure is simple with a reduced cost compared with the HPLC standard method.
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Acetaminofen , Cafeína , Acetaminofen/química , Cafeína/química , Ibuprofeno , Análise dos Mínimos Quadrados , Reprodutibilidade dos Testes , Espectrofotometria/métodos , Comprimidos/análiseRESUMO
Using the Färe-Primont index and instrumental variable fixed effect estimation for the data of small and medium-sized enterprises (SMEs), this study considers if receiving government financial support enables SMEs in Vietnam to become more productive. The paper discovers no evidence of linkage between financial support and firm productivity. However, access to financial support improves technological progress and growth in firm scale but has a negative effect on improvement in technical efficiency. The estimation results reveal that the use of productivity as an aggregated index in previous studies may hide the real effect of government support on firm productivity.
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INTRODUCTION: The COVID-19 pandemic has been an unprecedented threat to our health care system. Clinicians had to pivot and develop creative and timely "virtual" solutions to provide clinical care. Our aim was to develop a standardized approach to virtual "mask fitting" for children who are either being initiated or are already on existing long-term ventilation (LTV) at a pediatric hospital. CASE AND OUTCOMES: We present three cases involving the care of children who required mask fitting for noninvasive ventilation (NIV). LTV team consultations were delivered via videoconference or phone. With the guidance of the respiratory therapist (RT), the family caregiver (FC) took measurements on their child using a standardized clinical approach (developed by the LTV RTs). Based on the measurements, an appropriate mask was selected. Successful mask fit was based on patient/FC reports, as well as objective leak data obtained from the NIV download data. DISCUSSION: Virtual clinics used for managing patients in our LTV program were feasible and efficient resulting in improved workflow for the RTs and convenience for patients and FCs. Patients and FCs had significantly less pressure to attend in-person clinics and expressed high satisfaction in terms of their experience and importantly, meeting respiratory care needs. Within the context of COVID-19, remote patient education and intervention can be delivered effectively, while reducing the risk of exposure from in-person visits to hospital. CONCLUSION: A virtual/telemedicine program to manage pediatric patients requiring mask fitting for LTV was a feasible option during COVID-19.
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Zinc-finger structure, in which a Zn2+ ion binds to four cysteines or histidines in a tetrahedral structure, is a very common motif of nucleic acid-binding proteins. The corresponding interaction model is present in 3% of the genes in the human genome. As a result, the zinc finger has been extremely useful in various therapeutic and research capacities and in biotechnology. In a stable configuration of the zinc finger, the cysteine amino acids are deprotonated and become negatively charged. Thus, the Zn2+ ion is overscreened by four cysteine charges (overcharged). Whether this overcharged configuration is also stable when such a negatively charged zinc finger binds to a negatively charged DNA molecule is unknown. We investigated how the deprotonated state of cysteine influences its structure, dynamics, and function in binding to DNA molecules by using an all-atom molecular dynamics simulation up to the microsecond range of an androgen receptor protein dimer. Our results showed that the deprotonated state of cysteine residues is essential for the mechanical stabilization of the functional, folded conformation. This state stabilizes not only the protein structure but also the protein-DNA binding complex. The differences in the structural and energetic properties of the two sequence-identical monomers are also investigated and show the strong influence of DNA on the structure of the zinc-finger protein dimer upon complexation. Our result can potentially lead to a better molecular understanding of one of the most common classes of zinc fingers.
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Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Zinco/metabolismo , Sequência de Aminoácidos , DNA/química , DNA/genética , Proteínas de Ligação a DNA/genética , Humanos , Análise Serial de Proteínas , Zinco/química , Dedos de ZincoRESUMO
Macrocyclic natural products (NPs) and analogues thereof often show high affinity, selectivity, and metabolic stability, and methods for the synthesis of NP-like macrocycle collections are of major current interest. We report an efficient solid-phase/cyclorelease method for the synthesis of a collection of macrocyclic depsipeptides with bipartite peptide/polyketide structure inspired by the very potent F-actin stabilizing depsipeptides of the jasplakinolide/geodiamolide class. The method includes the assembly of an acyclic precursor chain on a polymeric carrier, terminated by olefins that constitute complementary fragments of the polyketide section and cyclization by means of a relay-ring-closing metathesis (RRCM). The method was validated in the first total synthesis of the actin-stabilizing cyclodepsipeptide seragamide A and the synthesis of a collection of structurally diverse bipartite depsipeptides.
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Produtos Biológicos/síntese química , Depsipeptídeos/síntese química , Produtos Biológicos/química , Ciclização , Depsipeptídeos/química , Técnicas de Síntese em Fase SólidaRESUMO
Apolipoprotein E (apoE), an antiatherogenic apolipoprotein, plays a significant role in the metabolism of lipoproteins. It lowers plasma lipid levels by acting as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins, in addition to playing a role in promoting macrophage cholesterol efflux in atherosclerotic lesions. The objective of this study is to examine the effect of acrolein modification on the structure and function of rat apoE and to determine the sites and nature of modification by mass spectrometry. Acrolein is a highly reactive aldehyde, which is generated endogenously as one of the products of lipid peroxidation and is present in the environment in pollutants such as tobacco smoke and heated oils. In initial studies, acrolein-modified apoE was identified by immunoprecipitation using an acrolein-lysine specific antibody in the plasma of 10-week old male rats that were exposed to filtered air (FA) or low doses of environmental tobacco smoke (ETS). While both groups displayed acrolein-modified apoE in the lipoprotein fraction, the ETS group had higher levels in the lipid-free fraction compared with the FA group. This observation provided the rationale to further investigate the effect of acrolein modification on rat apoE at a molecular level. Treatment of recombinant rat apoE with a 10-fold molar excess of acrolein resulted in (i) a significant decrease in lipid-binding and cholesterol efflux abilities, (ii) impairment in the LDLr- and heparin-binding capabilities, and (iii) significant alterations in the overall stability of the protein. The disruption in the functional abilities is attributed directly or indirectly to acrolein modification yielding an aldimine adduct at K149 and K155 (+38); a propanal adduct at K135 and K138 (+56); an N(ε)-(3-methylpyridinium)lysine (MP-lysine) at K64, K67, and K254 (+76), and an N(ε)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) derivative at position K68 (+94), as determined by matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). The loss of function may also be attributed to alterations in the overall fold of the protein as noted by changes in the guanidine HCl-induced unfolding pattern and to protein cross-linking. Overall, disruption of the structural and functional integrity of apoE by oxidative modification of essential lysine residues by acrolein is expected to affect its role in maintaining plasma cholesterol homeostasis and lead to dysregulation in lipid metabolism.
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Acroleína/farmacologia , Apolipoproteínas E/química , Apolipoproteínas E/metabolismo , Acroleína/química , Sequência de Aminoácidos , Animais , Humanos , Masculino , Espectrometria de Massas , Modelos Moleculares , Dados de Sequência Molecular , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: The objective of this investigation was to determine if kinase insert domain/vascular endothelial growth factor receptor 2 (KDR/VEGFR2) genetic variation was associated with the development of ovarian hyperstimulation syndrome (OHSS) in patients undergoing controlled ovarian hyperstimulation (COH). METHODS: This was a case-control study of 174 patients who underwent controlled ovarian stimulation. Patient blood samples were genotyped for single nucleotide polymorphisms (SNPs) spanning the KDR locus. OHSS development, clinical outcome variables, SNP and haplotype frequencies were compared between control (n = 155) and OHSS (n = 19) groups. RESULTS: Patients who developed OHSS had significantly higher response markers (estradiol levels of the day of hCG administration, number of follicles developed, number of eggs retrieved) than control patients. When adjusted for age and self-identified race, the rs2305945 G/T genotype was associated (P = 0.027) with a decreased risk (OR = 0.30; 95% CI = 0.10, 0.93) of developing OHSS using an overdominant model. The rs2305945 G/T variant was also associated with decreased COH response (number of follicles, number of eggs retrieved) in an overdominant model. The rs2305948, rs1870378, rs2305945 (C-T-G) haplotype was associated with both decreased COH response and OHSS risk (unadjusted OR = 0.10; 95% CI = 0.01, 0.80, P = 0.031). CONCLUSIONS: The KDR receptor is believed to play a central role OHSS development and is a target for pharmacological prevention of OHSS. These results indicate that genetic variation in the KDR gene may impact individual risk of developing OHSS from COH. In addition, the rs2305948 SNP and C-T-G haplotype might serve as potential biomarkers for poor ovarian response to COH.
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Síndrome de Hiperestimulação Ovariana/genética , Polimorfismo de Nucleotídeo Único , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Gonadotropina Coriônica/efeitos adversos , Gonadotropina Coriônica/farmacologia , District of Columbia , Resistência a Medicamentos , Estradiol/sangue , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Fármacos para a Fertilidade Feminina/farmacologia , Hormônio Foliculoestimulante/efeitos adversos , Hormônio Foliculoestimulante/farmacologia , Estudos de Associação Genética , Predisposição Genética para Doença , Hospitais Universitários , Humanos , Desequilíbrio de Ligação , Síndrome de Hiperestimulação Ovariana/sangue , Síndrome de Hiperestimulação Ovariana/metabolismo , Ovário/diagnóstico por imagem , Ovário/efeitos dos fármacos , Indução da Ovulação/efeitos adversos , Ultrassonografia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Natural products represent compound classes with high chemical and structural diversity and various biological activities. Libraries based on natural products are valuable starting point in the search for novel biologically active substances. Here we report on the identification of the natural product podoverine A from the plant Podophyllum versipelle Hance as a novel tubulin-acting agent. A natural product compound collection was subjected to a high-content screen that monitors changes in cytoskeleton and DNA and podoverine A was identified as inhibitor of mitosis. This natural product causes mitotic arrest and inhibits microtubule polymerization in vitro and in cells by targeting the vinca binding site on tubulin.
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Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Flavonas/farmacologia , Microtúbulos/efeitos dos fármacos , Podophyllum/química , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonas/química , Flavonas/isolamento & purificação , Células HeLa , Humanos , Células MCF-7 , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/isolamento & purificaçãoRESUMO
Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients.
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Neoplasias Colorretais , Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Animais , Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis , Neoplasias Colorretais/tratamento farmacológico , Linhagem Celular TumoralRESUMO
In terrestrial vertebrates, the olfactory system is divided into main (MOS) and accessory (AOS) components that process both volatile and nonvolatile cues to generate appropriate behavioral responses. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the vomeronasal organ (VNO), the accessory olfactory bulb (AOB), and the medial amygdala (MeA), we reveal that populations of neurons in the AOS can be molecularly subdivided based on their ongoing or prior expression of the transcription factors Foxp2 or Dbx1, which delineate separate populations of GABAergic output neurons in the MeA. We show that a majority of AOB neurons that project directly to the MeA are of the Foxp2 lineage. Using single-neuron patch-clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the frequency of excitatory input to MeA Dbx1- and Foxp2-lineage neurons differs between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons, and lineage and sex differences in patterns of connectivity.
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Complexo Nuclear Corticomedial , Órgão Vomeronasal , Animais , Feminino , Masculino , Bulbo Olfatório/fisiologia , Órgão Vomeronasal/fisiologia , Caracteres Sexuais , Neurônios GABAérgicosRESUMO
Apolipoprotein E (apoE) is an anti-atherogenic protein that plays a critical role in maintaining plasma cholesterol and triglyceride homeostasis by virtue of its ability to act as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins. In this study, we characterized the biochemical and biophysical features of recombinant rat apoE, in comparison with those of human apoE3. Rat apoE was overexpressed in Escherichia coli using a codon optimized system and purified by affinity chromatography. SDS-PAGE and RP-HPLC of rat apoE confirmed the purity, while immunoblot verified the identity and cross-reactivity with the LDLr-binding region of apoE3. The α-helical content was calculated to be ~45% by circular dichroism spectroscopy. The protein exists in a predominantly tetrameric form in lipid-free state. Chemical denaturation studies reveal that the unfolding pattern is biphasic with mid points of denaturation corresponding to 0.8 and 2.2 M guanidine hydrochloride, suggesting the presence of two domains. Rat apoE converts DMPC vesicles to smaller DMPC/apoE complexes with a first order rate constant of 0.12 min(-1). It has the ability to bind the LDLr and to heparin. Our studies indicate that although its sequence resembles apoE4, an isoform of apoE3, rat apoE displays the biophysical behavior of apoE3.
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Apolipoproteína E3/química , Apolipoproteína E4/química , Dimiristoilfosfatidilcolina/química , Sequência de Aminoácidos , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Dicroísmo Circular , Dimiristoilfosfatidilcolina/metabolismo , Eletroforese em Gel de Poliacrilamida , Escherichia coli/genética , Heparina/química , Heparina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Cinética , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Multimerização Proteica , Estrutura Secundária de Proteína , Desdobramento de Proteína , Ratos , Receptores de LDL/química , Receptores de LDL/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia Estrutural de ProteínaRESUMO
A Prins cyclization between a polymer-bound aldehyde and a homoallylic alcohol served as the key step in the synthesis of tetrahydropyran derivatives. A phenotypic screen led to the identification of compounds that inhibit mitosis (as seen by the accumulation of round cells with condensed DNA and membrane blebs). These compounds were termed tubulexins as they target the CSE1L protein and the vinca alkaloid binding site of tubulin.
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Proteína de Suscetibilidade a Apoptose Celular/metabolismo , Piranos/síntese química , Piranos/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Sítios de Ligação , Proteína de Suscetibilidade a Apoptose Celular/química , Células HeLa , Humanos , Células MCF-7 , Mitose/efeitos dos fármacos , Moduladores de Mitose , Piranos/química , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
Our study uses a small area estimation method to estimate the average and inequality of per capita kWh consumption for small areas in Vietnam. It shows evidence of a large spatial heterogeneity in the electric power consumption between districts and provinces in Vietnam. Households in the mountains and highlands consumed remarkably less electricity than those in the delta and coastal areas. Notably, we find a U-shaped relationship between the inequality of electricity consumption and economic levels in Vietnam. In poor districts and provinces, there is very high inequality in electricity consumption. Inequality is lower in middle-income districts and provinces.
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Desenvolvimento Econômico , Renda , Características da Família , Eletricidade , Vietnã/epidemiologiaRESUMO
This study examines the relationship between foreign direct investment (FDI), institutional quality and human development) in host countries from 2002 to 2019, using the Human Development Index [HDI] as the measure of human development. This study utilized a panel dataset of 143 countries, including both developed and developing economies, over a 17-year period. Additionally, the study employed a GMM (generalized method of moments) estimator to address unobservable heterogeneity and simultaneity. This study reveals a significant positive relationship between FDI and human development, with a stronger effect observed in developing countries compared to in developed countries. Notably, the impact of FDI-HDI nexus is larger in countries with moderately high-quality institutions, irrespective of their income level. Furthermore, good governance plays a crucial role in enhancing human development, as developing economies with high governance quality experience a greater impact of FDI on HDI compared to other countries. The findings of this study suggest that attracting FDI can be beneficial for enhancing the HDI, especially in developing countries. Additionally, the study highlights governance as a moderating factor in the relationship between FDI and HDI. Improving governance quality can enhance the positive impact of FDI on human development in host countries, especially in developing countries.
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Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.
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Melanoma Experimental , Esfingomielinas , Feminino , Camundongos , Animais , Receptor de Morte Celular Programada 1 , Melanoma Experimental/tratamento farmacológico , Oximas , Ativação Linfocitária , ImunoterapiaRESUMO
BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder that may result in neuromuscular weakness and respiratory insufficiency. Gene replacement therapy has changed the trajectory of this condition, but long-term outcomes related to sleep disordered breathing are not known. METHODS: This was a retrospective review of infants with SMA identified via newborn screening who subsequently received onasemnogene abeparvovec at the Hospital for Sick Children (Ontario, Canada). Polysomnograms were conducted at the time of confirmed diagnosis as well as regularly thereafter. RESULTS: Eleven children (4 female) were identified via newborn screen (7 with 2 copies of the SMN2 gene and 4 with 3 copies of the SMN2 gene) and received onasemnogene abeparvovec at a median age of 3.6 weeks. All eleven infants met criteria for sleep disordered breathing based on their first completed polysomnograms but improved over time. Three infants required respiratory technology, including a premature infant who was prescribed nocturnal supplemental oxygen therapy for central sleep apnea and two symptomatic infants with neuromuscular weakness who required nocturnal noninvasive ventilation. We did not find a correlation between motor scores and polysomnogram parameters. CONCLUSION: Children treated with onasemnogene abeparvovec have reduced sleep disordered breathing over time. Polysomnograms revealed abnormal parameters in all children, but the clinical significance of these findings was unclear for children who were asymptomatic for sleep disordered breathing or neuromuscular weakness. These results highlight the need to evaluate both motor scores and respiratory symptoms to ensure a holistic evaluation of clinical status.
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Atrofia Muscular Espinal , Síndromes da Apneia do Sono , Apneia do Sono Tipo Central , Atrofias Musculares Espinais da Infância , Criança , Recém-Nascido , Humanos , Lactente , Feminino , Triagem Neonatal , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/terapia , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/terapia , Ontário , Atrofias Musculares Espinais da Infância/diagnóstico , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/terapiaRESUMO
JAG1 expression is upregulated in high-grade metastatic prostate carcinomas and associated with poor disease-free survival of patients with prostate cancer. Intriguingly, all JAG1-positive prostate carcinomas express JICD although JICD function in prostate cancer (PC) cells is poorly understood. In this study, we found that JICD overexpression increased the expression levels of AR, especially AR-Vs, in PC cell lines and significantly enhanced androgen-independent and androgen-dependent function of ARs. Interestingly, JICD overexpression upregulated the expression of the PCSC marker CD133 in PC cells as the expression of self-renewal markers; namely, NANOG and OCT3/4 increased. In addition, JICD overexpression highly increased the expression of anti-apoptotic BCL-XL protein, while it little affected the expression of apoptotic BIM protein. In 3D cell culture assays, the spheres formed by JICD-overexpressing PC subline cells (C4-2 and CWR22Rv1) were larger than those formed by control (EV) subline cells with undifferentiated morphology. Although JICD overexpression caused quiescence in cell proliferation, it activated the expression of components in PCSC-related signaling pathways, increased PC cell mobility, and promoted in vivo xenograft mouse tumorigenesis. Therefore, JICD may play a crucial role in enhancing androgen independence and promoting stem-like properties in PC cells and should be considered a novel target for CRPC and PCSC diagnostic therapy.
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The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Database analysis revealed that TR3 expression level is elevated in prostate tumors, and is positively, although weakly, correlated with that of AR. TR3 overexpression increased the production of AR splice variants in addition to general upregulation of AR expression. TR3 interacted with some spliceosomal complex components and AR precursor mRNA, altering the splice junction rates between exons. TR3 also enhanced androgen-independent AR function. Furthermore, TR3 overexpression increased cell proliferation and mobility of AR-positive prostate cancer cells and stimulated tumorigenesis of androgen-independent prostate cancer cells in mouse xenograft models. This is the first study to report that TR3 is a multifunctional regulator of AR signaling in prostate cancer cells. TR3 alters AR expression, splicing process, and activity in prostate cancer cells, increasing the androgen independence of AR signaling. Therefore, TR3 may play a crucial role in the progression of prostate cancer to an advanced castration-resistant form.
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As the most important driving force for ensuring the effective supply of grain in the country, the production stability of the major grain-producing areas directly concerns the national security of China. In this paper, considering the "water-soil-energy-carbon" correlation, water, soil and energy resource factors, and carbon emission constraints were included in an index system, and the global common frontier boundary three-stage super-efficient EBM-GML model was used to measure the grain production resource utilization efficiency of the major grain-producing areas in China from 2000 to 2019. This paper also analyzed the static and dynamic spatiotemporal characteristics and the restrictions of utilization efficiency. The results showed that, under the measurement of the traditional data envelopment analysis model, the grain production resource utilization efficiency in the major producing areas is relatively high, but there is still room to improve by more than 20%, and grain production still has enormous growth potential. After excluding external environmental and random factors, it was found that the utilization efficiency of grain production resources in the major producing areas decreased, and the efficiency and ranking of provinces changed significantly. External factors inhibit pure technical efficiency and expand the scale efficiency. The utilization efficiency of Northeast China was much higher than that of the Huang-Huai-Hai region and the middle and upper reaches of the Yangtze River region, and its grain production resource allocation management had obvious advantages. The total factor productivity index of food production resources showed an upward trend as a whole, and its change was affected by both technological efficiency and technological progress, of which technological progress had the greater impact. Therefore, reducing the differences in the external environment of different regions while making adjustments in accordance with their own potential is an effective way to further improve the utilization efficiency of food production resources.