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Aptamers with fluorogenic ligands are emerging as useful tools to quantify and track RNA molecules. The RNA Mango family of aptamers have a useful combination of tight ligand binding, bright fluorescence, and small size. However, the simple structure of these aptamers, with a single base-paired stem capped by a G-quadruplex, can limit the sequence and structural modifications needed for many use-inspired designs. Here we report new structural variants of RNA Mango that have two base-paired stems attached to the quadruplex. Fluorescence saturation analysis of one of the double-stemmed constructs showed a maximum fluorescence that is â¼75% brighter than the original single-stemmed Mango I. A small number of mutations to nucleotides in the tetraloop-like linker of the second stem were subsequently analyzed. The effect of these mutations on the affinity and fluorescence suggested that the nucleobases of the second linker do not directly interact with the fluorogenic ligand (TO1-biotin), but may instead induce higher fluorescence by indirectly altering the ligand properties in the bound state. The effects of the mutations in this second tetraloop-like linker indicate the potential of this second stem for rational design and reselection experiments. Additionally, we demonstrated that a bimolecular mango designed by splitting the double-stemmed Mango can function when two RNA molecules are cotranscribed from different DNA templates in a single in vitro transcription. This bimolecular Mango has potential application in detecting RNA-RNA interactions. Together, these constructs expand the designability of the Mango aptamers to facilitate future applications of RNA imaging.
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Aptámeros de Nucleótidos , Mangifera , Mangifera/genética , Mangifera/química , Mangifera/metabolismo , Aptámeros de Nucleótidos/química , Ligandos , Colorantes Fluorescentes/química , ARN/químicaRESUMEN
The fundamental interest in actinide chemistry, particularly for the development of thorium-based materials, is experiencing a renaissance owing to the recent and rapidly growing attention to fuel cycle reactors, radiological daughters for nuclear medicine, and efficient nuclear stockpile development. Herein, we uncover fundamental principles of thorium chemistry on the example of Th-based extended structures such as metal-organic frameworks in comparison with the discrete systems and zirconium extended analogs, demonstrating remarkable over two-and-half-year chemical stability of Th-based frameworks as a function of metal node connectivity, amount of defects, and conformational linker rigidity through comprehensive spectroscopic and crystallographic analysis as well as theoretical modeling. Despite exceptional chemical stability, we report the first example of studies focusing on the reactivity of the most chemically stable Th-based frameworks in comparison with the discrete Th-based systems such as metal-organic complexes and a cage, contrasting multicycle recyclability and selectivity (>97%) of the extended structures in comparison with the molecular compounds. Overall, the presented work not only establishes the conceptual foundation for evaluating the capabilities of Th-based materials but also represents a milestone for their multifaceted future and foreshadows their potential to shape the next era of actinide chemistry.
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4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.
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Ácido Quinurénico , Fármacos Neuroprotectores , Ratas , Animales , Quinurenina , Analgésicos , Fármacos Neuroprotectores/metabolismoRESUMEN
Patients with high model for end-stage liver disease (MELD) scores waiting for liver transplantation in Australia and New Zealand (ANZ) have had limited access to deceased donor livers and therefore binational sharing of livers, for patients with a MELD score ≥35 was introduced in February 2016. Waiting list mortality, post-transplant outcomes and intention-to-treat survival were compared between patients whose MELD score reached 35 on the waiting list between October 2013 and April 2015 (Pre-Share 35 group, n = 23) and patients who were Share 35 listed between February 2016 and May 2022 (Share 35 group, n = 112). There was significantly reduced waiting list mortality in share 35 listed patients in comparison to the pre-Share 35 group (11.7% vs. 52.2%, OR .120 95% CI .044-.328, P < .001). Post-transplant patient and graft survival were not significantly different between the groups (5-year patient survival 82% vs. 84%, P = .991, 5-year graft survival 82% vs. 76%, P = .543). Intention-to-treat survival was superior in the Share 35 group (HR .302, 95% CI .149-.614, P < .001). Introduction of Share 35 in ANZ resulted in a 78% risk reduction in waiting list mortality, equivalent post-transplant survival and an improvement in intention-to-treat survival.
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Enfermedad Hepática en Estado Terminal , Trasplante de Hígado , Obtención de Tejidos y Órganos , Humanos , Enfermedad Hepática en Estado Terminal/cirugía , Nueva Zelanda/epidemiología , Índice de Severidad de la Enfermedad , Listas de EsperaRESUMEN
High temperature requirement A serine peptidase 1 (HTRA1) is a serine protease involved in an array of signaling pathways. It is also responsible for the regulation of protein aggregates via refolding, translocation, and degradation. It has subsequently been found that runaway proteolytic HTRA1 activity plays a role in a variety of diseases, including Age-Related Macular Degeneration (AMD), osteoarthritis, and Rheumatoid Arthritis. Selective inhibition of serine protease HTRA1 therefore offers a promising new strategy for the treatment of these diseases. Herein we disclose structure-activity-relationship (SAR) studies which identify key interactions responsible for binding affinity of small molecule inhibitors to HTRA1. The study results in highly potent molecules with IC50's less than 15 nM and excellent selectivity following a screen of 35 proteases.
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Serina Peptidasa A1 que Requiere Temperaturas Altas , Serina Endopeptidasas , Serina Peptidasa A1 que Requiere Temperaturas Altas/metabolismo , Relación Estructura-Actividad , Humanos , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/síntesis química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis químicaRESUMEN
In this work, we report the first example of the PCET reactivity for a boron cluster compound, the zwitterionic nido-carboranyl diphosphonium derivative 7-P(H)tBu2-10-P(H)iPr2-nido-C2B10H10. This main-group reagent efficiently transfers two electrons and two protons to quinones to yield hydroquinones and regenerate a neutral closo-carboranyl diphosphine, 1-PtBu2-2-PiPr2-closo-C2B10H10. As we have previously reported the conversion of this closo-carboranyl diphosphine into the zwitterionic nido- derivative upon reaction with main group hydrides, the transformation reported herein represents a complete synthetic cycle for the metal-free reduction of quinones, with the redox-active carboranyl diphosphine scaffold acting as a mediator. The proposed mechanism of this reduction, based on pKa determination, electrochemical studies, and kinetic isotope effect determination, involves the electron transfer from the nido- cluster to the quinone coupled with the delivery of protons.
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Neodymium is typically considered the best surrogate for trivalent americium and can be used to identify Am3+ containing materials that are likely to form. We have explored the alkaline-earth lanthanide borate phase space using alkaline-earth halide/carbonate fluxes. This resulted in the synthesis of new compounds AE5Ln(BO3)4X (AE = Ca, Sr; Ln = Pr, Nd, Eu, Tb; X = Cl, Br) and AE3Ln2(BO3)4 (AE = Sr, Ba; Ln = Pr, Nd) as well as the synthesis of two compounds of Ba8Ln2(BO3)6(B2O5) (Ln = Eu, Tb) crystallizing in a new structure type. Ba8Ln2(BO3)6(B2O5) crystallizes in the space group P21/n with lattice parameters a = 8.6002(3) Å, b = 7.9245(3) Å, c = 17.6697(7) Å, and ß = 91.3560(10)° for the Eu analogue, and the structure contains isolated LnO8 polyhedra connected into a framework by BO3 and B2O5 units. The fluorescence emission spectra of AE5Ln(BO3)4X (AE = Ca, Sr; Ln = Eu, Tb; X = Cl, Br) and Ba8Ln2(BO3)6(B2O5) (Ln = Eu, Tb) are reported.
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China has responded to a national land-system sustainability emergency via an integrated portfolio of large-scale programmes. Here we review 16 sustainability programmes, which invested US$378.5 billion (in 2015 US$), covered 623.9 million hectares of land and involved over 500 million people, mostly since 1998. We find overwhelmingly that the interventions improved the sustainability of China's rural land systems, but the impacts are nuanced and adverse outcomes have occurred. We identify some key characteristics of programme success, potential risks to their durability, and future research needs. We suggest directions for China and other nations as they progress towards the Sustainable Development Goals of the United Nations' Agenda 2030.
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Suelo , Desarrollo Sostenible/tendencias , Agricultura , Biodiversidad , China , Conservación de los Recursos Naturales , Abastecimiento de Alimentos , Bosques , Objetivos , Pradera , Desarrollo Sostenible/economía , Desarrollo Sostenible/legislación & jurisprudencia , Factores de Tiempo , Naciones Unidas , AguaRESUMEN
BACKGROUND: Preoperative anemia is associated with adverse outcomes in cardiac surgery, yet it remains unclear what proportion of this association is mediated through red blood cell (RBC) transfusions. METHODS: This is a historical observational cohort study of adults undergoing coronary artery bypass grafting or valve surgery on cardiopulmonary bypass at an academic medical center between May 1, 2008, and May 1, 2018. A mediation analysis framework was used to evaluate the associations between preoperative anemia and postoperative outcomes, including a primary outcome of acute kidney injury (AKI). Intraoperative RBC transfusions were evaluated as mediators of preoperative anemia and outcome relationships. The estimated total effect, average direct effect of preoperative anemia, and percent of the total effect mediated through transfusions are presented with 95% confidence intervals and P -values. RESULTS: A total of 4117 patients were included, including 1234 (30%) with preoperative anemia. Overall, 437 of 4117 (11%) patients went on to develop AKI, with a greater proportion of patients having preoperative anemia (219 of 1234 [18%] vs 218 of 2883 [8%]). In multivariable analyses, the presence of preoperative anemia was associated with increased postoperative AKI (6.4% [4.2%-8.7%] absolute difference in percent with AKI, P < .001), with incremental decreases in preoperative hemoglobin concentrations displaying greater AKI risk (eg, 11.9% [6.9%-17.5%] absolute increase in probability of AKI for preoperative hemoglobin of 9 g/dL compared to a reference of 14 g/dL, P < .001). The association between preoperative anemia and postoperative AKI was primarily due to direct effects of preoperative anemia (5.9% [3.6%-8.3%] absolute difference, P < .001) rather than mediated through intraoperative RBC transfusions (7.5% [-4.3% to 21.1%] of the total effect mediated by transfusions, P = .220). Preoperative anemia was also associated with longer hospital durations (1.07 [1.05-1.10] ratio of geometric mean length of stay, P < .001). Of this total effect, 38% (22%, 62%; P < .001) was estimated to be mediated through subsequent intraoperative RBC transfusion. Preoperative anemia was not associated with reoperation or vascular complications. CONCLUSIONS: Preoperative anemia was associated with higher odds of AKI and longer hospitalizations in cardiac surgery. The attributable effects of anemia and transfusion on postoperative complications are likely to differ across outcomes. Future studies are necessary to further evaluate mechanisms of anemia-associated postoperative organ injury and treatment strategies.
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Lesión Renal Aguda , Anemia , Procedimientos Quirúrgicos Cardíacos , Adulto , Humanos , Análisis de Mediación , Factores de Riesgo , Anemia/complicaciones , Anemia/diagnóstico , Anemia/epidemiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Hemoglobinas/análisis , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Estudios RetrospectivosRESUMEN
OBJECTIVE: Fasedienol (PH94B) is a pherine compound formulated as a nasal spray that is hypothesized to regulate olfactory-amygdala circuits of fear and anxiety. Fasedienol's effect on the local electrogram of nasal chemosensory neurons (EGNR) and autonomic nervous system (ANS) responses versus steroidal hormones and controls in healthy adults is reported. METHODS: Eight males and 8 females randomly received aerosolized control (propylene glycol) and study drugs (fasedienol, 17ß-estradiol, progesterone, cortisol, and testosterone, 0.4 µg each in propylene glycol) onto the nasal septum mucosal lining at 30-min intervals over 2 sessions. EGNR was continuously monitored; autonomic parameters were recorded before and after administration. RESULTS: Fasedienol significantly increased EGNR amplitude (males: 5.0 vs. 0.6 mV, p < 0.001; females:5.7 vs. 0.6 mV, p < 0.001), and rapidly reduced respiratory rate (p < 0.05), heart rate (p < 0.01), and electrodermal activity (p < 0.05) versus control. EGNR and ANS responses after steroidal hormone administration were similar to control. 81% reported feeling less tense/more relaxed after receiving fasedienol, but not after receiving either control or steroidal hormones. CONCLUSIONS: Intranasal fasedienol, but not control or steroidal hormones, activated EGNR and rapidly reduced ANS responses, consistent with sympatholytic effects. Combined with subjective reports, results suggest fasedienol may provide acute relief in anxiety conditions.
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Sistema Nervioso Autónomo , Rociadores Nasales , Adulto , Femenino , Humanos , Masculino , Sistema Nervioso Autónomo/fisiología , Estradiol , Voluntarios Sanos , Glicoles de PropilenoRESUMEN
OBJECTIVE: To examine the analgesic efficacy of postoperative deep parasternal intercostal plane (DPIP) blocks for patients having cardiac surgery via median sternotomy. DESIGN: This single-center retrospective study compared patients receiving bilateral DPIP blocks with a matched cohort of patients not receiving DPIP blocks. SETTING: Large quaternary referral center. PARTICIPANTS: Adult patients admitted to the authors' institution from January 1, 2016, to August 14, 2020, for elective cardiac surgery via median sternotomy. INTERVENTIONS: Patients received ultrasound-guided bilateral DPIP blocks. MEASUREMENTS AND MAIN RESULTS: A total of 113 patients received a DPIP block; 3,461 patients did not. The estimated multiplicative change in cumulative opioid consumption through 24 hours was 0.42 (95% CI 0.32-0.56; p < 0.001), indicating that patients receiving DPIP blocks required 60% fewer opioids than patients who did not. Proportional odds ratios for the average pain score on postoperative day (POD) 0 was 0.46 (95% CI 0.32-0.65; p < 0.001), and POD 1 was 0.67 (95% CI 0.47-0.94; p = 0.021), indicating lower pain scores for patients receiving blocks. The exploratory analysis identified an inverse correlation between DPIP blocks and atrial fibrillation incidence (2% v 15%; inverse probability of treatment weighting odds ratio 0.088, 95% CI 0.02-0.41; p = 0.002). CONCLUSIONS: The use of DPIP blocks in patients undergoing cardiac surgery via median sternotomy was associated with less opioid use and improved pain scores in the early postoperative period compared with patients not receiving blocks. Prospective randomized controlled studies should further elucidate the efficacy and risks of DPIP blocks in cardiac surgery.
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Analgesia , Procedimientos Quirúrgicos Cardíacos , Bloqueo Nervioso , Adulto , Humanos , Esternotomía/efectos adversos , Estudios Retrospectivos , Analgésicos Opioides , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/etiología , Estudios Prospectivos , Procedimientos Quirúrgicos Cardíacos/efectos adversosRESUMEN
OBJECTIVE: There is a lack of strong evidence for use of expensive bone substitutes. This study compares perioperative data and patient reported quality-of-life outcomes across the varied types of bone graft extenders. The study analyzes the existing Quality and Outcomes Database and evaluates patient reported outcomes for 1-3 level lumbar fusion procedures comparing across different types of biologics bone graft. METHODS: We retrospectively analyzed a prospectively collected data registry. Bone graft implant data were collected and grouped into the following categories: (1) Autograft with basic allograft (2) Enhanced, synthetic, or cellular allograft (3) Use of BMP. Preoperative and 1 year patient reported outcomes and perioperative data from the prospective collected registry were analyzed. RESULTS: There were 384 patients included in this study. There were 168 (43.8%) patients in group 1, 133 (34.6%) patients in group 2, and 83 (21.6%) in group 3. There were no group differences in baseline or 1 year back pain, leg pain, ODI, or EQ-5D. The GLM Repeated Measures results indicate a significant difference within each of the three groups between the preoperative and postoperative measures for back pain, leg pain, ODI, and EQ-5D. The change over time was not significantly different between the groups. CONCLUSIONS: Bone graft extenders are a significant contributor to the cost of lumbar fusion. This study demonstrates no difference in preoperative, and 1 year patient reported outcomes between the three groups. There was no significant difference in rate of reoperations across the three groups.
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Fusión Vertebral , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Estudios Prospectivos , Fusión Vertebral/métodos , Dolor de Espalda/cirugía , Vértebras Lumbares/cirugíaRESUMEN
Successful management of invasive species often requires working across public and private landownerships. A prime example of an invasive species that commonly occurs on privately and publicly owned and managed lands is the wild pig (Sus scrofa). Because of the multitude of negative impacts associated with wild pigs, management must occur across both private and public lands to achieve widespread control and sustained success. However, managing wild pigs across property boundaries is challenging as we know very little about differing management practices and landowner perspectives. To address this knowledge gap, we sought to understand wild pig management efforts on privately owned lands, the perceived economic, ecological, and human health impact of wild pigs, and beliefs related to policy. Generally, stakeholders believe wild pigs have negative impacts on wildlife, the economy, and ecological and public health, however less than half of landowners participate in wild pig control. Furthermore, stakeholders believe that the responsibility of managing and paying for damages associated with wild pigs lies with individual landowners. Our findings suggest that increased efficacy of wild pig control and collaboration between private and public landowners is not only possible but also necessary if wild pig population control is to be regionally successful.
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Animales Salvajes , Conservación de los Recursos Naturales , Animales , Humanos , Alabama , Especies Introducidas , PolíticasRESUMEN
As part of our exploration of plutonium-containing materials as potential nuclear waste forms, we report the first extended structure Pu(V) material and the first Pu(V) borate. Crystals of Na2(PuO2)(BO3) were grown out of mixed hydroxide/boric acid flux and found to crystallize in the orthorhombic space group Cmcm with lattice parameters of a = 9.9067(4) Å, b = 6.5909(2) Å, and c = 6.9724(2) Å. Na2(PuO2)(BO3) adopts a layered structure in which layers of PuO2(BO3)2- are separated by sodium cations. Plutonium is found in a pentagonal bipyramidal coordination environment, with axial Pu(V)-O plutonyl bond lengths of 1.876(3) Å and equatorial Pu-O bond lengths ranging from 2.325(5) to 2.467(3) Å. We find that the Pu(V)-O plutonyl bond lengths are approximately 0.1 Å longer than the reported Pu(VI)-O plutonyl bond lengths and shorter by approximately 0.033 Å than the corresponding U(V) uranyl bond lengths. Raman spectroscopy on single crystals was used to determine the PuO2+ plutonyl stretching and the equatorial breathing mode frequencies of the pentagonal bipyramidal coordination environment around plutonium. Density functional theory calculations were used to calculate the Raman spectrum to help identify the Raman bands at 690 and 630 cm-1 as corresponding to the plutonyl(V) ν1 stretch and the equatorial PuO5 breathing mode, respectively. UV-vis measurements on single crystals indicate semiconducting behavior with a band gap of â¼2.60 eV.
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Camelina neglecta is a diploid species from the genus Camelina, which includes the versatile oilseed Camelina sativa. These species are closely related to Arabidopsis thaliana and the economically important Brassica crop species, making this genus a useful platform to dissect traits of agronomic importance while providing a tool to study the evolution of polyploids. A highly contiguous chromosome-level genome sequence of C. neglecta with an N50 size of 29.1 Mb was generated utilizing Pacific Biosciences (PacBio, Menlo Park, CA) long-read sequencing followed by chromosome conformation phasing. Comparison of the genome with that of C. sativa shows remarkable coincidence with subgenome 1 of the hexaploid, with only one major chromosomal rearrangement separating the two. Synonymous substitution rate analysis of the predicted 34 061 genes suggested subgenome 1 of C. sativa directly descended from C. neglecta around 1.2 mya. Higher functional divergence of genes in the hexaploid as evidenced by the greater number of unique orthogroups, and differential composition of resistant gene analogs, might suggest an immediate adaptation strategy after genome merger. The absence of genome bias in gene fractionation among the subgenomes of C. sativa in comparison with C. neglecta, and the complete lack of fractionation of meiosis-specific genes attests to the neopolyploid status of C. sativa. The assembled genome will provide a tool to further study genome evolution processes in the Camelina genus and potentially allow for the identification and exploitation of novel variation for Camelina crop improvement.
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Arabidopsis , Brassica , Brassicaceae , Neglecta , Diploidia , Brassicaceae/genética , Arabidopsis/genética , Brassica/genética , Genoma de PlantaRESUMEN
Immune checkpoint inhibitors (ICIs) have achieved huge clinical success. However, many still have limited response rates, and are prohibitively costly. There is a need for effective and affordable ICIs, as well as local manufacturing capacity to improve accessibility, especially to low-to-middle income countries (LMICs). Here, we have successfully expressed three key ICIs (anti-PD-1 Nivolumab, anti-NKG2A Monalizumab, and anti-LAG-3 Relatimab) transiently in Nicotiana benthamiana and Nicotiana tabacum plants. The ICIs were expressed with a combination of different Fc regions and glycosylation profiles. They were characterized in terms of protein accumulation levels, target cell binding, binding to human neonatal Fc receptors (hFcRn), human complement component C1q (hC1q) and various Fcγ receptors, as well as protein recovery during purification at 100 mg- and kg-scale. It was found that all ICIs bound to the expected target cells. Furthermore, the recovery during purification, as well as Fcγ receptor binding, can be altered depending on the Fc region used and the glycosylation profiles. This opens the possibility of using these two parameters to fine-tune the ICIs for desired effector functions. A scenario-based production cost model was also generated based on two production scenarios in hypothetical high- and low-income countries. We have shown that the product accumulation and recovery of plant production platforms were as competitive as mammalian cell-based platforms. This highlights the potential of plants to deliver ICIs that are more affordable and accessible to a widespread market, including LMICs.
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Neoplasias , Nicotiana , Animales , Humanos , Nicotiana/genética , Inhibidores de Puntos de Control Inmunológico , Receptores de IgG , MamíferosRESUMEN
Herein, we probe the hydrogen bond-driven self-assembly of a triphenylamine (TPA) bis-urea macrocycle in the presence and absence of guests. Comprised of methylene urea-bridged TPAs with exterior tridodecyloxy benzene solubilizing groups, the macrocycle exhibits concentration-dependent aggregate formation in THF and H2 O/THF mixtures as characterized by 1 Hâ NMR and DOSY experiments. Its assembly processes were further probed by temperature-dependent UV/Vis and fluorescence spectroscopy. Upon heating, UV/Vis spectra exhibit a hypsochromic shift in the λmax , while fluorescence spectra show an increase in emission intensity. Conversely, the protected macrocycle that lacks hydrogen bond donors demonstrates no significant change. Thermodynamic analysis indicates a cooperative self-assembly pathway with distinct nucleation and elongation regimes. The morphology and structure of the aggregate were elucidated by dynamic light scattering, atomic force microscopy, scanning and transmission electron microscopy. Variable temperature emission spectra were utilized to monitor the impact of guests, such as diphenylacetylene, that can be bound in the columnar channels. The findings suggest that the elongation of assemblies is influenced by the presence of these guests. In comparison, diphenyl sulfoxide, likely functioning as a chain stopper, limited the assembly size. These studies suggest that judicious selection of (co)monomers may modulate the function and utility of these supramolecular systems.
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Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80 mg daily for 3 days), in chronic stable patients with schizophrenia (n = 26 analyzed). We focused on 3 T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p < 0.0001) and anterior cingulate/paracingulate (p = 0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r = -0.42, p = 0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism, which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment toward specific populations.
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Antipsicóticos , Receptores de Glutamato Metabotrópico , Esquizofrenia , Antipsicóticos/uso terapéutico , Método Doble Ciego , Humanos , Memoria a Corto Plazo , Proyectos Piloto , Esquizofrenia/tratamiento farmacológicoRESUMEN
BACKGROUND AND PURPOSE: Limited data guide the selection of patients with large vessel occlusion ischaemic stroke who may benefit from referral to a distant tertiary centre for mechanical thrombectomy (MT). We aimed to characterize this population, describe clinical outcomes and develop a screening system to identify patients most likely to benfit from delayed mechanical thrombectomy (MT). METHODS: We undertook a retrospective cohort analysis enrolling patients transferred from regional sites to one of two MT comprehensive stroke units with a time from non-contrast computed tomography (NCCT) of the brain to reperfusion of 4 h or more. We describe Alberta Stroke Programme Early Computed Tomography Score (ASPECTS), National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) in our patients and compare these patients to those in extended-time-window trials. Lastly, we developed and validated a scoring model to help clinicians identify appropriate patients based on variables associated with poor outcomes. RESULTS: We included 563 patients, 46% of whom received thrombolysis; the median (interquartile range [IQR]) ASPECTS was 8 (7-10) and the median (IQR) NIHSS score was 16 (11-20). The median (IQR) symptom to mechanical reperfusion time was 390 (300-580) min. Eight patients (1%) had a symptomatic haemorrhage. We achieved good clinical outcome (defined as mRS score ≤2) in 299 patients (54%). Age, diabetes, NIHSS score and ASPECTS were used to create a weighted scoring system with a validated area under the curve of 0.83 (95% confidence interval 0.74-0.92). CONCLUSION: Our study shows, in highly selected patients, that delayed MT many hours after baseline NCCT is associated with good clinical outcomes. However, older patients with diabetes, high NIHSS score and low ASPECTS may not benefit from transfer to a hub centre many hours away for MT in this model of care.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/cirugía , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/cirugía , Estudios Retrospectivos , Trombectomía/métodos , Resultado del Tratamiento , Accidente Cerebrovascular Isquémico/etiologíaRESUMEN
Mild hydrothermal synthesis was employed to grow high-quality single crystals of ternary fluoridohafnates at low temperatures. The series of new materials was characterized using single-crystal X-ray diffraction, and the crystal structures of AHfF6 (A = Mg and Sr), A2HfF8 (A = Ba and Pb), Ca5Hf3F22, and Cd2HfF8(H2O)6 are discussed herein. Although some material compositions have similar stoichiometries, all of the compositions adopt different structural motifs. A comparison of the crystal structures and synthesis techniques of ternary fluoridohafnates and ternary fluoridozirconates is also reported, and the impact of the subtle changes of synthesis conditions on overall structures is discussed.