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BACKGROUND: Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery. METHODS: We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major noncardiac surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery. RESULTS: A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to noncardiac surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, P<0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, P=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, P<0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]). CONCLUSIONS: Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before noncardiac surgery.
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Calcio , Infarto del Miocardio , Adulto , Humanos , Femenino , Anciano , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos X/métodos , Infarto del Miocardio/etiología , Medición de Riesgo/métodosRESUMEN
Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.
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Apolipoproteína E4 , Ácidos Docosahexaenoicos , Animales , Ratones , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Dieta , Suplementos Dietéticos , Ácidos Docosahexaenoicos/metabolismo , Corteza Entorrinal/metabolismo , Ácidos Grasos InsaturadosRESUMEN
We have developed a convergent method for the synthesis of allylic alcohols that involves a reductive coupling of terminal alkynes with α-chloro boronic esters. The new method affords allylic alcohols with excellent regioselectivity (anti-Markovnikov) and an E/Z ratio greater than 200:1. The reaction can be performed in the presence of a wide range of functional groups and has a substrate scope that complements the stoichiometric alkenylation of α-chloro boronic esters performed using alkenyl lithium and Grignard reagents. The transformation is stereospecific and allows for the robust and highly selective synthesis of chiral allylic alcohols. Our studies support a mechanism that involves hydrocupration of the alkyne and cross-coupling of the alkenyl copper intermediate with α-chloro boronic esters. Experimental evidence excludes a radical mechanism of the cross-coupling step and is consistent with the formation of a boron-ate intermediate and a 1,2-metalate shift.
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Premature birth is associated with a high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, yet the putative effects of hippocampal dysfunction remain poorly understood in preterm neonates. In particular, while asymmetry of the hippocampus has been well noted both structurally and functionally, how preterm birth impairs hippocampal development and to what extent the hippocampus is asymmetrically impaired by preterm birth have not been well delineated. In this study, we compared volumetric growth and shape development in the hippocampal hemispheres and structural covariance (SC) between hippocampal vertices and cortical thickness in cerebral cortex regions between two groups. We found that premature infants had smaller volumes of the right hippocampi only. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared with full-term peers, though preterm neonates exhibited an accelerated age-related change of hippocampal thickness in the left hippocampi. The SC between the left hippocampi and the limbic lobe of the premature infants was severely impaired compared with the term-born neonates. These findings suggested that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure with a high degree of asymmetry.
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Nacimiento Prematuro , Corteza Cerebral , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Imagen por Resonancia MagnéticaRESUMEN
During infection, the bacterial pathogen Legionella pneumophila manipulates a variety of host cell signaling pathways, including the Hippo pathway which controls cell proliferation and differentiation in eukaryotes. Our previous studies revealed that L. pneumophila encodes the effector kinase LegK7 which phosphorylates MOB1A, a highly conserved scaffold protein of the Hippo pathway. Here, we show that MOB1A, in addition to being a substrate of LegK7, also functions as an allosteric activator of its kinase activity. A crystallographic analysis of the LegK7-MOB1A complex revealed that the N-terminal half of LegK7 is structurally similar to eukaryotic protein kinases, and that MOB1A directly binds to the LegK7 kinase domain. Substitution of interface residues critical for complex formation abrogated allosteric activation of LegK7 both in vitro and within cells and diminished MOB1A phosphorylation. Importantly, the N-terminal extension (NTE) of MOB1A not only regulated complex formation with LegK7 but also served as a docking site for downstream substrates such as the transcriptional coregulator YAP1. Deletion of the NTE from MOB1A or addition of NTE peptides as binding competitors attenuated YAP1 recruitment to and phosphorylation by LegK7. By providing mechanistic insight into the formation and regulation of the LegK7-MOB1A complex, our study unravels a sophisticated molecular mimicry strategy that is used by L. pneumophila to take control of the host cell Hippo pathway.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Bacterianas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Legionella pneumophila/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Regulación Alostérica , Animales , Proteínas Bacterianas/genética , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Legionella pneumophila/patogenicidad , Enfermedad de los Legionarios/microbiología , Enfermedad de los Legionarios/patología , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Ratones , Simulación de Dinámica Molecular , Imitación Molecular , Fosforilación , Unión Proteica , Proteínas Quinasas/genética , Células RAW 264.7 , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden.
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Envejecimiento/genética , Reparación del ADN/genética , Longevidad/genética , Neoplasias/genética , Envejecimiento/patología , Reparación de la Incompatibilidad de ADN/genética , Replicación del ADN/genética , Genotipo , Humanos , Mutación/genética , Acumulación de Mutaciones , Tasa de Mutación , Neoplasias/patología , Fenotipo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Secuenciación Completa del GenomaRESUMEN
This paper describes a detailed mechanistic study of the silver-catalyzed Z-selective hydroalkylation of terminal alkynes. Considering the established mechanistic paradigms for Z-selective hydroalkylation of alkynes, we explored a mechanism based on the radical carbometalation of alkynes. Experimental results have provided strong evidence against the initially proposed radical mechanism and have led us to propose a new mechanism for the Z-selective hydroalkylation of alkynes based on boronate formation and a 1,2-metalate shift. The new mechanism provides a rationale for the excellent Z-selectivity observed in the reaction. A series of stoichiometric experiments has probed the feasibility of the proposed elementary steps and revealed an additional role of the silver catalyst in the protodeboration of an intermediate. Finally, a series of kinetic measurements, KIE experiments, and competition experiments allowed us to identify the turnover limiting step and the resting state of the catalyst. We believe that the results of this study will be useful in the further exploration and development of related transformations of alkynes.
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AlquenosRESUMEN
The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.
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Adaptación Fisiológica/genética , Aneuploidia , Estrés del Retículo Endoplásmico/genética , Regulación Fúngica de la Expresión Génica/fisiología , Saccharomyces cerevisiae/fisiología , Cromosomas Fúngicos/genética , Farmacorresistencia Fúngica/genética , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Pliegue de Proteína , Tunicamicina/farmacología , Respuesta de Proteína Desplegada/fisiologíaRESUMEN
Alkenes are an important class of compounds common among biologically active molecules and often are used as intermediates in organic synthesis. Many alkenes exist in two stereoisomeric forms (E and Z), which have different structures and different properties. The selective formation of the two isomers is an important synthetic goal that has long inspired the development of new synthetic methods. However, the efficient synthesis of diastereopure, thermodynamically less stable, Z-alkenes is still challenging. Here, we demonstrate an efficient synthesis of diastereopure Z-alkenes (Z:E > 300:1) through a silver-catalyzed hydroalkylation of terminal alkynes, using alkylboranes as coupling partners. We also describe the exploration of the substrate scope, which reveals the broad functional group compatibility of the new method. Preliminary mechanistic studies suggest that a 1,2-metalate rearrangement of the silver borate intermediate is the key step responsible for the stereochemical outcome of the reaction.
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Alquenos/síntesis química , Alquinos/química , Plata/química , Alquenos/química , Boratos/química , Capsaicina/análogos & derivados , Capsaicina/síntesis química , Catálisis , Diinos/síntesis química , Alcoholes Grasos/síntesis química , Estructura Molecular , EstereoisomerismoRESUMEN
Purpose: Multiple myeloma is an insidious haematological malignancy characterised by monoclonal proliferation of plasma cells in the bone marrow. Extramedullary plasmacytoma is a rare manifestation of multiple myeloma and usually occurs in the upper respiratory tract. Orbital involvement is particularly uncommon, but may be associated with devastating visual impairment and poor clinical outcomes. Therefore, this article aims to highlight the need for multidisciplinary management of orbital extramedullary plasmacytoma. Methods: This is a retrospective observational case series of five patients. All presented to the authors for management of orbital extramedullary plasmacytomas from 2004 to 2015 at Prince of Wales and Mater Hospitals in Sydney, Australia. Medical records were reviewed for pertinent information including demographics, disease features, management strategy, and clinical progress. The study met Medical Ethics Board standards and is in accordance with the Helsinki Agreements. Results: This case series of five patients underscores the poor prognosis of orbital extramedullary plasmacytoma. Despite aggressive multidisciplinary management, four of these five patients succumbed to their illness during the study period. However, multidisciplinary management did manage to minimise symptoms and preserve quality of life. Conclusions: On a case-by-case basis, patients may derive palliative benefit from orbital surgery in conjunction with radiotherapy and chemotherapy. Orbital surgeons are encouraged to work within a multidisciplinary framework of medical specialists, including haematologists and radiation oncologists, when determining the optimal management plan in cases of orbital extramedullary plasmacytoma.
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Neoplasias Orbitales/diagnóstico por imagen , Neoplasias Orbitales/terapia , Plasmacitoma/diagnóstico , Plasmacitoma/terapia , Anciano , Biopsia , Terapia Combinada , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Orbitales/tratamiento farmacológico , Neoplasias Orbitales/radioterapia , Grupo de Atención al Paciente , Plasmacitoma/tratamiento farmacológico , Plasmacitoma/radioterapia , Estudios RetrospectivosRESUMEN
We have developed a photoinduced copper-catalyzed alkylation of terminal alkynes with primary, secondary, or tertiary alkyl iodides as electrophiles. The reaction has a broad substrate scope and can be successfully performed in the presence of ester, nitrile, aryl halide, ketone, sulfonamide, epoxide, alcohol, and amide functional groups. The alkylation is promoted by blue light (λ≈450â nm) and proceeds at room temperature in the absence of any additional metal catalysts. The use of a terpyridine ligand is essential for the success of the reaction and is shown to prevent photoinduced copper-catalyzed polymerization of the starting materials.
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We have developed a catalytic method for the hydroalkylation of allenes using alkyl triflates as electrophiles and silane as a hydride source. The reaction has an excellent substrate scope and is compatible with a wide range of functional groups, including esters, aryl halides, aryl boronic esters, sulfonamides, alkyl tosylates, and alkyl bromides. We found evidence for a reaction mechanism that involves unusual dinuclear copper ally complexes as catalytic intermediates. The unusual structure of these complexes provides a rationale for their unexpected reactivity.
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OBJECTIVES: Physical examination can identify palpable splenomegaly easily, but evaluating lesser degrees of splenomegaly is problematic. Hand-carried ultrasound allows rapid bedside assessment of patients. We conducted this study to determine whether hand-carried ultrasound can reliably assess spleen size. METHODS: Patients with varying degrees of splenomegaly were studied. Two sonographers blindly measured spleen size in each patient using either a hand-carried or conventional ultrasound device in random order. Sonographers completed a data sheet indicating the adequacy of the image, clinical measurements of enlargement, and confidence in their observations. RESULTS: Sixteen patients (10 male and 6 female; mean age ± SEM, 60 ± 4 years) were recruited. Image quality was adequate or better in all scans with conventional ultrasound and in 15 of 16 scans with hand-carried ultrasound. The greatest longitudinal measurement recorded was statistically equivalent across ultrasound techniques, with mean values of 16.4 cm (95% confidence interval, 14.8-18.0 cm) for conventional ultrasound and 15.8 cm (95% confidence interval, 14.1-17.4 cm) for hand-carried ultrasound. The correlation between measurement techniques was r = 0.89 (P < .0001). Sonographers were somewhat or very confident in the outcomes of all scans with conventional ultrasound and in 15 of 16 cases with hand-carried ultrasound. In general, it took longer for sonographers to obtain images with hand-carried ultrasound. CONCLUSIONS: We have shown that hand-carried ultrasound can be used at the point of care by trained individuals to diagnose splenomegaly. However, hand-carried ultrasound images were less likely to be judged excellent, were accompanied by less diagnostic certainty, and took longer to obtain.
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Bazo/diagnóstico por imagen , Esplenomegalia/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Sistemas de Atención de Punto , Bazo/patología , Ultrasonografía/métodosRESUMEN
Objective: To determine if basal linear deposit (BLinD) is a specific lesion of age-related macular degeneration (AMD). Methods: The cohort was selected from a clinically and histopathologically validated archive (Sarks Archive) and consisted of 10 normal eyes (age 55-80 years) without any macular basal laminar deposit (BLamD) (Sarks Group I) and 16 normal aged eyes (age 57-88 years) with patchy BLamD (Sarks Group II). Only eyes with in vivo fundus assessment and corresponding high-resolution transmission electron microscopy (TEM) micrographs of the macula were included. Semithin sections and fellow-eye paraffin sections were additionally examined. BLinD was defined as a diffuse layer of electron-lucent vesicles external to the retinal pigment epithelium (RPE) basement membrane by TEM and was graded as follows: (i) Grade 0, absence of a continuous layer; (ii) Grade 1, a continuous layer up to three times the thickness of the RPE basement membrane (0.9 µm); (iii) Grade 2, a continuous layer greater than 0.9 µm. Bruch's membrane (BrM) hyalinisation and RPE abnormalities were determined by light microscopic examination of corresponding semithin and paraffin sections. Results: BLinD was identified in both normal (30%) and normal aged (62.5%) eyes. BLinD was thicker in normal aged eyes (p = 0.045; 95% CI 0.04-3.4). BLinD thickness positively correlated with both the degree of BrM hyalinisation (p = 0.049; 95% CI 0.05-2.69) and increasing microscopic RPE abnormalities (p = 0.022; 95% CI 0.188-2.422). RPE abnormalities were more likely to be observed in eyes with increased BrM hyalinisation (p = 0.044; 95% CI 0.61-4.319). Conclusions: BLinD is most likely an age-related deposit rather than a specific lesion of AMD. Its accumulation is associated with increasing BrM hyalinisation and microscopic RPE abnormalities, suggesting a relationship with dysregulated RPE metabolism and/or transport.
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Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among the closely related species or strains of a single species. Since mitochondrial-mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect.
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Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among the closely related species or strains of a single species. Since mitochondrial-mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect.
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The progress made in aging research using laboratory organisms is undeniable. Yet, with few exceptions, these studies are conducted in a limited number of isogenic strains. The path from laboratory discoveries to treatment in human populations is complicated by the reality of genetic variation in nature. To model the effect of genetic variation on the action of the drug rapamycin, here we use the growth of Drosophila melanogaster larvae. We screened 140 lines from the Drosophila Genetic References Panel for the extent of developmental delay and found wide-ranging variation in their response, from lines whose development time is nearly doubled by rapamycin, to those that appear to be completely resistant. Sensitivity did not associate with any single genetic marker, nor with any gene. However, variation at the level of genetic pathways was associated with rapamycin sensitivity and might provide insight into sensitivity. In contrast to the genetic analysis, metabolomic analysis showed a strong response of the metabolome to rapamycin, but only among the sensitive larvae. In particular, we found that rapamycin altered levels of amino acids in sensitive larvae, and in a direction strikingly similar to the metabolome response to nutrient deprivation. This work demonstrates the need to evaluate interventions across genetic backgrounds and highlights the potential of omic approaches to reveal biomarkers of drug efficacy and to shed light on mechanisms underlying sensitivity to interventions aimed at increasing lifespan.
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Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the "million-molecule challenge", an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.
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Longevidad , Robótica , Animales , Caenorhabditis elegans , EnvejecimientoRESUMEN
A woman in her 50's was diagnosed diffuse large B-cell lymphoma (DLBCL) after presenting to hospital in a critical condition, characterised by marked hyperleukocytosis (white cell count 290 x109/L). She subsequently developed painless blurred vision bilaterally, and was diagnosed with bilateral central retinal vein occlusion secondary to leukostasis. She was managed with non-Hodgkin lymphoma R-CHOEP14 (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone) immunochemotherapy, with her ocular signs and symptoms improving following treatment. Optical coherence tomography and funduscopic examination demonstrated no evidence of intraocular lymphoma. Visual acuity returned to 6/6 in each eye with subsequent resolution of her symptoms. Repeat examination demonstrated stable appearance of her ocular disease.
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OBJECTIVE: To assess depression and anxiety among college students during the COVID-19 pandemic and its association with race. PARTICIPANTS: Using a cross-sectional survey, depression and anxiety among college students at a Predominantly White (PWU) and a Historically Black University (HBU) during 2021 were evaluated. METHODS: The patient health questionnaire-9 (PHQ-9), general anxiety disorder-7 (GAD-7), and self-reported sociodemographic characteristics were collected. Chi-square and logistic regression tests examined differences in depression and anxiety based on race. RESULTS: Depression and anxiety among 3,102 students (87% female) were analyzed. Minority racial groups were associated with anxiety (p < 0.01) but not depression in the PWU. Moderately severe and severe depression was higher among the minority race at both the universities (1.76% compared to 0.53% at PWU, and 11.1% compared to 2.4% at HBU). CONCLUSIONS: Depression and anxiety among college students is influenced by racial status. First-generation students were more likely to report depression in both HBU and PWU.