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Generic open quantum systems are notoriously difficult to simulate unless one looks at specific regimes. In contrast, classical dissipative systems can often be effectively described by stochastic processes, which are generally less computationally expensive. Here, we use the paradigmatic case of a dissipative quantum oscillator to give a pedagogic introduction to the modeling of open quantum systems using quasiclassical methods, i.e., classical stochastic methods that use a "quantum" noise spectrum to capture the influence of the environment on the system. Such quasiclassical methods have the potential to offer insights into the impact of the quantum nature of the environment on the dynamics of the system of interest while still being computationally tractable.
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OBJECTIVE: The primary objective of this study was to quantify changes in performance of task-specific motor activities over 12 motor rehabilitation sessions with lumbosacral spinal cord stimulation (SCS) via either transcutaneous stimulation or epidural stimulation. Both stimulation modalities have been used in recent years to restore functions lost to spinal cord injury (SCI). Secondary outcomes examine participants' perspectives captured via the User Experience Questionnaire (UEQ) upon study completion to further understand their perception of SCS. METHODS: Six individuals with SCI completed 12 sessions with one modality of SCS during supine and/or side-lying, seated forward reaching, and standing activities. Changes in volitional lower extremity movement, the number of points of contact needed at hips and/or knees to facilitate standing, and changes in seated forward reaching distance were used to quantify performance. The UEQ was administered to gauge participants' perspectives following use of SCS to enable functions impaired due to SCI. RESULTS: For all participants, performance of motor activities improved with SCS compared to without stimulation. Responses for the UEQ showed an overall positive perception of trialing SCS with rehabilitation to enhance motor functions impaired by SCI. CONCLUSIONS: Regardless of injury severity, location of injury, time since SCI, or SCS modality, all participants experienced gains in motor function in the presence of SCS combined with a condensed rehabilitation program. However, no evidence of sustained motor functions was found in the absence of SCS. UEQ results highlight the positive perception of SCS with rehabilitation as well as the importance of consulting persons with lived experience of SCS during clinical trial design and protocol development.Trial registration: ClinicalTrials.gov identifier: NCT05095454.
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BACKGROUND: Natural killer (NK) cells are being extensively studied as a cell therapy for cancer. These cells are activated by recognition of ligands and antigens on tumor cells. Cytokine therapies, such as IL-15, are also broadly used to stimulate endogenous and adoptively transferred NK cells in patients with cancer. These stimuli activate the membrane protease ADAM17, which cleaves various cell-surface receptors on NK cells as a negative feedback loop to limit their cytolytic function. ADAM17 inhibition can enhance IL-15-mediated NK cell proliferation in vitro and in vivo. In this study, we investigated the underlying mechanism of this process. METHODS: Peripheral blood mononuclear cells (PBMCs) or enriched NK cells from human peripheral blood, either unlabeled or labeled with a cell proliferation dye, were cultured for up to 7 days in the presence of rhIL-15±an ADAM17 function-blocking antibody. Different fully human versions of the antibody were generated; Medi-1 (IgG1), Medi-4 (IgG4), Medi-PGLALA, Medi-F(ab')2, and TAB16 (anti-ADAM17 and anti-CD16 bispecific) to modulate CD16A binding. Flow cytometry was used to assess NK cell proliferation and phenotypic markers, immunoblotting to examine CD16A signaling, and IncuCyte-based live cell imaging to measure NK cell antitumor activity. RESULTS: The ADAM17 function-blocking monoclonal antibody (mAb) Medi-1 markedly increased early NK cell activation by IL-15. By using different engineered versions of the antibody, we demonstrate involvement by CD16A, an activating Fcγ receptor and well-described ADAM17 substrate. Hence, Medi-1 when bound to ADAM17 on NK cells is engaged by CD16A and blocks its shedding, inducing and prolonging its signaling. This process did not promote evident NK cell fratricide or dysfunction. Synergistic signaling by Medi-1 and IL-15 enhanced the upregulation of CD137 on CD16A+ NK cells and augmented their proliferation in the presence of PBMC accessory cells or an anti-CD137 agonistic mAb. CONCLUSIONS: Our data reveal for the first time that CD16A and CD137 underpin Medi-1 enhancement of IL-15-driven NK cell activation and proliferation, respectively, with the latter requiring PBMC accessory cells. The use of Medi-1 represents a novel strategy to enhance IL-15-driven NK cell proliferation, and it may be of therapeutic importance by increasing the antitumor activity of NK cells in patients with cancer.
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Proteína ADAM17 , Proliferación Celular , Interleucina-15 , Células Asesinas Naturales , Activación de Linfocitos , Receptores de IgG , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteína ADAM17/metabolismo , Interleucina-15/metabolismo , Interleucina-15/farmacología , Receptores de IgG/metabolismo , Proteínas Ligadas a GPI/metabolismoRESUMEN
Most chemistry and biology occurs in solution, in which conformational dynamics and complexation underlie behaviour and function. Single-molecule techniques1 are uniquely suited to resolving molecular diversity and new label-free approaches are reshaping the power of single-molecule measurements. A label-free single-molecule method2-16 capable of revealing details of molecular conformation in solution17,18 would allow a new microscopic perspective of unprecedented detail. Here we use the enhanced light-molecule interactions in high-finesse fibre-based Fabry-Pérot microcavities19-21 to detect individual biomolecules as small as 1.2 kDa, a ten-amino-acid peptide, with signal-to-noise ratios (SNRs) >100, even as the molecules are unlabelled and freely diffusing in solution. Our method delivers 2D intensity and temporal profiles, enabling the distinction of subpopulations in mixed samples. Notably, we observe a linear relationship between passage time and molecular radius, unlocking the potential to gather crucial information about diffusion and solution-phase conformation. Furthermore, mixtures of biomolecule isomers of the same molecular weight and composition but different conformation can also be resolved. Detection is based on the creation of a new molecular velocity filter window and a dynamic thermal priming mechanism that make use of the interplay between optical and thermal dynamics22,23 and Pound-Drever-Hall (PDH) cavity locking24 to reveal molecular motion even while suppressing environmental noise. New in vitro ways of revealing molecular conformation, diversity and dynamics can find broad potential for applications in the life and chemical sciences.
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Péptidos , Imagen Individual de Molécula , Difusión , Isomerismo , Luz , Péptidos/análisis , Péptidos/química , Péptidos/efectos de la radiación , Relación Señal-Ruido , Imagen Individual de Molécula/métodos , Soluciones , Conformación Proteica , Peso Molecular , Movimiento (Física)RESUMEN
Immune checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some patients with cancer. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer- and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. Consistent with current knowledge, stromal expression of CXCL9, CXCL13, and IFNG were the top determinants of favorable ICB response. In addition, we identified a group of potential immune-suppressive genes, including FCER1A, associated with poor response to ICB. Strikingly, PD-L1 expression in stromal cells, but not cancer cells, is correlated with ICB response across cancer types. Furthermore, the unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic expression signatures of ICB response conserved across tumor types, suggesting that cancer cells lack tissue-agnostic transcriptomic features of ICB response. SIGNIFICANCE: Our results challenge the prevailing dogma that cancer cells present tissue-agnostic molecular markers that modulate immune activity and ICB response, which has implications on the development of improved ICB diagnostics and treatments.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Transcriptoma , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismoRESUMEN
Background: NK cells are being extensively studied as a cell therapy for cancer. Their effector functions are induced by the recognition of ligands on tumor cells and by various cytokines. IL-15 is broadly used to stimulate endogenous and adoptively transferred NK cells in cancer patients. These stimuli activate the membrane protease ADAM17, which then cleaves assorted receptors on the surface of NK cells as a negative feedback loop to limit their activation and function. We have shown that ADAM17 inhibition can enhance IL-15-mediated NK cell proliferation in vitro and in vivo . In this study, we investigated the underlying mechanism of this process. Methods: PBMCs or enriched NK cells from human peripheral blood, either unlabeled or labeled with a cell proliferation dye, were cultured for up to 7 days in the presence of rhIL-15 +/- an ADAM17 function-blocking antibody. Different versions of the antibody were generated; Medi-1 (IgG1), Medi-4 (IgG4), Medi-PGLALA, Medi-F(ab') 2 , and TAB16 (anti-ADAM17 and anti-CD16 bispecific) to modulate CD16A engagement on NK cells. Flow cytometry was used to assess NK cell proliferation and phenotypic markers, immunoblotting to examine CD16A signaling, and IncuCyte-based live cell imaging to measure NK cell anti-tumor activity. Results: The ADAM17 function-blocking mAb Medi-1 markedly increased initial NK cell activation by IL-15. Using different engineered versions of the antibody revealed that the activating Fcγ receptor CD16A, a well-described ADAM17 substrate, was critical for enhancing IL-15 stimulation. Hence, Medi-1 bound to ADAM17 on NK cells can be engaged by CD16A and block its shedding, inducing and prolonging its signaling. This process did not promote evident NK cell fratricide, phagocytosis, or dysfunction. Synergistic activity by Medi-1 and IL-15 enhanced the upregulation of CD137 on CD16A + NK cells and augmented their proliferation in the presence of PBMC accessory cells. Conclusions: Our data reveal for the first time that CD16A and CD137 underpin Medi-1 enhancement of IL-15-driven NK cell activation and proliferation, respectively. The use of Medi-1 represents a novel strategy to enhance IL-15-driven NK cell proliferation, and it may be of therapeutic importance by increasing the anti-tumor activity of NK cells in cancer patients. What is already known on this topic: NK cell therapies are being broadly investigated to treat cancer. NK cell stimulation by IL-15 prolongs their survival in cancer patients. Various stimuli including IL-15 activate ADAM17 in NK cells, a membrane protease that regulates the cell surface density of various receptors as a negative feedback mechanism. What this study adds: Treating NK cells with the ADAM17 function-blocking mAb Medi-1 markedly enhanced their activation and proliferation. Our study reveals that the Fc and Fab regions of Medi-1 function synergistically with IL-15 in NK cell activation. Medi-1 treatment augments the upregulation of CD137 by NK cells, which enhances their proliferation in the presence of PBMC accessory cells. How this study might affect research practice or policy: Our study is of translational importance as Medi-1 treatment in combination with IL-15 could potentially augment the proliferation and function of endogenous or adoptively transferred NK cells in cancer patients.
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Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq data from a compendium of GC cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq data, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) and the epithelial (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) states in GC. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 Comparisons with bulk and single-cell RNA-seq data sets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis-regulatory elements flanking upregulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of GC heterogeneity and progression.
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Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Aprendizaje Automático , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Transición Epitelial-Mesenquimal/genética , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/genética , Línea Celular Tumoral , Fibrosis/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Variaciones en el Número de Copia de ADN , Subunidad alfa 2 del Factor de Unión al Sitio PrincipalRESUMEN
SUMMARY: Traditional endpoints such as progression-free survival and overall survival do not fully capture the pharmacologic and pharmacodynamic effects of a therapeutic intervention. Incorporating mechanism-driven biomarkers and validated surrogate proximal endpoints can provide orthogonal readouts of anti-tumor activity and delineate the relative contribution of treatment components on an individual level, highlighting the limitation of solely relying on aggregated readouts from clinical trials to facilitate go/no-go decisions for precision therapies.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de Precisión , Biomarcadores , Oncología Médica , Supervivencia sin ProgresiónRESUMEN
The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling processes in cancer cells; using patient "omics" datasets and single-cell and spatial approaches to investigate heterogeneity, understand therapy resistance, and identify targets; innovative strategies for inhibiting tumors, including rational drug combinations and improved drug delivery mechanisms; and advances in models that can facilitate screening for cancer vulnerabilities and drug testing. We hope the insights from this meeting will stimulate further progress in the field.
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Neoplasias , Investigación , Humanos , Muerte Celular , Sistemas de Liberación de Medicamentos , Neoplasias/terapiaRESUMEN
BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients' quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. METHODS: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. RESULTS: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. CONCLUSIONS: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.
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Estimulación Encefálica Profunda , Modelos Animales de Enfermedad , Oxidopamina , Núcleo Subtalámico , Animales , Oxidopamina/farmacología , Masculino , Conducta Animal/fisiología , Trastornos Parkinsonianos/terapia , Trastornos Parkinsonianos/fisiopatología , Ansiedad/etiología , Ansiedad/fisiopatología , Ratas , Ratas Sprague-Dawley , Reacción de Prevención/fisiología , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Non-small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in nonsmokers, alterations in these "nonsmoking-related oncogenes" (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and nonsmokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC data sets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to the regulation of the cell cycle. These findings suggest that, whereas the genomic landscape is similar between NSRO-driven NSCLC in smokers and nonsmokers, smoking still affects the tumor phenotype independently of genomic alterations. SIGNIFICANCE: Non-small cell lung cancers driven by nonsmoking-related oncogenes do not harbor genomic scars caused by smoking regardless of smoking history, indicating that the impact of smoking on these tumors is mainly nongenomic.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Oncogenes , Fumar , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Femenino , Oncogenes/genética , Fumar/efectos adversos , Fumar/genética , Persona de Mediana Edad , Anciano , AdultoRESUMEN
The evolution of the latitudinal diversity gradient (LDG), characterized by a peak in diversity toward the tropics, has captured significant attention in evolutionary biology and ecology. However, the inverse LDG (i-LDG) mechanism, wherein species richness increases toward the poles, remains inadequately explored. Cycads are among one of the oldest lineages of extant seed plants and have undergone extensive diversification in the tropics. Intriguingly, the extant cycad abundance exhibits an i-LDG pattern, and the underlying causes for this phenomenon remain largely elusive. Here, using 1,843 nuclear genes from a nearly complete sampling, we conducted comprehensive phylogenomic analyses to establish a robust species-level phylogeny for Cycas, the largest genus within cycads. We then reconstructed the spatial-temporal dynamics and integrated global environmental data to evaluate the roles of species ages, diversification rates, contemporary environment, and conservatism to ancestral niches in shaping the i-LDG pattern. We found Cycas experienced decreased diversification rates, coupled with the cooling temperature since its origin in the Eocene from continental Asia. Different regions have distinctively contributed to the formation of i-LDG for Cycas, with the northern hemisphere acting as evolutionary museums and the southern hemisphere serving as cradles. Moreover, water-related climate variables, specifically precipitation seasonality and potential evapotranspiration, were identified as paramount factors constraining Cycas species richness in the rainforest biome near the equator. Notably, the adherence to ancestral monsoonal climates emerges as a critical factor in sustaining the diversity pattern. This study underscores the imperative of integrating both evolutionary and ecological approaches to comprehensively unravel the mechanisms underpinning global biodiversity patterns.
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Biodiversidad , Evolución Biológica , Cycas , Filogenia , Cycas/genéticaRESUMEN
Background: Breathlessness is a troublesome and prevalent symptom in the population, but knowledge of related factors is scarce. The aim of this study was to identify the factors most strongly associated with breathlessness in the general population and to describe the shapes of the associations between the main factors and breathlessness. Methods: A cross-sectional analysis was carried out of the multicentre population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) of adults aged 50 to 64â years. Breathlessness was defined as a modified Medical Research Council breathlessness rating ≥2. The machine learning algorithm extreme gradient boosting (XGBoost) was used to classify participants as either breathless or nonbreathless using 449 factors, including physiological measurements, blood samples, computed tomography cardiac and lung measurements, lifestyle, health conditions and socioeconomics. The strength of the associations between the factors and breathlessness were measured by SHapley Additive exPlanations (SHAP), with higher scores reflecting stronger associations. Results: A total of 28 730 participants (52% women) were included in the study. The strongest associated factors for breathlessness were (in order of magnitude): body mass index ( SHAP score 0.39), forced expiratory volume in 1â s (0.32), physical activity measured by accelerometery (0.27), sleep apnoea (0.22), diffusing lung capacity for carbon monoxide (0.21), self-reported physical activity (0.17), chest pain when hurrying (0.17), high-sensitivity C-reactive protein (0.17), recent weight change (0.14) and cough (0.13). Conclusion: This large population-based study of men and women aged 50-64â years identified the main factors related to breathlessness that may be prevented or amenable to public health interventions.
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Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.
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Restricción Calórica , Ayuno , Proteoma , Humanos , Proteoma/metabolismo , Femenino , Masculino , Adulto , Pérdida de Peso , Proteómica/métodos , Adaptación FisiológicaRESUMEN
OBJECTIVE: The purpose of this paper is to investigate the persistence of nerve blockade beyond the duration of applying high frequency alternating current (HFAC) to thinly myelinated and non-myelinated fibers, also termed a "carry-over effect". METHODS: In this study, we used electrically-evoked compound action potentials from isolated rat vagus nerves to assess the influence of 5 kHz HFAC amplitude and duration on the degree of the carry-over effect. Current amplitudes from 1-10 mA and 5 kHz durations from 10-120 seconds were tested. RESULTS: By testing 20 different combinations of 5 kHz amplitude and duration, we found a significant interaction between 5 kHz amplitude and duration on influencing the carry-over effect. CONCLUSION: The degree of carry-over effect was dependent on 5 kHz amplitude, as well as duration. SIGNIFICANCE: Utilizing the carry-over effect may be useful in designing energy efficient nerve blocking algorithms for the treatment of diseases influenced by nerve activity.
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Conducción Nerviosa , Ratas Sprague-Dawley , Animales , Ratas , Conducción Nerviosa/fisiología , Potenciales de Acción/fisiología , Nervio Vago/fisiología , Bloqueo Nervioso/métodos , MasculinoRESUMEN
PREMISE: Cultivation and naturalization of plants beyond their natural range can bring previously geographically isolated taxa together, increasing the opportunity for hybridization, the outcomes of which are not predictable. Here, we explored the phenotypic and genomic effects of interspecific gene flow following the widespread cultivation of Mentha spicata (spearmint), M. longifolia, and M. suaveolens. METHODS: We morphologically evaluated 155 herbarium specimens of three Mentha species and sequenced the genomes of a subset of 93 specimens. We analyzed the whole genomes in a population and the phylogenetic framework and associated genomic classifications in conjunction with the morphological assessments. RESULTS: The allopolyploid M. spicata, which likely evolved in cultivation, had altered trichome characters, that is possibly a product of human selection for a more palatable plant or a byproduct of selection for essential oils. There were signs of genetic admixture between mints, including allopolyploids, indicating that the reproductive barriers between Mentha species with differences in ploidy are likely incomplete. Still, despite gene flow between species, we found that genetic variants associated with the cultivated trichome morphology continue to segregate. CONCLUSIONS: Although hybridization, allopolyploidization, and human selection during cultivation can increase species richness (e.g., by forming hybrid taxa), we showed that unless reproductive barriers are strong, these processes can also result in mixing of genes between species and the potential loss of natural biodiversity.
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Mentha , Aceites Volátiles , Humanos , Mentha/genética , Flujo Génico , Filogenia , Aceites Volátiles/farmacología , Hibridación GenéticaRESUMEN
BACKGROUND: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay. METHODS: This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples. RESULTS: The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p = .009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p < .0001). CONCLUSIONS: ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasia Residual , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Detección Precoz del Cáncer/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Adulto , Anciano de 80 o más Años , Reacción en Cadena de la Polimerasa Multiplex/métodosRESUMEN
Natural fiber-welded (NFW) biopolymer composites are rapidly garnering industrial and commercial attention in the textile sector, and a recent disclosure demonstrating the production of mesoporous NFW materials suggests a bright future as sorbents, filters, and nanoparticle scaffolds. A significant roadblock in the mass production of mesoporous NFW composites for research and development is their lengthy preparation time: 24 h of water rinses to remove the ionic liquid (IL) serving as a welding medium and then 72 h of solvent exchanges (polar to nonpolar), followed by oven drying to attain a mesoporous composite. In this work, the rinsing procedure is systematically truncated using the solution conductivity as a yardstick to monitor IL removal. The traditional water immersion rinses are replaced by a flow-through system (i.e., infinite dilution) using a peristaltic pump, reducing the required water rinse time for the maximum removal of IL to 30 min. This procedure also allows for easy in-line monitoring of solution conductivity and reclamation of an expensive welding solvent. Further, the organic solvent exchange is minimized to 10 min per solvent (from 24 h), resulting in a total combined rinse time of 1 h. This process acceleration reduces the overall solvent exposure time from 96 to 1 h, an almost 99% temporal improvement.
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Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.