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1.
Cell ; 187(7): 1745-1761.e19, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38518772

RESUMEN

Proprioception tells the brain the state of the body based on distributed sensory neurons. Yet, the principles that govern proprioceptive processing are poorly understood. Here, we employ a task-driven modeling approach to investigate the neural code of proprioceptive neurons in cuneate nucleus (CN) and somatosensory cortex area 2 (S1). We simulated muscle spindle signals through musculoskeletal modeling and generated a large-scale movement repertoire to train neural networks based on 16 hypotheses, each representing different computational goals. We found that the emerging, task-optimized internal representations generalize from synthetic data to predict neural dynamics in CN and S1 of primates. Computational tasks that aim to predict the limb position and velocity were the best at predicting the neural activity in both areas. Since task optimization develops representations that better predict neural activity during active than passive movements, we postulate that neural activity in the CN and S1 is top-down modulated during goal-directed movements.


Asunto(s)
Neuronas , Propiocepción , Animales , Propiocepción/fisiología , Neuronas/fisiología , Encéfalo/fisiología , Movimiento/fisiología , Primates , Redes Neurales de la Computación
2.
Cell ; 186(25): 5440-5456.e26, 2023 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-38065078

RESUMEN

Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), which directly analyzes raw sequencing data, using a statistical test to detect a signature of regulation: sample-specific sequence variation. SPLASH detects many types of variation and can be efficiently run at scale. We show that SPLASH identifies complex mutation patterns in SARS-CoV-2, discovers regulated RNA isoforms at the single-cell level, detects the vast sequence diversity of adaptive immune receptors, and uncovers biology in non-model organisms undocumented in their reference genomes: geographic and seasonal variation and diatom association in eelgrass, an oceanic plant impacted by climate change, and tissue-specific transcripts in octopus. SPLASH is a unifying approach to genomic analysis that enables expansive discovery without metadata or references.


Asunto(s)
Algoritmos , Genómica , Genoma , Análisis de Secuencia de ARN , Humanos , Antígenos HLA/genética , Análisis de la Célula Individual
3.
CA Cancer J Clin ; 74(1): 12-49, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38230766

RESUMEN

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries (through 2020) and mortality data collected by the National Center for Health Statistics (through 2021). In 2024, 2,001,140 new cancer cases and 611,720 cancer deaths are projected to occur in the United States. Cancer mortality continued to decline through 2021, averting over 4 million deaths since 1991 because of reductions in smoking, earlier detection for some cancers, and improved treatment options in both the adjuvant and metastatic settings. However, these gains are threatened by increasing incidence for 6 of the top 10 cancers. Incidence rates increased during 2015-2019 by 0.6%-1% annually for breast, pancreas, and uterine corpus cancers and by 2%-3% annually for prostate, liver (female), kidney, and human papillomavirus-associated oral cancers and for melanoma. Incidence rates also increased by 1%-2% annually for cervical (ages 30-44 years) and colorectal cancers (ages <55 years) in young adults. Colorectal cancer was the fourth-leading cause of cancer death in both men and women younger than 50 years in the late-1990s but is now first in men and second in women. Progress is also hampered by wide persistent cancer disparities; compared to White people, mortality rates are two-fold higher for prostate, stomach and uterine corpus cancers in Black people and for liver, stomach, and kidney cancers in Native American people. Continued national progress will require increased investment in cancer prevention and access to equitable treatment, especially among American Indian and Alaska Native and Black individuals.


Asunto(s)
Melanoma , Neoplasias , Masculino , Adulto Joven , Humanos , Femenino , Estados Unidos/epidemiología , Neoplasias/epidemiología , Neoplasias/terapia , Sistema de Registros , Incidencia , Fumar , Blanco
4.
Physiol Rev ; 103(2): 1025-1058, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36049112

RESUMEN

Adaptation is an essential feature of auditory neurons, which reduces their responses to unchanging and recurring sounds and allows their response properties to be matched to the constantly changing statistics of sounds that reach the ears. As a consequence, processing in the auditory system highlights novel or unpredictable sounds and produces an efficient representation of the vast range of sounds that animals can perceive by continually adjusting the sensitivity and, to a lesser extent, the tuning properties of neurons to the most commonly encountered stimulus values. Together with attentional modulation, adaptation to sound statistics also helps to generate neural representations of sound that are tolerant to background noise and therefore plays a vital role in auditory scene analysis. In this review, we consider the diverse forms of adaptation that are found in the auditory system in terms of the processing levels at which they arise, the underlying neural mechanisms, and their impact on neural coding and perception. We also ask what the dynamics of adaptation, which can occur over multiple timescales, reveal about the statistical properties of the environment. Finally, we examine how adaptation to sound statistics is influenced by learning and experience and changes as a result of aging and hearing loss.


Asunto(s)
Corteza Auditiva , Animales , Estimulación Acústica , Corteza Auditiva/fisiología , Percepción Auditiva/fisiología , Ruido , Adaptación Fisiológica/fisiología
5.
CA Cancer J Clin ; 73(1): 17-48, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36633525

RESUMEN

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.


Asunto(s)
Neoplasias Pulmonares , Melanoma , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias , Masculino , Humanos , Femenino , Estados Unidos/epidemiología , Persona de Mediana Edad , Anciano , Neoplasias/epidemiología , Sistema de Registros , Incidencia , Grupos Raciales , Neoplasias Pulmonares/epidemiología
6.
CA Cancer J Clin ; 72(5): 409-436, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35736631

RESUMEN

The number of cancer survivors continues to increase in the United States due to the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate triennially to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries, vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics, and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Database are presented for the most prevalent cancer types by race, and cancer-related and treatment-related side-effects are also briefly described. More than 18 million Americans (8.3 million males and 9.7 million females) with a history of cancer were alive on January 1, 2022. The 3 most prevalent cancers are prostate (3,523,230), melanoma of the skin (760,640), and colon and rectum (726,450) among males and breast (4,055,770), uterine corpus (891,560), and thyroid (823,800) among females. More than one-half (53%) of survivors were diagnosed within the past 10 years, and two-thirds (67%) were aged 65 years or older. One of the largest racial disparities in treatment is for rectal cancer, for which 41% of Black patients with stage I disease receive proctectomy or proctocolectomy compared to 66% of White patients. Surgical receipt is also substantially lower among Black patients with non-small cell lung cancer, 49% for stages I-II and 16% for stage III versus 55% and 22% for White patients, respectively. These treatment disparities are exacerbated by the fact that Black patients continue to be less likely to be diagnosed with stage I disease than White patients for most cancers, with some of the largest disparities for female breast (53% vs 68%) and endometrial (59% vs 73%). Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based strategies and equitable access to available resources are needed to mitigate disparities for communities of color and optimize care for people with a history of cancer. CA Cancer J Clin. 2022;72:409-436.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , American Cancer Society , Femenino , Humanos , Masculino , National Cancer Institute (U.S.) , Supervivencia , Estados Unidos/epidemiología
7.
CA Cancer J Clin ; 72(3): 202-229, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35143040

RESUMEN

African American/Black individuals have a disproportionate cancer burden, including the highest mortality and the lowest survival of any racial/ethnic group for most cancers. Every 3 years, the American Cancer Society estimates the number of new cancer cases and deaths for Black people in the United States and compiles the most recent data on cancer incidence (herein through 2018), mortality (through 2019), survival, screening, and risk factors using population-based data from the National Cancer Institute and the Centers for Disease Control and Prevention. In 2022, there will be approximately 224,080 new cancer cases and 73,680 cancer deaths among Black people in the United States. During the most recent 5-year period, Black men had a 6% higher incidence rate but 19% higher mortality than White men overall, including an approximately 2-fold higher risk of death from myeloma, stomach cancer, and prostate cancer. The overall cancer mortality disparity is narrowing between Black and White men because of a steeper drop in Black men for lung and prostate cancers. However, the decline in prostate cancer mortality in Black men slowed from 5% annually during 2010 through 2014 to 1.3% during 2015 through 2019, likely reflecting the 5% annual increase in advanced-stage diagnoses since 2012. Black women have an 8% lower incidence rate than White women but a 12% higher mortality; further, mortality rates are 2-fold higher for endometrial cancer and 41% higher for breast cancer despite similar or lower incidence rates. The wide breast cancer disparity reflects both later stage diagnosis (57% localized stage vs 67% in White women) and lower 5-year survival overall (82% vs 92%, respectively) and for every stage of disease (eg, 20% vs 30%, respectively, for distant stage). Breast cancer surpassed lung cancer as the leading cause of cancer death among Black women in 2019. Targeted interventions are needed to reduce stark cancer inequalities in the Black community.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Próstata , Negro o Afroamericano , American Cancer Society , Femenino , Humanos , Masculino , National Cancer Institute (U.S.) , Estados Unidos/epidemiología
8.
CA Cancer J Clin ; 72(1): 7-33, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35020204

RESUMEN

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.


Asunto(s)
Neoplasias de la Mama/epidemiología , Detección Precoz del Cáncer/estadística & datos numéricos , Neoplasias Pulmonares/epidemiología , Neoplasias de la Próstata/epidemiología , American Cancer Society , Neoplasias de la Mama/diagnóstico , Detección Precoz del Cáncer/tendencias , Femenino , Humanos , Incidencia , Neoplasias Pulmonares/diagnóstico , Masculino , Estadificación de Neoplasias , Neoplasias de la Próstata/diagnóstico , Programa de VERF/estadística & datos numéricos , Tasa de Supervivencia , Estados Unidos/epidemiología
9.
Annu Rev Neurosci ; 43: 441-464, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32283996

RESUMEN

As acquiring bigger data becomes easier in experimental brain science, computational and statistical brain science must achieve similar advances to fully capitalize on these data. Tackling these problems will benefit from a more explicit and concerted effort to work together. Specifically, brain science can be further democratized by harnessing the power of community-driven tools, which both are built by and benefit from many different people with different backgrounds and expertise. This perspective can be applied across modalities and scales and enables collaborations across previously siloed communities.


Asunto(s)
Macrodatos , Encéfalo/fisiología , Biología Computacional , Red Nerviosa/fisiología , Animales , Biología Computacional/métodos , Bases de Datos Genéticas , Expresión Génica/fisiología , Humanos
10.
CA Cancer J Clin ; 71(6): 466-487, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34545941

RESUMEN

The Hispanic/Latino population is the second largest racial/ethnic group in the continental United States and Hawaii, accounting for 18% (60.6 million) of the total population. An additional 3 million Hispanic Americans live in Puerto Rico. Every 3 years, the American Cancer Society reports on cancer occurrence, risk factors, and screening for Hispanic individuals in the United States using the most recent population-based data. An estimated 176,600 new cancer cases and 46,500 cancer deaths will occur among Hispanic individuals in the continental United States and Hawaii in 2021. Compared to non-Hispanic Whites (NHWs), Hispanic men and women had 25%-30% lower incidence (2014-2018) and mortality (2015-2019) rates for all cancers combined and lower rates for the most common cancers, although this gap is diminishing. For example, the colorectal cancer (CRC) incidence rate ratio for Hispanic compared with NHW individuals narrowed from 0.75 (95% CI, 0.73-0.78) in 1995 to 0.91 (95% CI, 0.89-0.93) in 2018, reflecting delayed declines in CRC rates among Hispanic individuals in part because of slower uptake of screening. In contrast, Hispanic individuals have higher rates of infection-related cancers, including approximately two-fold higher incidence of liver and stomach cancer. Cervical cancer incidence is 32% higher among Hispanic women in the continental US and Hawaii and 78% higher among women in Puerto Rico compared to NHW women, yet is largely preventable through screening. Less access to care may be similarly reflected in the low prevalence of localized-stage breast cancer among Hispanic women, 59% versus 67% among NHW women. Evidence-based strategies for decreasing the cancer burden among the Hispanic population include the use of culturally appropriate lay health advisors and patient navigators and targeted, community-based intervention programs to facilitate access to screening and promote healthy behaviors. In addition, the impact of the COVID-19 pandemic on cancer trends and disparities in the Hispanic population should be closely monitored.


Asunto(s)
Detección Precoz del Cáncer/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Neoplasias/etnología , Adolescente , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Neoplasias/prevención & control , Puerto Rico/epidemiología , Factores de Riesgo , Tasa de Supervivencia , Estados Unidos/epidemiología , Población Blanca/estadística & datos numéricos , Adulto Joven
11.
CA Cancer J Clin ; 71(1): 7-33, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33433946

RESUMEN

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.


Asunto(s)
Mortalidad/tendencias , Neoplasias/epidemiología , Programa de VERF/estadística & datos numéricos , American Cancer Society , Humanos , Incidencia , Neoplasias/terapia , Estados Unidos/epidemiología
12.
Am J Hum Genet ; 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38821058

RESUMEN

Both trio and population designs are popular study designs for identifying risk genetic variants in genome-wide association studies (GWASs). The trio design, as a family-based design, is robust to confounding due to population structure, whereas the population design is often more powerful due to larger sample sizes. Here, we propose KnockoffHybrid, a knockoff-based statistical method for hybrid analysis of both the trio and population designs. KnockoffHybrid provides a unified framework that brings together the advantages of both designs and produces powerful hybrid analysis while controlling the false discovery rate (FDR) in the presence of linkage disequilibrium and population structure. Furthermore, KnockoffHybrid has the flexibility to leverage different types of summary statistics for hybrid analyses, including expression quantitative trait loci (eQTL) and GWAS summary statistics. We demonstrate in simulations that KnockoffHybrid offers power gains over non-hybrid methods for the trio and population designs with the same number of cases while controlling the FDR with complex correlation among variants and population structure among subjects. In hybrid analyses of three trio cohorts for autism spectrum disorders (ASDs) from the Autism Speaks MSSNG, Autism Sequencing Consortium, and Autism Genome Project with GWAS summary statistics from the iPSYCH project and eQTL summary statistics from the MetaBrain project, KnockoffHybrid outperforms conventional methods by replicating several known risk genes for ASDs and identifying additional associations with variants in other genes, including the PRAME family genes involved in axon guidance and which may act as common targets for human speech/language evolution and related disorders.

13.
CA Cancer J Clin ; 70(1): 7-30, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31912902

RESUMEN

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.


Asunto(s)
American Cancer Society , Neoplasias/epidemiología , Sistema de Registros , Programa de VERF/estadística & datos numéricos , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología , Adulto Joven
14.
Proc Natl Acad Sci U S A ; 121(14): e2308814121, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38527194

RESUMEN

RNA decay is a crucial mechanism for regulating gene expression in response to environmental stresses. In bacteria, RNA-binding proteins (RBPs) are known to be involved in posttranscriptional regulation, but their global impact on RNA half-lives has not been extensively studied. To shed light on the role of the major RBPs ProQ and CspC/E in maintaining RNA stability, we performed RNA sequencing of Salmonella enterica over a time course following treatment with the transcription initiation inhibitor rifampicin (RIF-seq) in the presence and absence of these RBPs. We developed a hierarchical Bayesian model that corrects for confounding factors in rifampicin RNA stability assays and enables us to identify differentially decaying transcripts transcriptome-wide. Our analysis revealed that the median RNA half-life in Salmonella in early stationary phase is less than 1 min, a third of previous estimates. We found that over half of the 500 most long-lived transcripts are bound by at least one major RBP, suggesting a general role for RBPs in shaping the transcriptome. Integrating differential stability estimates with cross-linking and immunoprecipitation followed by RNA sequencing (CLIP-seq) revealed that approximately 30% of transcripts with ProQ binding sites and more than 40% with CspC/E binding sites in coding or 3' untranslated regions decay differentially in the absence of the respective RBP. Analysis of differentially destabilized transcripts identified a role for ProQ in the oxidative stress response. Our findings provide insights into posttranscriptional regulation by ProQ and CspC/E, and the importance of RBPs in regulating gene expression.


Asunto(s)
Perfilación de la Expresión Génica , Rifampin , Teorema de Bayes , Semivida , Transcriptoma , Proteínas de Unión al ARN/metabolismo , ARN/metabolismo , Salmonella/metabolismo , Estabilidad del ARN/genética
15.
Proc Natl Acad Sci U S A ; 121(16): e2322415121, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38602918

RESUMEN

Localized deformation and randomly shaped imperfections are salient features of buckling-type instabilities in thin-walled load-bearing structures. However, it is generally agreed that their complex interactions in response to mechanical loading are not yet sufficiently understood, as evidenced by buckling-induced catastrophic failures which continue to today. This study investigates how the intimate coupling between localization mechanisms and geometric imperfections combine to determine the statistics of the pressure required to buckle (the illustrative example of) a hemispherical shell. The geometric imperfections, in the form of a surface, are defined by a random field generated over the nominally hemispherical shell geometry, and the probability distribution of the buckling pressure is computed via stochastic finite element analysis. Monte-Carlo simulations are performed for a wide range of the shell's radius to thickness ratio, as well as the correlation length of the spatial distribution of the imperfection. The results show that over this range, the buckling pressure is captured by the Weibull distribution. In addition, the analyses of the deformation patterns observed during the simulations provide insights into the effects of certain characteristic lengths on the local buckling that triggers global instability. In light of the simulation results, a probabilistic model is developed for the statistics of the buckling load that reveals how the dimensionless radius plays a dual role which remained hidden in previous deterministic analyses. The implications of the present model for reliability-based design of shell structures are discussed.

16.
Am J Hum Genet ; 110(11): 1853-1862, 2023 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-37875120

RESUMEN

The heritability explained by local ancestry markers in an admixed population (hγ2) provides crucial insight into the genetic architecture of a complex disease or trait. Estimation of hγ2 can be susceptible to biases due to population structure in ancestral populations. Here, we present heritability estimation from admixture mapping summary statistics (HAMSTA), an approach that uses summary statistics from admixture mapping to infer heritability explained by local ancestry while adjusting for biases due to ancestral stratification. Through extensive simulations, we demonstrate that HAMSTA hγ2 estimates are approximately unbiased and are robust to ancestral stratification compared to existing approaches. In the presence of ancestral stratification, we show a HAMSTA-derived sampling scheme provides a calibrated family-wise error rate (FWER) of ∼5% for admixture mapping, unlike existing FWER estimation approaches. We apply HAMSTA to 20 quantitative phenotypes of up to 15,988 self-reported African American individuals in the Population Architecture using Genomics and Epidemiology (PAGE) study. We observe hˆγ2 in the 20 phenotypes range from 0.0025 to 0.033 (mean hˆγ2 = 0.012 ± 9.2 × 10-4), which translates to hˆ2 ranging from 0.062 to 0.85 (mean hˆ2 = 0.30 ± 0.023). Across these phenotypes we find little evidence of inflation due to ancestral population stratification in current admixture mapping studies (mean inflation factor of 0.99 ± 0.001). Overall, HAMSTA provides a fast and powerful approach to estimate genome-wide heritability and evaluate biases in test statistics of admixture mapping studies.


Asunto(s)
Negro o Afroamericano , Genética de Población , Humanos , Mapeo Cromosómico , Fenotipo , Polimorfismo de Nucleótido Simple/genética
17.
Brief Bioinform ; 25(4)2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38856173

RESUMEN

Multivariate analysis is becoming central in studies investigating high-throughput molecular data, yet, some important features of these data are seldom explored. Here, we present MANOCCA (Multivariate Analysis of Conditional CovAriance), a powerful method to test for the effect of a predictor on the covariance matrix of a multivariate outcome. The proposed test is by construction orthogonal to tests based on the mean and variance and is able to capture effects that are missed by both approaches. We first compare the performances of MANOCCA with existing correlation-based methods and show that MANOCCA is the only test correctly calibrated in simulation mimicking omics data. We then investigate the impact of reducing the dimensionality of the data using principal component analysis when the sample size is smaller than the number of pairwise covariance terms analysed. We show that, in many realistic scenarios, the maximum power can be achieved with a limited number of components. Finally, we apply MANOCCA to 1000 healthy individuals from the Milieu Interieur cohort, to assess the effect of health, lifestyle and genetic factors on the covariance of two sets of phenotypes, blood biomarkers and flow cytometry-based immune phenotypes. Our analyses identify significant associations between multiple factors and the covariance of both omics data.


Asunto(s)
Análisis de Componente Principal , Humanos , Análisis Multivariante , Biología Computacional/métodos , Fenotipo , Algoritmos , Genómica/métodos , Biomarcadores/sangre , Simulación por Computador
18.
CA Cancer J Clin ; 69(6): 452-467, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31390062

RESUMEN

Adults aged 85 years and older, the "oldest old," are the fastest-growing age group in the United States, yet relatively little is known about their cancer burden. Combining data from the National Cancer Institute, the North American Association of Central Cancer Registries, and the National Center for Health Statistics, the authors provide comprehensive information on cancer occurrence in adults aged 85 years and older. In 2019, there will be approximately 140,690 cancer cases diagnosed and 103,250 cancer deaths among the oldest old in the United States. The most common cancers in these individuals (lung, breast, prostate, and colorectum) are the same as those in the general population. Overall cancer incidence rates peaked in the oldest men and women around 1990 and have subsequently declined, with the pace accelerating during the past decade. These trends largely reflect declines in cancers of the prostate and colorectum and, more recently, cancers of the lung among men and the breast among women. We note differences in trends for some cancers in the oldest age group (eg, lung cancer and melanoma) compared with adults aged 65 to 84 years, which reflect elevated risks in the oldest generations. In addition, cancers in the oldest old are often more advanced at diagnosis. For example, breast and colorectal cancers diagnosed in patients aged 85 years and older are about 10% less likely to be diagnosed at a local stage compared with those diagnosed in patients aged 65 to 84 years. Patients with cancer who are aged 85 years and older have the lowest relative survival of any age group, with the largest disparities noted when cancer is diagnosed at advanced stages. They are also less likely to receive surgical treatment for their cancers; only 65% of breast cancer patients aged 85 years and older received surgery compared with 89% of those aged 65 to 84 years. This difference may reflect the complexities of treating older patients, including the presence of multiple comorbidities, functional declines, and cognitive impairment, as well as competing mortality risks and undertreatment. More research on cancer in the oldest Americans is needed to improve outcomes and anticipate the complex health care needs of this rapidly growing population.


Asunto(s)
Neoplasias/epidemiología , Factores de Edad , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Masculino , Neoplasias/diagnóstico , Neoplasias/terapia , Factores de Riesgo , Programa de VERF , Estados Unidos/epidemiología
19.
CA Cancer J Clin ; 69(3): 211-233, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30762872

RESUMEN

In the United States, African American/black individuals bear a disproportionate share of the cancer burden, having the highest death rate and the lowest survival rate of any racial or ethnic group for most cancers. To monitor progress in reducing these inequalities, every 3 years the American Cancer Society provides the estimated number of new cancer cases and deaths for blacks in the United States and the most recent data on cancer incidence, mortality, survival, screening, and risk factors using data from the National Cancer Institute, the North American Association of Central Cancer Registries, and the National Center for Health Statistics. In 2019, approximately 202,260 new cases of cancer and 73,030 cancer deaths are expected to occur among blacks in the United States. During 2006 through 2015, the overall cancer incidence rate decreased faster in black men than in white men (2.4% vs 1.7% per year), largely due to the more rapid decline in lung cancer. In contrast, the overall cancer incidence rate was stable in black women (compared with a slight increase in white women), reflecting increasing rates for cancers of the breast, uterine corpus, and pancreas juxtaposed with declining trends for cancers of the lung and colorectum. Overall cancer death rates declined faster in blacks than whites among both males (2.6% vs 1.6% per year) and females (1.5% vs 1.3% per year), largely driven by greater declines for cancers of the lung, colorectum, and prostate. Consequently, the excess risk of overall cancer death in blacks compared with whites dropped from 47% in 1990 to 19% in 2016 in men and from 19% in 1990 to 13% in 2016 in women. Moreover, the black-white cancer disparity has been nearly eliminated in men <50 years and women ≥70 years. Twenty-five years of continuous declines in the cancer death rate among black individuals translates to more than 462,000 fewer cancer deaths. Continued progress in reducing disparities will require expanding access to high-quality prevention, early detection, and treatment for all Americans.


Asunto(s)
Negro o Afroamericano/estadística & datos numéricos , Disparidades en el Estado de Salud , Disparidades en Atención de Salud/etnología , Neoplasias/etnología , Femenino , Humanos , Incidencia , Masculino , Neoplasias/mortalidad , Prevalencia , Factores de Riesgo , Programa de VERF , Estados Unidos/epidemiología
20.
CA Cancer J Clin ; 69(5): 363-385, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31184787

RESUMEN

The number of cancer survivors continues to increase in the United States because of the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate every 3 years to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries; vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics; and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Data Base are presented for the most prevalent cancer types. Cancer-related and treatment-related short-term, long-term, and late health effects are also briefly described. More than 16.9 million Americans (8.1 million males and 8.8 million females) with a history of cancer were alive on January 1, 2019; this number is projected to reach more than 22.1 million by January 1, 2030 based on the growth and aging of the population alone. The 3 most prevalent cancers in 2019 are prostate (3,650,030), colon and rectum (776,120), and melanoma of the skin (684,470) among males, and breast (3,861,520), uterine corpus (807,860), and colon and rectum (768,650) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost two-thirds (64%) are aged 65 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by follow-up care providers. Although there are growing numbers of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care.


Asunto(s)
Supervivientes de Cáncer/estadística & datos numéricos , Mortalidad/tendencias , Neoplasias/terapia , Programa de VERF/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , American Cancer Society , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , National Cancer Institute (U.S.)/estadística & datos numéricos , Neoplasias/epidemiología , Prevalencia , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto Joven
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