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During development, H3K9me3 heterochromatin is dynamically rearranged, silencing repeat elements and protein coding genes to restrict cell identity. Enhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized in fission yeast and recently shown to be required for H3K9me3 maintenance in human fibroblasts, but its function during development remains unknown. Here, we show that ERH is required for proper segregation of the inner cell mass and trophectoderm cell lineages during mouse development by repressing totipotent and alternative lineage programs. During human embryonic stem cell (hESC) differentiation into germ layer lineages, ERH is crucial for silencing naïve and pluripotency genes, transposable elements, and alternative lineage genes. Strikingly, ERH depletion in somatic cells reverts the H3K9me3 landscape to an hESC state and enables naïve and pluripotency gene and transposable element activation during iPSC reprogramming. Our findings reveal a role for ERH in initiation and maintenance of developmentally established gene repression.
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The majority of our genome is composed of repeated DNA sequences that assemble into heterochromatin, a highly compacted structure that constrains their mutational potential. How heterochromatin forms during development and how its structure is maintained are not fully understood. Here, we show that mouse heterochromatin phase-separates after fertilization, during the earliest stages of mammalian embryogenesis. Using high-resolution quantitative imaging and molecular biology approaches, we show that pericentromeric heterochromatin displays properties consistent with a liquid-like state at the two-cell stage, which change at the four-cell stage, when chromocenters mature and heterochromatin becomes silent. Disrupting the condensates results in altered transcript levels of pericentromeric heterochromatin, suggesting a functional role for phase separation in heterochromatin function. Thus, our work shows that mouse heterochromatin forms membrane-less compartments with biophysical properties that change during development and provides new insights into the self-organization of chromatin domains during mammalian embryogenesis.
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Cromatina , Heterocromatina , Animales , Ratones , Embrión de Mamíferos , Genoma , Mamíferos/genéticaRESUMEN
Individuals with spinal cord injuries (SCI) commonly present with component risk factors for cardiometabolic risk and combined risk factors for cardiometabolic syndrome (CMS). These primary risk factors include obesity, dyslipidemia, dysglycemia/insulin resistance, and hypertension. Commonly referred to as "silent killers", cardiometabolic risk and CMS increase the threat of cardiovascular disease, a leading cause of death after SCI. This narrative review will examine current data and the etiopathogenesis of cardiometabolic risk, CMS, and cardiovascular disease associated with SCI, focusing on pivotal research on cardiometabolic sequelae from the last five years. The review will also provide current diagnosis and surveillance criteria for cardiometabolic disorders after SCI, a novel obesity classification system based on percent total body fat, and lifestyle management strategies to improve cardiometabolic health.
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Although early studies suggest the Acuity Circles (AC) allocation policy has increased access to deceased donor liver transplants (DDLTs) for patients with the highest MELD scores, changes in center- and region-level practices among patients with the highest MELD scores in response to AC are not well-characterized. OPTN/UNOS data were analyzed to compare center-level changes in the number of DDLTs based on allocation-MELD (aMELD) categories used for AC sharing performed in the 18-month periods before and after AC enactment on February 4, 2020. There was large center-level variation in the number and proportion of aMELD ≥ 37 DDLTs performed from pre-AC to AC period; 13 centers accounted for 196 of the 198 total net increase in aMELD ≥ 37 DDLTs performed after AC, 5 of these being from UNOS region 5. Similar center-level variation was seen for MELD 33-36 and MELD 29-32 DDLTs, with 17 centers and 14 centers, respectively, accounting for the entire net increase in DDLTs in the aMELD categories. In conclusion, AC increased access to livers for transplantation for high MELD patients nationally, but imbalances remain in transplant practice patterns at the center and regional levels. Longer-term study is necessary to assess effectiveness of AC in improving equitability of liver transplantations.
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Trasplante de Hígado , Obtención de Tejidos y Órganos , Trasplantes , Humanos , Listas de Espera , Donadores Vivos , PolíticasRESUMEN
ABSTRACT: With more than 9 million recreational certified self-contained underwater breathing apparatus divers in the United States, clinicians should be aware of the unique diving-related injuries. One of the most common diving-related injuries is type 1 decompression sickness, or "the bends." The bends commonly manifest as localized joint pain, most often occurring within 24 h of surfacing and resolving over the following 1 to 2 d. We report a unique case of a patient who experienced an exacerbation of musculoskeletal joint pain following initial recovery. This 35-year-old man had nearly complete resolution of his joint pain following the bends, then developed severe right knee pain with swelling after a high-volume lower body workout. Following unremarkable imaging and unsuccessful conservative treatment, ultrasound-guided aspiration of his right knee was performed, which resolved the patient's symptoms. This case highlights a unique presentation of the bends and demonstrates a potentially beneficial treatment if recurrence of the bends is suspected.
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Enfermedad de Descompresión , Buceo , Adulto , Artralgia , Enfermedad de Descompresión/diagnóstico por imagen , Enfermedad de Descompresión/etiología , Buceo/efectos adversos , Buceo/lesiones , Humanos , MasculinoRESUMEN
Much has been learned since the early 1960s about histone post-translational modifications (PTMs) and how they affect DNA-templated processes at the molecular level. This understanding has been bolstered in the past decade by the identification of new types of histone PTM, the advent of new genome-wide mapping approaches and methods to deposit or remove PTMs in a locally and temporally controlled manner. Now, with the availability of vast amounts of data across various biological systems, the functional role of PTMs in important processes (such as transcription, recombination, replication, DNA repair and the modulation of genomic architecture) is slowly emerging. This Review explores the contribution of histone PTMs to the regulation of genome function by discussing when these modifications play a causative (or instructive) role in DNA-templated processes and when they are deposited as a consequence of such processes, to reinforce and record the event. Important advances in the field showing that histone PTMs can exert both direct and indirect effects on genome function are also presented.
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Histonas , Procesamiento Proteico-Postraduccional , ADN/genética , Reparación del ADN , Replicación del ADN , Histonas/genética , Histonas/metabolismoRESUMEN
OBJECTIVE: To evaluate program director (PD) demographics, training background, and academic productivity in 11 surgical specialties. SUMMARY BACKGROUND DATA: There is currently no comprehensive study comparing educational background, research output, and gender differences between PDs of surgical residencies in the United States. METHODS: The Accreditation Council for Graduate Medical Education (ACGME) and the Association of American Medical Colleges (AAMC) websites were used to identify residency PDs. Age, information related to service as PD, educational background, and research output were collected utilizing online searches including Doximity, PubMed, and Scopus.. The ACGME Data Resource Book was used to obtain data on the gender makeup of residents in each surgical specialty. Data collection occurred between December 14, 2019, and May 9, 2020. RESULTS: 1571 residency PDs across 11 surgical specialties were included. Significant differences between specialties were found with respect to PD gender, current age, age at appointment, years between residency and assignment, term duration, number of PubMed publications, and Scopus h-index. The current age (mean ± SD) ranged from 46.8 ± 8.5 years among Interventional Radiology (IR) PDs to 53.4 ± 9.1 years among Neurological Surgery (NEUROSURG) PDs. The proportion of female PDs ranged from 5.9% in NEUROSURG to 63.5% in Obstetrics and Gynecology (OB-GYN). Completion of a post-residency fellowship was least common for OB-GYN PDs at 9.1%, and most common for IR PDs at 98.8%. The number (mean ± SD) of PubMed publications and Scopus h-index ranged from 13.1 ± 22.3 publications and h index 4.5 ± 5.7 among OB-GYN PDs to 112.5 ± 103.0 publications and h index 27.4 ± 16.7 among Thoracic Surgery PDs. Age and academic productivity as measured by PubMed publications and Scopus h-index were significantly lower among female PDs in multiple surgical specialties. CONCLUSIONS: There were significant variations in the PDs of surgical specialties, particularly with respect to gender and academic productivity. Efforts should be made to support and encourage greater female representation in the role of surgical residency PD.
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Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene expression. A subset of individuals affected by imprinting disorders (IDs) displays multi-locus imprinting disturbances (MLID), which may result from aberrant establishment of imprinted differentially methylated regions (DMRs) in gametes or their maintenance in early embryogenesis. Here we investigated the extent of MLID in a family harbouring a ZFP57 truncating variant and characterize the interactions between human ZFP57 and the KAP1 co-repressor complex. By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins (KZNFs) recruit KAP1 prior to blastocyst formation. Furthermore, we uncover ZNF202 and ZNF445 as additional KZNFs likely to recruit KAP1 to imprinted loci during reprogramming in the absence of ZFP57. Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect.
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Metilación de ADN , Embrión de Mamíferos/metabolismo , Impresión Genómica , Células Germinativas/metabolismo , Oocitos/metabolismo , Proteínas Represoras/metabolismo , Síndrome de Beckwith-Wiedemann/metabolismo , Estudios de Cohortes , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Humanos , Análisis por Micromatrices , Mutación , Linaje , Seudohipoparatiroidismo/metabolismo , RNA-Seq , Proteínas Represoras/genética , Hermanos , Transcriptoma , Proteína 28 que Contiene Motivos TripartitoRESUMEN
Echo intensity (EI) is being increasingly utilized by investigators as an index of skeletal muscle quality. Previous studies have reported independent associations between EI versus both age and muscle strength. PURPOSE: We sought to determine whether EI is more strongly associated with age or strength. METHODS: Twenty-eight younger adults (13 men, 15 women; mean age = 22 years) and 25 older adults (10 men, 15 women; age = 71 years) participated. B-mode ultrasonography was utilized to acquire images of the vastus lateralis and rectus femoris. ImageJ software was used to quantify corrected EI and muscle cross-sectional area (CSA). Each participant performed 40 maximal concentric isokinetic muscle actions of the knee extensors (velocity = 180°·s-1). The mean peak torque of the best three attempts was used to quantify muscle strength. Specific torque was calculated as strength relative to CSA. Fatigability was also quantified. Statistical analyses included independent samples t-tests and stepwise regression. RESULTS: There were large differences between age groups for strength (p < .001, d = 1.831) and CSA (p = .003, d = 0.872). When corrected for subcutaneous tissue thickness, the difference in EI between age groups was small (p = .184, d = 0.371). Stepwise regression revealed that muscle strength was the single best predictor of EI (R2 = 0.206), with age, CSA, specific torque, and fatigability explaining no unique variance. CONCLUSION: Concentric isokinetic muscle strength is a better predictor of EI than age.
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Fuerza Muscular , Músculo Esquelético , Anciano , Femenino , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Cuádriceps/diagnóstico por imagen , Torque , UltrasonografíaRESUMEN
Following fertilization in mammals, the gametes are reprogrammed to create a totipotent zygote, a process that involves de novo establishment of chromatin domains. A major feature occurring during preimplantation development is the dramatic remodelling of constitutive heterochromatin, although the functional relevance of this is unknown. Here, we show that heterochromatin establishment relies on the stepwise expression and regulated activity of SUV39H enzymes. Enforcing precocious acquisition of constitutive heterochromatin results in compromised development and epigenetic reprogramming, which demonstrates that heterochromatin remodelling is essential for natural reprogramming at fertilization. We find that de novo H3K9 trimethylation (H3K9me3) in the paternal pronucleus after fertilization is catalysed by SUV39H2 and that pericentromeric RNAs inhibit SUV39H2 activity and reduce H3K9me3. De novo H3K9me3 is initially non-repressive for gene expression, but instead bookmarks promoters for compaction. Overall, we uncover the functional importance for the restricted transmission of constitutive heterochromatin during reprogramming and a non-repressive role for H3K9me3.
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Centrómero/genética , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario , Heterocromatina/metabolismo , Histonas/metabolismo , ARN/metabolismo , Animales , Núcleo Celular/genética , Núcleo Celular/metabolismo , Epigénesis Genética , Femenino , Heterocromatina/genética , Histonas/genética , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , ARN/genéticaRESUMEN
Ultrasonography-derived cross-sectional area (CSA) and echo intensity (EI) are increasingly utilized by investigators to study muscle size and quality, respectively. We sought to examine age, sex, and region (proximal, middle, distal) differences in vastus lateralis and rectus femoris CSA and EI, and determine whether correction for subcutaneous fat thickness influences the magnitude of EI differences. Fifteen younger men (mean age = 23 years), 15 younger women (aged 21 years), 11 older men (aged 74 years), and 15 older women (aged 70 years) participated. Clear differences were observed among age, sex, and region for vastus lateralis CSA (p ≤ 0.013, d = 0.38-0.73), whereas rectus femoris CSA was only different between younger and older participants at the proximal region (p = 0.017, d = 0.65). Uncorrected EI was greatest at the distal region of both muscles (p < 0.001, d = 0.59-1.38), with only the younger men having significantly lower EI values than the other groups (p ≤ 0.043, d = 0.37-0.63). Subcutaneous fat correction resulted in a marked increase in the magnitude of sex-specific EI differences (p ≤ 0.032, d ≥ 0.42). Additionally, subcutaneous fat correction increased the uniformity of EI throughout the thigh. These findings highlight considerable region-specific differences in muscle size and quality among younger and older men and women and highlight the need to correct for subcutaneous fat thickness when examining EI. Novelty Rectus femoris CSA is similar between younger and older adults except at the most proximal site evaluated. Age- and sex-specific differences in uncorrected EI are nonuniform across the thigh. Correction for subcutaneous fat thickness substantially increased EI in women, resulting in greater sex differences.
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Músculo Cuádriceps/diagnóstico por imagen , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Tamaño de los Órganos , Músculo Cuádriceps/anatomía & histología , Factores Sexuales , Grasa Subcutánea/diagnóstico por imagen , Ultrasonografía , Adulto JovenRESUMEN
In most eukaryotes, constitutive heterochromatin is associated with H3K9me3 and HP1α. The latter has been shown to play a role in heterochromatin formation through liquid-liquid phase separation. However, many other proteins are known to regulate and/or interact with constitutive heterochromatic regions in several species. We postulate that some of these heterochromatic proteins may play a role in the regulation of heterochromatin formation by liquid-liquid phase separation. Indeed, an analysis of the constitutive heterochromatin proteome shows that proteins associated with constitutive heterochromatin are significantly more disordered than a random set or a full nucleome set of proteins. Interestingly, their expression begins low and increases during preimplantation development. These observations suggest that the preimplantation embryo is a useful model to address the potential role for phase separation in heterochromatin formation, anticipating exciting research in the years to come.
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Blastocisto/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Heterocromatina/metabolismo , Histonas/metabolismo , Animales , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/aislamiento & purificación , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Heterocromatina/genética , Código de Histonas , Histonas/aislamiento & purificación , Proteínas Intrínsecamente Desordenadas/aislamiento & purificación , Proteínas Intrínsecamente Desordenadas/metabolismo , Espectrometría de Masas , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Numerical anchoring effects describe the assimilative effect of a previously presented number on subsequent numerical estimates. Such effects are robust and consequential. A number of different accounts have been proposed to explain these effects. What is currently unclear is under which situations different mechanisms play more or less critical roles. An extant test from the literature is proposed as a "signature test" for the operation of selective accessibility mechanisms. Four experiments were conducted to ascertain the evidence for selective accessibility with this test, evidence which was not obtained. A fifth experiment employed a different methodology, and again failed to show evidence for selective accessibility. Subsequent discussion suggests that the robustness of anchoring effects is remarkable, but the theoretical basis for some previous tests of the selective accessibility account of anchoring is shaky, and we advise against their use in this capacity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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Toma de Decisiones/fisiología , Juicio/fisiología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
INTRODUCTION: Echo intensity reflects both intramuscular adiposity and fibrous tissue content. Recently, equations that allow investigators to estimate the percentage of intramuscular fat for individual muscles via measurements of echo intensity and subcutaneous fat were created. However, as the trial-to-trial consistency of these values has not been reported in the literature, it is unclear if they can be used to track changes during physical activity and/or nutritional interventions. The purpose of this study was to examine the test-retest reliability of rectus femoris percent intramuscular fat. METHODS: Nineteen healthy adults (mean ± SD age = 22 ± 3 year; ten females, nine males) with a body mass index ≤ 30 kg/m2 participated. On three occasions, B-mode ultrasonography was used to acquire panoramic images of the dominant rectus femoris in the transverse plane. ImageJ software was used to quantify echo intensity, subcutaneous fat thickness and cross-sectional area. Rectus femoris percent intramuscular fat was estimated with sex-specific equations. RESULTS: Uncorrected and corrected echo intensity, subcutaneous fat and cross-sectional area exhibited excellent consistency (P > 0·05, intraclass correlation coefficients [ICCs] ≥ .900, standard errors of measurement [SEMs] ≤ 7·26%). Percent intramuscular fat for all participants also demonstrated satisfactory reliability (ICC = 0·980, SEM = 3·07%), with similar findings for males (ICC = 0·970, SEM = 3·63%) and females (ICC = 0·968, SEM = 1·41%). DISCUSSION: The high ICCs and low SEMs suggest that ultrasonography-derived rectus femoris percent fat may be a reliable tool for tracking changes in lower extremity intramuscular adiposity.
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Recently, an equation that allows investigators to correct echo intensity for subcutaneous fat was developed. We evaluated correlations between uncorrected and corrected echo intensity versus measures of lower-extremity function. Twenty-three older adults (11 men, 12 women; mean age = 72 y) participated. B-Mode ultrasonography was used to quantify rectus femoris echo intensity and subcutaneous fat thickness. Knee extensor isometric peak torque and rate of torque development at 200 ms (RTD200) were determined (joint angle = 90°). Fast gait speed was evaluated at 10- and 400-m distances. Partial correlations between normalized peak torque, RTD200 and 10- and 400-m gait speed versus uncorrected echo intensity were weak and insignificant. Correction for subcutaneous fat strengthened the correlations (peak torque r = -0.500, RTD200 r= -0.425, 10-m r = -0.409, 400-m r = -0.410). Correcting echo intensity values for subcutaneous fat strengthened the associations with lower-extremity muscle function in older adults.
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Evaluación Geriátrica/métodos , Fuerza Muscular , Músculo Esquelético/fisiopatología , Grasa Subcutánea/diagnóstico por imagen , Ultrasonografía/métodos , Anciano , Anciano de 80 o más Años , Envejecimiento , Femenino , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagenRESUMEN
Extensive chromatin remodeling after fertilization is thought to take place to allow a new developmental program to start. This includes dynamic changes in histone methylation and, in particular, the remodeling of constitutive heterochromatic marks such as histone H4 Lys20 trimethylation (H4K20me3). While the essential function of H4K20me1 in preimplantation mouse embryos is well established, the role of the additional H4K20 methylation states through the action of the SUV4-20 methyltransferases has not been addressed. Here we show that Suv4-20h1/h2 are mostly absent in mouse embryos before implantation, underscoring a rapid decrease of H4K20me3 from the two-cell stage onward. We addressed the functional significance of this remodeling by introducing Suv4-20h1 and Suv4-20h2 in early embryos. Ectopic expression of Suv4-20h2 leads to sustained levels of H4K20me3, developmental arrest, and defects in S-phase progression. The developmental phenotype can be partially overcome through inhibition of the ATR pathway, suggesting that the main function for the remodeling of H4K20me3 after fertilization is to allow the timely and coordinated progression of replication. This is in contrast to the replication program in somatic cells, where H4K20me3 has been shown to promote replication origin licensing, and anticipates a different regulation of replication during this early developmental time window.