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We aimed to identify prevalence and association of comorbid chronic kidney disease (CKD), acute kidney injury (AKI) and utilization prevalence of continuous renal replacement therapy (CRRT) in COVID-19-hospitalized patients as a function of severity status. With the ongoing struggle across the globe to combat COVID-19 disease, published literature has described the role of kidney disease in COVID-19 patients based on single/multicenter experiences across the globe. We extracted data from observational studies describing comorbid CKD, AKI and CRRT and outcomes and severity of COVID-19-hospitalized patients from December 1, 2019–August 20, 2020 following PRISMA guidelines. Severity of COVID-19 includes intensive care unit admission, oxygen saturation

Rewiring of cellular programmes in malignant cells generates cancer-specific vulnerabilities. Here, using an unbiased screening strategy aimed at identifying non-essential genes required by tumour cells to sustain unlimited proliferative capacity, we identify the male-specific lethal (MSL) acetyltransferase complex as a vulnerability of genetically unstable cancers. We find that disruption of the MSL complex and consequent loss of the associated H4K16ac mark do not substantially alter transcriptional programmes but compromise chromosome integrity and promote chromosomal instability (CIN) that progressively exhausts the proliferative potential of cancer cells through a p53-independent mechanism. This effect is dependent on pre-existing genomic instability, and normal cells are insensitive to MSL disruption. Using cell- and patient-derived xenografts from multiple cancer types, we show that excessive CIN induced by MSL disruption inhibits tumour maintenance. Our findings suggest that targeting MSL may be a valuable means to increase CIN beyond the level tolerated by cancer cells without inducing severe adverse effects in normal tissues.

Over the last 6 years, there has been a high percentage of unfilled cardiac electrophysiology (EP) training spots each year. The authors aimed to investigate potential explanations for the unfilled positions based on a survey from the current Fellows-In-Training (FITs).An attempt was made to reach the current cardiology FITs across all programs of the U.S. via email. An anonymous questionnaire was created consisting of 14 questions. Questions posed were regarding factors affecting each participant's interest in or lack of pursuing an EP fellowship. Descriptive statistics of the responses were performed.A total of 26% (35/134) respondents expressed their interest in applying to an EP fellowship. The most common reasons to apply to EP were: Interest in EP, procedural specialty, and work-life balance. Of the 99 respondents that were not applying to EP, the most common reasons not to apply were: Less interest in EP, two-year training duration, and complexity of the specialty. The top reasons for the fellows to believe there is a dearth of EP FITs were: two-year training duration, lack of interest in EP, and the complexity of the specialty. The changes that would encourage EP fellowship interest were: More exposure to EP training during general cardiology fellowship, shortening the EP training duration, and having more information available regarding employment opportunities.The study was able to identify factors responsible for vacancies in EP fellowship positions from the view of current cardiology FITs. Stakeholders at the national level involved in framing policies related to fellowship education would be able to utilize this information to address the shortage of EP FITs and increase recruitment to EP fellowships.

SMAD2, an effector of the NODAL/Activin signalling pathway, regulates developmental processes by sensing distinct chromatin states and interacting with different transcriptional partners. However, the network of factors that controls SMAD2 chromatin binding and shapes its transcriptional programme over time is poorly characterised. Here, we combine ATAC-seq with computational footprinting to identify temporal changes in chromatin accessibility and transcription factor activity upon NODAL/Activin signalling. We show that SMAD2 binding induces chromatin opening genome wide. We discover footprints for FOXI3, FOXO3 and ZIC3 at the SMAD2-bound enhancers of the early response genes, Pmepa1 and Wnt3, respectively, and demonstrate their functionality. Finally, we determine a mechanism by which NODAL/Activin signalling induces delayed gene expression, by uncovering a self-enabling transcriptional cascade whereby activated SMADs, together with ZIC3, induce the expression of Wnt3. The resultant activated WNT pathway then acts together with the NODAL/Activin pathway to regulate expression of delayed target genes in prolonged NODAL/Activin signalling conditions. This article has an associated First Person interview with the first author of the paper.

Background Early detection of Atrial Fibrillation (AF) is a public health priority across the globe because AF-related strokes are preventable. Despite an ongoing stroke epidemic in India, a public health strategy for AF screening and treatment is missing because the epidemiology of AF in India remains poorly defined. Methods This population-based study used mobile technology to derive age and sex-stratified AF prevalence by screening 7 participants in each of six age and sex strata (age 40–55, 56–65, 65+, and male and female) from 50 villages (2100 participants). A health worker from each village used a handheld digital electrocardiogram (iECG) device (Kardia) to screen for AF on 3 separate days, and administered a questionnaire. All abnormal (AF or unclassified) iECGs were reviewed by the Indian cardiologist and AF determination confirmed by a US-based cardiac electrophysiologist. Results Of the 2100 individuals enrolled, iECGs were collected from 2074 participants (98.8%) and 1947 (92.7%) participants responded to the questionnaire. AF was identified in 33 participants (1.6%), two-thirds on the first iECG. AF prevalence was higher among males (2.3% vs 1.0%, p = 0.03) and in older people (0.6%, 0.9%, 2.1%, 5.6%; p Conclusions The prevalence of AF observed in our population-based sample is comparable to rates found in studies from North America and Western Europe and increases similarly with age. AF screening using village health workers in rural India is feasible and presents an opportunity for a strategy to address the stroke epidemic in India through primary prevention.

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat’s antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients., Targeting self-renewing cancer cells without deleterious side effects in normal tissues has proven challenging. Here, the authors show that the well-tolerated HDAC inhibitor Quisinostat safely inhibits tumor maintenance and disease relapse by restoring high levels of histone H1.0.

Mutations in the

BACKGROUND: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidization, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53. We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. METHOD: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor. We characterized adapted and acute tetraploidization in a variety of flow cytometry and biochemical assays and tested our findings against human tumours through bioinformatics analysis of the TCGA dataset. RESULTS: Cyclin D1 was found to be specifically overexpressed in early but not late passage tetraploid clones, and this overexpression was sufficient to promote tolerance to spontaneous and pharmacologically induced tetraploidy. We provide evidence that this role extends to D-type cyclins and their overexpression confers specific proliferative advantage to tetraploid cells. We demonstrate that tetraploid clones exhibit elevated levels of functional p53 and p21 but override the p53/p21 checkpoint by elevated expression of cyclin D1, via a stoichiometry-dependent and CDK activity-independent mechanism. Tetraploid cells do not exhibit increased sensitivity to abemaciclib, suggesting that cyclin D-overexpressing tumours might not be specifically amenable to treatment with CDK4/6 inhibitors. CONCLUSION: Our study suggests that D-type cyclin overexpression is an acute event, permissive for rapid adaptation to a genome-doubled state in TP53 wild-type tumours and that its overexpression is dispensable in later stages of tumour progression.

Epigenetic regulators are often hijacked by cancer cells to sustain malignant phenotypes. How cells repurpose key regulators of cell identity as tumour‐promoting factors is unclear. The antithetic role of the Polycomb component EZH2 in normal brain and glioma provides a paradigm to dissect how wild‐type chromatin modifiers gain a pathological function in cancer. Here, we show that oncogenic signalling induces redistribution of EZH2 across the genome, and through misregulation of homeotic genes corrupts the identity of neural cells. Characterisation of EZH2 targets in de novo transformed cells, combined with analysis of glioma patient datasets and cell lines, reveals that acquisition of tumorigenic potential is accompanied by a transcriptional switch involving de‐repression of spinal cord‐specifying HOX genes and concomitant silencing of the empty spiracles homologue EMX2, a critical regulator of neurogenesis in the forebrain. Maintenance of tumorigenic potential by glioblastoma cells requires EMX2 repression, since forced EMX2 expression prevents tumour formation. Thus, by redistributing EZH2 across the genome, cancer cells subvert developmental transcriptional programmes that specify normal cell identity and remove physiological breaks that restrain cell proliferation.

Descending cervical mediastinitis (DCM) is defined as spread of oropharyngeal or odontogenic infection into the mediastinum. It occurs uncommonly and has a high mortality rate. Six patients underwent surgery at our centre for DCM between November 2013 and October 2016. Five of six patients underwent drainage of neck collections via a cervical approach, and all six patients subsequently underwent thoracic surgery for drainage of pleural and mediastinal collections. Four patients required further surgical intervention, of which two subsequently required a third thoracic operation. The average length of stay was 73 days (range 4–193). There were no in-hospital deaths and all patients were discharged from our hospital. Following diagnosis, prompt surgical intervention from ENT and cardiothoracic surgeons is essential. Our experience demonstrates that favourable outcomes can be achieved in patients with DCM when they are managed aggressively and promptly in specialist centres with appropriate multidisciplinary team involvement.

The development of targeted therapies for both germline and somatic DNA mutations has increased the need for molecular profiling assays to determine the mutational status of specific genes. Moreover, the potential of off-label prescription of targeted therapies favors classifying tumors based on DNA alterations rather than traditional tissue pathology. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext, which can detect single nucleotide variants, small insertions and deletions in 142 genes that are frequently mutated in somatic and/or germline cancers. TumorNext also detects gene fusions and structural variants, such as tandem duplications and inversions, in 15 frequently disrupted oncogenes and tumor suppressors. The assay uses a matched control and custom bioinformatics pipeline to differentiate between somatic and germline mutations, allowing precise variant classification. We tested 170 previously characterized samples, of which > 95% were formalin-fixed paraffin embedded tissue from 8 different cancer types, and highlight examples where lack of germline status may have led to the inappropriate prescription of therapy. We also describe the validation of the Affymetrix OncoScan platform, an array technology for high resolution copy number variant detection for use in parallel with the NGS panel that can detect single copy amplifications and hemizygous deletions. We analyzed 80 previously characterized formalin-fixed paraffin-embedded specimens and provide examples of hemizygous deletion detection in samples with known pathogenic germline mutations. Thus, the TumorNext combined approach of NGS and OncoScan potentially allows for the identification of the "second hit" in hereditary cancer patients.

IRES-mediated translation of key cell fate regulating genes has been implicated in tumorigenesis. Concerted action of canonical eukaryotic initiation factors and IRES transacting factors (ITAFs) was shown to regulate cellular IRES mediated translation; however, the precise molecular mechanism of ribosome recruitment to cellular IRESes remains unclear. Here we show that the X-linked inhibitor of apoptosis (XIAP) IRES operates in an evolutionary conserved viral like mode and the structural integrity, particularly in the vicinity of AUG, is critical for ribosome recruitment. The binding of eIF3 together with PABP potentiates ribosome recruitment to the IRES. Our data support the model in which eIF3 binds directly to the XIAP IRES RNA in a structure-dependent manner and acts as a scaffold for IRES RNA, PABP and the 40S ribosome.

OBJECTIVE To assess the prevalence of bullying, identifying bullies, victims and their associations. Methods Questionnaire having 'Peer Interaction in Primary Schools' and 'Strength and Difficulty Questionnaire' scales, and demographic information was administered to 7th, 8th and 9th graders (N=1106). RESULTS Prevalence of bullying was 49%. Boys were more likely to be bullies (P=0.03), whereas students having less friends (P=0.001), overweight/obese (P=0.02), and boys (P

An innovative technique is presented for salvage of a failed total ankle replacement resulting from talar subsidence with the use of a custom 3-dimensional printed articulating talar component with a titanium truss cage. This introduces a better alternative to an ankle arthrodesis with which ankle joint function and range of motion may be preserved.

Humans have the inherent ability to perform highly dexterous tasks with their arms, involving maintenance of posture, movement, and interaction with the environment. The latter requires the human to control the dynamic characteristics of the upper limb musculoskeletal system. These characteristics are quantitatively represented by inertia, damping, and stiffness, which are measures of mechanical impedance. Many previous studies have shown that arm posture is a dominant factor in determining the end point impedance on a horizontal plane. This paper presents the characterization of the end point impedance of the human arm in 3-D space. Moreover, it models the regulation of the arm impedance with muscle cocontraction. The characterization is made by route of experimental trials where human subjects maintained arm posture while their arms were perturbed by a robot arm. Furthermore, the subjects were asked to control the level of their arm muscles' cocontraction, using visual feedback, in order to investigate the effect of muscle cocontraction on the arm impedance. The results of this study show an anisotropic increase of arm stiffness due to muscle cocontraction. These results could improve our understanding of the human arm biomechanics, as well as provide implications for human motor control-specifically the control of arm impedance through muscle cocontraction.

The cohesin complex is at the heart of many chromosomal activities, including sister chromatid cohesion and transcriptional regulation. Cohesin loading onto chromosomes depends on the Scc2-Scc4 cohesin loader complex, but the chromatin features that form cohesin loading sites remain poorly understood. Here we show that the RSC chromatin remodeling complex recruits budding yeast Scc2-Scc4 to broad nucleosome-free regions, which the cohesin loader helps to maintain. Consequently, inactivation of either the cohesin loader or the RSC complex has similar effects on nucleosome positioning, gene expression and sister chromatid cohesion. These results show an intimate link between local chromatin structure and higher-order chromosome architecture. Our findings pertain to the similarities between two severe human disorders, Cornelia de Lange syndrome, which is caused by alterations in the human cohesin loader, and Coffin-Siris syndrome, which results from alterations in human RSC complex components. Both syndromes can arise from gene misregulation due to related changes in the nucleosome landscape.

INTRODUCTION Cancer arises from clonal expansion of a single cell. Yet, most human cancers are characterized by extensive intratumor heterogeneity and comprise various subpopulations of cells with distinct phenotypes and biological properties. Intratumor heterogeneity poses major challenges in understanding cancers, managing patients, and designing effective treatment strategies. Functional heterogeneity within individual tumors is partly due to the presence of genetically distinct subclonal cell populations. Furthermore, interactions between cancer cells and the tumor microenvironment can alter the phenotype of cancer cells via nongenetic mechanisms. The combination of cell-intrinsic and cell-extrinsic changes occurring during tumor growth generates functionally distinct subsets of cells that differentially contribute to tumor maintenance. RATIONALE In many cancers, phenotypic and functional heterogeneity can be mapped to distinct differentiation states, suggesting that cellular hierarchies established during tumor growth may affect the long-term proliferative potential of cancer cells. To shed light on the mechanisms responsible for the generation of these hierarchies, we searched for epigenetic mechanisms that determine which cancer cells can preserve unlimited proliferative potential, and thus the ability to drive long-term tumor growth, and which cells lose this ability through a differentiation process. RESULTS We found that, in several cancer types, individual tumors exhibit high heterogeneity of the major chromatin protein linker histone H1.0, showing strongly reduced H1.0 levels in cells characterized by long-term self-renewal ability and tumorigenic potential and higher levels in nontumorigenic cells. Combined analysis of pan-cancer patient data sets and experimental alteration of the H1F0 locus in tumor cells revealed that heterogeneous H1.0 expression patterns are partly due to differential methylation of an enhancer region that dynamically modulates H1.0 expression within tumors. Using a controlled system to model functional intratumor heterogeneity, we showed that maintenance of cell tumorigenic potential required silencing of H1.0 to avoid loss of unlimited proliferative capacity through differentiation. Mechanistically, absence of H1.0 led to destabilization of nucleosome-DNA interactions in AT-rich genomic regions and coordinated derepression of large sets of neighboring genes, resulting in activation of transcriptional programs that support cancer cell self-renewal. Gene expression changes induced by H1.0 loss were reversible, and epigenetic states restricting cell proliferative potential were reestablished upon H1.0 reexpression. In multiple cancer types, in agreement with the observed inhibition of cancer cell self-renewal by H1.0, patients expressing overall strongly reduced levels of H1.0 showed a significantly worse outcome than patients expressing higher H1.0 levels. CONCLUSION Intratumor heterogeneity has emerged as a general feature of cancer, but the molecular features underlying functionally diverse cellular phenotypes have been elusive. Our results uncover epigenetic determinants of tumor-maintaining cells and identify an integral component of chromatin as an important regulator of cell differentiation states within tumors. We propose that only cells insensitive to extracellular differentiation cues, capable of permanently silencing H1.0, can act as self-renewing tumor-maintaining cells and that such a mechanism supports maintenance of several types of cancer. Our results suggest that intervention aimed at restoring high levels of H1.0 in all cancer cells may enhance the differentiation process that naturally occurs during tumor growth and may be beneficial for therapeutic purposes. Epigenetic heterogeneity within tumors. In many cancer types, self-renewing and differentiated epigenetic states coexist in individual tumors. ( Left ) Image of a breast cancer section showing heterogeneous levels of the linker histone H1.0 (red). ( Right ) Schematic depiction of the chromatin status of cancer cells in which H1.0 is down-regulated (blue) or expressed at high levels (red).

IntroductionAtrial fibrillation (AF), the world’s most common arrhythmia, often goes undetected and untreated in low-resource communities, including India, where AF epidemiology is undefined. AF is an important risk factor for stroke, which plagues an estimated 1.6 million Indians annually. As such, early detection of AF and management of high-risk patients is critically important to decrease stroke burden in individuals with AF. This study aims to describe the epidemiology of AF in Anand District, Gujarat, India, characterise the clinical profile of individuals who are diagnosed with AF and determine the performance of two mobile technologies for community-based AF screening.MethodsThis observational study builds on findings from a previous feasibility study and leverages two novel technologies as well as an existing community health programme to perform door-to-door AF screening for 2000 people from 60 villages of Anand District, Gujarat, India using local health workers. A single-lead ECG and a pulse-based application is used to screen each individual for AF three times over a period of 5 days. Participants with suspected arrhythmias are followed up by study cardiologist who makes final diagnoses. Participants diagnosed with AF are initiated on treatment based on current anticoagulation guidelines and clinical reasoning.Analytical planAge-stratified and sex-stratified prevalence of AF in the Anand District will be calculated for sample and estimated for Anand distribution using survey design weights. Sociodemographic and clinical factors associated with AF will be evaluated using multivariable regression methods. Performance of each mobile technology in detecting AF will be evaluated using a 12-lead ECG interpretation as the gold standard.Ethics and disseminationThis protocol was approved separately by the Institutional Review Board of University of Massachusetts Medical School and the Human Research Ethics Committee at Charutar Arogya Mandal. The findings of this study will be disseminated through peer-reviewed journals and scientific conferences.

Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.

A growing body of evidence suggests that Polycomb group (PcG) proteins, key regulators of lineage specific gene expression, also participate in the repair of DNA double-strand breaks (DSBs) but evidence for direct recruitment of PcG proteins at specific breaks remains limited. Here we explore the association of Polycomb repressive complex 1 (PRC1) components with DSBs generated by inducible expression of the AsiSI restriction enzyme in normal human fibroblasts. Based on immunofluorescent staining, the co-localization of PRC1 proteins with components of the DNA damage response (DDR) in these primary cells is unconvincing. Moreover, using chromatin immunoprecipitation and deep sequencing (ChIP-seq), which detects PRC1 proteins at common sites throughout the genome, we did not find evidence for recruitment of PRC1 components to AsiSI-induced DSBs. In contrast, the S2056 phosphorylated form of DNA-PKcs and other DDR proteins were detected at a subset of AsiSI sites that are predominantly at the 5' ends of transcriptionally active genes. Our data question the idea that PcG protein recruitment provides a link between DSB repairs and transcriptional repression.

Robots are increasingly used in tasks that include physical interaction with humans. Examples can be found in the area of rehabilitation robotics, power augmentation robots, as well as assistive and orthotic devices. However, current methods of physically coupling humans with robots fail to provide intrinsic safety, adaptation and efficiency, which limit the application of wearable robotics only to laboratory and controlled environments. In this paper we present the design and verification of a novel mechanism for physically coupling humans and robots. The device is intrinsically safe, since it is based on passive, non-electric features that are not prone to malfunctions. The device is capable of transmitting forces and torques in all directions between the human user and the robot. Moreover, its re-configurable nature allows for easy and consistent adjustment of the decoupling force. The latter makes the mechanism applicable to a wide range of human-robot coupling applications, ranging from low-force rehabilitation-therapy scenarios to high-force augmentation cases.

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.

In the post-genomic era, the biochemical information for individual compounds, enzymes, reactions to be found within named organisms has become readily available. The well-known KEGG and BioCyc databases provide a comprehensive catalogue for this information and have thereby substantially aided the scientific community. Using these databases, the complement of enzymes present in a given organism can be determined and, in principle, used to reconstruct the metabolic network. However, such reconstructed networks contain numerous properties contradicting biological expectation. The metabolic networks for a number of organisms are reconstructed from KEGG and BioCyc databases, and features of these networks are related to properties of their originating database.

Background: Polycomb group proteins form multicomponent complexes that are important for establishing lineage-specific patterns of gene expression. Mammalian cells encode multiple permutations of the prototypic Polycomb repressive complex 1 (PRC1) with little evidence for functional specialization. An aim of this study is to determine whether the multiple orthologs that are co-expressed in human fibroblasts act on different target genes and whether their genomic location changes during cellular senescence. Results: Deep sequencing of chromatin immunoprecipitated with antibodies against CBX6, CBX7, CBX8, RING1 and RING2 reveals that the orthologs co-localize at multiple sites. PCR-based validation at representative loci suggests that a further six PRC1 proteins have similar binding patterns. Importantly, sequential chromatin immunoprecipitation with antibodies against different orthologs implies that multiple variants of PRC1 associate with the same DNA. At many loci, the binding profiles have a distinctive architecture that is preserved in two different types of fibroblast. Conversely, there are several hundred loci at which PRC1 binding is cell type-specific and, contrary to expectations, the presence of PRC1 does not necessarily equate with transcriptional silencing. Interestingly, the PRC1 binding profiles are preserved in senescent cells despite changes in gene expression. Conclusions: The multiple permutations of PRC1 in human fibroblasts congregate at common rather than specific sites in the genome and with overlapping but distinctive binding profiles in different fibroblasts. The data imply that the effects of PRC1 complexes on gene expression are more subtle than simply repressing the loci at which they bind.