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BL Lac objects have been found to be the largest population of emitters in gamma-ray band. However, since they are relatively weak radio sources, their parsec scale structure and most of their radio properties are poorly known. To increase our knowledge of the BL Lac object population, we selected a sample of BL Lacs from the BZ Cat at low redshift (z < 0.2), with no constrain on the radio flux density and gamma-ray activity. We present here the results of a first VLBA observation at 8 and 15 GHz and shortly discuss their properties

Aims. We investigate the stellar mass assembly history of ultramassive (M⋆ ≳ 1011M⊙) dense (Σ = M⋆/2πRe2> 2500M⊙ pc-2) early-type galaxies (ETGs, elliptical and spheroidal galaxies) selected on basis of visual classification over the last 9 Gyr. Methods. We traced the evolution of the comoving number density ρ of ultramassive dense ETGs and compared their structural (effective radius Re and stellar mass M⋆) and dynamical (velocity dispersion σe) parameters over the redshift range 0 < z < 1.6. We derived the number density ρ at 1.6 0.3 ± 0.8 implying a decrease of ~25% of the population of ultramassive dense ETGs since z = 1.6. By comparing the structural and dynamical properties of high-z ultramassive dense ETGs over the range 0 ≲ z < 1.6 in the [Re, M⋆, σe] plane, we find that all of the ETGs of the high-z sample have counterparts with similar properties in the local Universe. This implies either that the majority (~70%) of ultramassive dense ETGs already completed the assembly and shaping at ⟨ z ⟩ = 1.4, or that, if a significant portion of dense ETGs evolves in size, new ultramassive dense ETGs must form at z < 1.5 to maintain their number density at almost constant. The difficulty in identify good progenitors for these new dense ETGs at z ≲ 1.5 and the stellar populations properties of local ultramassive dense ETGs point towards the first hypothesis. In this case, the ultramassive dense galaxies missing in the local Universe could have joined, in the last 9 Gyr, the so colled non-dense ETGs population through minor mergers, thus contributing to mean size growth. In any case, the comparison between their number density and the number density of the whole population of ultramassive ETGs relegates their contribution to the mean size evolution to a secondary process. [ABSTRACT FROM AUTHOR]

Aims. This paper aims at understanding whether the normalization of the stellar initial mass function (IMF) of massive galaxies varies with cosmic time and/or with mean stellar mass density Σ = M*/(2πRe5). Methods. We have tackled this question by taking advantage of a spectroscopic sample of 18 dense (Σ > 2500 Mʘ pc-2) massive early-type galaxies (ETGs) that we collected at 1.2 ≲ z ≲ 1.6. Each galaxy in the sample was selected in order to have available: i) a high-resolution deep HST-F160W image to visually classify it as an ETG; ii) an accurate velocity dispersion estimate; iii) stellar mass derived through the fit of multiband photometry; and iv) structural parameters (i.e. effective radius Re and Sersic index n) derived in the F160W-band. We have constrained the mass-normalization of the IMF of dense high-z ETGs by comparing the true stellar masses of the ETGs in the sample (Mtrue) derived through virial theorem, hence IMF independent, with those inferred through the fit of the photometry which assume a reference IMF (Mref). Adopting the virial estimator as proxy of the true stellar mass, we have implicitly assumed that these systems have zero dark matter. However, recent dynamical analysis of massive local ETGs have shown that the dark matter fraction within Re in dense ETGs is negligible (<5-10%) and simulations of dissipationless mergers of spheroidal galaxies have shown that this fraction decreases going back with time. Accurate dynamical models of local ETGs performed by the ATLAS3D team have shown that the virial estimator is prone to underestimating or overestimating the total masses. We have considered this, and based on the results of ATLAS3D we have shown that for dense ETGs the mean value of total masses derived through the virial estimator with a non-homologous virial coefficient and Sersic-Re are perfectly in agreement with the mean value of those derived through more sophisticated dynamical models, although, of course, the estimates show higher uncertainties. Results. Tracing the variation of the parameter Γ = Mtrue/Mref with velocity dispersion σe, we have found that, on average, dense ETGs at 〈z〉 = 1.4 follow the same IMF-σe trend of typical local ETGs, but with a lower mass-normalization. The observed lower normalization could be evidence of i) an evolution of the IMF with time or ii) a correlation with σ. To discriminate between the two possibilities, we have compared the IMF-σe trend that we have found for high-z dense ETGs with that of local ETGs with similar mean stellar mass density and velocity dispersion and we have found that the IMF of massive dense ETGs does not depend on redshift. The similarity between the IMF-σe trends observed both in dense high-z and low-z ETGs over 9 Gyr of evolution and their lower massnormalization with respect to the mean value of local ETGs suggests that, independently of formation redshift, the physical conditions which characterized the formation of a dense spheroid on average lead to a mass spectrum of newly formed stars with a higher ratio of high- to low-mass stars with respect to the IMF of normal local ETGs. In the direction of our findings, recent hydrodynamical simulations show that the higher star-formation rate that should have characterized the early stage of star formation of dense ETGs is expected to inhibit the formation of low-mass stars. Hence, compact ETGs should have higher ratio of high- to low-mass stars than normal spheroids, as we observe. [ABSTRACT FROM AUTHOR]

This article addresses the demand for trauma-based interventions tailored to the distinctive challenges confronting young men during the reentry phase, approximately 4-6 months prior to release and a year postrelease. We introduce the Resiliency in Stressful Experiences (RISE) program as a response to this need, drawing on two foundational conceptual frameworks: the trauma-based reentry framework and the well-being development model. These frameworks guide RISE in addressing lifetime traumatic experiences and trauma symptoms within the broader reentry context. In the article, the process of developing the RISE curriculum is delineated, which involved a literature review, adaptation of pertinent interventions, and collaborative engagement with a community advisory board consisting of formerly incarcerated individuals. The resulting curriculum seamlessly integrates trauma-informed cognitive-behavioral principles with well-being-oriented reentry programming, with a primary objective of augmenting emotion regulation, coping skills, and community stabilization. Finally, we discuss the ongoing randomized controlled trial of the RISE intervention that aims to evaluate the impact of RISE on community stability, posttraumatic stress disorder symptom management, and recidivism rates among individuals in a southeastern state. The potential for successful implementation and dissemination of the RISE curriculum is considered, emphasizing accessibility, ease of implementation, and acceptability. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

SP140, a lymphocytic-restricted protein, is an epigenetic reader working as a corepressor of genes implicated in inflammation and orchestrating macrophage transcriptional programs to maintain cellular identity. Reduced SP140 expression is associated both to autoimmune diseases and blood cancers. However, the molecular mechanisms that link SP140 altered protein levels to detrimental effects on the immune response and cellular growth, as well as the interactors through which SP140 promotes gene silencing, remain elusive. In this work, we have applied a multi-omics approach (i.e. interactomics, ChIP-seq and proteomics) in two Burkitt lymphoma cell lines to identify both interactors and target genes of endogenous SP140. We found that SP140 interacts with the PRC2 and NuRD complexes, and we showed that these interactions are functional as SP140 directs H3K27me3 deposition and NuRD binding on a set of target genes implicated in cellular growth and leukemia progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Polycomb proteins are a fundamental repressive system that plays crucial developmental roles by orchestrating cell-type-specific transcription programs that govern cell identity. Direct alterations of Polycomb activity are indeed implicated in human pathologies, including developmental disorders and cancer. General Polycomb repression is coordinated by three distinct activities that regulate the deposition of two histone post-translational modifications: tri-methylation of histone H3 lysine 27 (H3K27me3) and histone H2A at lysine 119 (H2AK119ub1). These activities exist in large and heterogeneous multiprotein ensembles consisting of common enzymatic cores regulated by heterogeneous non-catalytic modules composed of a large number of accessory proteins with diverse biochemical properties. Here, we have analyzed the current molecular knowledge, focusing on the functional interaction between the core enzymatic activities and their regulation mediated by distinct accessory modules. This provides a comprehensive analysis of the molecular details that control the establishment and maintenance of Polycomb repression, examining their underlying coordination and highlighting missing information and emerging new features of Polycomb-mediated transcriptional control., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cell fate is determined by specific transcription programs that are essential for tissue homeostasis and regeneration. The E3-ligases RING1A and B represent the core activity of the Polycomb repressive complex 1 (PRC1) that deposits repressive histone H2AK119 mono-ubiquitination (H2AK119ub1), which is essential for mouse intestinal homeostasis by preserving stem cell functions. However, the specific role of different PRC1 forms, which are defined by the six distinct PCGF1-6 paralogs, remains largely unexplored in vivo. We report that PCGF6 regulates mouse intestinal Tuft cell differentiation independently of H2AK119ub1 deposition. We show that PCGF6 chromatin occupancy expands outside Polycomb repressive domains, associating with unique promoter and distal regulatory elements. This occurs in the absence of RING1A/B and involves MGA-mediated E-BOX recognition and specific H3K9me2 promoter deposition. PCGF6 inactivation induces an epithelial autonomous accumulation of Tuft cells that was not phenocopied by RING1A/B loss. This involves direct PCGF6 association with a Tuft cell differentiation program that identified Polycomb-independent properties of PCGF6 in adult tissues homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology.

Introduction: Nearly half of the individuals who release from state prisons each year are under the age of 35; 89% are men. These young men are highly likely to be re-incarcerated. Research suggests untreated trauma symptoms contribute to high rates of incarceration and re-incarceration. As trauma symptomatology can increase during reentry, implementing trauma treatment during this time is critical. The current study fills an important gap by implementing an evidence-driven trauma intervention with young, incarcerated men and extending treatment post-release in the community., Methods: This study evaluates the impact of the Resiliency in Stressful Experiences (RISE) program for 18-35-year-old incarcerated males releasing to participating counties. RISE is a multi-phased comprehensive trauma-based reentry program designed according to the transitional nature of reentry. The researchers will assess the influence of RISE on post-release housing and employment stability and recidivism and identify key mechanisms of change. Participants (n = 400) are randomly assigned 1:1 to RISE or a Treatment as Usual control group., Discussion: This study will provide critical information about how trauma-informed reentry programming impacts traditional reentry outcomes (e.g., recidivism, housing, employment) and identify key mechanisms of action (e.g., reduced impulsivity and aggression). Coping with trauma symptomatology is a largely untapped area of scientific inquiry for criminal justice-involved populations, despite the significant role trauma plays in individuals' lives. Results advance identification of critical components of trauma-informed reentry interventions for moderate- to high-risk young men. This study provides critical data to support policymakers and corrections professionals eager for innovative approaches to improve post-release outcomes., (Copyright © 2022. Published by Elsevier Inc.)

Cell identity is tightly controlled by specific transcriptional programs which require post-translational modifications of histones. These histone modifications allow the establishment and maintenance of active and repressed chromatin domains. Histone H2A lysine 119 ubiquitination (H2AK119ub1) has an essential role in building repressive chromatin domains during development. It is regulated by the counteracting activities of the Polycomb repressive complex 1 (PRC1) and the Polycomb repressive-deubiquitinase (PR-DUB) complexes, two multi-subunit ensembles that write and erase this modification, respectively. We have catalogued the recurrent genetic alterations in subunits of the PRC1 and PR-DUB complexes in both neurodevelopmental disorders and cancer. These genetic lesions are often shared across disorders, and we highlight common mechanisms of H2AK119ub1 dysregulation and how they affect development in multiple disease contexts., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

BAP1 is mutated or deleted in many cancer types, including mesothelioma, uveal melanoma, and cholangiocarcinoma. It is the catalytic subunit of the PR-DUB complex, which removes PRC1-mediated H2AK119ub1, essential for maintaining transcriptional repression. However, the precise relationship between BAP1 and Polycombs remains elusive. Using embryonic stem cells, we show that BAP1 restricts H2AK119ub1 deposition to Polycomb target sites. This increases the stability of Polycomb with their targets and prevents diffuse accumulation of H2AK119ub1 and H3K27me3. Loss of BAP1 results in a broad increase in H2AK119ub1 levels that is primarily dependent on PCGF3/5-PRC1 complexes. This titrates PRC2 away from its targets and stimulates H3K27me3 accumulation across the genome, leading to a general chromatin compaction. This provides evidence for a unifying model that resolves the apparent contradiction between BAP1 catalytic activity and its role in vivo, uncovering molecular vulnerabilities that could be useful for BAP1-related pathologies., Competing Interests: Declarations of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The proteolytic cleavage of histone tails, also termed histone clipping, has been described as a mechanism for permanent removal of post-translational modifications (PTMs) from histone proteins. Such activity has been ascribed to ensure regulatory function in key cellular processes such as differentiation, senescence and transcriptional control, for which different histone-specific proteases have been described. However, all these studies were exclusively performed using cell lines cultured in vitro and no clear evidence that histone clipping is regulated in vivo has been reported. Here we show that histone H3 N-terminal tails undergo extensive cleavage in the differentiated cells of the villi in mouse intestinal epithelium. Combining biochemical methods, 3D organoid cultures and in vivo approaches, we demonstrate that intestinal H3 clipping is the result of multiple proteolytic activities. We identified Trypsins and Cathepsin L as specific H3 tail proteases active in small intestinal differentiated cells and showed that their proteolytic activity is differentially affected by the PTM pattern of histone H3 tails. Together, our findings provide in vivo evidence of H3 tail proteolysis in mammalian tissues, directly linking H3 clipping to cell differentiation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Both onco-suppressor PREP1 and the oncogene MEIS1 bind to PBX1. This interaction stabilizes the two proteins and allows their translocation into the nucleus and thus their transcriptional activity. Here, we have combined cross-linking mass-spectrometry and systematic mutagenesis to detail the binding geometry of the PBX1-PREP1 (and PBX1-MEIS1) complexes, under native in vivo conditions. The data confirm the existence of two distinct interaction sites within the PBC domain of PBX1 and unravel differences among the highly similar binding sites of MEIS1 and PREP1. The HR2 domain has a fundamental role in binding the PBC-B domain of PBX1 in both PREP1 and MEIS1. The HR1 domain of MEIS1, however, seem to play a less stringent role in PBX1 interaction with respect to that of PREP1. This difference is also reflected by the different binding affinity of the two proteins to PBX1. Although partial, this analysis provides for the first time some ideas on the tertiary structure of the complexes not available before. Moreover, the extensive mutagenic analysis of PREP1 identifies the role of individual hydrophobic HR1 and HR2 residues, both in vitro and in vivo.

Melanoma progression is generally associated with increased transcriptional activity mediated by the Yes-associated protein (YAP). Mechanical signals from the extracellular matrix are sensed by YAP, which then activates the expression of proliferative genes, promoting melanoma progression and drug resistance. Which extracellular signals induce mechanotransduction, and how this is mediated, is not completely understood. Here, using secretome analyses, we reveal the extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), in metastatic melanoma, together with proteins that assist amyloid maturation into fibrils. We also confirm the accumulation of amyloid-like aggregates, similar to those detected in Alzheimer disease, in metastatic cell lines, as well as in human melanoma biopsies. Mechanistically, beta-secretase 2 (BACE2) regulates the maturation of these aggregates, which in turn induce YAP activity. We also demonstrate that recombinant PMEL fibrils are sufficient to induce mechanotransduction, triggering YAP signaling. Finally, we demonstrate that BACE inhibition affects cell proliferation and increases drug sensitivity, highlighting the importance of amyloids for melanoma survival, and the use of beta-secretase inhibitors as potential therapeutic approach for metastatic melanoma., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Polycomb group proteins (PcGs) maintain transcriptional repression to preserve cellular identity in two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial. Using a fully catalytic inactive RING1B mutant, we demonstrated that H2AK119ub1 deposition is essential to maintain PcG-target gene repression in embryonic stem cells (ESCs). Loss of H2AK119ub1 induced a rapid displacement of PRC2 activity and a loss of H3K27me3 deposition. This preferentially affected PRC2.2 variant with respect to PRC2.1, destabilizing canonical PRC1 activity. Finally, we found that variant PRC1 forms can sense H2AK119ub1 deposition, which contributes to their stabilization specifically at sites where this modification is highly enriched. Overall, our data place H2AK119ub1 deposition as a central hub that mounts PcG repressive machineries to preserve cell transcriptional identity., Competing Interests: Declarations of Interests The authors declare no competing interests., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) control cell identity by establishing facultative heterochromatin repressive domains at common sets of target genes. PRC1, which deposits H2Aub1 through the E3 ligases RING1A/B, forms six biochemically distinct subcomplexes depending on the assembled PCGF protein (PCGF1-PCGF6); however, it is yet unclear whether these subcomplexes have also specific activities. Here we show that PCGF1 and PCGF2 largely compensate for each other, while other PCGF proteins have high levels of specificity for distinct target genes. PCGF2 associates with transcription repression, whereas PCGF3 and PCGF6 associate with actively transcribed genes. Notably, PCGF3 and PCGF6 complexes can assemble and be recruited to several active sites independently of RING1A/B activity (therefore, of PRC1). For chromatin recruitment, the PCGF6 complex requires the combinatorial activities of its MGA-MAX and E2F6-DP1 subunits, while PCGF3 requires an interaction with the USF1 DNA binding transcription factor., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Human Sp140 protein is a leukocyte-specific member of the speckled protein (Sp) family (Sp100, Sp110, Sp140, Sp140L), a class of multi-domain nuclear proteins involved in intrinsic immunity and transcriptional regulation. Sp140 regulates macrophage transcriptional program and is implicated in several haematologic malignancies. Little is known about Sp140 structural domains and its post-translational modifications., Methods: We used mass spectrometry and biochemical experiments to investigate endogenous Sp140 SUMOylation in Burkitt's Lymphoma cells and Sp140 SUMOylation sites in HEK293T cells, FLAG-Sp140 transfected and His 6 -SUMO-1 T95K infected. NMR spectroscopy and in vitro SUMOylation reactions were applied to investigate the role of Sp140 PHD finger in the SUMOylation of the adjacent BRD., Results: Endogenous Sp140 is a SUMO-1 target, whereby FLAG-Sp140 harbors at least 13 SUMOylation sites distributed along the protein sequence, including the BRD. NMR experiments prove direct binding of the SUMO E2 ligase Ubc9 and SUMO-1 to PHD-BRD Sp140 . In vitro SUMOylation reactions show that the PHD Sp140 behaves as SUMO E3 ligase, assisting intramolecular SUMOylation of the adjacent BRD., Conclusions: Sp140 is multi-SUMOylated and its PHD finger works as versatile protein-protein interaction platform promoting intramolecular SUMOylation of the adjacent BRD. Thus, combinatorial association of Sp140 chromatin binding domains generates a multifaceted interaction scaffold, whose function goes beyond the canonical histone recognition., General Significance: The addition of Sp140 to the increasing lists of multi-SUMOylated proteins opens new perspectives for molecular studies on Sp140 transcriptional activity, where SUMOylation could represent a regulatory route and a docking surface for the recruitment and assembly of leukocyte-specific transcription regulators., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Sp140 is a nuclear leukocyte-specific protein involved in primary biliary cirrhosis and a risk factor in chronic lymphocytic leukemia. The presence of several chromatin related modules such as plant homeodomain (PHD), bromodomain and SAND domain suggests a role in chromatin-mediated regulation of gene expression; however, its real function is still elusive. Herein we present the solution structure of Sp140-PHD finger and investigate its role as epigenetic reader in vitro. Sp140-PHD presents an atypical PHD finger fold which does not bind to histone H3 tails but is recognized by peptidylprolyl isomerase Pin1. Pin1 specifically binds to a phosphopeptide corresponding to the L3 loop of Sp140-PHD and catalyzes cis-trans isomerization of a pThr-Pro bond. Moreover co-immunoprecipitation experiments demonstrate FLAG-Sp140 interaction with endogenous Pin1 in vivo. Overall these data include Sp140 in the list of the increasing number of Pin1 binders and expand the regulatory potential of PHD fingers as versatile structural platforms for diversified interactions., (© 2013 FEBS.)

Malignant melanoma involving the foot has typically been documented in cases whereby the primary lesion was subungually located. Characteristic clinical features usually assist the physician in diagnosing the suspicious lesion. The case study that follows illustrates an atypical presentation of skeletally metastatic malignant melanoma of the foot where the primary lesion was not identified.

The authors introduce a unique and clinically oriented technique for evaluation of hallux abducto valgus deformity and its operative correction. A new concept in the application of the Austin osteotomy is also presented.