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Introduction: NSCLC transformation to SCLC has been best characterized with EGFR-mutant NSCLC, with emerging case reports seen in ALK, RET, and KRAS-altered NSCLC. Previous reports revealed transformed SCLC from EGFR-mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed TP53 and RB1 loss of function increase the risk of SCLC transformation. Little has been reported on the detailed clinicogenomic characteristics and potential therapeutic targets for this patient population. Methods: In this study, we conducted a single-center retrospective analysis of clinical and genomic characteristics of patients with EGFR-mutant NSCLC transformed to SCLC. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. Kaplan-Meier analyses were used to estimate survival outcomes. Next generation sequencing-based assays was used to identify EGFR and co-occurring genetic alterations in tissue or plasma before and after SCLC transformation. Single-cell RNA sequencing (scRNA-seq) was performed on a patient-derived-xenograft model generated from a patient with EGFR-NSCLC transformed SCLC tumor. Results: A total of 34 patients were identified in our study. Median age at initial diagnosis was 58, and median time to SCLC transformation was 24.2 months. 68% were female and 82% were never smokers. 79% of patients were diagnosed as stage IV disease, and over half had brain metastases at baseline. Median overall survival of the entire cohort was 38.3 months from initial diagnoses and 12.4 months from time of SCLC transformation. Most patients harbored EGFR exon19 deletions as opposed to exon21 L858R alteration. Continuing EGFR tyrosine kinase inhibitor post-transformation did not improve overall survival compared with those patients where tyrosine kinase inhibitor was stopped in our cohort. In the 20 paired pretransformed and post-transformed patient samples, statistically significant enrichment was seen with PIK3CA alterations (p = 0.04) post-transformation. Profiling of longitudinal liquid biopsy samples suggest emergence of SCLC genetic alterations before biopsy-proven SCLC, as shown by increasing variant allele frequency of TP53, RB1, PIK3CA alterations. ScRNA-seq revealed potential therapeutic targets including DLL3, CD276 (B7-H3) and PTK7 were widely expressed in transformed SCLC. Conclusions: SCLC transformation is a potential treatment resistance mechanism in driver-mutant NSCLC. In our cohort of 34 EGFR-mutant NSCLC, poor prognosis was observed after SCLC transformation. Clinicogenomic analyses of paired and longitudinal samples identified genomic alterations emerging post-transformation and scRNA-seq reveal potential therapeutic targets in this population. Further studies are needed to rigorously validate biomarkers and therapeutic targets for this patient population.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Abstract Background Epithelial-to-mesenchymal transition (EMT) results in changes that promote de-differentiation, migration, and invasion in non-small cell lung cancer (NSCLC). While it is recognized that EMT promotes altered energy utilization, identification of metabolic pathways that link EMT with cancer progression is needed. Work presented here indicates that mesenchymal NSCLC upregulates glutamine-fructose-6-phosphate transaminase 2 (GFPT2). GFPT2 is the rate-limiting enzyme in the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the obligate activator of O-linked N-acetylglucosamine transferase (OGT). Methods Analysis of our transcriptomic data indicates that GFPT2 is one of the most significantly upregulated metabolic genes in mesenchymal NSCLC. Ectopic GFPT2 expression, as well as gene silencing strategies were used to determine the importance of this metabolic enzyme in regulating EMT-driven processes of cell motility and invasion. Results Our work demonstrates that GFPT2 is transcriptionally upregulated by NF-κB and repressed by the NAD+-dependent deacetylase SIRT6. Depletion of GFPT2 expression in NSCLC highlights its importance in regulating cell migration and invasion during EMT. Conclusions Consistent with GFPT2 promoting cancer progression, we find that elevated GFPT2 expression correlates with poor clinical outcome in NSCLC. Modulation of GFPT2 activity offers a potentially important therapeutic target to combat NSCLC disease progression.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

A new methodology for the preparation of substituted naphthalenes starting from readily available indenones, organometal reagents, and trimethylsilyldiazomethane via a catalytic rearrangement process is described. Hindered biaryl naphthalenes, including triortho-substituted biaryls, can be accessed through our method. Our results are consistent with a mechanism involving a benzobenzvalene intermediate. [ABSTRACT FROM AUTHOR]

Cancer is caused by mutations that drive aberrant growth, proliferation, and invasion, thus overriding regulatory mechanisms that normally link these processes to organismal needs and cellular physiology. This imposes demands for the production of energy and biomass and for survival in microenvironments that are often nonphysiologic and nutrient-poor, which are met by rewiring of cellular metabolism. The resultant dependence of tumor cells on altered metabolism can induce sensitivity to specific metabolic perturbations that can be exploited for cancer therapy. Some cancers are caused by mutations that impart a novel function to metabolic enzymes, leading to the production of a tumor-promoting metabolite that is dispensable in normal cells, representing an ideal therapeutic target. Tumors can also exploit metabolic regulation of cellular immunity to evade antitumor immune responses, and deciphering this biology has revealed potential targets for therapeutic intervention. Here, we discuss a number of illustrative examples highlighting the therapeutic potential and the challenges of targeting metabolism for cancer therapy., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

A key challenge in understanding subcellular organization is quantifying interpretable measurements of intracellular structures with complex multi-piece morphologies in an objective, robust and generalizable manner. Here we introduce a morphology-appropriate representation learning framework that uses 3D rotation invariant autoencoders and point clouds. This framework is used to learn representations of complex multi-piece morphologies that are independent of orientation, compact, and easy to interpret. We apply our framework to intracellular structures with punctate morphologies (e.g. DNA replication foci) and polymorphic morphologies (e.g. nucleoli). We systematically compare our framework to image-based autoencoders across several intracellular structure datasets, including a synthetic dataset with pre-defined rules of organization. We explore the trade-offs in the performance of different models by performing multi-metric benchmarking across efficiency, generative capability, and representation expressivity metrics. We find that our framework, which embraces the underlying morphology of multi-piece structures, facilitates the unsupervised discovery of sub-clusters for each structure. We show how our approach can also be applied to phenotypic profiling using a dataset of nucleolar images following drug perturbations. We implement and provide all representation learning models using CytoDL, a python package for flexible and configurable deep learning experiments., Competing Interests: Declaration of interests The authors declare no competing interests.

To investigate the fundamental question of how cellular variations arise across spatiotemporal scales in a population of identical healthy cells, we focused on nuclear growth in hiPS cell colonies as a model system. We generated a 3D timelapse dataset of thousands of nuclei over multiple days, and developed open-source tools for image and data analysis and an interactive timelapse viewer for exploring quantitative features of nuclear size and shape. We performed a data-driven analysis of nuclear growth variations across timescales. We found that individual nuclear volume growth trajectories arise from short timescale variations attributable to their spatiotemporal context within the colony. We identified a strikingly time-invariant volume compensation relationship between nuclear growth duration and starting volume across the population. Notably, we discovered that inheritance plays a crucial role in determining these two key nuclear growth features while other growth features are determined by their spatiotemporal context and are not inherited., Competing Interests: Declaration of interests The authors declare no competing interests.

Background: Improved coronavirus disease 2019 (COVID-19) prevention is needed for immunocompromised individuals., Methods: A prospective study was performed of health care workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccine doses and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFN-γ/TNF-α T-cell responses were assessed in a subset., Results: In total, 536 participants were included: 492 immunocompromised (206 solid organ transplant [SOT], 128 autoimmune, 80 hematologic malignancy [HM], 48 solid tumor, 25 HIV), and 44 HCW. D3 significantly increased spike IgG levels among all, but SOT and HM participants had the lowest median antibody levels post-D3 (increase from 0.09 to 0.83 and 0.27 to 1.92, respectively), versus HCW and persons with HIV, autoimmune conditions, and solid tumors (increases from 4.44 to 19.79, 2.9 to 15.75, 3.82 to 16.32, and 4.1 to 25.54, respectively). Seropositivity post-D3 was lowest for SOT (49.0%) and HM (57.8%), versus others (>90%). Neutralization post-D3 was lowest among SOT and HM. Predictors of lower antibody levels included low baseline levels and shorter intervals between vaccines. T-cell responses against spike increased significantly among HCW and nonsignificantly among immunocompromised individuals., Conclusions: D3 significantly improves serological but not T-cell responses among immunocompromised individuals. SOT and HM patients have suboptimal responses to D3., Competing Interests: Potential conflicts of interest. G. H. is a recipient of research grants from Allovir, Karius, and AstraZeneca; serves on the scientific advisory boards of Karius and AstraZeneca; and has received honoraria from the International AIDS Society, MDOutlook, and PeerView Medial Education. J. W. M. is a consultant to Gilead Sciences and Allovir; and owns share options in Infectious Disease Connection and Galapagos, NV, unrelated to the current work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this review is to identify the barriers and facilitators of assistive technology adoption and use in adults with intellectual disabilities living in supported accommodation. This will inform the development of an assistive technology adoption framework for these settings., Introduction: Assistive technology has the potential to increase the independence and well-being of people with intellectual disabilities; however, it is often not adopted. Generic models of technology adoption exist, and a recent systematic review has explored factors influencing access to assistive technology by people with intellectual disabilities. However, no review has presented a framework of adoption or use of technology specifically for people with intellectual disabilities living in supported accommodation., Inclusion Criteria: This review will include qualitative, quantitative, and mixed method studies as well as gray literature published from 1989 to 2023 on the barriers and facilitators of technology adoption and use by adults with intellectual disabilities living in supported accommodation. Systematic reviews and theses will be excluded., Methods: The review will be conducted in accordance with the JBI methodology for mixed methods systematic reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases to be searched will include PubMed, Scopus, Web of Science Core Collection, CINAHL, IEEE Xplore, and SocINDEX. Two independent reviewers will screen titles and abstracts for relevance and quality. Data will be extracted by 1 reviewer and validated by a second, independently. Data analysis will use a convergent integrated approach, with quantitative data "qualitized" using thematic analysis to allow comparison. All data will be mapped onto an existing framework of technological adoption via framework synthesis., Systematic Review Registration Number: PROSPERO CRD42022353732., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 JBI.)

Background: Familial Alzheimer's disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD., Objective: Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred., Methods: Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method., Results: Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques., Conclusion: These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo ., Competing Interests: The authors have no conflict of interest to report., (© 2021 – The authors. Published by IOS Press.)

The classical Gibbs paradox concerns the entropy change upon mixing two gases. Whether an observer assigns an entropy increase to the process depends on their ability to distinguish the gases. A resolution is that an "ignorant" observer, who cannot distinguish the gases, has no way of extracting work by mixing them. Moving the thought experiment into the quantum realm, we reveal new and surprising behaviour: the ignorant observer can extract work from mixing different gases, even if the gases cannot be directly distinguished. Moreover, in the macroscopic limit, the quantum case diverges from the classical ideal gas: as much work can be extracted as if the gases were fully distinguishable. We show that the ignorant observer assigns more microstates to the system than found by naive counting in semiclassical statistical mechanics. This demonstrates the importance of accounting for the level of knowledge of an observer, and its implications for genuinely quantum modifications to thermodynamics.

Background: Pathological analysis of brain tissue from animals and humans with a history of traumatic brain injury (TBI) suggests that TBI could be one of the risk factors facilitating onset of dementia with possible Alzheimer's disease (AD), but medications to prevent or delay AD onset are not yet available., Methods: This study explores four medication classes (angiotensin-converting enzyme inhibitors (ACEI), beta blockers, metformin, and statins) approved by the Food and Drug Administration (FDA) for other indications and evaluates their influence when used in combination on the risk of possible AD development for patients with a history of TBI. We identified patients with history of TBI from an existing Department of Veterans Affairs (VA) national database. Among 1,660,151 veterans who used VA services between the ages of 50 to 89 years old, we analyzed 733,920 patients, including 15,450 patients with a history of TBI and 718,470 non-TBI patients. The TBI patients were followed for up to 18.5 years, with an average of 7.7 ± 4.7 years, and onset of dementia with possible AD was recorded based on International Statistical Classification of Diseases (ICD) 9 or 10 codes. The effect of TBI on possible AD development was evaluated by multivariable logistic regression models adjusted by age, gender, race, and other comorbidities. The association of ACEI, beta blockers, metformin, statins, and combinations of these agents over time from the first occurrence of TBI to possible AD onset was assessed using Cox proportional hazard models adjusted for demographics and comorbidities., Results: Veterans with at least two TBI occurrences by claims data were 25% (odds ratio (OR) = 1.25, 95% confidence intervals (CI) (1.13, 1.37)) more likely to develop dementia with possible AD, compared to those with no record of TBI. In multivariable logistic regression models (propensity score weighted or adjusted), veterans taking a combination of ACEI and statins had reduced risk in developing possible AD after suffering TBI, and use of this medication class combination was associated with a longer period between TBI occurring and dementia with possible AD onset, compared to patients who took statins alone or did not take any of the four target drugs after TBI., Conclusions: The combination of ACEI and statins significantly lowered the risk of development of dementia with possible AD in a national cohort of people with a history of TBI, thus supporting a clinical approach to lowering the risk of dementia with possible AD.

Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer's disease (fAD) is an early-onset and aggressive form of Alzheimer's disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson's disease, dementia onset is known to follow neurofibrillary tangle deposition., Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson's disease, and epilepsy donors., Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue., Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell., Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson's disease.

The reaction-coordinate mapping is a useful technique to study complex quantum dissipative dynamics into structured environments. In essence, it aims to mimic the original problem by means of an "augmented system," which includes a suitably chosen collective environmental coordinate-the "reaction coordinate." This composite then couples to a simpler "residual reservoir" with short-lived correlations. If, in addition, the residual coupling is weak, a simple quantum master equation can be rigorously applied to the augmented system, and the solution of the original problem just follows from tracing out the reaction coordinate. But, what if the residual dissipation is strong? Here, we consider an exactly solvable model for heat transport-a two-node linear "quantum wire" connecting two baths at different temperatures. We allow for a structured spectral density at the interface with one of the reservoirs and perform the reaction-coordinate mapping, writing a perturbative master equation for the augmented system. We find that (a) strikingly, the stationary state of the original problem can be reproduced accurately by a weak-coupling treatment even when the residual dissipation on the augmented system is very strong, (b) the agreement holds throughout the entire dynamics under large residual dissipation in the overdamped regime; and (c) such a master equation can grossly overestimate the stationary heat current across the wire, even when its nonequilibrium steady state is captured faithfully. These observations can be crucial when using the reaction-coordinate mapping to study the largely unexplored strong-coupling regime in quantum thermodynamics.

We study the process of assisted work distillation. This scenario arises when two parties share a bipartite quantum state ρ_{AB} and their task is to locally distill the optimal amount of work when one party is restricted to thermal operations, whereas the other can perform general quantum operations and they are allowed to communicate classically. We demonstrate that this question is intimately related to the distillation of classical and quantum correlations. In particular, we show that the advantage of one party performing global measurements over many copies of ρ_{AB} is related to the nonadditivity of the entanglement of formation. We also show that there may exist work bound in the quantum correlations of the state that is only extractable under the wider class of local Gibbs-preserving operations.

Objectives: Goal intentions are the key proximal determinant of behavior in a number of key models applied to predicting health behavior. However, relatively little previous research has examined how characteristics of goals moderate the intention-health-behavior relations. The present research examined the effects of goal priority and goal conflict as moderators of the intention-health-behavior relationship., Method: The main outcome measures were self-reported performance of physical activity (Studies 1, 2, and 3) and other health behaviors (Study 4), and objectively measured physical activity (Study 3). Studies 1 and 4 used prospective correlational designs to predict later behavior from earlier cognitions. Studies 2 and 3 were experimental studies manipulating goal priority and goal conflict. Studies 1 and 2 used between-subjects designs while Studies 3 and 4 used within-subjects designs., Results: Goal priority significantly moderated the intention-health-behavior relationship for physical activity (Study 1) and a range of protective and risk health behaviors (Study 4). Manipulations of goal priority significantly increased the intention-physical-activity relationship when self-reported (Study 2) and objectively measured (Study 3). In contrast, inconsistent effects were observed for goal conflict as an intention-behavior moderator., Conclusions: When goal priority is high, then intentions are strong predictors of health behaviors. Further studies testing manipulations of goal conflict and in particular goal priority in combination with goal intentions are required to confirm their value as a means to change health behavior. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

The present research focused upon the power of different messages to increase self-reported physical activity (PA). Five hundered and ninety six participants were randomised to one of five conditions that varied in the content of message: short-term affective, short-term cognitive, long-term affective, long-term cognitive and a no message control. PA was measured at baseline and follow-up (seven days later) was done using the Godin Leisure Time Exercise Questionnaire over the subsequent seven day period. The affective short-term message (ASM) was shown to be equally effective at increasing self-reported PA as a cognitive long-term message. Furthermore, when controlling for baseline activity levels, the ASM emerged as being the message that produced the highest levels of self-reported PA at follow-up. The findings point to the value of distinguishing between health messages in terms of the focus on affective and cognitive outcomes and the temporal nature of the outcomes (short-term or long-term).

The E3 ubiquitin ligase CRL4(Cdt2) targets proteins for destruction in S phase and after DNA damage by coupling ubiquitylation to DNA-bound proliferating cell nuclear antigen (PCNA). Coupling to PCNA involves a PCNA-interacting peptide (PIP) degron motif in the substrate that recruits CRL4(Cdt2) while binding to PCNA. In vertebrates, CRL4(Cdt2) promotes degradation of proteins whose presence in S phase is deleterious, including Cdt1, Set8, and p21. Here, we show that CRL4(Cdt2) targets thymine DNA glycosylase (TDG), a base excision repair enzyme that is involved in DNA demethylation. TDG contains a conserved and nearly perfect match to the PIP degron consensus. TDG is ubiquitylated and destroyed in a PCNA-, Cdt2-, and PIP degron-dependent manner during DNA repair in Xenopus egg extract. The protein can also be destroyed during DNA replication in this system. During Xenopus development, TDG first accumulates during gastrulation, and its expression is down-regulated by CRL4(Cdt2). Our results expand the group of vertebrate CRL4(Cdt2) substrates to include a bona fide DNA repair enzyme., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage-dependent manner., (Copyright © 2012 Wiley Periodicals, Inc.)