Design and manufacture of an ultra-compact, 1.5 T class, controlled-contact resistance, REBCO, brain imaging MRI magnet.

Brain imaging MRI comprises a significant proportion of MRI scans, but the requirement for including the shoulders in the magnet bore means there is not a significant size reduction in the magnet compared to whole-body magnets. Here we present a new design approach for brain imaging MRI magnets targeting ±20 kHz B 0 variation over the imaging volume rather than the more usual ±200 Hz making use of novel high-bandwidth MRI pulse sequences and distortion correction. Using this design approach, we designed and manufactured a 1.5 T class ReBCO cryogen-free magnet. The magnet is dome-like in form, completely excludes the shoulders and is <400 mm long. The magnet was wound using no-insulation style coils with a conductive epoxy encapsulant where the contact resistance of the coils was controlled so the emergency shut-down time of the magnet was less than 30 s. Despite acceptable coil testing results ahead of manufacture, during testing of the magnet, several of the epoxy coils showed signs of damage limiting stable performance to <55 A compared to the designed 160 A. These coils were replaced with insulated paraffin encapsulated coils. Subsequently the magnet was re-ramped and was stable at 81 A, generating 0.71 T as several other coils had sustained damage not visible in the first magnet iteration. The magnet has been passive shimmed to ±20 kHz B 0 variation over the imaging volume and integrated into an MRI scanner. The stability of the magnet has been evaluated and found to be acceptable for MRI.

The mechanism of peptidoglycan O-acetylation in Gram-negative bacteria typifies bacterial MBOAT-SGNH acyltransferases.

Bacterial cell envelope polymers are commonly modified with acyl groups that provide fitness advantages. Many polymer acylation pathways involve pairs of membrane-bound O-acyltransferase (MBOAT) and SGNH family proteins. As an example, the MBOAT protein PatA and the SGNH protein PatB are required in Gram-negative bacteria for peptidoglycan O-acetylation. The mechanism for how MBOAT-SGNH transferases move acyl groups from acyl-CoA donors made in the cytoplasm to extracellular polymers is unclear. Using the peptidoglycan O-acetyltransferase proteins PatAB, we explore the mechanism of MBOAT-SGNH pairs. We find that the MBOAT protein PatA catalyzes auto-acetylation of an invariant Tyr residue in its conserved C-terminal hexapeptide motif. We also show that PatB can use a synthetic hexapeptide containing an acetylated tyrosine to donate an acetyl group to a peptidoglycan mimetic. Finally, we report the structure of PatB, finding that it has structural features that shape its activity as an O-acetyltransferase and distinguish it from other SGNH esterases and hydrolases. Taken together, our results support a model for peptidoglycan acylation in which a tyrosine-containing peptide at the MBOAT's C-terminus shuttles an acyl group from the MBOAT active site to the SGNH active site, where it is transferred to peptidoglycan. This model likely applies to other systems containing MBOAT-SGNH pairs, such as those that O-acetylate alginate, cellulose, and secondary cell wall polysaccharides. The use of an acyl-tyrosine intermediate for MBOAT-SGNH acyl transfer is also shared with AT3-SGNH proteins, a second major group of acyltransferases that modify cell envelope polymers.

Psychometric Evidence That Paraphilia Is a Natural Kind.

Is the category paraphilia a natural kind? That is, do different paraphilias share anything scientifically interesting or are they classified together because they are unusual and sometimes problematic? We investigated this question systematically in 11 samples of paraphilic males (N = 4,617) and 11 samples of control males (N = 1,494). Primary data consisted of responses to the 11-item Paraphilic Interests Scale. Contrary to our initial hypothesis, the scale mean was similar for paraphilic and control samples. Using logistic regression and the same items, we derived three highly correlated measures that robustly discriminated paraphilic and control samples (ds ranging from 0.86 to 0.92). These successful measures capitalized on the unanticipated fact that some items (especially those assessing transvestism and masochistic humiliation) were positively associated with membership in paraphilic samples, while others (especially those assessing voyeurism) were negatively associated with such membership. Subsequent analyses focused on one of the measures, the Paraphilic Interests Scale Contrast (PISC). Consistent with prior findings distinguishing paraphilias and homosexual orientation, PISC was not elevated among homosexual males compared with heterosexual males among the control groups. Within four paraphilic samples, PISC was positively associated with additional paraphilic phenomena. Results provide tentative support for both the proposition that paraphilia is a natural kind and the usefulness of PISC as a measure of paraphilia.

Selective Liquid-Liquid Extraction of Thorium(IV) from Rare-Earth Element Mixtures.

One of the major challenges in processing rare-earth element (REE) materials arises from the large amounts of radioactive thorium (Th) that are often found within REE minerals, encouraging enhanced metal separation procedures. We report here a study aimed at developing improved systems for REE processing with the goal of efficient extraction of Th(IV) from acidic solution. A tripodal ligand, TRPN-CMPO-Ph, was prepared that utilizes carbamoylmethylphosphine oxide (CMPO) chelators tethered to a tris(3-aminopropyl)amine (TRPN) capping scaffold. The ligand and its metal complexes were characterized by using elemental analysis, NMR, Fourier transform infrared spectroscopy, mass spectrometry, and luminescence spectroscopy. Using a liquid-liquid metal extraction protocol, TRPN-CMPO-Ph selectively extracts Th(IV) at an efficiency of 79% from a mixture of Th(IV), UO22+, and all rare-earth metal cations (except promethium) dissolved in nitric acid into an organic solvent. Th(IV) extraction selectivity is maintained upon extraction from a mixture that approximates a typical monazite leach solution containing several relevant lanthanide ions, including two ions at higher concentration relative to Th(IV). Comparative studies with a tris(2-aminoethyl)amine (TREN)-capped derivative are presented and support the need for a larger TRPN capping scaffold in achieving Th(IV) extraction selectivity.

Outcomes of Total Hip Arthroplasty in Patients Who Have Ehlers-Danlos Syndrome: A Matched Cohort Study.

BACKGROUND: Total hip arthroplasty (THA) is an effective surgical treatment for severe osteoarthritis of the hip. While THA is considered a reliable and safe procedure, outcome data on patients who have Ehlers-Danlos syndrome (EDS) is limited. The purpose of this study was to compare rates of postoperative complications after primary THA in patients who have EDS against matched controls. METHODS: A large national database was searched to identify patients who underwent THA between 2009 and 2020. Patients younger than 18 years, those who have a history of prior THA, and those undergoing THA for a hip fracture were excluded from analysis. Propensity score matching was utilized to match patients who had EDS with patients who did not have EDS at a 1:4 ratio. Rates of medical and surgical complications at 90 days and 2 years were queried and compared between the cohorts using multivariable logistic regression. We identified 118 patients who had EDS and underwent primary THA, who were then matched with 418 controls. RESULTS: At 90 days, the EDS cohort had greater rates of dislocation (8.5 versus 3.8%, P = 0.038). At 2 years, the EDS cohort had greater odds of dislocation (OR [odds ratio] 2.47, P = 0.018), aseptic loosening (OR 6.91, P = 0.002), and aseptic revision (OR 2.66, P = 0.02). CONCLUSIONS: Patients who have EDS possess significantly higher odds of complications after THA compared to matched controls, including dislocation, aseptic loosening, and aseptic revision. Careful surgical planning in these patients should be made to prevent dislocation and potentially minimize the risk of other prosthesis-related complications leading to revision.

Cerebral hypoperfusion exacerbates traumatic brain injury in male but not female mice.

Mild-moderate traumatic brain injuries (TBIs) are prevalent, and while many individuals recover, there is evidence that a significant number experience long-term health impacts, including increased vulnerability to neurodegenerative diseases. These effects are influenced by other risk factors, such as cardiovascular disease. Our study tested the hypothesis that a pre-injury reduction in cerebral blood flow (CBF), mimicking cardiovascular disease, worsens TBI recovery. We induced bilateral carotid artery stenosis (BCAS) and a mild-moderate closed-head TBI in male and female mice, either alone or in combination, and analyzed CBF, spatial learning, memory, axonal damage, and gene expression. Findings showed that BCAS and TBI independently caused a ~10% decrease in CBF. Mice subjected to both BCAS and TBI experienced more significant CBF reductions, notably affecting spatial learning and memory, particularly in males. Additionally, male mice showed increased axonal damage with both BCAS and TBI compared to either condition alone. Females exhibited spatial memory deficits due to BCAS, but these were not worsened by subsequent TBI. Gene expression analysis in male mice highlighted that TBI and BCAS individually altered neuronal and glial profiles. However, the combination of BCAS and TBI resulted in markedly different transcriptional patterns. Our results suggest that mild cerebrovascular impairments, serving as a stand-in for preexisting cardiovascular conditions, can significantly worsen TBI outcomes in males. This highlights the potential for mild comorbidities to modify TBI outcomes and increase the risk of secondary diseases.

Outcomes of Total Knee Arthroplasty in Patients Who Have Ehlers-Danlos Syndrome: A Matched Cohort Study.

BACKGROUND: Total knee arthroplasty (TKA) is an excellent surgical option for patients who have end-stage knee osteoarthritis. While rates of major postoperative complications have steadily decreased with modern implants and operative techniques, contemporary outcome data for patients who have Ehlers-Danlos syndrome (EDS) are scarce. The goal of this study was to compare complication rates after primary TKA in patients who have EDS versus matched controls. METHODS: A large administrative database was used to identify patients who underwent primary TKA from 2009 to 2020. Patients who had a diagnosis of EDS were identified by International Classification of Diseases Coding. Propensity scores were utilized to match these patients with controls at a 1:4 ratio based on age, sex, and various comorbidities. Multivariable logistic regression analysis was used to compare the rates of medical and surgical complications at 90 days and 2 years. A total of 188 patients who had EDS and 752 controls were included in this study. RESULTS: After univariate analysis, Ehlers-Danlos patients exhibited significantly higher rates of wound complications (4.8 versus 0.9%, P = .001) at 90 days. When adjusted for comorbidities, Ehlers-Danlos patients still exhibited significantly increased odds of developing wound complications (odds ratio: 7.06; P < .001). CONCLUSIONS: Patients who have EDS undergoing TKA exhibited significantly higher rates of wound complications within 90 days postoperatively compared to matched controls. Rates of instability, manipulation under anesthesia, periprosthetic joint infection, aseptic loosening, and aseptic revision arthroplasty did not significantly differ between the cohorts. This study found generally favorable short-term outcomes of TKA in this population; however, the inability to control for implant type and other confounding variables may have influenced the lack of difference in complication rates at 2 years. Surgeons should monitor for the potentially increased risk of wound complications and consider the possible need for increased constraint in this population during preoperative planning.

Epithelial regulation of microbiota-immune cell dynamics.

The mammalian gastrointestinal tract hosts a diverse community of trillions of microorganisms, collectively termed the microbiota, which play a fundamental role in regulating tissue physiology and immunity. Recent studies have sought to dissect the cellular and molecular mechanisms mediating communication between the microbiota and host immune system. Epithelial cells line the intestine and form an initial barrier separating the microbiota from underlying immune cells, and disruption of epithelial function has been associated with various conditions ranging from infection to inflammatory bowel diseases and cancer. From several studies, it is now clear that epithelial cells integrate signals from commensal microbes. Importantly, these non-hematopoietic cells also direct regulatory mechanisms that instruct the recruitment and function of microbiota-sensitive immune cells. In this review, we discuss the central role that has emerged for epithelial cells in orchestrating intestinal immunity and highlight epithelial pathways through which the microbiota can calibrate tissue-intrinsic immune responses.

The SelfSTarT intervention for low back pain patients presenting to first contact physiotherapists: A mixed methods service evaluation.

INTRODUCTION: Globally, back pain is the leading cause of years of disability. In the United Kingdom, over 20 million people live with musculoskeletal (MSK) pain, with low back pain being one of the most common causes. National strategies promote self-management and the use of digital technologies to empower populations. AIMS: To evaluate the uptake and impact of providing the SelfSTart approach (STarT Back and SelfBACK App) when delivered by a First Contact Physiotherapist (FCP) to people presenting with low back pain in primary care. METHODS: Patients presenting with a new episode of low back pain underwent routine assessment and completion of a STarT Back questionnaire. Patients with low/medium scores were offered the SelfBACK App. A control population was provided by the MIDAS-GP study. Patient Experience, outcome measures, healthcare utilisation and retention were captured through the app and clinical systems (EMIS). Interviews with five FCPs explored the experiences of using the SelfSTart approach. RESULTS: SelfSTarT was taken up by almost half (48%) of those to whom it was offered. Compared to MIDAS-GP, users were more likely to be younger, male, in work, and with higher health literacy. SelfSTarT users reported significant improved experiences relating to receiving an agreed care plan and receiving sufficient information. There were no significant differences in treatments offered. FCPs were positive about the app and felt it had value but wanted feedback on patient progress. They recognised that a digital solution would not be suitable for all. CONCLUSION: This approach offers an opportunity to empower and support self-management, using robustly evaluated digital technology.

'Low' faecal immunochemical test (FIT) colorectal cancer: a 4-year comparison of the Nottingham '4F' protocol with FIT10 in symptomatic patients.

AIM: The aim of this work was to evaluate colorectal cancer (CRC) outcomes after 'low' (sub-threshold) faecal immunochemical test (FIT) results in symptomatic patients tested in primary care. METHOD: This work comprised a retrospective audit of 35 289 patients with FIT results who had consulted their general practitioner with lower gastrointestinal symptoms and had subsequent CRC diagnoses. The Rapid Colorectal Cancer Diagnosis pathway was introduced in November 2017 to allow incorporation of FIT into clinical practice. The local '4F' protocol combined FIT results with blood tests and digital rectal examination (DRE): FIT, full blood count, ferritin and finger [DRE]. The outcome used was detection rates of CRC, missed CRC and time to diagnosis in local 4F protocols for patients with a subthreshold faecal haemoglobin (fHb) result compared with thresholds of 10 and 20 µg Hb/g faeces. RESULTS: A single threshold of 10 µg Hb/g faeces identifies a population in whom the risk of CRC is 0.2%, but this would have missed 63 (10.5%) of 599 CRCs in this population. The Nottingham 4F protocol would have missed fewer CRCs [42 of 599 (7%)] despite using a threshold of 20 µg Hb/g faeces for patients with normal blood tests. Subthreshold FIT results in patients subsequently diagnosed with a palpable rectal tumour yielded the longest delays in diagnosis. CONCLUSION: A combination of FIT with blood results and DRE (the 4F protocol) reduced the risk of missed or delayed diagnosis. Further studies on the impact of such protocols on the diagnostic accuracy of FIT are expected. The value of adding blood tests to FIT may be restricted to specific parts of the fHb results spectrum.

Evaluation of the diphenyl herbicide, oxyfluorfen, for effects on thyroid hormones in the juvenile rat.

Recently, oxyfluorfen, a pre- and post-emergent diphenyl ether herbicide, was identified in our laboratory as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), the first key step in the synthesis of thyroid hormones (THs). This inhibition was observed in vitro, using both a human NIS engineered cell line (hNIS-HEK293T-EPA) and a rat thyroid follicular cell line (FRTL-5). Oxyfluorfen was found to be a potent inhibitor of NIS activity with an EC50 of approximately 2 µM in both cell lines with no observed cytotoxicity at any concentration tested up to 100 µM. The current research tested the hypothesis that oxyfluorfen alters circulating concentrations of THs. This hypothesis was first tested in a pilot study with both juvenile male and female rats exposed to oxyfluorfen for 4 days at 0, 125, 250 and 500 mg/kg/day. Once we identified that this short-term 4-day oxyfluorfen exposure suppressed both total serum thyroxine (T4) and triiodothyronine (T3) at all doses, we tested seven lower concentrations of oxyfluorfen (0.8125 to 62.5 mg/kg day) in an 8-day exposure paradigm to more closely evaluate the dose-response. We found that oxyfluorfen suppressed serum T4 with a LOEL of 3.25 mg/kg/day and T3 with a LOEL 62.5 mg/kg/day. Analytical chemistry of the serum showed an accumulation over time following oral exposure to oxyfluorfen in both the 4- and 8-day groups. Analytical chemistry of the thyroid glands in the 8-day study revealed higher accumulation in the thyroid as compared to the serum (2 to 3- fold at 62.5 mg/kg). No changes in thyroid weight or serum TSH were observed following the 8-day exposure. This study is the first to demonstrate an effect of oxyfluorfen on serum thyroid hormones in the rat. Additional studies are needed to further evaluate the effects on thyroid homeostasis with extended exposures and the potential implications of the observed effects.

Impact of Nonionic Surfactants on Reactions of IREDs. Applications to Tandem Chemoenzymatic Sequences in Water.

The influence of added surfactant to aqueous reaction mixtures containing various IREDs has been determined. Just the presence of a nonionic surfactant tends to increase both rates and extent of conversion to the targeted amines. The latter can be as much as >40% relative to buffer alone. Several tandem sequences featuring several steps that combine use of an IRED together with various types of chemocatalysis are also presented, highlighting the opportunities for utilizing chemoenzymatic catalysis, all in water.

Detransition and Desistance Among Previously Trans-Identified Young Adults.

Persons who have renounced a prior transgender identification, often after some degree of social and medical transition, are increasingly visible. We recruited 78 US individuals ages 18-33 years who previously identified as transgender and had stopped identifying as transgender at least six months prior. On average, participants first identified as transgender at 17.1 years of age and had done so for 5.4 years at the time of their participation. Most (83%) participants had taken several steps toward social transition and 68% had taken at least one medical step. By retrospective reports, fewer than 17% of participants met DSM-5 diagnostic criteria for Gender Dysphoria in Childhood. In contrast, 53% of participants believed that "rapid-onset gender dysphoria" applied to them. Participants reported a high rate of psychiatric diagnoses, with many of these prior to trans-identification. Most participants (N = 71, 91%) were natal females. Females (43%) were more likely than males (0%) to be exclusively homosexual. Participants reported that their psychological health had improved dramatically since detransition/desistance, with marked decreases in self-harm and gender dysphoria and marked increases in flourishing. The most common reason given for initial trans-identification was confusing mental health issues or reactions to trauma for gender dysphoria. Reasons for detransition were more likely to reflect internal changes (e.g., the participants' own thought processes) than external pressures (e.g., pressure from family). Results suggest that, for some transgender individuals, detransition is both possible and beneficial.

Human RAD52 double-ring remodels replication forks restricting fork reversal.

Human RAD52 1,2 is a multifunctional DNA repair protein involved in several cellular events that support genome stability including protection of stalled DNA replication forks from excessive degradation 3-7 . In its gatekeeper role, RAD52 binds to and stabilizes stalled replication forks during replication stress protecting them from reversal by SMARCAL1 5 . The structural and molecular mechanism of the RAD52-mediated fork protection remains elusive. Here, using P1 nuclease sensitivity, biochemical and single-molecule analyses we show that RAD52 dynamically remodels replication forks through its strand exchange activity. The presence of the ssDNA binding protein RPA at the fork modulates the kinetics of the strand exchange without impeding the reaction outcome. Mass photometry and single-particle cryo-electron microscopy show that the replication fork promotes a unique nucleoprotein structure containing head-to-head arrangement of two undecameric RAD52 rings with an extended positively charged surface that accommodates all three arms of the replication fork. We propose that the formation and continuity of this surface is important for the strand exchange reaction and for competition with SMARCAL1.

Genome-scale analysis of essential gene knockout mutants to identify an antibiotic target process.

We describe a genome-scale approach to identify the essential biological process targeted by a new antibiotic. The procedure is based on the identification of essential genes whose inactivation sensitizes a Gram-negative bacterium (Acinetobacter baylyi) to a drug and employs recently developed transposon mutant screening and single-mutant validation procedures. The approach, based on measuring the rates of loss of newly generated knockout mutants in the presence of antibiotic, provides an alternative to traditional procedures for studying essential functions using conditional expression or activity alleles. As a proof of principle study, we evaluated whether mutations enhancing sensitivity to the ß-lactam antibiotic meropenem corresponded to the known essential target process of the antibiotic (septal peptidoglycan synthesis). We found that indeed mutations inactivating most genes needed for peptidoglycan synthesis and cell division strongly sensitized cells to meropenem. Additional classes of sensitizing mutations in essential genes were also identified, including those that inactivated capsule synthesis, DNA replication, or envelope stress response regulation. The essential capsule synthesis mutants appeared to enhance meropenem sensitivity by depleting a precursor needed for both capsule and peptidoglycan synthesis. The replication mutants may sensitize cells by impairing division. Nonessential gene mutations sensitizing cells to meropenem were also identified in the screen and largely corresponded to functions subordinately associated with the essential target process, such as in peptidoglycan recycling. Overall, these results help validate a new approach to identify the essential process targeted by an antibiotic and define the larger functional network determining sensitivity to it.

Characterizing mechanisms of caregiver-mediated naturalistic developmental behavioral interventions for autistic toddlers: A randomized clinical trial.

LAY ABSTRACT: Caregiver-mediated early interventions support caregivers' use of strategies to improve their young autistic child's communication. In the current clinical trial, we sought to isolate the most effective strategies to improve short-term and long-term child communication outcomes. Results demonstrated how children may benefit from caregiver prompts to facilitate long-term language outcomes. In conclusion, the current study improves our understanding of how early intervention facilitates child communication outcomes.

ACD15, ACD21, and SLN regulate the accumulation and mobility of MBD6 to silence genes and transposable elements.

DNA methylation mediates silencing of transposable elements and genes in part via recruitment of the Arabidopsis MBD5/6 complex, which contains the methyl-CpG binding domain (MBD) proteins MBD5 and MBD6, and the J-domain containing protein SILENZIO (SLN). Here, we characterize two additional complex members: α-crystalline domain (ACD) containing proteins ACD15 and ACD21. We show that they are necessary for gene silencing, bridge SLN to the complex, and promote higher-order multimerization of MBD5/6 complexes within heterochromatin. These complexes are also highly dynamic, with the mobility of MBD5/6 complexes regulated by the activity of SLN. Using a dCas9 system, we demonstrate that tethering the ACDs to an ectopic site outside of heterochromatin can drive a massive accumulation of MBD5/6 complexes into large nuclear bodies. These results demonstrate that ACD15 and ACD21 are critical components of the gene-silencing MBD5/6 complex and act to drive the formation of higher-order, dynamic assemblies at CG methylation (meCG) sites.

Prosocial motives underlie scientific censorship by scientists: A perspective and research agenda.

Science is among humanity's greatest achievements, yet scientific censorship is rarely studied empirically. We explore the social, psychological, and institutional causes and consequences of scientific censorship (defined as actions aimed at obstructing particular scientific ideas from reaching an audience for reasons other than low scientific quality). Popular narratives suggest that scientific censorship is driven by authoritarian officials with dark motives, such as dogmatism and intolerance. Our analysis suggests that scientific censorship is often driven by scientists, who are primarily motivated by self-protection, benevolence toward peer scholars, and prosocial concerns for the well-being of human social groups. This perspective helps explain both recent findings on scientific censorship and recent changes to scientific institutions, such as the use of harm-based criteria to evaluate research. We discuss unknowns surrounding the consequences of censorship and provide recommendations for improving transparency and accountability in scientific decision-making to enable the exploration of these unknowns. The benefits of censorship may sometimes outweigh costs. However, until costs and benefits are examined empirically, scholars on opposing sides of ongoing debates are left to quarrel based on competing values, assumptions, and intuitions.

Main Mechanisms of Remote Monitoring Programs for Cardiac Rehabilitation and Secondary Prevention: A SYSTEMATIC REVIEW.

PURPOSE: The objective of this report was to identify the main mechanisms of home-based remote monitoring programs for cardiac rehabilitation (RM CR) and examine how these mechanisms vary by context. METHODS: This was a systematic review using realist synthesis. To be included, articles had to be published in English between 2010 and November 2020 and contain specific data related to mechanisms of effect of programs. MEDLINE All (1946-) via Ovid, Embase (1974-) via Ovid, APA PsycINFO (1806-), CINAHL via EBSCO, Scopus databases, and gray literature were searched. RESULTS: From 13 747 citations, 91 focused on cardiac conditions, with 23 reports including patients in CR. Effective RM CR programs more successfully adapted to different patient home settings and broader lives, incorporated individualized patient health data, and had content designed specifically for patients in cardiac rehabilitation. Relatively minor but common technical issues could significantly reduce perceived benefits. Patients and families were highly receptive to the programs and viewed themselves as fortunate to receive such services. The RM CR programs could be improved via incorporating more connectivity to other patients. No clear negative effects on perceived utility or outcomes occurred by patient age, ethnicity, or sex. Overall, the programs were seen to best suit highly motivated patients and consolidated rather than harmed existing relationships with health care professionals and teams. CONCLUSIONS: Remote monitoring CR programs are perceived by patients to be beneficial and attractive. Future RM CR programs should consider adaptability to different home settings, incorporate individualized health data, and contain content specific to patient needs.

ACD15, ACD21 and SLN regulate accumulation and mobility of MBD6 to silence genes and transposable elements.

DNA methylation mediates silencing of transposable elements and genes in part via recruitment of the Arabidopsis MBD5/6 complex, which contains the methyl-CpG-binding domain (MBD) proteins MBD5 and MBD6, and the J-domain containing protein SILENZIO (SLN). Here we characterize two additional complex members: α-crystalline domain containing proteins ACD15 and ACD21. We show that they are necessary for gene silencing, bridge SLN to the complex, and promote higher order multimerization of MBD5/6 complexes within heterochromatin. These complexes are also highly dynamic, with the mobility of complex components regulated by the activity of SLN. Using a dCas9 system, we demonstrate that tethering the ACDs to an ectopic site outside of heterochromatin can drive massive accumulation of MBD5/6 complexes into large nuclear bodies. These results demonstrate that ACD15 and ACD21 are critical components of gene silencing complexes that act to drive the formation of higher order, dynamic assemblies.