Effectiveness of physical rehabilitation on physical functioning and quality of life for long-term care residents with dementia: a systematic review and meta-analysis.

OBJECTIVE: The objective of this review was to evaluate the effectiveness of physical rehabilitation versus non-rehabilitation comparators on physical functioning and quality of life for long-term care (LTC) residents with dementia. INTRODUCTION: LTC residents living with dementia often have impaired physical functioning and quality of life. Physical rehabilitation can improve physical functioning and quality of life for individuals living with dementia; however, many LTC residents with dementia do not receive physical rehabilitation and providers are unsure what interventions to employ. A synthesis of studies examining physical rehabilitation will help guide practice in the LTC sector where most residents live with dementia. Previous syntheses have focused on all residents in LTC, specific professions, interventions, or people with dementia in the community. Our review focuses on LTC residents with dementia and a broader definition of physical rehabilitation. INCLUSION CRITERIA: This review includes studies that evaluate physical rehabilitation in comparison with non-rehabilitation controls among LTC residents with any severity of dementia. We included studies that measure the effect on activities of daily living, performance-based physical functioning, and self- or proxy-rated quality of life. METHODS: Searches were conducted in APA PsycINFO (EBSCOhost), CINAHL (EBSCOhost), PubMed (National Library of Medicine), Embase, Scopus, and the Cochrane CENTRAL database with no date or language limitations. Two independent reviews assessed the studies against the inclusion criteria. Two independent reviewers extracted data and conducted a quality assessment using a structured extraction form. Certainty of evidence was ascertained using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Where possible, studies were pooled in meta-analyses; otherwise, a narrative synthesis was performed. RESULTS: Thirty-three studies were included (n = 3072 participants); 27 were randomized control trials and the remaining 6 were non-randomized trials. The overall risk of bias of the included studies was low to unclear. Many of the included studies focused on increasing activity or walking, while few were individually tailored or at an intensity appropriate to induce therapeutic effects on physical function. Physical function was also measured via several outcome measures, limiting our ability to pool results. There was low certainty evidence that physical rehabilitation improved activities of daily living (12 RCTs, 1348 participants, SMD 0.78; 95% CI 0.27 to 1.30) and the Short Physical Performance Battery Score (3 RCTs, 258 participants, MD 3.01 points; 95% CI 1.37 to 4.66) compared with non-rehabilitation interventions. There was low to moderate certainty evidence that physical rehabilitation demonstrated no change in the 30-Second Sit to Stand Test (2 RCTs, 293 participants, MD 0.79 repetitions; 95% CI -0.45 to 2.03), 6-Minute Walk Test (4 RCTs, 363 participants, MD 17.32 meters; 95% CI -29.41 to 64.05), gait speed (4 RCTs, 400 participants, MD 0.10 meters/seconds; 95% CI -0.02 to 0.22), Timed Up and Go Test (3 studies, 275 participants, MD -2.89 seconds; 95% CI -6.62 to 0.84), or quality of life (4 RCTs, 419 participants, SMD 0.20; 95% CI -0.08 to 0.47). CONCLUSIONS: This review demonstrates that physical rehabilitation may improve activities of daily living for LTC residents living with dementia, though the evidence is of low certainty. The effect of physical rehabilitation on specific functional tasks, like gait speed and quality of life, are less clear. Future research should examine the effects of individualized, progressive interventions on outcome measures that reflect the capacity and preferences of LTC residents with more advanced dementia. REVIEW REGISTRATION: PROSPERO CRD42022308444.

FLT3-TKD Measurable Residual Disease Detection Using Droplet Digital PCR and Clinical Applications in Acute Myeloid Leukemia.

The tyrosine kinase domain of the FMS-Like tyrosine kinase 3 (FLT3-TKD) is recurrently mutated in acute myeloid leukemia (AML). Common molecular techniques used in its detection include PCR and capillary electrophoresis, Sanger sequencing and next-generation sequencing with recognized sensitivity limitations. This study aims to validate the use of droplet digital PCR (ddPCR) in the detection of measurable residual disease (MRD) involving the common FLT3-TKD mutations (D835Y, D835H, D835V, D835E). Twenty-two diagnostic samples, six donor controls, and a commercial D835Y positive control were tested using a commercial Bio-rad® ddPCR assay. All known variants were identified, and no false positives were detected in the wild-type control (100% specificity and sensitivity). The assays achieved a limit of detection suitable for MRD testing at 0.01% variant allelic fraction. Serial samples from seven intensively-treated patients with FLT3-TKD variants at diagnosis were tested. Five patients demonstrated clearance of FLT3-TKD clones, but two patients had FLT3-TKD persistence in the context of primary refractory disease. In conclusion, ddPCR is suitable for the detection and quantification of FLT3-TKD mutations in the MRD setting; however, the clinical significance and optimal management of MRD positivity require further exploration.

Growth factor-induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression.

Extracellular signals are transmitted through kinase cascades to modulate gene expression, but it remains unclear how epigenetic changes regulate this response. Here, we provide evidence that growth factor-stimulated changes in the transcript levels of many responsive genes are accompanied by increases in histone phosphorylation levels, specifically at histone H3 serine-10 when the adjacent lysine-9 is dimethylated (H3K9me2S10). Imaging and proteomic approaches show that epidermal growth factor (EGF) stimulation results in H3K9me2S10 phosphorylation, which occurs in genomic regions enriched for regulatory enhancers of EGF-responsive genes. We also demonstrate that the EGF-induced increase in H3K9me2S10ph is dependent on the nuclear kinase MSK2, and this subset of EGF-induced genes is dependent on MSK2 for transcription. Together, our work indicates that growth factor-induced changes in chromatin state can mediate the activation of downstream genes.

Glucocorticoid prescribing in neurology.

Glucocorticoids are commonly used for neurological disorders, but they can have significant adverse effects, including adrenal insufficiency, hyperglycaemia, osteoporosis and increased infection risk. Long-term use of corticosteroids requires the prescriber to plan risk mitigation, including monitoring and often coprescribing. This article highlights the potential risks of corticosteroid prescribing and draws together up-to-date guidance with multispecialty input to clarify ways of reducing those risks. We discuss home blood glucose monitoring and consider a steroid safety checklist to promote safer steroid prescribing.

High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.

BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.

Experiences of implementing the 'Making Every Contact Count' initiative into a UK integrated care system: an interview study.

BACKGROUND: The 'Making Every Contact Count' (MECC) approach is in line with the current National Health Service (NHS) strategy to improve and prevent health conditions in England. Despite its importance and value for preventative healthcare, implementation of MECC varies. The aim of this study was to explore the barriers and facilitators of implementing MECC and MECC training into an integrated care system (ICS). METHODS: Remote semi-structured interviews were conducted with staff across an ICS in the North West of England who were involved in implementing and delivering MECC across the region. Data were analysed initially using an inductive thematic analysis approach and then interpreted using the 'Capability, Opportunity, Motivation = Behaviour' (COM-B) model of behaviour change. RESULTS: We interviewed nine stakeholders and identified three superordinate themes: (1) macro-level barriers and facilitators, e.g. funding; (2) organizational level barriers and facilitators, e.g. time and resource; and (3) individual-level barriers/facilitators for both MECC trainers and MECC agents. CONCLUSIONS: MECC has potential to meet the needs of the public's health, but barriers to its implementation exist. MECC must be successfully embedded into organizations and regions in which it is implemented, which relies on further development of an appropriate infrastructure including sustainable funding and a shift in culture to value preventative healthcare.

The Roles of Coenzyme A Binding Pocket Residues in Short and Medium Chain Acyl-CoA Synthetases.

Short- and medium-chain acyl-CoA synthetases catalyze similar two-step reactions in which acyl substrate and ATP bind to form an enzyme-bound acyl-adenylate, then CoA binds for formation of the acyl-CoA product. We investigated the roles of active site residues in CoA binding in acetyl-CoA synthetase (Acs) and a medium-chain acyl-CoA synthetase (Macs) that uses 2-methylbutyryl-CoA. Three highly conserved residues, Arg193, Arg528, and Arg586 of Methanothermobacter thermautotrophicus Acs (AcsMt), are predicted to form important interactions with the 5'- and 3'-phosphate groups of CoA. Kinetic characterization of AcsMt variants altered at each of these positions indicates these Arg residues play a critical role in CoA binding and catalysis. The predicted CoA binding site of Methanosarcina acetivorans Macs (MacsMa) is structurally more closely related to that of 4-chlorobenzoate:coenzyme A ligase (CBAL) than Acs. Alteration of MacsMa residues Tyr460, Arg490, Tyr525, and Tyr527, which correspond to CoA binding pocket residues in CBAL, strongly affected CoA binding and catalysis without substantially affecting acyl-adenylate formation. Both enzymes discriminate between 3'-dephospho-CoA and CoA, indicating interaction between the enzyme and the 3'-phosphate group is important. Alteration of MacsMa residues Lys461 and Lys519, located at positions equivalent to AcsMt Arg528 and Arg586, respectively, had only a moderate effect on CoA binding and catalysis. Overall, our results indicate the active site architecture in AcsMt and MacsMa differs even though these enzymes catalyze mechanistically similar reactions. The significance of this study is that we have delineated the active site architecture with respect to CoA binding and catalysis in this important enzyme superfamily.

Circulating trans fatty acids are associated with prostate cancer in Ghanaian and American men.

The association between fatty acids and prostate cancer remains poorly explored in African-descent populations. Here, we analyze 24 circulating fatty acids in 2934 men, including 1431 prostate cancer cases and 1503 population controls from Ghana and the United States, using CLIA-certified mass spectrometry-based assays. We investigate their associations with population groups (Ghanaian, African American, European American men), lifestyle factors, the fatty acid desaturase (FADS) genetic locus, and prostate cancer. Blood levels of circulating fatty acids vary significantly between the three population groups, particularly trans, omega-3 and omega-6 fatty acids. FADS1/2 germline genetic variants and lifestyle factors explain some of the variation in fatty acid levels, with the FADS1/2 locus showing population-specific associations, suggesting differences in their control by germline genetic factors. All trans fatty acids, namely elaidic, palmitelaidic, and linoelaidic acids, associated with an increase in the odds of developing prostate cancer, independent of ancestry, geographic location, or potential confounders.

Glycogen Metabolism and Its Role in Growth and Encystation in Entamoeba histolytica.

Entamoeba histolytica is a parasitic protozoan that causes diarrheal disease in approximately 100 million people worldwide every year. E. histolytica has two forms, the growing trophozoite and the infectious cyst. Trophozoites colonizing the large intestine form cysts that are released into the environment. The ingestion of the cysts in contaminated food and water continues the disease cycle. Here, we investigated the role of glycogen in trophozoite growth and encystation. Glycogen is thought to provide precursors for the synthesis of chitin, a major component of the protective cyst wall. We propose that glycogen also serves as an energy source during metabolic adaptation to different nutrient environments. We examined the role of glycogen in E. histolytica by analyzing the growth and encystation of RNAi strains with reduced expression of the single gene-encoding glycogen synthase (GYS) or two of three genes encoding glycogen phosphorylase (PYG). The GYS RNAi strain had a greatly reduced glycogen accumulation, and both the GYS and PYG RNAi strains exhibited reduced growth in the glucose-poor medium. Both RNAi strains also showed reduced cyst production. Our results suggest glycogen synthesis and degradation are vital to the growth and adaptation of E. histolytica to a low-glucose environment such as that encountered in the large intestine.

Systemic Inflammation Indices and Association with Prostate Cancer Survival in a Diverse Patient Cohort.

There is a lack of investigations assessing the performance of systemic inflammation indices as outcome predictive tools in African Americans with prostate cancer. This study aims to assess the relationships between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation (SII), and systemic inflammation response index (SIRI) with survival outcomes among 680 diverse men with prostate cancer. Routine blood results were collected from self-identified African American and European American patients. We applied multivariable Cox regression modeling to examine the associations of systemic inflammation indices with overall and prostate cancer-specific survival. The median survival follow-up was 5.9 years, with 194 deaths. NLR, SII, and SIRI, but not PLR, showed associations with all-cause and prostate cancer-specific mortality when coded as dichotomized and continuous variables. NLR and SIRI were significantly associated with prostate cancer-specific mortality among all men (hazard ratio (HR) 2.56 for high vs. low NLR; HR 3.24 for high vs. low SIRI) and African American men (HR 2.96 for high vs. low NLR; HR 3.19 for high vs. low SIRI). Among European Americans, only SII showed an association with prostate cancer-specific survival. These observations suggest that inflammation indices merit further study as predictors of prostate cancer mortality.

The YGetIt? Program: A Mobile Application, PEEP, and Digital Comic Intervention to Improve HIV Care Outcomes for Young Adults.

INTRODUCTION: In New York State (NYS), young adults account for the largest number of new human immunodeficiency virus (HIV) infections and struggle to seek and remain in HIV care. Digital interventions and access to peer support have demonstrated positive influences on the HIV care continuum and health outcomes. The New York State Department of Health (NYS DOH) developed YGetIt? (YGI) that combines a mobile application, GET!, peer navigation (PEEPs), and a compelling digital comic series, "Tested," to facilitate the timely entry of young people into HIV care, to prevent vulnerable youth from dropping out of care, and to achieve sustained viral load suppression among those in care. This article describes the development and early implementation of the YGI digital intervention. Intervention Design. GET! provided a high level of confidentiality and security, ease of access, and Wi-Fi accessibility. YGI enrolled 113 HIV-positive participants from a clinical setting who were individually randomized at a 1:1 ratio to receive access to GET! plus PEEPs (n = 53) or the app alone (n = 60). LESSONS LEARNED: For recruitment, staff and organization buy-in was essential to the success of the intervention, and building relationships was critical. GET! development was an iterative process. Peer Engagement Educator Professionals (PEEPs) who were tech savvy, representative of the priority population, and had shared life experience with participants were most impactful. Interest in apps declines over time and participants in the APP alone arm were less engaged. CONCLUSION: GET! is a communication and engagement tool that supports HIV care and may serve as a model for like digital interventions.

PRR14 organizes H3K9me3-modified heterochromatin at the nuclear lamina.

The eukaryotic genome is organized in three dimensions within the nucleus. Transcriptionally active chromatin is spatially separated from silent heterochromatin, a large fraction of which is located at the nuclear periphery. However, the mechanisms by which chromatin is localized at the nuclear periphery remain poorly understood. Here we demonstrate that Proline Rich 14 (PRR14) protein organizes H3K9me3-modified heterochromatin at the nuclear lamina. We show that PRR14 dynamically associates with both the nuclear lamina and heterochromatin, and is able to reorganize heterochromatin in the nucleus of interphase cells independent of mitosis. We characterize two functional HP1-binding sites within PRR14 that contribute to its association with heterochromatin. We also demonstrate that PPR14 forms an anchoring surface for heterochromatin at the nuclear lamina where it interacts dynamically with HP1-associated chromatin. Our study proposes a model of dynamic heterochromatin organization at the nuclear lamina via the PRR14 tethering protein.

Effectiveness of physical rehabilitation in improving physical functioning and quality of life for long-term-care residents with dementia: a systematic review protocol.

OBJECTIVE: The objective of this review is to evaluate the effectiveness of physical rehabilitation versus non-rehabilitation control in improving physical functioning and quality of life in long-term care residents with dementia. INTRODUCTION: Many long-term-care residents live with dementia and have impaired physical function and poor quality of life. Physical rehabilitation can improve physical function and quality of life for people living with dementia, yet many long-term-care residents with dementia do not receive this intervention, and health care providers are unsure of which rehabilitation interventions are effective. Studies synthesizing effective rehabilitation programs are needed to guide practice in the long-term-care sector where many residents live with dementia. Previous studies have focused broadly on long-term care, specific professions, interventions or outcomes, or people with dementia in the community. Our review will focus on long-term-care residents living with dementia and a broader definition of physical rehabilitation. INCLUSION CRITERIA: This review will include studies that evaluate physical rehabilitation in comparison with non-rehabilitation controls among long-term-care residents with any severity of dementia. We will include studies that measure the effect on performance-based physical functioning and self- or proxy-reported quality of life. METHODS: Searches will be conducted in APA PsycINFO (EBSCO), CINAHL (EBSCO), MEDLINE (Ovid), Embase, Scopus, and the Cochrane CENTRAL database with no date or language limitations. Two independent reviewers will conduct a critical appraisal of eligible studies, assess methodological quality, and extract the data. Where possible, studies will be pooled in a statistical meta-analysis. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42022308444.

Serum proteomics links suppression of tumor immunity to ancestry and lethal prostate cancer.

There is evidence that tumor immunobiology and immunotherapy response may differ between African American and European American prostate cancer patients. Here, we determine if men of African descent harbor a unique systemic immune-oncological signature and measure 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men. Protein signatures for suppression of tumor immunity and chemotaxis are elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer, pointing to clinical importance. Moreover, two markers, pleiotrophin and TNFRSF9, predict poor disease survival specifically among African American men. These findings indicate that immune-oncology marker profiles differ between men of African and European descent. These differences may contribute to the disproportionate burden of lethal prostate cancer in men of African ancestry. The elevated peripheral suppression of tumor immunity may have important implication for guidance of cancer therapy which could particularly benefit African American patients.

Impact of Heroin and HIV on Gut Integrity and Immune Activation.

BACKGROUND: Altered gut integrity is central to HIV-related immune activation. Opioids may promote similar changes in gut permeability and/or increase systemic inflammation, potentially augmenting processes already occurring in people with HIV (PWH). SETTING: Urban hospital systems in Cleveland, Ohio, and surrounding communities. METHODS: This is a prospectively enrolled, cross-sectional study including people with and without HIV using heroin and people with and without HIV who have never used heroin, matched by age, sex, and CD4+ T-cell count (PWH only) to compare markers of gut integrity, microbial translocation, systemic inflammation, and immune activation. RESULTS: A total of 100 participants were enrolled. Active heroin use was associated with higher concentrations of lipopolysaccharide-binding protein (LBP), beta-D-glucan (BDG), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor-α-receptors I and II, soluble CD163, inflammatory monocytes, and activated CD4+ lymphocytes in adjusted models. HIV status tended to modify the effect between heroin use and LBP, BDG, hsCRP, patrolling monocytes, and activated CD4+ lymphocytes (P < 0.15 for interactions); however, it was not as expected. The effect of heroin on these markers (except patrolling monocytes) was greatest among those without HIV rather than among those with HIV. CONCLUSIONS: Heroin use is associated with heightened microbial translocation, systemic inflammation, and immune activation. Concurrent HIV infection in virologically suppressed individuals does not seem to substantially worsen the effects heroin has on these markers.

Evaluation of Disease Severity and Molecular Relationships Between Peronospora variabilis Isolates on Chenopodium Species in New Hampshire.

Quinoa is a potential new crop for New England; however, its susceptibility to downy mildew, caused by Peronospora variabilis, is a key obstacle for cultivation. The objectives of this study were to evaluate differential resistance within the Chenopodium genus, identify novel sources of resistance for use in future genetic studies or breeding programs, and investigate phylogenetic relationships of P. variabilis isolates from different Chenopodium hosts. The long-term goal of this research is to develop a resistant variety of quinoa to be grown in New England. Field trials conducted at the University of New Hampshire evaluated downy mildew disease severity on 10 Chenopodium accessions representing four species. Disease severity for each treatment was compared and significant differences in disease severity were observed between accessions. C. berlandieri var. macrocalycium ecotypes collected from Rye Beach, New Hampshire and Appledore Island, Maine exhibited the lowest disease severity over the growing season. P. variabilis was isolated from each accession, and COX2 sequences were compared. Phylogenetic analyses suggest no effect of host species on P. variabilis sequence similarity; however, isolates are shown to cluster by geographic location. This research provides the first step in identifying potential New England native sources of resistance to downy mildew within the genus Chenopodium and provides preliminary information needed to further investigate resistance at the genomic level in Chenopodium spp.

The Role of Acetate Kinase in the Human Parasite Entamoeba histolytica.

The human parasite Entamoeba histolytica, which causes approximately 100 million cases of amoebic dysentery each year, relies on glycolysis as the major source of ATP production from glucose as it lacks a citric acid cycle and oxidative phosphorylation. Ethanol and acetate, the two major glycolytic end products for E. histolytica, are produced at a ratio of 2:1 under anaerobic conditions, creating an imbalance between NADH production and utilization. In this study we investigated the role of acetate kinase (ACK) in acetate production during glycolysis in E. histolytica metabolism. Analysis of intracellular and extracellular metabolites demonstrated that acetate levels were unaffected in an ACK RNAi cell line, but acetyl-CoA levels and the NAD+/NADH ratio were significantly elevated. Moreover, we demonstrated that glyceraldehyde 3-phosphate dehydrogenase catalyzes the ACK-dependent conversion of acetaldehyde to acetyl phosphate in E. histolytica. We propose that ACK is not a major contributor to acetate production, but instead provides a mechanism for maintaining the NAD+/NADH balance during ethanol production in the extended glycolytic pathway.

Urinary Thromboxane B2 and Lethal Prostate Cancer in African American Men.

BACKGROUND: Thromboxane A2 (TXA2) is a platelet- and cyclooxygenase-derived eicosanoid that has been linked to metastasis. We investigated the role of TXA2 in the development of lethal prostate cancer in African American (AA) and European American (EA) men. METHODS: We measured urinary 11-dehydrothromboxane B2 (TXB2), a stable metabolite of TXA2, with mass spectrometry. Samples were obtained from 977 cases and 1022 controls at time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of TXB2 with prostate cancer and patient survival. The median survival follow-up was 8.4 years, with 246 deaths among cases. Aspirin use was assessed with a questionnaire. Race was self-reported. RESULTS: Urinary TXB2 was inversely associated with aspirin use. High (>median) TXB2 was associated with prostate cancer in AA (adjusted odds ratio [OR] = 1.50, 95% confidence interval [CI] = 1.13 to 2.00) but not EA men (OR = 1.07, 95% CI = 0.82 to 1.40), suggesting upregulated TXA2 synthesis in AA men with prostate cancer. High TXB2 was positively associated with metastatic prostate cancer (OR = 2.60, 95% CI = 1.08 to 6.28) compared with low (≤median) TXB2. Furthermore, high TXB2 was also associated with all-cause (adjusted hazard ratio = 1.59, 95% CI = 1.06 to 2.40) and prostate cancer-specific mortality (hazard ratio = 4.74, 95% CI = 1.62 to 13.88) in AA men only. CONCLUSIONS: We report a distinct association of TXB2 with prostate cancer outcomes in AA men. In this high-risk group of men, upregulation of TXA2 synthesis may promote metastasis and lethal disease. Our observation identifies a potential benefit of aspirin in preventing lethal prostate cancer through inhibition of TXA2 synthesis.

BRD4 orchestrates genome folding to promote neural crest differentiation.

Higher-order chromatin structure regulates gene expression, and mutations in proteins mediating genome folding underlie developmental disorders known as cohesinopathies. However, the relationship between three-dimensional genome organization and embryonic development remains unclear. Here we define a role for bromodomain-containing protein 4 (BRD4) in genome folding, and leverage it to understand the importance of genome folding in neural crest progenitor differentiation. Brd4 deletion in neural crest results in cohesinopathy-like phenotypes. BRD4 interacts with NIPBL, a cohesin agonist, and BRD4 depletion or loss of the BRD4-NIPBL interaction reduces NIPBL occupancy, suggesting that BRD4 stabilizes NIPBL on chromatin. Chromatin interaction mapping and imaging experiments demonstrate that BRD4 depletion results in compromised genome folding and loop extrusion. Finally, mutation of individual BRD4 amino acids that mediate an interaction with NIPBL impedes neural crest differentiation into smooth muscle. Remarkably, loss of WAPL, a cohesin antagonist, rescues attenuated smooth muscle differentiation resulting from BRD4 loss. Collectively, our data reveal that BRD4 choreographs genome folding and illustrates the relevance of balancing cohesin activity for progenitor differentiation.