EPOP Restricts PRC2.1 Targeting to Chromatin by Directly Modulating Enzyme Complex Dimerization.

Polycomb repressive complex 2 (PRC2) mediates developmental gene repression as two classes of holocomplexes, PRC2.1 and PRC2.2. EPOP is an accessory subunit specific to PRC2.1, which also contains PCL proteins. Unlike other accessory subunits that collectively facilitate PRC2 targeting, EPOP was implicated in an enigmatic inhibitory role, together with its interactor Elongin BC. We report an unusual molecular mechanism whereby EPOP regulates PRC2.1 by directly modulating its oligomerization state. EPOP disrupts the PRC2.1 dimer and weakens its chromatin association, likely by disabling the avidity effect conferred by the dimeric complex. Congruently, an EPOP mutant specifically defective in PRC2 binding enhances genome-wide enrichments of MTF2 and H3K27me3 in mouse epiblast-like cells. Elongin BC is largely dispensable for the EPOP-mediated inhibition of PRC2.1. EPOP defines a distinct subclass of PRC2.1, which uniquely maintains an epigenetic program by preventing the over-repression of key gene regulators along the continuum of early differentiation.

Partial Lipodystrophy Affecting the Extremities in a Young Woman With Autoimmune Polyglandular Syndrome 1.

Autoimmune polyglandular syndrome 1 (APS1) is an autosomal recessive disorder due to biallelic pathogenic variants in the autoimmune regulator (AIRE) gene that manifests with chronic mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. We report a 39-year-old woman with APS1 who developed partial lipodystrophy during adulthood. She presented with diaper rashes, oral thrush, and tetany during infancy due to candidiasis and hypoparathyroidism. During childhood, she developed hypothyroidism, primary adrenal insufficiency, and ovarian insufficiency. At age 14, she received a sibling-matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At age 35, her serum triglycerides were 914 mg/dL (10.32 mmol/L) and she had loss of subcutaneous fat from the upper and lower extremities and hips. A whole-body dual-energy x-ray absorptiometry revealed lower-extremity fat at less than the first percentile. Whole-exome sequencing on DNA extracted from saliva revealed pathogenic variants, p.Leu28Pro and p.Arg257* in AIRE but none in the known lipodystrophy genes. Phage-immunoprecipitation-sequencing revealed the presence of autoantibodies to MAGEB1, MAGEB4, and RFX6, which have been previously reported in APS1. Our case suggests that patients with APS1 may develop partial lipodystrophy due to autoantibodies against novel adipocyte-expressed proteins. A causal relationship of high levels of autoantibodies in our patient to adipose tissue-expressed ODC1, NUCKS1, or FNBP1L and lipodystrophy remains uncertain.

Increased Risk of Glaucoma in Fuchs Endothelial Corneal Dystrophy Is Independent of TCF4 Trinucleotide Repeat Expansion.

PURPOSE: The purpose of this study was to determine the prevalence of glaucoma and/or ocular hypertension (G/OHTN) in patients with Fuchs endothelial corneal dystrophy (FECD) and correlate with FECD severity and TCF4 cytosine-thymine-guanine18.1 (CTG18.1) trinucleotide repeat expansion genotype. METHODS: We included 167 FECD probands and 110 controls from the University of Texas Southwestern Medical Center FECD Genetics Study to estimate the association between FECD and G/OHTN. Participants underwent slit-lamp microscopy for the assessment of Krachmer grade disease severity of FECD. The diagnosis of G/OHTN was ascertained using a patient-reported history of G/OHTN, previous glaucoma surgery and/or glaucoma laser procedure, and use of glaucoma drops. Genomic DNA from blood of participants was used to genotype the CTG18.1 repeat polymorphism by fragment analysis using short tandem repeat and triplet repeat primed polymerase chain reaction assays. RESULTS: We observed a 19.2% prevalence of G/OHTN in the FECD probands compared with that of 7.3% in controls. The odds ratio of developing G/OHTN in FECD cases compared with controls was estimated to be 3.34 with a 95% confidence interval of 1.42-7.79 adjusting for age and sex. Among FECD cases, the likelihood of developing G/OHTN correlated positively with Krachmer grade (P = 0.043) and age (P = 0.026). There was no statistical difference of the proportions of patients developing G/OHTN between FECD cases with and without TCF4 CTG18.1 repeat expansion (16 out of 94 and 15 out of 72, respectively, P > 0.05). CONCLUSIONS: Patients with clinically significant FECD should be routinely monitored for the development of glaucoma regardless of their TCF4 repeat expansion genotype.

CT-Guided Microwave Ablation with Vertebral Augmentation for Spinal Metastases with Posterior Wall Defects.

Purpose: To evaluate the efficacy and safety of combined microwave ablation (MWA) and vertebral augmentation (VA) in the treatment of spinal metastases with posterior wall defects. Patients and Methods: A retrospective review was conducted for 67 patients (42 men, 25 women) with painful spine metastases and posterior wall defects who underwent MWA combined with VA. Among these patients, 52 vertebrae had no epidural invasion and 33 had mild invasion but did not compress the spinal cord. Procedural effectiveness was determined by comparing visual analog scale (VAS) scores and Oswestry disability index (ODI) scores before the procedure and during the follow-up period. Results: The procedure was technically successful in all patients. The mean VAS score declined significantly from 6.85 ± 1.81 before the procedure to 3.27 ± 1.97 at 24 h, 1.96 ± 1.56 at 1 week, 1.84 ± 1.50 at 4 weeks, 1.73 ± 1.45 at 12 weeks, and 1.71 ± 1.52 at 24 weeks post-procedure (p < 0.01). The mean ODI score was lower post-procedure than before the procedure (p < 0.001). Transient nerve injury occurred in two patients (SIR classification D), and the incidence of asymptomatic bone cement (SIR classification A) was 43.5% (37/85). Conclusion: MWA combined with VA is an effective and safe treatment for painful spine metastases with posterior wall defects.

New resorcylic acid derivatives of Lysimachia tengyuehensis against MRSA and VRE by interfering with bacterial metabolic imbalance.

The abuse of antibiotics leads to the rapid spread of bacterial resistance, which seriously threatens human life and health. Now, 8 resorcylic acid derivatives, including 4 new compounds (1-4) were isolated from Lysimachia tengyuehensis by bio-guided isolation, and they inhibited both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (MIC = 4-8 µg/mL). Notably, 1 and 2 rapidly killed MRSA and VRE within 40 min without drug resistance in 20 days. Mechanically, they potently disrupted biofilm and cell membrane by interfering with bacterial metabolic imbalance. The structure-activity relationship (SAR) revealed that the lipophilic long carbon chains (C-5/C-6) and hydrophilic hydroxyl/carboxyl groups were essential for the anti-MRSA and VRE bioactivity. Additionally, they effectively recovered MRSA-infected skin wounds and VRE-infected peritoneal in vivo. Resorcylic acid derivatives showed significant anti-MRSA and VRE bioactivity in vitro and in vivo with potential application for the first time.

Identification of FDA-approved drugs that induce heart regeneration in mammals.

Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.

Crystal Water in Minerals Modulates Oxygen Activation for Hydrogen Peroxide Photosynthesis.

Sunlight-responsive minerals contribute significantly to biogeochemical cycles by activating oxygen (O2) to generate reactive oxygen species (ROS). However, the role of crystal water, incorporated into minerals through hydration during rock cycles, in O2 activation remains largely unexplored. Here, we construct tungstite models containing oxygen vacancies to elucidate the modulation of mineral-based ROS dynamics by the synergy between oxygen vacancy and crystal water. Crystal water promotes the protonation process of superoxide anion radicals to produce hydrogen peroxide (H2O2) and alleviates its decomposition. This mineral-based H2O2 photosynthesis system efficiently eliminates organic pollutants in a sequential light-dark reaction. Furthermore, this synergy effect can extend to other metal oxide minerals such as TiO2, SnO2, CuO, ZnO, and Bi2O3. Our results illuminate an overlooked pathway for modulating the protonation process by immobilized water in hydrous minerals, playing a crucial role in ROS storage and migration and pollutant dynamics in a natural environment throughout the day/night cycle.

Lysozyme 1 Inflamed CCR2+ Macrophages Promote Obesity-Induced Cardiac Dysfunction.

BACKGROUND: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response. METHODS: In this study, we used single-cell RNA-sequencing analysis of Cd45+CD11b+F4/80+ cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2+ (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation. RESULTS: We find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity. CONCLUSIONS: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.

Analysis of blasting vibration duration considering frequency and energy and its application.

Blasting vibration's effect on ground vibration is essentially an energy transfer and transformation process (Hongtao et al., 2010) [1]. In engineering, the blasting vibration duration is often used as an objective index to evaluate the blasting vibration hazard. Thus, this study on the factors influencing blasting vibration duration is essential. In this study, the blasting vibration duration prediction formula uses frequency and energy as independent parameters, which are analysed using a statistical t probability distribution. With the blasting vibration duration prediction formula, the delay time taken for the structure to reach the resonance frequency is obtained by calculating the dominant frequency of the structure. The results indicate that the frequency and energy of the blasting vibration signal are highly correlated with the duration of blasting vibration, and their introduction as independent parameters in the prediction formula can better improve the prediction accuracy. The dominant frequency should not be neglected in blasting vibration safety evaluations, and the use of blasting vibration duration prediction to calculate the dominant frequency can better avoid the resonance phenomenon in the structure.

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome ß5 active-site (Pfß5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto ß7. Inhibition of Pfß5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the ß5/ß6/ß3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.

Association between Pre-operative Body Mass Index and Surgical Infection in Perihilar Cholangiocarcinoma Patients Treated with Curative Resection: A Multi-center Study.

Background: The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Methods: Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m2), normal BMI (18.5-24.9 kg/m2), and high BMI (≥25.0 kg/m2). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. Results: A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. Conclusions: The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.

Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

Construction and evaluation of a practical model for measuring health-adjusted life expectancy (HALE) in China.

BACKGROUND: HALE is now a regular strategic planning indicator for all levels of the Chinese government. However, HALE measurements necessitate comprehensive data collection and intricate technology. Therefore, effectively converting numerous diseases into the years lived with disability (YLD) rate is a significant challenge for HALE measurements. Our study aimed to construct a simple YLD rate measurement model with high applicability based on the current situation of actual data resources within China to address challenges in measuring HALE target values during planning. METHODS: First, based on the Chinese YLD rate in the Global Burden of Disease (GBD) 2019, Pearson correlation analysis, the global optimum method, etc., was utilized to screen the best predictor variables from the current Chinese data resources. Missing data for predictor variables were filled in via spline interpolation. Then, multiple linear regression models were fitted to construct the YLD rate measurement model. The Sullivan method was used to measure HALE. The Monte Carlo method was employed to generate 95% uncertainty intervals. Finally, model performances were assessed using the mean absolute error (MAE) and mean absolute percentage error (MAPE). RESULTS: A three-input-parameter model was constructed to measure the age-specific YLD rates by sex in China, directly using the incidence of infectious diseases, the incidence of chronic diseases among persons aged 15 and older, and the addition of an under-five mortality rate covariate. The total MAE and MAPE for the combined YLD rate were 0.0007 and 0.5949%, respectively. The MAE and MAPE of the combined HALE in the 0-year-old group were 0.0341 and 0.0526%, respectively. There were slightly fewer males (0.0197, 0.0311%) than females (0.0501, 0.0755%). CONCLUSION: We constructed a high-accuracy model to measure the YLD rate in China by using three monitoring indicators from the Chinese national routine as predictor variables. The model provides a realistic and feasible solution for measuring HALE at the national and especially regional levels, considering limited data.

Interaction energy flow paths analysis of PMSG-based wind power integrated systems during LVRT and its parameter adjustment strategy.

To solve the problem of oscillation instability in permanent magnetic synchronous generator (PMSG)-based wind power connected systems during low-voltage ride through (LVRT) process, a parameter adjustment strategy based on interaction energy path optimization is proposed in this paper. Firstly, a modular state-space model of PMSG under fault transient conditions is constructed, and the system is divided into five subsystems. Then, the dynamic energy function of subsystems reflecting the oscillation stability of the system is derived. Based on that, the dynamic energy flow path is described considering the introduction of LVRT control. On this basis, the interaction energy between LVRT control links and subsystems is analyzed, and the coupling mechanism of voltage support and damping characteristics in the LVRT process is explained. Further, aiming at the optimal change rate of the total interaction energy in the LVRT process, the adjustment strategy of LVRT control parameters is constructed to meet voltage and damping requirements. Finally, a PMSG-connected system model is built on the MATLAB/Simulink platform to verify the effectiveness of the adjustment strategy. The results show that the proposed method can effectively improve the damping level under the fault transient condition, as well as supporting system voltage.

Evaluation of the clinical application value of cytokine expression profiles in the differential diagnosis of prostate cancer.

BACKGROUND: The significance of tumor-secreted cytokines in tumor development has gained substantial attention. Nevertheless, the precise role of tumor-related inflammatory cytokines in prostate cancer (PCa) remains ambiguous. OBJECTIVES: To gain deeper insights into the inflammatory response in the process of PCa. METHODS: A total of 233 cases were collected, including 80 cases of prostate hyperplasia as disease control, 65 cases of postoperative prostate cancer and 36 cases of prostate cancer as PCa group. Additionally, 52 patients undergoing physical examinations during the same period were collected as the healthy control. The levels of 12 inflammatory cytokines in peripheral blood samples were analyzed using flow cytometric bead array technology. The levels of total prostate-specific antigen (TPSA) and free prostate-specific antigen (FPSA) in peripheral blood samples were analyzed using electrochemiluminescence technology. RESULTS: Our findings revealed significant increases in serum IL-8 levels in PCa group compared to the healthy control group. Additionally, IL-6, IL-10, IFN-γ and IL-12p70 levels were markedly elevated in the PCa group compared to the disease control group (all p < 0.05). Conversely, the level of IL-4, TNF-α, IL-1ß, IL-17A and IFN-α were lower in the PCa group compared to those in control group. Following surgery, the concentration of IL-6 decreased; whereas, the concentrations of IL-4, TNF-α, IL-17A, IL-1ß, IL-12p70, and IFN-α increased, demonstrating significant differences (p < 0.05). The differential upregulation of IL-6 or downregulation of IL-17A in peripheral blood exhibited diagnostic efficacy in PCa patients. Moreover, we observed a significant increase in IL-17A levels, accompanied by decreased of IL-2, IL-4, IL-10, TNF-a, IFN-γ, IL-1ß, and IL-12P70 in patients with distant metastasis. CONCLUSION: The peripheral blood cytokines are closely associated with the occurrence and development of prostate cancer, especially the serum levels of IL-6 and IL-17A may be useful as potential predictors of PCa diagnosis.

Construction of an exogenously and endogenously Co-activated DNA logic amplifier for highly reliable intracellular MicroRNA imaging.

DNA-based molecular amplifiers offer significant promise for molecular-level disease diagnosis and treatment, yet tailoring their activation for precise timing and localization remains a challenge. Herein, we've pioneered a dual activation strategy harnessing external light and internal ATP to create a highly controlled DNA logic amplifier (FDLA) for accurate miRNA monitoring in cancer cells. The FDLA was constructed by tethered the two functionalized catalytic hairpin assembly (CHA) hairpin modules (ATP aptamer sealed hairpin aH1 and photocleavable (PC-linker) sites modified hairpin pH2) to DNA tetrahedron (DTN). The FDLA system incorporates ATP aptamers and PC-linkers as logic control units, allowing them to respond to both exogenous UV light and endogenous ATP present within cancer cells. This response triggers the release of CHA hairpin modules, enabling amplified FRET miRNA imaging through an AND-AND gate. The DTN structure could improve the stability of FDLA and accelerate the kinetics of the strand displacement reaction. It is noteworthy that the UV and ATP co-gated DNA circuit can control the DNA bio-computing at specific time and location, offering spatial and temporal capabilities that can be harnessed for miRNA imaging. Furthermore, the miRNA-sensing FDLA amplifier demonstrates reliable imaging of intracellular miRNA with minimal background noise and false-positive signals. This highlights the feasibility of utilizing both exogenous and endogenous regulatory strategies to achieve spatial and temporal control of DNA molecular circuits within living cancer cells. Such advancements hold immense potential for unraveling the correlation between miRNA and associated diseases.

The subcommissural organ regulates brain development via secreted peptides.

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. Here, to explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3 and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely, thymosin beta 4, thymosin beta 10 and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.

Adducin Regulates Sarcomere Disassembly During Cardiomyocyte Mitosis.

BACKGROUND: Recent interest in understanding cardiomyocyte cell cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow the abscission of daughter cardiomyocytes. METHODS: Here, we use a proteomics screen to identify adducin, an actin capping protein previously not studied in cardiomyocytes, as a regulator of sarcomere disassembly. We generated many adeno-associated viruses and cardiomyocyte-specific genetic gain-of-function models to examine the role of adducin in neonatal and adult cardiomyocytes in vitro and in vivo. RESULTS: We identify adducin as a regulator of sarcomere disassembly during mammalian cardiomyocyte mitosis. α/γ-adducins are selectively expressed in neonatal mitotic cardiomyocytes, and their levels decline precipitously thereafter. Cardiomyocyte-specific overexpression of various splice isoforms and phospho-isoforms of α-adducin in vitro and in vivo identified Thr445/Thr480 phosphorylation of a short isoform of α-adducin as a potent inducer of neonatal cardiomyocyte sarcomere disassembly. Concomitant overexpression of this α-adducin variant along with γ-adducin resulted in stabilization of the adducin complex and persistent sarcomere disassembly in adult mice, which is mediated by interaction with α-actinin. CONCLUSIONS: These results highlight an important mechanism for coordinating cytoskeletal morphological changes during cardiomyocyte mitosis.

A Novel Subtype of Acquired Generalized Lipodystrophy Associated With Subcutaneous Panniculitis-Like T-cell Lymphoma.

Acquired generalized lipodystrophy (AGL) is an extremely rare disease that is characterized by loss of body fat affecting nearly all parts of the body. It is often associated with autoimmune diseases or panniculitis, whereas in other patients the underlying etiology is unclear. We report a 52-year-old male individual who was diagnosed with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) that spontaneously went into remission. Years later he developed new subcutaneous nodules most concerning for relapse SPTCL or lupus panniculitis, followed by onset of hemophagocytic lymphohistiocytosis (HLH) that was treated with allogeneic stem cell transplantation. Notably, around the same time, he also developed generalized subcutaneous fat loss of both upper and lower extremities, chest, abdomen, and face that persisted after treatment of the HLH. Whole exome sequencing was performed to search for pathogenic variants that are associated with SPTCL, including those in hepatitis A virus cellular receptor 2 (HAVCR2), but did not detect any potential disease-causing variant. Our report brings to the attention a novel subtype of panniculitis-variety of AGL. Whether generalized loss of subcutaneous fat in this patient is due to lymphoma-associated panniculitis or due to development of adipose tissue-directed autoantibodies as a paraneoplastic "autoimmune" manifestation of SPTCL remains unclear.

The subcommissural organ regulates brain development via secreted peptides.

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. To explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3, and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely thymosin beta 4, thymosin beta 10, and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.