Mechanistic insights into nucleosomal H2B monoubiquitylation mediated by yeast Bre1-Rad6 and its human homolog RNF20/RNF40-hRAD6A.

Histone H2B monoubiquitylation plays essential roles in chromatin-based transcriptional processes. A RING-type E3 ligase (yeast Bre1 or human RNF20/RNF40) and an E2 ubiquitin-conjugating enzyme (yeast Rad6 or human hRAD6A), together, precisely deposit ubiquitin on H2B K123 in yeast or K120 in humans. Here, we developed a chemical trapping strategy and successfully captured the transient structures of Bre1- or RNF20/RNF40-mediated ubiquitin transfer from Rad6 or hRAD6A to nucleosomal H2B. Our structures show that Bre1 and RNF40 directly bind nucleosomal DNA, exhibiting a conserved E3/E2/nucleosome interaction pattern from yeast to humans for H2B monoubiquitylation. We also find an uncanonical non-hydrophobic contact in the Bre1 RING-Rad6 interface, which positions Rad6 directly above the target H2B lysine residue. Our study provides mechanistic insights into the site-specific monoubiquitylation of H2B, reveals a critical role of nucleosomal DNA in mediating E3 ligase recognition, and provides a framework for understanding the cancer-driving mutations of RNF20/RNF40.

Myeloma extracellular vesicle-derived RAGE increases inflammatory responses and myotube atrophy in multiple myeloma through activation of the TLR4/NF-κB p65 pathway.

Sarcopenia manifests as muscle atrophy and loss that is complicated with malignancy. This study explored the mechanism of extracellular vesicles (EVs) in multiple myeloma (MM) with sarcopenia. SP2/0 conditioned medium (CM) was collected to isolate SP2/0-EVs. C2C12 cells were incubated with SP2/0 CM or SP2/0-EVs. ROS, TNF-α, IL-6, MuRF1 and MyHC levels were detected by DCF-DA fluorescent probe, ELISA, and Western blot. GW4869 was used to inhibit EV secretion in SP2/0 to confirm its effect on muscle atrophy. Serum was collected from MM patients with or without sarcopenia to detect RAGE mRNA expression. SP2/0 cells were transfected with RAGE siRNA and C2C12 cells were treated with the isolated si-RAGE-EVs or/and TLR4 agonist. SP2/0 tumor-bearing mouse model was established. Healthy mice and SP2/0-tumor bearing mice were treated with SP2/0-EVs or si-RAGE-EVs. SP2/0 CM or SP2/0-EVs stimulated ROS, inflammatory responses, and myotube atrophy in C2C12 cells. GW4869 blocked EV secretion and the effects of SP2/0 CM. RAGE mRNA expression in serum EVs was increased in MM&Sarcopenia patients and RAGE knockdown in SP2/0-EVs partially nullified SP2/0-EVs' effects. SP2/0-EVs activated the TLR4/NF-κB p65 pathway by translocating RAGE. SP2/0-EVs-derived RAGE elevated ROS production, inflammation, and myotube atrophy in C2C12 cells and caused muscle loss in SP2/0 tumor-bearing mice by activating the TLR4/NF-κB p65 pathway. SP2/0-EVs partially recapitulated muscle loss in healthy mice. SP2/0-EVs-derived RAGE increased ROS production, inflammation, and myotube atrophy in MM through TLR4/NF-κB p65 pathway activation.

KIAA1429 increases FOXM1 expression through YTHDF1-mediated m6A modification to promote aerobic glycolysis and tumorigenesis in multiple myeloma.

OBJECTIVE: Multiple myeloma (MM) is a deadly plasma cell malignancy with elusive pathogenesis. N6-methyladenosine (m6A) is critically engaged in hematological malignancies. The function of KIAA1429, the largest component of methyltransferases, is unknown. This study delved into the mechanism of KIAA1429 in MM, hoping to offer novel targets for MM therapy. METHODS: Bone marrow samples were attained from 55 MM patients and 15 controls. KIAA1429, YTHDF1, and FOXM1 mRNA levels were detected and their correlation was analyzed. Cell viability, proliferation, cell cycle, and apoptosis were testified. Glycolysis-enhancing genes (HK2, ENO1, and LDHA), lactate production, and glucose uptake were evaluated. The interaction between FOXM1 mRNA and YTHDF1, m6A-modified FOXM1 level, and FOXM1 stability were assayed. A transplantation tumor model was built to confirm the mechanism of KIAA1429. RESULTS: KIAA1429 was at high levels in MM patients and MM cells and linked to poor prognoses. KIAA1429 knockdown restrained MM cell viability, and proliferation, arrested G0/G1 phase, and increased apoptosis. KIAA1429 mRNA in plasma cells from MM patients was positively linked with to glycolysis-enhancing genes. The levels of glycolysis-enhancing genes, glucose uptake, and lactate production were repressed after KIAA1429 knockdown, along with reduced FOXM1 levels and stability. YTHDF1 recognized KIAA1429-methylated FOXM1 mRNA and raised FOXM1 stability. Knockdown of YTHDF1 curbed aerobic glycolysis and malignant behaviors in MM cells, which was nullified by FOXM1 overexpression. KIAA1429 knockdown also inhibited tumor growth in animal experiments. CONCLUSION: KIAA1429 knockdown reduces FOXM1 expression through YTHDF1-mediated m6A modification, thus inhibiting MM aerobic glycolysis and tumorigenesis.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Analysis of the efficacy of separation surgery for severe neurological compression in multiple myeloma: a retrospective analysis of 35 cases.

PURPOSE: To investigate the effectiveness and safety of separation surgery for Epidural Spinal Cord Compression (ESCC) graded ≥ 2 in patients with Multiple Myeloma (MM), analyze factors influencing surgical outcomes, and develop a preliminary treatment decision framework for these patients. METHODS: A retrospective analysis was conducted on clinical data from 35 MM patients who underwent separation surgery for ESCC graded ≥ 2 between 2013 and 2018. Patient data, including baseline information, surgical details, complications, and pre-operative as well as one-month post-operative efficacy evaluation indicators were recorded. Statistical analysis was performed on pre-operative and post-operative efficacy indicators to determine if there were significant improvements (p < 0.05). Ordered logistic regression was utilized to assess factors associated with an unfavorable post-operative quality of life outcome. RESULTS: Compared to pre-operative values, at one-month post-surgery, patients showed significant improvements in Frankel Score Classification (4 vs 5, p < 0.05), Karnofsky Performance Score (30 vs 70, p < 0.05), and Visual Analogue Scale (8 vs 3, p < 0.05). Complications occurred in 7 cases (20%). The number of segments with ESCC (OR = 0.171, p < 0.05) and pre-operative chemotherapy (OR = 5.202, p = 0.05) were identified as independent factors influencing patient outcomes. Patients with more than two vertebral segments with ESCC exhibited significantly worse post-operative conditions. CONCLUSIONS: Separation surgery effectively alleviates pain, improves neurological function, and enhances the quality of life in patients with ESCC graded ≥ 2 due to MM.

Which factors are associated with adverse prognosis in multiple myeloma patients after surgery? - preliminary establishment and validation of the nomogram.

BACKGROUND: To investigate the prognosis of patients with Multiple Myeloma (MM) after surgery, analyze the risk factors leading to adverse postoperative outcomes, and establish a nomogram. METHODS: Clinical data from 154 patients with MM who underwent surgery at our institution between 2007 and 2019 were retrospectively analyzed. Assessing and comparing patients' pain levels, quality of life, and functional status before and after surgery (P < 0.05) were considered statistically significant. The Kaplan-Meier survival curve was used to estimate the median survival time. Adverse postoperative outcomes were defined as worsened symptoms, lesion recurrence, complication grade ≥ 2, or a postoperative survival period < 1 year. Logistic regression analysis was used to determine the prognostic factors. Based on the logistic regression results, a nomogram predictive model was developed and calibrated. RESULTS: Postoperative pain was significantly alleviated in patients with MM, and there were significant improvements in the quality of life and functional status (P < 0.05). The median postoperative survival was 41 months. Forty-nine patients (31.8%) experienced adverse postoperative outcomes. Multivariate logistic regression analysis identified patient age, duration of MM, International Staging System, preoperative Karnofsky Performance Status, and Hb < 90 g/L as independent factors influencing patient prognosis. Based on these results, a nomogram was constructed, with a C-index of 0.812. The calibration curve demonstrated similarity between the predicted and actual survival curves. Decision curve analysis favored the predictive value of the model at high-risk thresholds from 10% to-69%. CONCLUSION: This study developed a nomogram risk prediction model to assist in providing quantifiable assessment indicators for preoperative evaluation of surgical risk.

Visible-Light-Mediated Activation of Remote C(sp3)-H Bonds by Carbon-Centered Biradical via Intramolecular 1,5- or 1,6-Hydrogen Atom Transfer.

In this study, we introduce a novel intramolecular hydrogen atom transfer (HAT) reaction that efficiently yields azetidine, oxetane, and indoline derivatives through a mechanism resembling the carbon analogue of the Norrish-Yang reaction. This process is facilitated by excited triplet-state carbon-centered biradicals, enabling the 1,5-HAT reaction by suppressing the critical 1,4-biradical intermediates from undergoing the Norrish Type II cleavage reaction, and pioneering unprecedented 1,6-HAT reactions initiated by excited triplet-state alkenes. We demonstrate the synthetic utility and compatibility of this method across various functional groups, validated through scope evaluation, large-scale synthesis, and derivatization. Our findings are supported by control experiments, deuterium labeling, kinetic studies, cyclic voltammetry, Stern-Volmer experiments, and density functional theory (DFT) calculations.

Chemical Synthesis of Post-Translationally Modified H2AX Reveals Redundancy in Interplay between Histone Phosphorylation, Ubiquitination, and Methylation on the Binding of 53BP1 with Nucleosomes.

The chemical synthesis of homogeneously modified histones is a powerful approach to quantitatively decipher how post-translational modifications (PTMs) modulate epigenetic events. Herein, we describe the expedient syntheses of a selection of phosphorylated and ubiquitinated H2AX proteins in a strategy integrating expressed protein hydrazinolysis and auxiliary-mediated protein ligation. These modified H2AX proteins were then used to discover that although H2AXS139 phosphorylation can enhance the binding of the DNA damage repair factor 53BP1 to either an unmodified nucleosome or that bearing a single H2AXK15ub or H4K20me2 modification, it augments 53BP1's binding only weakly to nucleosomes bearing both H2AXK15ub and H4K20me2. To better understand why such a trivalent additive effect is lacking, we solved the cryo-EM structure (3.38 Å) of the complex of 53BP1 with the H2AXK15ub/S139ph_H4K20me2 nucleosome, which showed that H2AXS139 phosphorylation distorts the interaction interface between ubiquitin and 53BP1's UDR motif. Our study revealed that there is redundancy in the interplay of multiple histone PTMs, which may be useful for controlling the dynamic distribution of effector proteins onto nucleosomes bearing different histone variants and PTMs in a time-dependent fashion, through specific cellular biochemical events.

Intestinirhabdus alba gen. nov., sp. nov., a novel genus of the family Enterobacteriaceae, isolated from the gut of plastic-eating larvae of the Coleoptera insect Zophobas atratus.

A bacterial strain, BIT-B35T, was isolated from the gut of plastic-eating larvae of the Coleoptera insect Zophobas atratus. Its taxonomic position was determined by using a polyphasic approach. Cells were white-pigmented, Gram-stain-negative, motile short rods with terminal flagella. The 16S rRNA gene sequence (1411 bp) of strain BIT-B35T showed highest similarity (98.1%) to Escherichia fergusonii ATCC 35469T and Citrobacter koseri LMG 5519T. The results of phylogenetic analyses, based on the 16S rRNA gene, concatenated sequences of seven housekeeping genes (atpD, gyrB, infB, rpoB, pyrG, fusA and leuS) and genome sequences, placed strain BIT-B35T in a separate lineage among the family of Enterobacteriaceae. The major fatty acids were C16 : 0, C17 : 0 cyclo and C19 : 0 cyclo ω8c. The genomic DNA G+C content of strain BIT-B35T was 57.1 mol%. The chemotaxonomic data plus results of physiological and biochemical tests also distinguished strain BIT-B35T from members of other genera within the family Enterobacteriaceae. Therefore, strain BIT-B35T is considered to represent a novel species of a novel genus within the family Enterobacteriaceae, for which the name Intestinirhabdus alba gen. nov., sp. nov. is proposed. The type strain is BIT-B35T (=CGMCC 1.17042T=KCTC 72448T).

Distribution spectrum and clinical significance of glomerular exostosin (EXT1) deposits in PLA2R-positive membranous nephropathy.

BACKGROUND: The discovery of antigen phospholipase A2 receptor (PLA2R) in 2009 ushered in the antigen-based study of membranous nephropathy. The further putative antigen exostosin 1/2 (EXT1/2) was described in 2019. However, the distribution spectrum of glomerular EXT1 deposits in membranous nephropathy has not been fully elucidated. METHODS: We conducted a retrospective cohort study of biopsy-proven membranous nephropathy patients. Patients with complete baseline data and adequate tissue specimens were included in this study. Tests for glomerular expression of PLA2R and EXT1 and circulating anti-PLA2R antibodies were performed. Clinicopathological and outcome data were reviewed. RESULTS: We included 626 patients, namely, 487 (77.8%) PLA2R-positive patients and 54 (8.6%) EXT1-positive patients; 32 (5.1%) patients were dual-positive for PLA2R and EXT1 (PLA2R + /EXT1 +). A higher percentage of dual-positive patients had low C3 levels (P < 0.001) and were more likely to have autoimmune diseases (P = 0.013) than PLA2R-positive and EXT1-negative (PLA2R + /EXT1-) patients. Kidney biopsy findings revealed that there was a higher percentage of glomerular IgG1, IgG2, IgA, C4, and C1q deposits (P < 0.05), "full-house" staining (P < 0.001), and stronger intensity of C1q staining (P = 0.002) in PLA2R + /EXT1 + patients. Based on Kaplan-Meier analysis, a higher percentage of PLA2R + /EXT1 + patients exhibited partial or complete remission of proteinuria. Furthermore, EXT1-positive expression was a favourable predictor for proteinuria remission, whereas interstitial fibrosis/tubular atrophy was an unfavourable predictor. A complement C3 level < 0.79 g/L was independently associated with EXT1 positivity in PLA2R-positive membranous nephropathy. CONCLUSIONS: We describe a subgroup of PLA2R and EXT1 dual-positive patients. Patients in this subset exhibited more signs of autoimmunity and more frequent clinical remission. In PLA2R-positive membranous nephropathy, a complement C3 level < 0.79 g/L was independently associated with EXT1 positivity, which was a favourable predictor for proteinuria remission.

Deciphering behaviors of 6:2 chlorinated polyfluorinated ether sulfonate (alternative-PFOS) on anammox processes: Nitrogen removal efficiency and microbial adaptability.

This study investigates the behaviors and effects of F-53B, an alternative to perfluorooctane sulfonate on anaerobic ammonium oxidation (anammox) processes. Results showed that the nitrogen removal efficiency (NRE) reached 83.8 % at a F-53B concentration of 0.5 mg·L-1, while NRE decreased to 66.9 % with 5 mg·L-1 of F-53B. The defluorination rates of 17.8 % (0.5 mg·L-1) and 9.3 % (5 mg·L-1) were observed, respectively, suggesting the occurrence of F-53B degradation. The relative abundance of Ca. Kuenenia decreased from 26.1 % to 16.2 % with the F-53B concentration increasing from 0.5 mg·L-1 to 5 mg·L-1. Meanwhile, Denitratisoma was selectively enriched with a relative abundance of 40.7 % at an F-53B concentration of 0.5 mg·L-1. Ca. Kuenenia could reduce reactive oxygen species induced by F-53B to maintain the balance of oxidative stress. This study gains insight into the behaviors and metabolic mechanisms of F-53B in anammox consortia, suggesting the feasibility of anammox processes for industrial wastewater.

Identification and validation of a prognostic signature based on six immune-related genes for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy with high mortality and morbidity rates. Although the significant efficacy of immunotherapy is well established, it is only beneficial for a limited number of individuals with CRC. METHODS: Differentially expressed immune-related genes (DE-IRGs) were retrieved from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ImmPort databases. A prognostic signature comprising DE-IRGs was developed using univariate, LASSO, and multivariate Cox regression analyses. A nomogram integrating the independent prognostic factors was also developed. CIBERSORT was used to assess immune cell infiltration (ICI). Furthermore, wound-healing, colony formation, migration, and invasion assays were performed to study the involvement of ACTG1 in CRC. RESULTS: A signature including six DE-IRGs was developed. The overall survival (OS) rate was accurately estimated for TCGA and GSE38832 cohorts. The risk score (RS) of the signature was an independent factor for OS. Moreover, a nomogram encompassing age, RS, and pathological T stage accurately predicted the long-term OS probability of individuals with CRC. The high-risk group had an elevated proportion of patients treated with ICIs, including native B cells, relative to the low-risk group. Additionally, ACTG1 expression was upregulated, which supported the proliferation, migration, and invasion abilities of CRC cells. CONCLUSIONS: An immune-related prognostic signature was developed for predicting OS and for determining the immune status of individuals with CRC. The present study provides new insights into accurate immunotherapy for individuals with CRC. Moreover, ACTG1 may serve as a new immune biomarker.

Modified tibial cortex transverse transport for diabetic foot ulcers with Wagner grade ≥ II: a study of 98 patients.

Background: Diabetic foot ulcers constitute a substantial healthcare burden on a global scale and present challenges in achieving healing. Our objective was to assess the efficacy of modified tibial cortex transverse transport surgery in managing refractory diabetic foot ulcers. Methods: We retrospectively analyzed clinical data from 98 patients suffering from diabetic foot ulcers classified as Wagner grade ≥II who were admitted to our medical facility between January 2020 and June 2022. All the patients were treated by modified tibial cortex transverse transport surgery, wherein the osteotomy scope was reduced to two rectangular bone windows measuring 1.5cm × 1.5cm each. Record the patient's general information and ulcer healing time; ulcer area, ankle-brachial index, WIFi classification, and visual analogue scale before and 3 months following the surgical intervention. Results: The average duration of diabetes of 98 patients with diabetic foot ulcer was 20.22 ± 8.02 years, 52 patients had more than one toe gangrene on admission. The postoperative wound healing rate was 95.83% and the average healing time was 53.18 ± 20.18 days. The patients showed significant improvement in ankle-brachial index, WIFi classification, and visual analogue scale at 3 months postoperatively compared to preoperatively, with statistically significant differences (P< 0.05). Eight patients experienced complications, and the incidence of complications was 8.16%. Throughout the follow-up period, there were no instances of ulcer recurrence noted. Conclusion: Modified tibial cortex transverse transport surgery demonstrates effectiveness in the management of diabetic foot ulcers by enhancing lower limb microcirculation and facilitating the process of wound healing.

From Novice to Mastery: Learning Curve and Efficacy Analysis of Short-Term Spinal Cord Stimulation for Diabetic Foot Ulcers.

BACKGROUND: To analyze the learning curve of novices in mastering short-term Spinal Cord Stimulation (st-SCS) for diabetic foot, evaluating the efficacy, safety, and difficulty of this technique. METHODS: A retrospective review of diabetic foot patients treated with st-SCS at our hospital was conducted. All procedures were performed by the same physician and patients were sequentially numbered according to the order of surgery. Learning curves were plotted using segmented linear regression and cumulative sum curves based on surgery duration. Patients were divided into two groups according to the inflection points on the learning curve: the learning group and the mastery group. Pre- and post-operative efficacy indicators were recorded and compared, along with general patient data, perioperative parameters, and incidence of complications. RESULTS: A total of 36 patients were included. Significant improvements were observed post-st-SCS in ulcer size (from 7.00 cm2 to 4.00 cm2), visual analog scale (from 7.00 to 3.00), foot temperature (from 30.06°C to 32.37°C), and pittsburgh sleep quality index (from 14.42 to 8.36) (P<0.05). The physician could proficiently perform st-SCS after 9 cases. Surgery time was significantly shorter in the mastery group (1-9 cases) compared to the learning group (10-36 cases) (28.04 vs 43.56 min, P<0.05). There were no significant differences between the two groups in baseline data, improvement in efficacy indicators, or complications (P>0.05). CONCLUSIONS: St-SCS is beneficial for wound healing, pain relief, improving peripheral circulation, and improving sleep quality. Surgeons can master this simple and safe technique in about nine cases.

Correlation between initial alkaline phosphatase levels and overall survival in newly diagnosed multiple myeloma patients.

Background: Alkaline phosphatase (ALP) reflects changes in the condition of multiple myeloma (MM) patients to some extent. However, the relationship of ALP in MM remains uncertain. Our study aimed to determine the association between initial ALP levels and overall survival in newly diagnosed MM patients. Methods: Clinical data from 202 newly diagnosed MM patients at Beijing Chaoyang Hospital between 2012 and 2016 were collected. Baseline characteristics, disease progression staging, serum markers, and patient survival data were recorded. The cut-off value for ALP was calculated based on patient survival data, and patients were divided into groups. Differences in patients' 3- and 5-year survival rates, liver function, bone disease and other indicators among different groups were compared. Independent risk factors influencing newly diagnosed MM patients were identified using COX regression analysis. Results: Patients were categorized into three groups based on ALP cut-off points: Group 1 (ALP <70 U/L), Group 2 (ALP 70 to <120 U/L), and Group 3 (ALP ≥120 U/L). Significant differences were observed in lactate dehydrogenase, serum calcium, white blood cell count, hemoglobin, and liver function indicators (including alanine aminotransferase, aspartate aminotransferase, albumin, and γ-glutamyl transferase) among different ALP groups (P<0.05). ALP levels varied significantly among patients with different bone disease grades (P<0.05). Median survival times for Groups 1, 2, and 3 were 25, 52, and 31 months, respectively. Group 2 exhibited significantly higher 3-year survival compared to the other two groups (P=0.006), while no significant difference was observed in 5-year survival among the three groups (P=0.51). Age, International Staging System staging, aspartate aminotransferase, ß2-microglobulin, ALP grading, and severe bone disease were identified as independent factors influencing survival in newly diagnosed patients (P<0.05). Conclusions: ALP levels are correlated with the prognosis of MM patients, and an ALP range of 70 to <120 U/L reflects a better survival expectation.

Synovial sarcoma X breakpoint 1 protein uses a cryptic groove to selectively recognize H2AK119Ub nucleosomes.

The cancer-specific fusion oncoprotein SS18-SSX1 disturbs chromatin accessibility by hijacking the BAF complex from the promoters and enhancers to the Polycomb-repressed chromatin regions. This process relies on the selective recognition of H2AK119Ub nucleosomes by synovial sarcoma X breakpoint 1 (SSX1). However, the mechanism underlying the selective recognition of H2AK119Ub nucleosomes by SSX1 in the absence of ubiquitin (Ub)-binding capacity remains unknown. Here we report the cryo-EM structure of SSX1 bound to H2AK119Ub nucleosomes at 3.1-Å resolution. Combined in vitro biochemical and cellular assays revealed that the Ub recognition by SSX1 is unique and depends on a cryptic basic groove formed by H3 and the Ub motif on the H2AK119 site. Moreover, this unorthodox binding mode of SSX1 induces DNA unwrapping at the entry/exit sites. Together, our results describe a unique mode of site-specific ubiquitinated nucleosome recognition that underlies the specific hijacking of the BAF complex to Polycomb regions by SS18-SSX1 in synovial sarcoma.

Neuroimaging mechanisms in short-term heroin- and methamphetamine-abstinent users: Similarities and differences.

Heroin and methamphetamine cause great damage to individuals and society. However, numerous withdrawal mechanisms remain unidentified. In this study, 19 heroin short-term abstinent (HSTA) patients, 20 methamphetamine short-term abstinent (MSTA) patients, and 27 healthy controls (HCs) were scanned using multimodal magnetic resonance imaging. Degraded nodes of fiber tracts were identified using automated fiber quantification. Voxel- and surface-based morphometric measurements were performed to determine the gray matter volume and cortical thickness. The MSTA and HSTA groups had abnormal diffusion metrics in a variety of bilateral corticospinal tract (CST) and left superior longitudinal tract (SLT) nodes compared with the HC group. The MSTA patients reported more severely disrupted diffusion metrics in certain nodes of the bilateral anterior thalamic radiation and left inferior fronto-occipital tract than the HSTA patients. The MSTA and HSTA groups exhibited identical cortical damage in the fusiform and superior temporal gyri, as well as in the superior frontal gyrus, posterior cerebellum, and precentral gyrus. Extensive differences in gray matter lesions were observed between the MSTA and HSTA groups. Neuroimaging mechanisms of short-term abstinence may aid in the development of rehabilitation strategies.

Learning curve of tibial cortex transverse transport: a cumulative sum analysis.

OBJECTIVE: This study aimed to describe the learning curve of surgeons performing tibial cortex transverse transport (TTT) and explore its safety and effectiveness during the initial stages of surgeon's learning. METHODS: The clinical data of patients with diabetic foot ulcers classified as Wagner grade ≥ 2, who underwent TTT at our hospital from January 2020 to July 2021, were included in this retrospective analysis. The same physician performed all procedures. Patients were numbered according to the chronological order of their surgery dates. The cumulative sum and piecewise linear regression were used to evaluate the surgeon's learning curve, identify the cut-off point, and divide the patients into learning and mastery groups. A minimum follow-up period of 3 months was ensured for all patients. Baseline data, perioperative parameters, complications, and efficacy evaluation indicators were recorded and compared between the two groups. RESULTS: Sixty patients were included in this study based on the inclusion and exclusion criteria. After completing 20 TTT surgeries, the surgeon reached the cut-off point of the learning curve. Compared to the learning group, the mastery group demonstrated a significant reduction in the average duration of the surgical procedure (34.88 min vs. 54.20 min, P < 0.05) along with a notable decrease in intraoperative fluoroscopy (9.75 times vs. 16.9 times, P < 0.05) frequency, while no significant difference was found regarding intraoperative blood loss (P = 0.318). Of the patients, seven (11.7%) experienced complications, with three (15%) and four cases (10%) occurring during the learning phase and the mastery phase, respectively. The postoperative ulcer area was significantly reduced, and the overall healing rate was 94.8%. Significant improvements were observed in postoperative VAS, ABI, and WIFI classification (P < 0.05). There were no significant differences in the occurrence of complications or efficacy indicators between the learning and mastery groups (P > 0.05). CONCLUSION: Surgeons can master TTT after completing approximately 20 procedures. TTT is easy, secure, and highly efficient for treating foot ulcers. Furthermore, TTT's application by surgeons can achieve almost consistent clinical outcomes in the initial implementation stages, comparable to the mastery phase.

Case report: Giant atypical granular cell tumor of the median nerve.

Granular cell tumors are extremely uncommon soft tissue neoplasms that mostly occur in the head and neck regions. Granular cell tumors are generally benign, asymptomatic, and rarely involve the median nerve. Due to the lack of awareness about granular cell tumors, they are easily misdiagnosed and mistreated in primary hospitals. Here, we report a giant atypical granular cell tumor located on the median nerve, approximately 12 cm in size, with unusual symptoms of median nerve damage. Magnetic resonance imaging revealed a fusiform mass that was hyperintense on T2-weighted images and iso-hypointense on T1-weighted images. The mass was subsequently biopsied and found to be a granular cell tumor. The tumor was resected, and a pathological examination was performed. Pathological examination revealed necrotic foci, abundant eosinophilic granules, pustular ovoid bodies, and multiple mitoses. Immunohistochemical staining revealed that the tumor cells were positive for S-100, CD68, SMA, SOX-10, Calretinin, and TFE3. The integrated diagnosis was an atypical granular cell tumor. To the best of our knowledge, this is the first report of an atypical granular cell tumor involving the median nerve. Furthermore, we comprehensively reviewed the existing literature to provide a concise summary of the diagnostic criteria, imaging findings, and pathological features of granular cell tumors. Given the high recurrence and metastasis rates of this disease, granular cell tumors of the median nerve should be considered when a patient presents with symptoms of median nerve impairment. The diagnosis of atypical granular cell tumors relies on pathological examination. In addition, extensive resection and long-term follow-up are necessary to improve prognosis.

The Complement System in Metabolic-Associated Kidney Diseases.

Metabolic syndrome (MS) is a group of clinical abnormalities characterized by central or abdominal obesity, hypertension, hyperuricemia, and metabolic disorders of glucose or lipid. Currently, the prevalence of MS is estimated about 25% in general population and is progressively increasing, which has become a challenging public health burden. Long-term metabolic disorders can activate the immune system and trigger a low-grade chronic inflammation named "metaflammation." As an important organ involved in metabolism, the kidney is inevitably attacked by immunity disequilibrium and "metaflammation." Recently, accumulating studies have suggested that the complement system, the most important and fundamental component of innate immune responses, is actively involved in the development of metabolic kidney diseases. In this review, we updated and summarized the different pathways through which the complement system is activated in a series of metabolic disturbances and the mechanisms on how complement mediate immune cell activation and infiltration, renal parenchymal cell damage, and the deterioration of renal function provide potential new biomarkers and therapeutic options for metabolic kidney diseases.