Single-cell multiplex chromatin and RNA interactions in ageing human brain.

Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA1-3. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells4-7. Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and RNA-chromatin associations within individual nuclei. When applied to 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types and states. We observed that nuclei exhibiting fewer short-range chromatin interactions were correlated with both an 'older' transcriptomic signature and Alzheimer's disease pathology. Furthermore, the cell type exhibiting chromatin contacts between cis expression quantitative trait loci and a promoter tends to be that in which these cis expression quantitative trait loci specifically affect the expression of their target gene. In addition, female cortical cells exhibit highly heterogeneous interactions between XIST non-coding RNA and chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploration of chromatin architecture and transcription at cellular resolution in complex tissues.

Sleep Quality in Patients With Ocular Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.

OBJECTIVES: To investigate the sleep quality in patients with ocular graft-versus-host disease (oGVHD) compared with patients without oGVHD after allogeneic hematopoietic stem cell transplantation (alloHCT) and healthy controls. METHODS: This cross-sectional study analyzed 142 patients after alloHCT including 94 patients with oGVHD and 48 without. Fifty healthy controls were also enrolled. oGVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group (ICOGCG) criteria. Sleep quality was assessed by the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). Poor sleep quality was defined as CPQSI score greater than 6. RESULTS: Patients after alloHCT demonstrated a significantly higher CPQSI score than those of controls {7.0 [interquartile range (IQR) 5.0-10.0] vs. 5.5 [IQR 4.8-7.0], P =0.002}, especially in the oGVHD subgroup (7.5 [IQR 5.0-11.0] vs. 6.0 [IQR 5.0-8.0], P =0.04) with nearly double prevalence of poor sleep quality (58 [62%] vs. 18 [37%], P =0.006). Poor sleep quality was strikingly correlated with oGVHD diagnosis (adjusted odds ratio [OR]=2.55, 95% confidence interval [CI]: 1.02-6.34, P =0.04) and systemic immunosuppressants (adjusted OR=2.61, 95% CI: 1.32-5.71, P =0.02). Among the ocular parameters, poor sleep quality was significantly associated with higher ICOGCG score (adjusted OR=1.20, 95% CI: 1.03-1.39, P =0.02) and lower tear film break-up time (adjusted OR=0.85, 95% CI: 0.74-0.99, P =0.05). CONCLUSIONS: Poor sleep quality was associated with an increased severity of oGVHD and tear film instability in the long-term alloHCT survivorship.

The predictive value of atherogenic index of plasma for cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention with LDL-C below 1.8mmol/L.

BACKGROUND: The potential predictive significance of atherogenic index of plasma (AIP) for cardiovascular outcomes in patients with acute coronary syndrome (ACS) and who have undergone percutaneous coronary intervention (PCI), with low-density lipoprotein-cholesterol (LDL-C) below 1.8mmol/L, has not been well explored. METHODS: The retrospective cohort analysis included 1,133 patients with ACS and LDL-C levels below 1.8mmol/L who underwent PCI. AIP is calculated as log (triglyceride/high-density lipoprotein-cholesterol). Patients were divided into two groups according to the median value of AIP. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), a composite of all-cause death, nonfatal myocardial infarction, ischemic stroke or unplanned repeat revascularization. The association between AIP and the prevalence of MACCE was evaluated using multivariable Cox proportional hazard models. RESULTS: Over a median follow-up of 26 months, the incidence of MACCE was higher in the high AIP group compared to the low AIP group (9.6% vs. 6.0%, P log-rank = 0.020), and the difference was mainly derived from an increased risk of unplanned repeat revascularization (7.6% vs. 4.6%, P log-rank = 0.028). After adjusting for multiple variables, elevated AIP was independently associated with an increased risk of MACCE, regardless of whether AIP was considered a nominal or continuous variable (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.04-2.53 or HR 2.01, 95% CI 1.09-3.73). CONCLUSIONS: The present study demonstrates that AIP is a significant predictor of adverse outcomes in ACS patients undergoing PCI with LDL-C < 1.8mmol/L. These results suggest that AIP may offer supplementary prognostic information for ACS patients with optimally managed LDL-C levels.

Vision-specific and cancer-specific quality of life in ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

PURPOSE: To compare the vision-specific and cancer-specific quality of life (QOL) between patients with and without ocular graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS: This cross-sectional observational study analyzed 142 patients after alloHCT including 94 patients with oGVHD and 48 without. oGVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group (ICOGCG) criteria. QOL was assessed by using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). RESULTS: Compared with non-oGVHD patients, patients with oGVHD had worse vision-specific (NEI VFQ-25: 64.3 ± 20.3 vs. 77.6 ± 19.3, P < 0.001) and cancer-specific (EORTC QLQ-C30: 59.9 ± 20.3 vs. 67.4 ± 17.5, P = 0.03) QOL, as well as impaired cognitive function (72.7 ± 22.1 vs. 82.3 ± 19.0, P = 0.01). The vision-specific QOL was significantly correlated with ICOGCG score (ß = - 1.88, 95%CI: - 3.35 to - 0.41, P = 0.01) and post-alloHCT medical expense (ß = - 5.70, 95%CI: - 10.35 to - 1.05, P = 0.02), while cancer-specific QOL was strikingly correlated with post-alloHCT medical expense (ß = - 9.91, 95%CI: - 14.43 to - 5.39, P < 0.001), frequency of ophthalmic medication (ß = - 0.93, 95%CI: - 1.64 to - 0.21, P = 0.01), education (ß = - 6.97, 95%CI: - 13.31 to - 0.62, P = 0.03), and peripheral blood stem cell use (ß = - 6.42, 95%CI: - 12.59 to - 0.25, P = 0.04). CONCLUSIONS: Patients with oGVHD experienced significant impairment in both vision-specific and cancer-specific QOL including cognitive function when compared with those without after alloHCT. Multidimensional QOL assessment should be included in the long-term alloHCT survivorship care.

Heterointerface Engineered Core-Shell Fe2O3@TiO2 for High-Performance Lithium-Ion Storage.

The rational design of the heterogeneous interfaces enables precise adjustment of the electronic structure and optimization of the kinetics for electron/ion migration in energy storage materials. In this work, the built-in electric field is introduced to the iron-based anode material (Fe2O3@TiO2) through the well-designed heterostructure. This model serves as an ideal platform for comprehending the atomic-level optimization of electron transfer in advanced lithium-ion batteries (LIBs). As a result, the core-shell Fe2O3@TiO2 delivers a remarkable discharge capacity of 1342 mAh g-1 and an extraordinary capacity retention of 82.7% at 0.1 A g-1 after 300 cycles. Fe2O3@TiO2 shows an excellent rate performance from 0.1 A g-1 to 4.0 A g-1. Further, the discharge capacity of Fe2O3@TiO2 reached 736 mAh g-1 at 1.0 A g-1 after 2000 cycles, and the corresponding capacity retention is 83.62%. The heterostructure forms a conventional p-n junction, successfully constructing the built-in electric field and lithium-ion reservoir. The kinetic analysis demonstrates that Fe2O3@TiO2 displays high pseudocapacitance behavior (77.8%) and fast lithium-ion reaction kinetics. The capability of heterointerface engineering to optimize electrochemical reaction kinetics offers novel insights for constructing high-performance iron-based anodes for LIBs.

Prophylactic bilateral central neck dissection should be evaluated based on prospective randomized study of 581 PTC patients.

BACKGROUND: Prophylactic central lymph node dissection (PCND) was a basic consensus for patients with papillary thyroid carcinoma (PTC) in China. However, unilateral or bilateral central lymph node dissection (CND) was still controversial. This study aimed at investigating the safety and long-term benefit for the patients undergone with bilateral central lymph node dissection (BCCD). METHODS: 581 patients were enrolled and divided randomly into the test and control groups according to range of CND. 285 patients were prospectively assigned to undergo thyroid lobectomy plus BCND in the test group, other 296 patients were assigned to undergo thyroid lobectomy plus ipsilateral central lymph node dissection (ICND) in the control group. RESULTS: We found that the numbers of total LN and pN1a in the test group were more than that of the control group (p = 0.002,0.004), but there was no difference in the number of metastasized lymph nodes (p = 0.857) and tumor recurrence (p = 0.308). Additionally, in the aspect of postoperative complication (1 day after surgery), the serum levels of parathyroid hormone in the BCND group were lower than that in the ICND group (P = 0.010), and the numbers of transient laryngeal nerve palsy were more than that(p = 0.033). Meanwhile, we further found that pathological tumor size larger than 1 cm and tumor side lymph node metastasis were independent risk factors for contralateral central lymph node metastasis(p = 0.002,0.001). CONCLUSION: BCND may be an alternative for patients with tumor sizes larger than 1 cm, but it would significantly increase the rate of transient vocal cord palsy, parathyroid auto transplantation and decreased PTH, but the risk of permanent complications was similar to the ICND group.

Triglyceride-glucose index level and variability and outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention: an observational cohort study.

BACKGROUND: The associations between the long-term triglyceride-glucose (TyG) index level and variability and clinical outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) have not been well studied. METHODS: A total of 1,694 ACS patients with at least three postbaseline TyG index measurements within 2 years after PCI were included in the present study. The TyG index was defined as ln (fasting triglycerides [mg/dL] × fasting plasma glucose [mg/dL]/2). Multivariable-adjusted Cox proportional hazard models were used to examine the association between baseline and mean TyG index levels and TyG index variability and the risk of major adverse cardiovascular and cerebrovascular events (MACCEs). RESULTS: During the median follow-up of 31 months, the overall incidence of MACCE was 5.9%. Both high baseline and mean TyG index levels were independently associated with an increased risk of MACCEs after adjustment for multiple potential confounders (hazard ratio [HR) 1.76 95% confidence interval [CI] 1.06-2.93; and HR 2.73 95% CI 1.57-4.74). Similarly, higher TyG index variability by successive variation (SD) was well related to a higher prevalence of MACCEs (HR 2.17 95% CI 1.28-3.68). In addition, the mean TyG index level showed a stronger risk prediction for MACCEs than the baseline TyG index level and TyG index-SD (AUCs 0.618 vs 0.566 vs 0.566). CONCLUSIONS: The risk of MACCEs significantly increased with higher baseline and mean TyG index levels, as well as TyG index variability, in patients with ACS undergoing PCI. In particular, the mean TyG index level exhibited the highest predicting ability for MACCEs. Therefore, monitoring the long-term pattern of the TyG index deserves attention in clinical practice.

High-Resolution Mapping of Amino Acid Residues in DNA-Protein Cross-Links Enabled by Ribonucleotide-Containing DNA.

DNA-protein cross-links have broad applications in mapping DNA-protein interactions and provide structural insights into macromolecular structures. However, high-resolution mapping of DNA-interacting amino acid residues with tandem mass spectrometry remains challenging due to difficulties in sample preparation and data analysis. Herein, we developed a method for identifying cross-linking amino residues in DNA-protein cross-links at single amino acid resolution. We leveraged the alkaline lability of ribonucleotides and designed ribonucleotide-containing DNA to produce structurally defined nucleic acid-peptide cross-links under our optimized ribonucleotide cleavage conditions. The structurally defined oligonucleotide-peptide heteroconjugates improved ionization, reduced the database search space, and facilitated the identification of cross-linking residues in peptides. We applied the workflow to identifying abasic (AP) site-interacting residues in human mitochondrial transcription factor A (TFAM)-DNA cross-links. With sub-nmol sample input, we obtained high-quality fragmentation spectra for nucleic acid-peptide cross-links and identified 14 cross-linked lysine residues with the home-built AP_CrosslinkFinder program. Semi-quantification based on integrated peak areas revealed that K186 of TFAM is the major cross-linking residue, consistent with K186 being the closest (to the AP modification) lysine residue in solved TFAM:DNA crystal structures. Additional cross-linking lysine residues (K69, K76, K136, K154) support the dynamic characteristics of TFAM:DNA complexes. Overall, our combined workflow using ribonucleotide as a chemically cleavable DNA modification together with optimized sample preparation and data analysis offers a simple yet powerful approach for mapping cross-linking sites in DNA-protein cross-links. The method is amendable to other chemical or photo-cross-linking systems and can be extended to complex biological samples.

Synthesis of substituted 2H-chromenes catalyzed by lipase immobilized on magnetic multiwalled carbon nanotubes.

Porcine pancreas lipase (PPL) was immobilized on magnetic multiwalled carbon nanotubes successfully for the synthesis of substituted 2H-chromenes. The catalytic activity of immobilized PPL was much higher than that of free PPL. Effects of reaction medium, temperature, and enzyme dosage were also investigated. Under optimum reaction conditions (acetylacetone (1 mmol), salicylaldehyde (1 equivalent), methanol (10 equivalent), and immobilized PPL (protein content: 30 mg; 65 °C; DMF 5 mL; 5 H), the immobilized PPL showed an excellent catalytic performance on the synthesis of substituted 2H-chromenes. Moreover, the immobilized PPL exhibited satisfactory thermostability, operational simplicity, and reusability in this reaction.

Characterization of a major quantitative trait locus on the short arm of chromosome 4B for spike number per unit area in common wheat (Triticum aestivum L.).

KEY MESSAGE: An InDel marker closely linked with a major and stable quantitative trait locus (QTL) on chromosome 4BS, QSnpa.cau-4B, controlling spike number per unit area will benefit wheat yield improvement. Spike number per unit area (SNPA) is an essential yield-related trait, and analyzing its genetic basis is important for cultivar improvement in wheat (Triticum aestivum L.). In this study, we used the F2 population derived from a cross between two wheat accessions displaying significant differences in SNPA to perform quantitative trait locus (QTL) analysis. Through bulked segregant analysis, a major and stable QTL that explained 18.11-82.11% of the phenotypic variation was identified on chromosome 4BS. The QTL interval was validated using F4:5 and F6:7 families and narrowed it to a 24.91-38.36 Mb region of chromosome 4BS according to the 'Chinese Spring' reference genome sequence. In this region, variations in 16 genes caused amino acid changes and three genes were present in only one parent. Among these, we annotated a gene orthologous to TB1 in maize (Zea mays), namely TraesCS4B01G042700, which carried a 44-bp deletion in its promoter in the higher-SNPA parent. An InDel marker based on the insertion/deletion polymorphism was designed and used to diagnose the allelic distribution within a natural population. The frequency of the 44-bp deletion allele associated with higher SNPA was relatively low (13.24%), implying that this favorable allele has not been widely utilized and could be valuable for wheat yield improvement. In summary, we identified a major and stable QTL for SNPA and developed a diagnostic marker for the more-spiked trait, which will be beneficial for molecular-assisted breeding in wheat.

Identification of differentially expressed genes in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease that affects exocrine glands. To study the molecular mechanism and identify crucial genes/pathways in pSS pathogenesis, the microarray-based whole-genome gene expression profiles from salivary glands of patients with pSS and non-sicca controls were retrieved. After normalization and subsequent batch effect adjustment, significance analysis of microarrays method was applied to five available datasets, and 379 differentially expressed genes (DEGs) were identified. The 300 upregulated DEGs were enriched in Gene Ontology terms of immune and inflammatory responses, including antigen processing and presentation, interferon-mediated signaling pathway, and chemotaxis. Previously reported pSS-associated genes, including HLA-DRA, TAP2, PRDM1, and IFI16, were found to be significantly upregulated. The downregulated DEGs were enriched in pathways of salivary secretion, carbohydrate digestion and absorption, and starch and sucrose metabolism, implying dysfunction of salivary glands during pathogenesis. Next, a protein-protein interaction network was constructed, and B2M, an upregulated DEG, was shown to be a hub, suggesting its potential involvement in pSS development. In summary, we found the activation of pSS-associated genes in pathogenesis, and provide clues for salivary glands dysfunction. Experimental investigation on the identified DEGs in this study will deepen our understanding on pSS.

A Novel Technology for Localization of Parathyroid Adenoma: Ultrasound-Guided Fine Needle Aspiration Combined With Rapid Parathyroid Hormone Detection and Nano-Carbon Technology.

OBJECTIVE: The study aims to evaluate the clinic feasibility of rapid parathyroid hormone (PTH) detection and nano-carbon technology in preoperative diagnosis and localization of parathyroid adenoma. METHODS: With the guidance of ultrasound, the operator performed the parathyroid puncture and tested the PTH value by using a PTH test kit, and then injected nano-carbon into parathyroid adenoma as a marker to observe whether the parathyroid adenoma was stained black during the final operation. Meanwhile, a part of excised specimen was made into homogenate and detected rapidly again by using the PTH test kit. The remaining was confirmed by intraoperative frozen pathological examination. RESULT: The sensitivity (12/12) of preoperative diagnosis was significantly higher than that of ultrasound (6/12), magnetic resonance imaging (7/12), and MIBI (9/12). During the operation, we found that the inner part of the parathyroid adenoma was stained black, and the PTH value of the specimen homogenate confirmed as parathyroid adenoma was more than 3000 pg/mL. CONCLUSION: This novel technology, as a very positive method for localization of parathyroid adenoma, plays an important role in guaranteeing the surgical reliability of parathyroid adenoma with help of nano-carbon technology.

Modified Tumescent Solution for Creating Working Space During Endoscopic Thyroidectomy.

OBJECTIVE: To study the feasibility of gas-liquid mixing tumescent solution for creating a working space (WS) in endoscopic thyroidectomy (ET). MATERIALS AND METHODS: A prospective study was performed on 186 patients with thyroid tumor who had undergone ET via chest and breast approach. Patients were randomly divided into 2 groups to receive traditional tumescent solution as group A and modified tumescent solution (gas-liquid mixing tumescent solution) as group B. This study compares the following surgical outcome parameters between the 2 groups, including changes of blood pressure, heart rate, and oxygen saturation before and after creating a WS, time for creating a WS, operative time, hemorrhage volume for creating a WS, overall hemorrhage volume, overall postoperative drainage volume, postoperative pain score, postoperative hospitalization, number of retrieved lymph nodes, total serum calcium, serum parathyroid hormone, and cases of transient and permanent recurrent laryngeal nerve palsy. RESULTS: No postoperative bleeding, permanent recurrent laryngeal nerve palsy, incision and surgical site infection, air embolism, flap injury occurred in both groups. The mean time for creating a WS and the whole operation in group B was significantly shorter than that in group A ( P < .05). There were no statistically significant differences in both groups in terms of other observation index ( P > .05). CONCLUSION: The clinical application of gas-liquid mixing tumescent solution can effectively reduce the time for creating a WS and whole operative time, and worthy of being widely used in ET as a safe and effective technique.

[Clinical utility of needlescopic in hemithyroidectomy and central neck dissection through bilateral breast approach].

OBJECTIVE: To study application of needlescopic assisted hemithyroidectomy and central neck dissection using bilateral breast approach. METHODS: Totally 145 cases of papillary thyroid cancer patients received endoscopic hemithyroidectomy in Fujian Medical University Union Hospital were randomized to needle assisted endoscopic group (NE group, n=81) and conventional endoscopic group (CE group, n=64). The average age of the patients was 35.9 years and 11 patients were male.All patients underwent hemithyroidectomy and central neck dissection through bilateral breast approach, the NE group additional used the MiniLap-assisted intraoperation.The operative time, postoperative complications and cosmetic results were analyzed by t-test and χ(2) test. RESULTS: The operation time of thyroid gland in NE and CE Group was (42±7) min and (31±7) min(t=9.082, P=0.000), respectively. The operation time of central neck dissection was (33±6) min and (26±3) min (t=9.050, P=0.000), respectively.There were 4 cases occurs transient recurrent laryngeal nerve paralysis in CE group and no case occur in NE group(χ(2)=5.206, P=0.036). There was no significant different in other postoperative complications and cosmetic results. CONCLUSIONS: Hemithyroidectomy and central neck dissection using bilateral breast approach and needlescopic assisted technique isa safe and reliable approach, with high cosmetic effect. Application needle assistive devices can shorten the operation time while no significant increase trauma in patients, it will makes endoscopic thyroid surgery easier to promote.

Mitochondrial transcription factor A (TFAM) has 5'-deoxyribose phosphate lyase activity in vitro.

Mitochondrial DNA (mtDNA) plays a key role in mitochondrial and cellular functions. mtDNA is maintained by active DNA turnover and base excision repair (BER). In BER, one of the toxic repair intermediates is 5'-deoxyribose phosphate (5'dRp). Human mitochondrial DNA polymerase γ has weak dRp lyase activities, and another known dRp lyase in the nucleus, human DNA polymerase ß, can also localize to mitochondria in certain cell and tissue types. Nonetheless, whether additional proteins have the ability to remove 5'dRp in mitochondria remains unknown. Our prior work on the AP lyase activity of mitochondrial transcription factor A (TFAM) has prompted us to examine its ability to remove 5'dRp residues in vitro. TFAM is the primary DNA-packaging factor in human mitochondria and interacts with mitochondrial DNA extensively. Our data demonstrate that TFAM has the dRp lyase activity with different DNA substrates. Under single-turnover conditions, TFAM removes 5'dRp residues at a rate comparable to that of DNA polymerase (pol) ß, albeit slower than that of pol λ. Among the three proteins examined, pol λ shows the highest single-turnover rates in dRp lyase reactions. The catalytic effect of TFAM is facilitated by lysine residues of TFAM via Schiff base chemistry, as evidenced by the observation of dRp-lysine adducts in mass spectrometry experiments. The catalytic effect of TFAM observed here is analogous to the AP lyase activity of TFAM reported previously. Together, these results suggest a potential role of TFAM in preventing the accumulation of toxic DNA repair intermediates.

Associations Between Life's Essential 8 and Insulin Resistance Among Nondiabetic Adults.

BACKGROUND: Insulin resistance (IR) is closely linked to cardiometabolic diseases. Preventing and improving IR in nondiabetic populations is critically important. We aimed to investigate the relationship between Life's Essential 8 (LE8), the latest tool from the American Heart Association quantifying cardiovascular health, and IR among nondiabetic populations in the United States. METHODS AND RESULTS: This cross-sectional study used data on 11 246 nondiabetic adults aged ≥20 years from the 2005 to 2018 the National Health and Nutrition Examination Survey. The LE8 score was classified into 2 subscale scores: health factor score and health behavior score. IR was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Weighted logistic and linear regression models analyzed associations among the LE8 score, health behavior score, health factor score, and IR. Restricted cubic spline models assessed dose-response relationships. Adjusted subgroup analyses and inverse probability of treatment weighting method also evaluated the LE8-IR relationship. Of the 11 246 participants, 4860 (43.2%) had IR. The mean LE8 score was 70.07 (95% CI, 69.57-70.58). In fully adjusted models, higher LE8 scores were associated with lower IR odds (odds ratio per 10-unit increase, 0.57 [95% CI, 0.54-0.61]). Nonlinear LE8-IR dose-response was observed. Similar patterns were seen for health behavior and health factor subscores, with stronger IR correlations for health factors. The inverse LE8-IR association was significantly more pronounced among White participants and those with higher education, higher income, and without hypertension, cardiovascular disease, or chronic kidney disease. Significant negative LE8-IR associations persisted after inverse probability of treatment weighting. CONCLUSIONS: LE8 and subscale scores are negatively associated with IR in a nonlinear relationship. Promoting optimal cardiovascular health adherence may improve IR in nondiabetic populations.

USP15 promotes the progression of papillary thyroid cancer by regulating HMGB1 stability through its deubiquitination.

Purpose: Papillary thyroid cancer (PTC) stands as one of the most prevalent types of thyroid cancers, characterized by a propensity for in-situ recurrence and distant metastasis. The high mobility group protein (HMGB1), a conserved nuclear protein, plays a pivotal role in carcinogenesis by stimulating tumor cell growth and migration. Nevertheless, the underlying mechanism driving aberrant HMGB1 expression in PTC necessitates further elucidation. Materials and methods: Our study unraveled the impact of low and overexpression of USP15 on the proliferation, invasion, and metastasis of PTC cells. Through a comprehensive array of molecular techniques, we uncovered the intricate relationship between HMGB1 and USP15 in the progression of PTC. Results: In this study, we identified USP15, a deubiquitinase in the ubiquitin-specific proteases family, as a true deubiquitylase of HMGB1 in PTC. USP15 was shown to interact with HMGB1 in a deubiquitination activity-dependent manner, deubiquitinating and stabilizing HMGB1. USP15 depletion significantly decreased PTC cell proliferation, migration, and invasion. In addition, the effects induced by USP15 depletion could be rescued by further HMGB1 overexpression. But when HMGB1 is knocked down, even overexpression of USP15 could not promote the progression of PTC cells. Conclusion: In essence, our discoveries shed light on the previously uncharted catalytic role of USP15 as a deubiquitinating enzyme targeting HMGB1, offering a promising avenue for potential therapeutic interventions in the management of PTC.

Multimodal Technologies for Closed-Loop Neural Modulation and Sensing.

Existing methods for studying neural circuits and treating neurological disorders are typically based on physical and chemical cues to manipulate and record neural activities. These approaches often involve predefined, rigid, and unchangeable signal patterns, which cannot be adjusted in real time according to the patient's condition or neural activities. With the continuous development of neural interfaces, conducting in vivo research on adaptive and modifiable treatments for neurological diseases and neural circuits is now possible. In this review, current and potential integration of various modalities to achieve precise, closed-loop modulation, and sensing in neural systems are summarized. Advanced materials, devices, or systems that generate or detect electrical, magnetic, optical, acoustic, or chemical signals are highlighted and utilized to interact with neural cells, tissues, and networks for closed-loop interrogation. Further, the significance of developing closed-loop techniques for diagnostics and treatment of neurological disorders such as epilepsy, depression, rehabilitation of spinal cord injury patients, and exploration of brain neural circuit functionality is elaborated.

Single-cell multiplex chromatin and RNA interactions in aging human brain.

The dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA (caRNA) 1-3. Chromatin complex compositions change during cellular differentiation and aging, and are expected to be highly heterogeneous among terminally differentiated single cells 4-7. Here we introduce the Multi-Nucleic Acid Interaction Mapping in Single Cell (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression, and RNA-chromatin associations within individual nuclei. Applied to 14 human frontal cortex samples from elderly donors, MUSIC delineates diverse cortical cell types and states. We observed the nuclei exhibiting fewer short-range chromatin interactions are correlated with an "older" transcriptomic signature and with Alzheimer's pathology. Furthermore, the cell type exhibiting chromatin contacts between cis expression quantitative trait loci (cis eQTLs) and a promoter tends to be the cell type where these cis eQTLs specifically affect their target gene's expression. Additionally, the female cortical cells exhibit highly heterogeneous interactions between the XIST non-coding RNA and Chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploring chromatin architecture and transcription at cellular resolution in complex tissues.