Impaired autophagy-mediated macrophage polarization contributes to age-related hyposalivation.

Age-related dysfunction of salivary glands (SGs) leading to xerostomia or dry mouth is typically associated with increased dental caries and difficulties in mastication, deglutition or speech. Inflammaging-induced hyposalivation plays a significant role in aged SGs; however, the mechanisms by which ageing shapes the inflammatory microenvironment of SGs remain unclear. Here, we show that reduced salivary secretion flow rate in aged human and mice SGs is associated with impaired autophagy and increased M1 polarization of macrophages. Our study reveals the crucial roles of SIRT6 in regulating macrophage autophagy and polarization through the PI3K/AKT/mTOR pathway, as demonstrated by generating two conditional knock out mice. Furthermore, triptolide (TP) effectively rejuvenates macrophage autophagy and polarization via targeting this pathway. We also design a local delivery of TP-loaded apoptotic extracellular vesicles (ApoEVs) to improve age-related SGs dysfunction therapeutically. Collectively, our findings uncover a previously unknown link between SIRT6-regulated autophagy and macrophage polarization in age-mediated hyposalivation, while our locally therapeutic strategy exhibits potential preventive effects for age-related hyposalivation.

[Evaluation of a modified maxillary protraction appliance for the treatment of patients with skeletal Class â ¢ malocclusion associated with crowding].

PURPOSE: To investigate the efficacy of a modified maxillary protraction appliance in patients of skeletal Class Ⅲ with crowding. METHODS: Forty patients with skeletal Class Ⅲ malocclusion were divided into two groups, with 20 patients in each group. The experimental group had molar in a neutral or distal relationship and applied a modified maxillary protraction appliance, while the control group had molar mesial relationship and applied a conventional maxillary protraction appliance. Lateral cephalometric radiographs were taken before and after treatment in both groups for comparison. SPSS 22.0 software package was used for data analysis. RESULTS: The angle measurements taken before and after treatment showed a significant increase in SNA, ANB, SN-MP and U4-SN(P＜0.01), while SNB decreased(P＜0.01) in both groups. SN-OL changes were statistically different before and after treatment in the experimental group(P＜0.05). The sagittal measurements before and after treatment in both groups showed significant alterations in all(P＜0.05) but the length of the maxillary arch in both groups. For vertical measurements, U1-PP, L1-MP, U4-SN, U6-SN, and ANS-ME all increased (P＜0.05), while the changes of U4-PP and U6-PP in the two groups before and after treatment were statistically different(P＜0.05). Compared with the control group, the experimental group had a significantly increased maxillary arch length, a more remote location at U6, and a less variable molar relationship after treatment(P＜0.01). The two groups showed a variable amount of cephalometric measurements before and after treatment: the experimental group had a significant increase in maxillary arch length, a more remote position at U6, and a smaller change in molar relationship compared to the control group(P＜0.01). CONCLUSIONS: The modified maxillary protraction appliance showed good results for maxillary protraction and pushing the molar distally in patients with skeletal Class Ⅲ with crowding at neutral or distal molar relationship.

Diagnostic and Prognostic Value of Plasma lncRNA SRA1 in Chronic Heart Failure.

Background: The pathogenesis and development of chronic heart failure (CHF) may involve long non-coding ribonucleic acid (lncRNA) steroid receptor RNA activator 1 (SRA1), a known cardiomyopathy risk factor and regulator of cardiac myofibroblast activation. This study aimed to investigate the application of SRA1 in the early detection and prediction of CHF. Methods: SRA1 plasma expression was determined in CHF patients and healthy individuals/using real time-quantitative polymerase chain reaction (RT-qPCR). The diagnostic and prognostic value of SRA1 was assessed using receiver operating curve (ROC) and Cox regression analyses. Results: Compared with the healthy controls, the patients with CHF had increased brain natriuretic peptide (BNP) levels, left atrial end-systolic diameter (LAD), left ventricular end-diastolic diameter (LVDd), and decreased left ventricular ejection fraction (LVEF). SRA1 was significantly upregulated in CHF patients as well as positively correlated with BNP level, LAD, and LVDd, and negatively correlated with LVEF. SRA1 could sensitively discriminate CHF patients from healthy individuals and was an independent predictor of adverse event-free survival in CHF patients. Conclusions: Upregulated plasma SRA1 can discriminate patients with CHF from healthy individuals and predict adverse outcomes in CHF patients. Thus, SRA1 is a potential molecular indicator for monitoring chronic heart failure development.

The predictive value of albumin to alkaline phosphatase ratio for vertebral refractures in postmenopausal women.

INTRODUCTION: To investigate the clinical value of serum albumin to alkaline phosphatase ratio (AAPR) in predicting the risk of osteoporotic vertebral refractures group (OVRFs) after percutaneous vertebral augmentation (PVA) in postmenopausal women. MATERIALS AND METHODS: This is a retrospective case-control study including a series of postmenopausal women patients with osteoporotic vertebral fracture (OVF) and underwent PVA. Patients were divided into OVRFs and non-OVRFs. COX model was used to evaluate the correlation between preoperative AAPR and OVRFs after PVA. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were used to analyze the predictive value of AAPR for the incidence of OVRFs. RESULTS: A total of 305 patients were included in the final study, and the incidence of postoperative OVRFs was 28.9%. Multivariate COX analysis showed that advanced age (HRs = 1.062, p = 0.002), low BMI (HRs = 0.923, p = 0.036), low AAPR (HRs = 0.019, p = 0.001), previous fall history (HRs = 3.503, p = 0.001), denosumab treatment (HRs = 0.409, p = 0.007), low L3 BMD (HRs = 0.977, p = 0.001) and low L3 paravertebral muscle density (PMD)value (HRs = 0.929, p = 0.001)) were closely related to the incidence of OVRFs. The area under the curve (AUC) of AAPR for predicting OVRFs was 0.740 (p < 0.001), and the optimal diagnostic cut-off value was 0.49. Kaplan-Meier curve analysis showed that low AAPR group (< 0.49) was significantly associated with lower OVRFs-free survival (p = 0.001; log-rank test). CONCLUSION: AAPR is an independent risk factor for OVRFs after PVA in postmenopausal women, and it can be used as an effective index to predict OVRFs.

Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer.

Background: Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions. Materials and methods: A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions. Results: The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS. Conclusion: A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.

Regulatory T cells protect against diabetic cardiomyopathy in db/db mice.

AIMS/INTRODUCTION: Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM) using a db/db mouse model. MATERIALS AND METHODS: Eight-week-old male db/db mice were randomly divided into four groups: the control group, administered 200 µL phosphate-buffered saline; the small-dose Treg group, administered 105 Tregs; the large-dose Treg group, administered 106 Tregs; and the PC group, administered 100 µg anti-CD25 specific antibody (PC61) and 106 Tregs. After 12 weeks, mice were euthanized. Transthoracic echocardiography was carried out at the beginning and end of the experiment. Relevant basic experiments to evaluate the effects of Tregs on DCM were carried out. RESULTS: Echocardiography showed that the impaired diastolic and systolic functions were significantly improved in mice administered large-dose Tregs. Large-dose Tregs significantly ameliorated myocardial hypertrophy and fibrosis, and decreased hypertrophic gene expression and collagen deposition. The protective effects of Tregs on diabetic hearts were associated with decreased oxidative stress, inflammatory response and apoptosis. In addition, Tregs promoted the activation of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, whereas they inhibited extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase phosphorylation, which might be responsible for the cardioprotective role of Tregs against DCM. CONCLUSIONS: Tregs ameliorated myocardial hypertrophy and fibrosis, improved cardiac dysfunction, and protected against DCM progression in db/db mice. The mechanisms involved a decrease of inflammatory response, oxidative stress and apoptosis, which might be mediated by phosphatidylinositol 3-kinase-protein kinase B and mitogen-activated protein kinase pathways. Hence, Tregs might serve as a promising therapeutic approach for DCM treatment.

The efficacy of nutritional screening indexes in predicting the incidence of osteosarcopenia and major osteoporotic fracture in the elderly.

INTRODUCTION: The effect of nutritional status on osteosarcopenia (OS) and major osteoporotic fracture (MOF) among the elderly is still unclear. So we aimed to compare the efficacy of the Mini-Nutrition Assessment-Short Form (MNA-sf), the Geriatric Nutritional Risk Index (GNRI) and Controlling Nutritional Status (CONUT) for predicting OS and MOF among the elderly. MATERIALS AND METHODS: A total of 409 participants were enrolled in this prospective study. Blood biochemical indexes, nutritional status, and bone- and muscle-related examinations were assessed at initial visit to the outpatient. Participants were divided into 4 groups: (1) control; (2) osteopenia/osteoporosis; (3) sarcopenia; (4) osteosarcopenia, and then followed for 5 years, recording the occurrence time of MOF. RESULTS: The frequency values of osteopenia/osteoporosis, sarcopenia, and OS, at baseline, were respectively 13.4, 16.1, and 12% among the study samples. Correlation analysis showed that nutritional status scores were associated with body mass index, handgrip strength, albumin, bone mineral density, and physical functions. According to multivariate models, poor nutritional status was significantly associated with a higher risk of OS and MOF (P < 0.05). Survival analysis showed that the MOF rate in malnutrition group was significantly higher than normal nutrition group (P < 0.05). The receiver operator characteristic curve shows that the value of MNA-sf to diagnose OS and MOF is greater (P < 0.05). CONCLUSION: The poor nutritional status was associated with a higher risk of both OS and MOF. MNA-sf showed a superior diagnostic power for OS and MOF among the elderly. Early nutrition assessments and interventions may be key strategies to prevent OS and fractures.

Precise Modulation of the Coordination Environment of Single Cu Site Catalysts to Regulate the Peroxymonosulfate Activation Pathway for Water Remediation.

Single atom site catalysts (SACs) with atomically dispersed active sites can be expected to be potential ideal catalysts for accurately modulating the persulfate activation pathway during the water remediation process because of their well-defined structure and the maximum metallic atom utilization. In this paper, a series of Cu SACs with different coordination environments were synthesized to elaborately regulate the peroxymonosulfate activation pathway in AOPs to clarify active species generation and transformation in water remediation. The degradation rate constants (kobs) of Cu-N2, Cu-N3, and Cu-N4 were 0.028, 0.021, and 0.015 min-1, respectively. Cu-N2 SACs exhibited a noticeable enhanced performance for bisphenol A (BPA) removal from water compared to that of the Cu-Nx SACs (x = 3, 4), accompanied by peroxymonosulfate (PMS) activation pathway variation. As shown by experimental and theoretical results, the PMS activation pathway was transformed from ROS to electron transfer with nitrogen coordination numbers decreasing from 4 to 2, which can be ascribed to the uneven charge distribution of Cu sites as well as upshifts in the d-band center, and thereby optimized electron transfer for PMS activation. Furthermore, the increasing nitrogen vacancies of single Cu site catalysts can also result in more unoccupied 3d orbitals of Cu atoms in SACs, thereby improving the intermediates' (PMS and BPA) adsorption-desorption process and BPA removal performance. These findings provided a beneficial approach for the coordination number regulation of SACs in water remediation.

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

[The Efficacy and Safety of Venetoclax Combined with Azacitidine in the Treatment of Adult Patients with Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy].

OBJECTIVE: To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. METHODS: The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively. RESULTS: After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred. CONCLUSION: VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.

BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.

Vitamin D delays intervertebral disc degeneration and improves bone quality in ovariectomized rats.

Known to be involved in bone-cartilage metabolism, Vitamin D (VD) may play a role in human's disc pathophysiology. Given that postmenopausal women are prone to suffer VD deficiency and intervertebral disc degeneration (IDD), this study is intended to investigate whether VD can delay IDD in ovariectomized rats by improving bone microstructure and antioxidant stress. Female Sprague-Dawley rats were randomly allocated into four groups: sham, oophorectomy (OVX)+VD deficiency (VDD), OVX, and OVX+VD supplementation (VDS). In vivo, after a 6-month intervention, imaging and pathology slice examinations showed that IDD induced by OVX was significantly alleviated in VDS and deteriorated by VDD. The expressions of aggrecan and Collagen II in intervertebral disc were reduced by OVX and VDD, and elevated by VDS. Compared with the OVX+VDD and OVX group vertebrae, OVX+VDS group vertebrae showed significantly improved endplate porosity and lumbar bone mineral density with increased percent bone volume and trabecular thickness. Furthermore, 1α,25(OH)2D3 restored the redox balance (total antioxidant capacity, ratio of oxidized glutathione/glutathione) in the disc. The cocultivation of 1α,25(OH)2D3 and nucleus pulposus cells (NPCs) was conducted to observe its potential ability to resist excessive oxidative stress damage induced by H2O2. In vitro experiments revealed that 1α,25(OH)2D3 reduced the senescence, apoptosis, and extracellular matrix degradation induced by H2O2 in NPCs. In conclusion, VDS exhibits protective effects in OVX-induced IDD, partly by regulating the redox balance and preserving the microstructure of endplate. This finding provides a new idea for the prevention and treatment of IDD.

The Effects of Abdominal Obesity and Sagittal Imbalance on Sacroiliac Joint Pain After Lumbar Fusion.

BACKGROUND: Postoperative sacroiliac joint pain (SIJP) is a common manifestation of failed back surgery syndrome after a posterior lumbar interbody fusion (PLIF). However, there is currently no consensus on the risk factors for SIJP after PLIF. OBJECTIVES: We explored the effects of abdominal obesity and sagittal imbalance on SIJP after PLIF. STUDY DESIGN: This is a prospective observational cohort study. SETTING: This study occurred at the Department of Spinal Surgery at a hospital affiliated with a medical university. METHODS: A total of 401 patients who underwent PLIF from June 2018 to June 2021 were enrolled in this study. 36 patients experienced postoperative SIJP. In contrast, a matched group comprised 72 non-SIJP patients. We used 1:2 propensity score matching to compare obesity features and sagittal spine parameters in the 2 groups. Inflammatory cytokines and visual analog scale (VAS) scores were measured in the SIJP group. RESULTS: A total of 36 patients (8.98%) experienced SIJP during the follow-up. Compared with the non-SIJP group, patients with postoperative SIJP had a higher body mass index (BMI), greater abdominal obesity, a higher incidence of pelvic incidence-lumbar lordosis greater than 10°, and a higher incidence of a sagittal vertical axis greater than 5 cm (P < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve for waist circumference was greater than that for BMI (0.762 vs. 0.650, P = 0.049). Logistic regression analysis revealed that the risk factors for SIJP were abdominal obesity, a pelvic incidence-lumbar lordosis of greater than 10°, and a sagittal vertical axis greater than 5 cm (P < 0.05). In patients with SIJP, interleukin 6, tumor necrosis factor-α, and VAS scores were higher in the abdominal obesity group than in the non-abdominal obesity group (P < 0.05). LIMITATIONS: There was no uniform diagnosis of SIJP, so the incidence rate of SIJP might not be accurate. CONCLUSIONS: The significant predictors of SIJP were abdominal obesity and sagittal imbalance. Patients with abdominal obesity showed higher levels of inflammatory markers and pain intensity. More attention should be paid to body shape and the angle of correction of lumbar lordosis before lumbar surgery.

Molecular mechanisms of Chengshi Beixie Fenqing Decoction based on network pharmacology: pivotal roles of relaxin signaling pathway and its associated target proteins against Benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski's rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4'-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4'-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways.Communicated by Ramaswamy H. Sarma.

Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation.

CTCF plays an important role in 3D genome organization by adjusting the strength of chromatin insulation at TAD boundaries, where clustered CBS (CTCF-binding site) elements are often arranged in a tandem array with a complex divergent or convergent orientation. Here, using Pcdh and HOXD loci as a paradigm, we look into the clustered CTCF TAD boundaries and find that, counterintuitively, outward-oriented CBS elements are crucial for inward enhancer-promoter interactions as well as for gene regulation. Specifically, by combinatorial deletions of a series of putative enhancer elements in mice in vivo or CBS elements in cultured cells in vitro, in conjunction with chromosome conformation capture and RNA-seq analyses, we show that deletions of outward-oriented CBS elements weaken the strength of long-distance intra-TAD promoter-enhancer interactions and enhancer activation of target genes. Our data highlight the crucial role of outward-oriented CBS elements within the clustered CTCF TAD boundaries in developmental gene regulation and have interesting implications on the organization principles of clustered CTCF sites within TAD boundaries.

SARS-CoV-2 subgenomic RNA: formation process and rapid molecular diagnostic methods.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which caused coronavirus disease-2019 (COVID-19) is spreading worldwide and posing enormous losses to human health and socio-economic. Due to the limitations of medical and health conditions, it is still a huge challenge to develop appropriate discharge standards for patients with COVID-19 and to use medical resources in a timely and effective manner. Similar to other coronaviruses, SARS-CoV-2 has a very complex discontinuous transcription process to generate subgenomic RNA (sgRNA). Some studies support that sgRNA of SARS-CoV-2 can only exist when the virus is active and is an indicator of virus replication. The results of sgRNA detection in patients can be used to evaluate the condition of hospitalized patients, which is expected to save medical resources, especially personal protective equipment. There have been numerous investigations using different methods, especially molecular methods to detect sgRNA. Here, we introduce the process of SARS-CoV-2 sgRNA formation and the commonly used molecular diagnostic methods to bring a new idea for clinical detection in the future.

Identification and validation of ubiquitination-related signature and subgroups in immune microenvironment of tuberculosis.

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the bacterial pathogen responsible for causing tuberculosis (TB), a severe public health concern that results in numerous deaths worldwide. Ubiquitination (Ub) is an essential physiological process that aids in maintaining homeostasis and contributes to the development of TB. Therefore, the main objective of our study was to investigate the potential role of Ub-related genes in TB. METHODS: Our research entailed utilizing single sample gene set enrichment analysis (ssGSEA) in combination with several machine learning techniques to discern the Ub-related signature of TB and identify potential diagnostic markers that distinguish TB from healthy controls (HC). RESULTS: In summary, we used the ssGSEA algorithm to determine the score of Ub families (E1, E2, E3, DUB, UBD, and ULD). Notably, the score of E1, E3, and UBD were lower in TB patients than in HC individuals, and we identified 96 Ub-related differentially expressed genes (UbDEGs). Employing machine learning algorithms, we identified 11 Ub-related hub genes and defined two distinct Ub-related subclusters. Notably, through GSVA and functional analysis, it was determined that these subclusters were implicated in numerous immune-related processes. We further investigated these Ub-related hub genes in four TB-related diseases and found that TRIM68 exhibited higher correlations with various immune cells in different conditions, indicating that it may play a crucial role in the immune process of these diseases. CONCLUSION: The observed enrichment of Ub-related gene expression in TB patients emphasizes the potential involvement of ubiquitination in the progression of TB. These significant findings establish a basis for future investigations to elucidate the molecular mechanisms associated with TB, select suitable diagnostic biomarkers, and design innovative therapeutic interventions for combating this fatal infectious disease.

Lysosomal dysfunction in carbon black-induced lung disorders.

Carbon black (CB), a component of environmental particulate pollution derived from carbon sources, poses a significant threat to human health, particularly in the context of lung-related disease. This study aimed to investigate the detrimental effects of aggregated CB in the average micron scale on lung tissues and cells in vitro and in vivo. We observed that CB particles induced lung disorders characterized by enhanced expression of inflammation, necrosis, and fibrosis-related factors in vivo. In alveolar epithelial cells, CB exposure resulted in decreased cell viability, induction of cell death, and generation of reactive oxidative species, along with altered expression of proteins associated with lung disorders. Our findings suggested that the damaging effects of CB on the lung involved the targeting of lysosomes. Specifically, CB promoted lysosomal membrane permeabilization, while lysosomal alkalization mitigated the harmfulness of CB on lung cells. Additionally, we explored the protective effects of alkaloids derived from Nelumbinis plumula, with a focus on neferine, against CB-induced lung disorders. In conclusion, these findings contribute to a deeper understanding of the pathophysiological effects of CB particles on the lungs and propose a potential therapeutic approach for pollution-related diseases.

[Risk Factors of Multiple Myeloma Complicated with Venous Thromboembolism].

OBJECTIVE: To analyze the clinical characteristics of venous thromboembolism (VTE) in patients with multiple myeloma (MM) and to identify the risk factors of VTE in MM patients. METHODS: 179 newly diagnosed MM (NDMM) patients admitted to The Second Hospital of Shanxi Medical University from January 2014 to December 2020 who were followed up for more than 6 months were collected, and they were divided into VTE group and control group according to whether combined with VTE. The clinical and laboratory data were compared between the two groups. Mann-whitney U test was used for inter-group comparison of measurement data, Chi-square test or Fisher's exact test was used for inter-group comparison of count data, and multivariate logistic regression analysis was performed to explore the risk factors of VTE in MM patients. RESULTS: Compared with control group, the serum albumin (ALB) level in VTE group was significantly lower (P =0.033), the fibrinogen (FIB) level was significantly higher (P =0.016), and the proportion of patients with D-dimer≥2 000 ng/ml was significantly higher than that in the control group (26.3% vs 4.4%, P =0.002). There was a significant difference in M-component type between the two groups (P =0.028), and the proportion of IgG type in VTE group was higher. There were no statistically significant differences between two groups in age, sex, body mass index (BMI), the proportions of patients with hypertension, diabetes, coronary heart disease and cerebral infarction, white blood cell (WBC) count, platelet (PLT) count, liver and kidney function, plasma cells ratio in bone marrow, serum globulin (GLO), lactate dehydrogenase (LDH), ß2-microglobulin (ß2-MG) level, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), prothrombin time (PT), activated partial thromboplastin time (APTT), disease stage, thrombosis prevention and the use of immunomodulators (P >0.05). Multivariate logistic regression analysis showed that FIB level (OR=1.578, 95%CI:1.035-2.407, P =0.034), D-dimer≥2 000 ng/ml (OR=5.467, 95%CI:1.265-23.621, P =0.023) and IgG type (OR=4.780, 95%CI: 1.221-18.712, P =0.025) were independent risk factors for VTE in MM patients. CONCLUSION: MM patients are prone to VTE, and FIB level, D-dimer≥2 000 ng/ ml and IgG type are independent risk factors for VTE in MM patients.