Insulin signaling establishes a developmental trajectory of adipose regulatory T cells.

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.

[Intraspinal Metastasis of Thymic Carcinoma:Report of One Case].

Intraspinal metastasis from malignant carcinomas in other body parts is rarely reported.Intraspinal metastases are often epidural,with primary tumors mostly from the lung and prostate.The extramedullary subdural metastasis of thymic carcinoma is particularly rare and prone to misdiagnosis due to overlapping imaging features with primary intraspinal tumors.This article reports one case of intraspinal metastasis of thymic carcinoma,with the main diagnostic clues including a history of thymic carcinoma,fast growth rate,and irregular shape.

In Situ Constructed Perovskite-Chalcogenide Heterojunction for Photocatalytic CO2 Reduction.

Perovskite nanocrystals (PNCs) are promising candidates for solar-to-fuel conversions yet exhibit low photocatalytic activities mainly due to serious recombination of photogenerated charge carriers. Constructing heterojunction is regarded as an effective method to promote the separation of charge carriers in PNCs. However, the low interfacial quality and non-directional charge transfer in heterojunction lead to low charge transfer efficiency. Herein, a CsPbBr3 -CdZnS heterojunction is designed and prepared via an in situ hot-injection method for photocatalytic CO2 reduction. It is found that the high-quality interface in heterojunction and anisotropic charge transfer of CdZnS nanorods (NRs) enable efficient spatial separation of charge carriers in CsPbBr3 -CdZnS heterojunction. The CsPbBr3 -CdZnS heterojunction achieves a higher CO yield (55.8 µmol g-1  h-1 ) than that of the pristine CsPbBr3 NCs (13.9 µmol g-1  h-1 ). Furthermore, spectroscopic experiments and density functional theory (DFT) simulations further confirm that the suppressed recombination of charge carriers and lowered energy barrier for CO2 reduction contribute to the improved photocatalytic activity of the CsPbBr3 -CdZnS heterojunction. This work demonstrates a valid method to construct high-quality heterojunction with directional charge transfer for photocatalytic CO2 reduction. This study is expected to pave a new avenue to design perovskite-chalcogenide heterojunction.

Does resection after neoadjuvant chemotherapy of docetaxel, oxaliplatin, and S-1 (DOS regimen) benefit for gastric cancer patients with single non-curable factor? a multicenter, prospective cohort study (Neo-REGATTA).

BACKGROUND: The Neo-REGATTA study evaluated the effectiveness and safety of Docetaxel, oxaliplatin, and S-1 (DOS regimen) followed by radical resection vs. chemotherapy in advanced gastric adenocarcinoma patients with single non-curable factor. METHODS: This cohort study prospectively enrolled advanced gastric adenocarcinoma patients with single non-curable factor between November 2017 and June 2021. Patients without progression after four cycles of DOS were divided into resection group and chemotherapy group. The outcomes included overall survival (OS), progression-free survival (PFS) and safety. Effectiveness analysis was also performed by propensity score matching (PSM). RESULTS: A total of 73 patients were enrolled and 13 patients were withdrawn due to disease progression after 4 cycles of DOS. Afterwards, 35 and 25 participants were in the resection and chemotherapy groups, respectively. After a median follow-up time of 30.0 months, the median PFS and OS were 9.0 months, and 18.0 months for the chemotherapy group, but not reached in the resection group. After PSM, 19 matched participants were in each group, and the median PFS and OS were longer in resection group than that in chemotherapy group. The most common grade 3 or 4 adverse events both in the resection group and chemotherapy groups were neutropenia (5.7%, 8.0%) and leukopenia (5.7%, 8.0%). CONCLUSIONS: Radical resection might provide survival benefit compared with continuous chemotherapy alone in advanced gastric adenocarcinoma patients who had a disease control after DOS, with a good safety profile. TRIAL REGISTRATION: The study protocol was registered on ClinicalTrial.gov (NCT03001726, 23/12/2016).

Periampullary tumors in a patient with pancreatic divisum and neurofibromatosis type 1: a case report.

INTRODUCTION: We present a case of a male patient with neurofibromatosis type 1 diagnosed with pancreatic divisum and several gastrointestinal tumors. A 55-year-old man was admitted to the hospital with recurrent chronic pancreatitis, indicating a large mass in the ampulla. In addition, genetic testing revealed two unique germline mutations in the neurofibromin (NF1) gene, and their potential interaction in promoting cancer was further investigated. CONCLUSION: The first similar case was reported in 2020. The current case was distinct from other cases since an additional two NF1 mutations were found in the patient. In conjunction with prior case reports, our findings imply that genetic testing in patients diagnosed with neurofibromatosis type 1 could be helpful in the development of effective treatments.

One-step preparation of MoOx/ZnS/ZnO composite and its excellent performance in piezocatalytic degradation of Rhodamine B under ultrasonic vibration.

This paper synthesized a new type of ternary piezoelectric catalyst MoOx/ZnS/ZnO (MZZ) by a one-step method. The catalytic degradation of Rhodamine B (RhB) solution (10 µg/g, pH = 7.0) shows that the composite catalyst has excellent piezoelectric catalytic activity under ultrasonic vibration (40 kHz). The piezoelectric degradation rate of the optimal sample reached 0.054 min-1, which was about 2.5 times that of pure ZnO. X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Raman, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and electrochemical impedance spectroscopy (EIS) technologies were used to analyze the structure, morphology, and interface charge transfer properties of the MZZ piezocatalysts. The results showed that the composite catalyst may have a core-shell structure. ZnS is coated on the surface of ZnO, while MoOx adheres to the surface of ZnS. This structure endowed MZZ larger specific surface area than ZnO, which benefits the RhB adsorption. More importantly, the formed heterojunction structure between ZnS and ZnO promotes the separation of positive and negative charges induced by the piezoelectric effect. MoOx species may act as a charge trap to further promote more carriers to participate in the reaction. In addition, MoOx may also be beneficial in adsorbing dyes. Active species capture experiments show that superoxide radicals and holes are the main active species in piezoelectric catalytic reactions on MZZ catalysts.

Atomically Precise Copper Nanoclusters for Highly Efficient Electroreduction of CO2 towards Hydrocarbons via Breaking the Coordination Symmetry of Cu Site.

We propose an effective highest occupied d-orbital modulation strategy engendered by breaking the coordination symmetry of sites in the atomically precise Cu nanocluster (NC) to switch the product of CO2 electroreduction from HCOOH/CO to higher-valued hydrocarbons. An atomically well-defined Cu6 NC with symmetry-broken Cu-S2 N1 active sites (named Cu6 (MBD)6 , MBD=2-mercaptobenzimidazole) was designed and synthesized by a judicious choice of ligand containing both S and N coordination atoms. Different from the previously reported high HCOOH selectivity of Cu NCs with Cu-S3 sites, the Cu6 (MBD)6 with Cu-S2 N1 coordination structure shows a high Faradaic efficiency toward hydrocarbons of 65.5 % at -1.4 V versus the reversible hydrogen electrode (including 42.5 % CH4 and 23 % C2 H4 ), with the hydrocarbons partial current density of -183.4 mA cm-2 . Theoretical calculations reveal that the symmetry-broken Cu-S2 N1 sites can rearrange the Cu 3d orbitals with d x 2 - y 2 ${d_{x^2 - y^2 } }$ as the highest occupied d-orbital, thus favoring the generation of key intermediate *COOH instead of *OCHO to favor *CO formation, followed by hydrogenation and/or C-C coupling to produce hydrocarbons. This is the first attempt to regulate the coordination mode of Cu atom in Cu NCs for hydrocarbons generation, and provides new inspiration for designing atomically precise NCs for efficient CO2 RR towards highly-valued products.

The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.

Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.

The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation.

The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear. Here, we identify the ubiquitin-specific peptidase 44 (USP44) as a novel deubiquitinase for FOXP3. USP44 interacts with and stabilizes FOXP3 by removing K48-linked ubiquitin modifications. Notably, TGF-ß induces USP44 expression during iTreg differentiation. USP44 co-operates with USP7 to stabilize and deubiquitinate FOXP3. Tregs genetically lacking USP44 are less effective than their wild-type counterparts, both in vitro and in multiple in vivo models of inflammatory disease and cancer. These findings suggest that USP44 plays an important role in the post-translational regulation of Treg function and is thus a potential therapeutic target for tolerance-breaking anti-cancer immunotherapy.

[Hematoma Segmentation of Spontaneous Intracerebral Hemorrhage Based on Watershed and Region-Growing Algorithm].

Objective: To establish a brain hematoma CT image segmentation method based on watershed and region-growing algorithm so as to measure hematoma volume quickly and accurately, to explore the consistency between the results of this segmentation method and those of manual segmentation, the clinical gold standard, and to compare the results of this method with the calculation of the two Tada formulas commonly used in clinical practice. Methods: The preoperative CT images of 152 patients who were treated for spontaneous cerebral hemorrhage at the Department of Neurosurgery, West China Hospital, Sichuan University between January 2018 and June 2019 were retrospectively collected. The CT images were randomly assigned, by using a random number table, to the training set, the test set and the validation set, which contained 100 patients, 22 patients and 30 patients, respectively. The labeling results of the training set and the test set were used in algorithm training and testing. Four methods, namely, manual segmentation, algorithm segmentation, i.e., segmentation calculation based on watershed and regional growth algorithm, Tada formula, i.e., the traditional Tada formula calculation, and accurate Tada formula, i.e., accurate Tada formula calculation based on 3D-Slicer, were applied on the validation set to measure the hematoma volume. The Digital Imaging and Communications in Medicine (DICOM) data of subjects meeting the selection criteria of the study were manually segmented by two experienced neurosurgeons. The hematoma segmentation model was built based on watershed algorithm and regional growth algorithm. Seed point selected by neurosurgeons was taken as the starting point of growth. Regional grayscale difference criterion combined with manual segmentation validation were adopted to determine the regional growth threshold that met the segmentation precision requirements for intracranial hematoma. Using manual segmentation as the gold standard, Bland-Altman consistency analysis was used to verify the consistency of the three other methods for measuring hematoma volume. Results: With manual segmentation as the gold standard, among the three methods of measuring hematoma volume, algorithm segmentation had the smallest percentage error, the narrowest range of difference, the highest intra-group correlation coefficient (0.987), good consistency, and the narrowest 95% limits of agreement ( LoA). The percentage error of its segmentation was not statistically significant for hematomas of different volumes. Conclusion: The segmentation method of spontaneous intracerebral hemorrhage based on watershed and regional growth algorithm shows stable measurement performance and good consistency with the clinical gold standard, which has considerable clinical significance, but it still needs further validation with more clinical samples.

[Application of Improved Unet Network in the Recognition and Segmentation of Hemorrhage Regions in Brain CT Images].

OBJECTIVE: To examine the performance and application value of improved Unet network technology in the recognition and segmentation of hemorrhage regions in brain CT images. METHODS: A total of 476 brain CT images of patients with spontaneous intracerebral hemorrhage (SICH) were retrospectively included. The improved Unet network was used to identify and segment the hemorrhage regions in the patients' brain CT images. The CT imaging data of the hemorrhage regions were manually labelled by clinicians. After randomized sorting, 430 data sets from 106 patients were selected for inclusion in the training set and 46 data sets from 11 patients were included in the test set. After data enhancement, the experimental data set underwent network training and model testing in order to assess the segmentation performance. The segmentation results were compared with the those of the Unet network (Base), FCN-8s network and Unet++ network. RESULTS: In the segmentation of brain CT image hemorrhage region with the improved Unet network, the three evaluation indicators of Dice similarity coefficient, positive predictive value (PPV), and sensitivity coefficient (SC) reached 0.8738, 0.9011 and 0.8648, respectively, increasing by 8.80%, 7.14% and 8.96%, respectively, compared with those of FCN-8s, and increasing by 4.56%, 4.44% and 4.15%, respectively, compared with those of Unet network (Base). The improved Unet network also showed better segmentation performance than that of Unet++ network. CONCLUSION: The improved method based on Unet network proposed in this report displayed good performance in the recognition and segmentation of hemorrhage regions in brain CT images, and is an appropriate method for the recognition and segmentation of hemorrhage regions in brain CT images, showing potential application value for assisting clinical decision-making and preventing early hematoma expansion.

KPNA2 promotes renal cell carcinoma proliferation and metastasis via NPM.

Karyopherin α2 (KPNA2), involved in nucleocytoplasmic transport, has been reported to be up-regulated in tumorigenesis. However, comprehensive studies of KPNA2 functions in renal cell carcinoma (RCC) are still lacking. In this study, we aim to investigate the roles of KPNA2 in kidney tumour development. Our results showed that down-regulation of KPNA2 inhibited the proliferation and invasion of kidney tumour cell cells in vitro, while the cell cycle arrest and cellular apoptosis were induced once KPNA2 was silenced. Repression of KPNA2 was proved to be efficient to repress tumorigenesis and development of kidney tumour in in nude mice. Furthermore, one related participator, NPM, was identified based on Co-IP/MS and bioinformatics analyses. The up-regulation of NPM attenuates the efficiency of knockdown KPNA2. These results indicated that KPNA2 may regulate NPM to play a crucial role for kidney tumour development.

Retraction: Convenient synthesis of pyrimidine 2'-deoxyribonucleoside monophosphates with important epigenetic marks at the 5-position.

Retraction of 'Convenient synthesis of pyrimidine 2'-deoxyribonucleoside monophosphates with important epigenetic marks at the 5-position' by Song Zheng et al., Org. Biomol. Chem., 2020, 18, 5164-5173, DOI: 10.1039/D0OB00884B.

The cAMP-Adenosine Feedback Loop Maintains the Suppressive Function of Regulatory T Cells.

Therapeutic manipulation of regulatory T cells (Tregs) has been regarded as a promising approach for the treatment of immune disorders. However, a better understanding of the immunomodulatory mechanisms of Tregs and new safe and effective methods to improve the therapeutic effects of Tregs are highly desired. In this study, we have identified the key roles of a cAMP-adenosine positive feedback loop in the immunomodulatory function of Tregs. Adult male C57BL/6J mice were used for an experimental autoimmune uveitis (EAU) model, Tregs, and uveitogenic T cells (UTs). In established EAU, induced Tregs (iTregs) administration alleviated the inflammatory response. In vitro, iTregs inhibited UTs proliferation and inflammatory cytokine production. Mechanistically, cAMP is partially responsible for iTreg-mediated inhibition on UTs. Importantly, intracellular cAMP regulates CD39 expression and CD39-dependent adenosine production in iTregs, and cAMP directly participates in iTreg-derived adenosine production by a CD39 signaling-independent extracellular cAMP-adenosine pathway. Moreover, extracellular adenosine increases the intracellular cAMP level in Tregs. More importantly, increasing the cAMP level in iTregs before transfer improves their therapeutic efficacy in established EAU. Notably, the cAMP-adenosine loop exists in both iTregs and naturally occurring Tregs. These findings provide new insights into the immunosuppressive mechanisms of Tregs and suggest a new strategy for improving the therapeutic efficacy of Tregs in established autoimmune disease.

Profiling sirtuin activity using Copper-free click chemistry.

The mammalian sirtuins are a group of posttranslational modification enzymes that remove acyl modifications from lysine residues in an NAD+-dependent manner. Although initially proposed as histone deacetylases (HDACs), they are now known to target other cellular enzymes and proteins as well. Sirtuin-catalyzed simple amide hydrolysis has profound biological consequences including suppression of gene expression, promotion of DNA damage repair, and regulation of glucose and lipid metabolism. Human sirtuins have been intensively pursued by both academia and industry as potential therapeutic targets for the treatment of diseases such as cancer and neurodegeneration. To gain a better understanding of their roles in various cellular events, innovative chemical probes are highly sought after. This current study focuses on the development of activity-based chemical probes (ABPs) for the profiling of sirtuin activity in biological samples. Cyclooctyne-containing and azido-containing probes were synthesized to enable the subsequent copper-free "click" conjugation to either a fluorophore or biotin. The two groups of structurally related ABPs demonstrated different labeling efficiency and selectivity: the cyclooctyne-containing probes failed to label recombinant sirtuins to any appreciable level, while the azido-containing ABPs showed good isoform selectivity. The azido-containing ABPs were further analyzed for their ability to label an individual sirtuin isoform in protein mixtures and cell lysates. These biocompatible ABPs allow the study of dynamic cellular protein activity change to become possible.

Subcutaneous panniculitis-like T cell lymphoma presented as erythema nodosum: A case report.

Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is an extremely rare subtype of primary cutaneous T cell lymphomas mimicking panniculitis. Clinically, patients are usually presented with subcutaneous nodules, which usually leads to initial misdiagnosis as a benign cutaneous condition. Here, we report a 40-year-old female who presented with subcutaneous erythematous nodules on her extremities with fever. On the basis of the clinical presentations, histopathological features and immunohistochemical findings, a diagnosis of SPTCL was made. The patient was treated with the injection of recombinant human interferon α-1b (30 µg) every other day for 3 months. The lesions gradually regressed. No new erythema nodules reappeared during the 10-month follow-up.

B7-H1 Promotes the Functional Effect of Human Gingiva-Derived Mesenchymal Stem Cells on Collagen-Induced Arthritis Murine Model.

Recent studies found that mesenchymal stem cells (MSCs), by virtue of their tissue recovery and immunoregulatory properties, have shown a broad prospect for applications in various autoimmune and degenerative diseases. Although the potential therapeutic use of MSCs is considerable, studies and clinical treatment efficacy are preliminary due to the heterogeneity of MSCs. Herein, based on RNA-sequencing (RNA-seq) and single cell sequence properties, we demonstrated that B7-H1 plays an important role in the immunosuppressive function of human gingiva-derived mesenchymal stem cells (GMSCs) in a collagen-induced arthritis murine model that is dependent on STAT3 signaling. Our data offer convincing evidence that B7-H1 expression by GMSCs helps to identify a new subpopulation of MSCs with a greater immunosuppressive property. The approach provides a unique and additional strategy for stem cells-based therapies of autoimmune and other inflammatory diseases.

CD4+CD126low/- Foxp3+ Cell Population Represents a Superior Subset of Regulatory T Cells in Treating Autoimmune Diseases.

CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining homeostasis and preventing autoimmune diseases. Nonetheless, we and others have previously reported that natural Treg cells are unstable and dysfunctional in the inflamed environment with a high-salt diet, limiting the Treg function in disease control. In this study, we made an innovative observation showing a high degree of heterogeneity within the Treg pool. We identified that CD126, interleukin (IL)-6 receptor alpha chain, contributed to Treg cell instability. Using a series of in vitro and in vivo experimental approaches, we demonstrated that CD126Lo/- Treg cells presented greater function and were more stable than CD126Hi nTreg cells, even in the presence of IL-6 and inflammation. Blockade of programmed death-1 (PD-1) interrupted CD126Lo/- nTreg cell stability. Additionally, CD126Lo/- Treg cells can treat colitis and established collagen-induced arthritis, while the CD126Hi cell population failed to do this. Moreover, we noted that CD126 expression of Treg cells had a positive correlation to rheumatoid arthritis (RA) severity and the stability of Treg cells. Our results strongly suggest that the manipulation of CD126Lo/- nTreg cells could be a novel strategy for the treatment of autoimmune diseases and for other conditions associated with a deficit of Treg cells.

CD39 Produced from Human GMSCs Regulates the Balance of Osteoclasts and Osteoblasts through the Wnt/ß-Catenin Pathway in Osteoporosis.

Osteoporosis is a disease in which the density and quality of bone are reduced, causing bones to become weak and so brittle that a fall or even mild stresses can cause a fracture. Current drug treatment consists mainly of antiresorptive agents that are unable to stimulate new bone formation. Our recent studies have defined a critical role of gingiva-derived mesenchymal stem cells (GMSCs) in attenuating autoimmune arthritis through inhibition of osteoclast formation and activities, but it remains to be ruled out whether the administration of GMSCs to patients with osteoporosis could also regulate osteoblasts and eventually affect bone formation and protection. With the use of an ovariectomized mouse model, we here demonstrated that adoptive transfer of GMSCs regulated the balance of osteoclasts and osteoblasts, eventually contributing to dynamic bone formation. Validation by RNA sequencing (RNA-seq), single-cell sequencing, revealed a unique population of CD39+ GMSC that plays an important role in promoting bone formation. We further demonstrated that CD39 produced from GMSC exerted its osteogenic capacity through the Wnt/ß-catenin pathway. Our results not only establish a previously unidentified role and mechanism of GMSC for bone promotion but also a potential therapeutic target for management of patients with osteoporosis and other bone loss conditions.

Regulatory T Cells: Concept, Classification, Phenotype, and Biological Characteristics.

Regulatory T cells (Treg) play an indispensable role in maintaining the body's immune nonresponse to self-antigens and suppressing the body's unwarranted and potentially harmful immune responses. Their absence, reduction, dysfunction, transformation, and instability can lead to numerous autoimmune diseases. There are several distinct subtypes of the Treg cells, although they share certain biological characteristics and have unique phenotypes with different regulatory functions, as well as mechanistic abilities. In this book chapter, we introduce the latest advances in Treg cell subtypes pertaining to classification, phenotype, biological characteristics, and mechanisms. We also highlight the relationship between Treg cells and various diseases, including autoimmune, infectious, as well as tumors and organ transplants.