New clinical classification of stiff skin syndrome.

BACKGROUND: Stiff skin syndrome (SSS) is a rare disease characterized by thickened, indurated skin and limited joint movement. Multiple diverse phenotypes have been reported, and the correlation of severity with the clinical heterogeneity and histopathological findings of SSS needs to be refined. OBJECTIVE: To define subtypes based on clinical features and predict the prognosis of a new SSS classification. METHODS: Eighty-three patients with SSS were retrospectively reviewed for clinicopathological manifestations and routine laboratory workup, including 59 cases obtained from a PubMed search between 1971 and 2022 and 24 cases diagnosed in our department between 2003 and 2022. RESULTS: Among the 83 patients, 27.7, 41, and 31.3% had classic widespread, generalized segmental, and localized SSS, respectively. Joint immobility was present in 100, 71, and 20% of classic, generalized, and localized cases, respectively. Histopathologic findings were common among the 3 groups, and based on that, we further found a difference in the distribution of proliferative collagen. 54.5% of classic and 50% of generalized cases occurred throughout the dermis or the subcutis, whereas 76% of localized cases were mainly involved in the reticular dermis or subcutis. In patients with incipient localized SSS, 42% (21/50) developed generalized SSS, and only 6% (3/50) progressed to classic SSS, whereas more than half of the incipient generalized SSS cases (60.6%, 20/33) developed classic SSS. LIMITATIONS: This retrospective study was limited to previously published cases with limited data. CONCLUSIONS: We propose a distinct clinical classification characterized by lesion distribution, including classic widespread, generalized segmental, and localized SSS, associated with disease severity and prognosis.

Guaranteed minimum withdrawal benefits with high-water mark fee structure.

The Guaranteed Minimum Withdrawal Benefit (GMWB), an adjunct incorporated within variable annuities, commits to reimbursing the entire initial investment regardless of the performance of the underlying funds. While extensive research exists in financial and actuarial literature regarding the modeling and valuation techniques of GMWBs, much of it is founded on a static fee structure. Our study introduces an innovative fee structure based on the high-water mark (HWM) principle and a regime-switch jump-diffusion model for the pricing of GMWBs, employing numerical solutions through the Monte Carlo method for solving the stochastic differential equation (SDE). Furthermore, a companion piece of research addresses the risk management of GMWBs within the same analytical framework as the pricing component, an aspect that has received limited attention in the existing literature. In assessing the necessary capital reserves for unforeseen losses, our methodology involves the computation of two risk metrics associated with the tail distribution of net liability from the insurer's perspective, Value-at-Risk (VaR) and Conditional-Tail-Expectation (CTE). Comprehensive numerical results and sensitivity analyses are also provided.

A Fluorescence Light-Up 3D DNA Walker Driven and Accelerated by Endogenous Adenosine-5'-triphosphate for Sensitive and Rapid Label-Free MicroRNA Detection and Imaging in Living Cells.

Herein, a fluorescence light-up 3D DNA walker (FLDW) was powered and accelerated by endogenous adenosine-5'-triphosphate (ATP) molecules to construct a biosensor for sensitive and rapid label-free detection and imaging of microRNA-221 (miRNA-221) in malignant tumor cells. Impressively, ATP as the driving force and accelerator for FLDW could significantly accelerate the operation rate of FLDW, reduce the likelihood of errors in signaling, and improve the sensitivity of detection and imaging. When FLDW was initiated by output DNA H1-op transformed by target miRNA-221, G-rich sequences in the S strand, anchored to AuNP, were exposed to form G-quadruplexes (G4s), and thioflavin T (ThT) embedded in the G4s emitted intense fluorescence to realize sensitive and rapid detection of target miRNA-221. Meanwhile, the specific binding of ThT to G4 with a weak background fluorescence response was utilized to enhance the signal-to-noise ratio of the label-free assay straightforwardly and cost-effectively. The proposed FLDW system could realize sensitive detection of the target miRNA-221 in the range of 1 pM to 10 nM with a detection limit of 0.19 pM by employing catalytic hairpin assembly (CHA) to improve the conversion of the target. Furthermore, by harnessing the abundant ATP present in the tumor microenvironment, FLDW achieved rapid and accurate imaging of miRNA-221 in cancer cells. This strategy provides an innovative and high-speed label-free approach for the detection and imaging of biomarkers in cancer cells and is expected to be a powerful tool for bioanalysis, diagnosis, and prognosis of human diseases.

Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in the MYC Promoter and Inhibit Topoisomerase I.

G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.

Immune profiling analysis of double-negative T cells in patients with systemic sclerosis.

OBJECTIVE: To construct a molecular immune map of patients with systemic sclerosis (SSc) by mass flow cytometry, and compare the number and molecular expression of double-negative T (DNT) cell subsets between patients and healthy controls (HC). METHODS: Peripheral blood mononuclear cells (PBMCs) were extracted from the peripheral blood of 17 SSc patients and 9 HC. A 42-channel panel was set up to perform mass cytometry by time of flight (CyTOF) analysis for DNT subgroups. Flow cytometry was used to validate subpopulation functions. The clinical data of patients were collected for correlation analysis. RESULTS: Compared with HC, the number of total DNT cells decreased in SSc patients. Six DNT subsets were obtained from CyTOF analysis, in which the proportion of cluster1 increased, while the proportion of cluster3 decreased. Further analysis revealed that cluster1 was characterized by high expression of CD28 and CCR7, and cluster3 was characterized by high expression of CD28 and CCR5. After in vitro stimulation, cluster1 secreted more IL-4 and cluster3 secreted more IL-10 in SSc patients compared to HC. Clinical correlation analysis suggested that cluster1 may play a pathogenic role while cluster3 may play a protective role in SSc. ROC curve analysis further revealed that cluster3 may be a potential indicator for determining disease activity in SSc patients. CONCLUSION: We found a new CCR5+CD28+ DNT cell subset, which played a protective role in the pathogenesis of SSc. Key Points • The number of DNT cells decreased in SSc patients' peripheral blood. • DNT cells do not infiltrate in the skin but secrete cytokines to participate in the pathogenesis of SSc. • A CCR5+CD28+ DNT cell population may play a protective role in SSc.

Orderly Aggregated Catalytic Hairpin Assembly for Synchronous Ultrasensitive Detecting and High-Efficiency Co-Localization Imaging of Dual-miRNAs in Living Cells.

In this work, the orderly aggregated catalytic hairpin assembly (OA-CHA) was developed for synchronous ultrasensitive detection and high-efficiency colocalization imaging of dual-miRNAs by a carefully designed tetrahedral conjugated ladder DNA structure (TCLDS). Exactly, two diverse hairpin probes were fixed on tetrahedron conjugated DNA nanowires to form the TCLDS without fluorescence response, which triggered OA-CHA in the aid of output DNA 1 and output DNA 2 produced by targets miRNA-217 and miRNA-196a cycle to generate TCLDS with remarkable fluorescence response. Impressively, compared with the traditional CHA strategy, OA-CHA avoided the fluorescence group and quenching group from approaching again because of the spatial confinement effect to significantly enhance the fluorescence signal, resulting in the simultaneous ultrasensitive detection of dual-miRNAs with detection limits of 21 and 32 fM for miRNA-217 and miRNA-196a, respectively. Meanwhile, the TCLDS with lower diffusivity could achieve accurate localization imaging for reflecting the spatial distribution of dual-miRNAs in living cells. The strategy based on OA-CHA provided a flexible and programmable nucleic amplification method for the synchronous ultrasensitive detection and precise imaging of multiple biomarkers and had potential in disease diagnostics..

pH-Stimulated Self-Locked DNA Nanostructure for the Effective Discrimination of Cancer Cells and Simultaneous Detection and Imaging of Endogenous Dual-MicroRNAs.

In this study, a pH-stimulated self-locked DNA nanostructure (SLDN) was developed to efficiently distinguish cancer cells from other cells for the simultaneous detection and imaging of endogenous dual-microRNAs (miRNAs). Impressively, the SLDN was specifically unlocked in the acidic environment of cancer cells to form unlocked-SLDN to disengage the i-motif sequence with a labeled fluorophore for the recovery of a fluorescence signal, resulting in the differentiation of cancer cells from normal cells. Meanwhile, unlocked-SLDN could combine and recognize the targets miRNA-21 and miRNA-155 simultaneously to trigger the hybridization chain reaction (HCR) amplification for sensitive dual-miRNA detection, with detection limits of 1.46 pM for miRNA-21 and 0.72 pM for miRNA-155. Significantly, compared with the current miRNA imaging strategy based on the traditional DNA nanostructure, the strategy proposed here remarkably eliminates the interference of normal cells to achieve high-resolution colocation imaging of miRNAs in tumor cells with an ultralow background signal. This work provided a specific differentiation method for tumor cells to materialize sensitive biomarker detection and distinguishable high-definition live-cell imaging for precise cancer diagnosis and multifactor research of tumor progression.

Substitutive proprioception feedback of a prosthetic wrist by electrotactile stimulation.

Objective: Sensory feedback of upper-limb prostheses is widely desired and studied. As important components of proprioception, position, and movement feedback help users to control prostheses better. Among various feedback methods, electrotactile stimulation is a potential method for coding proprioceptive information of a prosthesis. This study was motivated by the need for proprioception information for a prosthetic wrist. The flexion-extension (FE) position and movement information of the prosthetic wrist are transmitted back to the human body through multichannel electrotactile stimulation. Approach: We developed an electrotactile scheme to encode the FE position and movement of the prosthetic wrist and designed an integrated experimental platform. A preliminary experiment on the sensory threshold and discomfort threshold was performed. Then, two proprioceptive feedback experiments were performed: a position sense experiment (Exp 1) and a movement sense experiment (Exp 2). Each experiment included a learning session and a test session. The success rate (SR) and discrimination reaction time (DRT) were analyzed to evaluate the recognition effect. The acceptance of the electrotactile scheme was evaluated by a questionnaire. Main results: Our results showed that the average position SRs of five able-bodied subjects, amputee 1, and amputee 2 were 83.78, 97.78, and 84.44%, respectively. The average movement SR, and the direction and range SR of wrist movement in five able-bodied subjects were 76.25, 96.67%, respectively. Amputee 1 and amputee 2 had movement SRs of 87.78 and 90.00% and direction and range SRs of 64.58 and 77.08%, respectively. The average DRT of five able-bodied subjects was less than 1.5 s and that of amputees was less than 3.5 s. Conclusion: The results indicate that after a short period of learning, the subjects can sense the position and movement of wrist FE. The proposed substitutive scheme has the potential for amputees to sense a prosthetic wrist, thus enhancing the human-machine interaction.

Use of the cardiopulmonary coupling index based on refined composite multiscale entropy for prognostication of acute type A aortic dissection.

Objectives: The aim of this study is to assess the influence of cardiopulmonary coupling (CPC) based on RCMSE on the prediction of complications and death in patients with acute type A aortic dissection (ATAAD). Background: The cardiopulmonary system may be nonlinearly regulated, and its coupling relationship with postoperative risk stratification in ATAAD patients has not been studied. Methods: This study was a single-center, prospective cohort study (ChiCTR1800018319). We enrolled 39 patients with ATAAD. The outcomes were in-hospital complications and all-cause readmission or death at 2 years. Results: Of the 39 participants, 16 (41.0%) developed complications in the hospital, and 15 (38.5%) died or were readmitted to the hospital during the two-year follow-up. When CPC-RCMSE was used to predict in-hospital complications in ATAAD patients, the AUC was 0.853 (p < 0.001). When CPC-RCMSE was used to predict all-cause readmission or death at 2 years, the AUC was 0.731 (p < 0.05). After adjusting for age, sex, ventilator support (days), and special care time (days), CPC-RCMSE remained an independent predictor of in-hospital complications in patients with ATAAD [adjusted OR: 0.8 (95% CI, 0.68-0.94)]. Conclusion: CPC-RCMSE was an independent predictor of in-hospital complications and all-cause readmission or death in patients with ATAAD.

Serum metabolite differences detected by HILIC UHPLC-Q-TOF MS in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by extensive fibrosis and vascular damage. Vasculopathy, activation of the immune system, and diffuse fibrosis are all involved in the fatal pathogenesis of SSc. However, little metabolomic research has been conducted in SSc. METHODS: This study included 30 SSc patients and 30 healthy individuals. The metabolite differences in serum samples were analyzed using ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry. Meanwhile, serum metabolites were analyzed in patients with systemic involvement (lung or skin fibrosis). RESULTS: A total of 2360 ion peaks were detected, all of which were attributable to 38 metabolites. These metabolites primarily consisted of fatty acids, amino acids, and glycerophospholipids, which were the major metabolic pathways altered in SSc patients. Glutamine metabolism was the main pathway altered in SSc patients with lung involvement, whereas amino acid metabolism and steroid hormone biosynthesis were the main pathways altered in SSc patients with skin involvement. CONCLUSION: These findings suggested that metabolic profiles and pathways differed between SSc patients and healthy people, potentially providing new targets for SSc-directed therapeutics and diagnostics. Key Points • Metabolic profiles and pathways differed between SSc patients and healthy people. • The levels of trans-dehydroandrosterone are substantially lower in lcSSc than in dcSSc, potentially providing new targets for SSc patients with skin involvement. • L-glutamine could be used as a serum metabolic marker and a therapeutic target for SSc patients with lung involvement.

Single-Cell Characterization of Hepatic CD8+ T Cells in a Murine Model of Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC), an organ-specific autoimmune disease, is characterized by injury to small bile ducts, inflammatory cell infiltrates within the liver, progressive cholestasis, and in some cases, cirrhosis with unclear pathogenesis. We aimed to clarify the importance role of hepatic immunce cells in the pathogenesis of human and experimental PBC.The dominant-negative TGFß receptor type II transgenic (dnTGFßRII) mice, a well-studied and established murine model of PBC were used to identify changes of immune cells, especially the pathogenic CD8+ T cells. The high-throughput single-cell RNA sequencing technology were applied and found functional heterogeneity among the hepatic CD8+ T cells subsets in dnTGFßRII mice. CD8+ T cells were confirmed the key cells leading to the pathogenesis of PBC in dnTGFßRII mice, and identified the terminally differentiated CD8αα T cells and CD8αß T cell subsets in the liver of dnTGFßRII mice. While terminally differentiated CD8αα T cells have higher cytokine production ability and cytotoxicity, the terminally differentiated CD8αß T cells retain their proliferative profile. Our work suggests that there are developmental and differentiated trajectories of pathogenic CD8+ T cell subsets in the pathogenesis of PBC. A further clarification of their roles would be helpful to our understanding of the pathogenesis of PBC and may potentially lead to identifying novel therapeutic modalities.

In Vivo Generation of SSA/Ro Antigen-Specific Regulatory T Cells Improves Experimental Sjögren's Syndrome in Mice.

OBJECTIVE: Sjögren's syndrome (SS) is a systemic autoimmune disease, and T cells play an important role in the initiation and perpetuation of the disease. In this study, we developed an immunotherapy for NOD/LtJ mice with SS-like symptoms by combining a transient depletion of CD4+ T cells with the administration of autoantigen-specific peptide Ro480. METHODS: NOD/LtJ mice were treated with single anti-CD4 monoclonal antibody (mAb) followed 2 days later by a series of 6 intraperitoneal injections of Ro480-494 every other day. Salivary flow rates were determined pre- and posttreatment once a week. Mice were euthanized 6 weeks after the initial anti-CD4 mAb treatment, salivary glands (SGs) were collected for analyses of histologic disease scores and inflammatory cell infiltration, polymerase chain reaction determination of genes was conducted, and flow cytometry analysis including major histocompatibility complex class II tetramer staining of immune cells was performed. In addition, adoptive transfer of Treg cells was administrated to investigate the function of the newly generating Treg cells in vivo. RESULTS: The combination of anti-CD4 mAb with autoantigen-specific peptide Ro480 generated SSA/Ro antigen-specific Treg cells in vivo, which can suppress interferon-γ production of CD4+ T cells and inflammation infiltration in SGs and maintain the function of SGs. CONCLUSION: Our findings provide a new approach to generating antigen-specific Treg cells in vivo for SS treatment, which may have implications for potential therapy for patients with SS.

Adipose-mesenchymal stromal cells suppress experimental Sjögren syndrome by IL-33-driven expansion of ST2+ regulatory T cells.

Adipose-derived mesenchymal stromal cells (ADSCs) play important roles in the alleviation of inflammation and autoimmune diseases. Interleukin-33 (IL-33), a member of the IL-1 family, has been shown to regulate innate and adaptive immunity. However, it is still unknown whether ADSCs regulate immune responses via IL-33. We show here that ADSCs produced IL-33 in response to IL-1ß stimulation, which depended on TAK1, ERK, and p38 pathways. ADSCs-derived IL-33 drove the proliferation of CD4+Foxp3+ST2+ regulatory T cells (Tregs) and alleviated experimental autoimmune Sjögren syndrome in mice. Importantly, human ADSCs also produced IL-33 in response to IL-1ß. Thus, we have revealed a previously unrecognized immunoregulatory function of ADSCs by IL-33 production in experimental autoimmunity, which may have clinical applications for human immunopathology.

A pilot study of mandibular expansion in combination with a fixed-appliance for increasing the effective space of the mandibular arch: Finite element analysis and three-dimensional cone-beam computed tomography.

ABSTRACT: Techniques for enhancing the effective space of the mandibular arch are urgently needed. Therefore, this study aimed to perform mandibular expansion in combination with a fixed-appliance technique, with preliminary monitoring by finite element analysis and 3-dimensional cone-beam computed tomography (CBCT).Finite element models were structured according to CBCT images of a 14-year-old girl. The von Mises stress of the alveolar bone and tooth displacement were assessed in different models. The technique was also applied in an 11-year-old boy. CBCT was performed at post-expansion, post-retention, post-treatment and 2 years after treatment. Tooth movement and alveolar bone stress were assessed by the CAD software.Finite element analysis suggested that the teeth tended to stand upright in the buccal side in the expander model compared with the expander-remove model. However, minimum tooth change was observed in the normal model, indicating highest stability. The von Mises stress of the alveolar bone was decreased in the normal model compared with the expander model, suggesting that buccal-inclined teeth could more easily lead to alveolar bone stress than normal ones. Based on CBCT data and the 3D mandibular dentition model fitting, mandibular teeth tended to be upright in the buccal side after retention compared with the post-expansion condition, which somewhat differed from finite element analysis results. Furthermore, dehiscence and fenestration were not observed.This expansion technique is expected to increase the effective space after mandibular expansion and reduce buccal alveolar bone stress.

The Cytokine TGF-ß Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching.

Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31-/- mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-ß1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-ß-IL-31 axis with implications for treatment of wound itching.

Efficacy of different designs of mandibular expanders: A 3-dimensional finite element study.

INTRODUCTION: Nonsurgical mandibular expansion has been increasingly performed in recent years because it can effectively expand the mandibular dental arch. However, many types of mandibular expanders have been used in previous studies. No relevant studies have compared the biomechanical responses of different designs of mandibular expansion appliances with screws. Therefore, the purpose of this study was to analyze the stress distribution and displacement of the dentoalveolar structures according to different designs of mandibular screw expanders. METHODS: Cone-beam computed tomography scans were used for 3-dimensional reconstruction of the mandibular finite element model. Four different designs of mandibular expanders, 1 removable expander (type A) and 3 fixed expanders (types B, C, and D), were added to the finite element models. Expanders were activated transversely for 0.2 mm. The initial tooth displacement and von Mises stress distribution were evaluated. RESULTS: All the expanders enlarged the arch dimensions. In types A and B, the stress was mainly concentrated in the region of the anterior teeth, along with greater tooth displacement, whereas in types C and D, greater stress and displacement occurred in the region of the posterior teeth. Type A showed the greatest amount of transverse displacement. Type D was more efficient in the region of the posterior teeth. CONCLUSIONS: Types A and B should be used with great caution in the clinic because of their incompatible expansion pattern. Type D is the recommended mandibular expansion appliance because of its appropriate expansion pattern.

Robotics-assisted versus conventional manual approaches for total hip arthroplasty: A systematic review and meta-analysis of comparative studies.

BACKGROUND: Several studies have compared robotics-assisted (RA) and conventional manual (CM) approaches for total hip arthroplasty (THA), but their results are controversial. METHODS: A literature search was conducted for controlled clinical trials (CCTs) comparing the clinical efficacy of the RA and CM approaches for THA and published between August 1998 and August 2018. The obtained data were analyzed using the statistical software Review Manager 5.3. RESULTS: Fourteen articles were included in the meta-analysis, which revealed that the RA group had less intraoperative complications, better cup angle, and more cases of cup placement in the safe zone than the CM group. However, the operation time required for the CM group was less than that required for the RA group. Moreover, postoperative complications (eg, dislocation and revision surgery) were less frequent in the CM group than in the RA group. However, the two groups had similar functional scores, total number of complications, and rate of occurrence of limb length discrepancy. CONCLUSION: Compared with the CM approach, the RA approach yields better radiological outcomes and fewer intraoperative complications in THA, but similar functional scores.

Dormancy activation mechanism of tracheal stem cells.

Accurate markers and molecular mechanisms of stem cell dormancy and activation are poorly understood. In this study, the anti-cancer drug, 5-fluorouracil, was used to selectively kill proliferating cells of human bronchial epithelial (HBE) cell line. This method can enrich and purify stem cell population. The dormant versus active status of stem cells was determined by phosphorylation of RNAp II Ser2. The surviving stem cells were cultured to form stem cell spheres expressing stem cell markers and transplanted into nude mice to form a teratoma. The results demonstrated the properties of stem cells and potential for multi-directional differentiation. Bisulfite sequencing polymerase chain reaction showed that demethylation of the Sox2 promoter by 5-FU resulted in Sox2 expression in the dormant stem cells. This study shows that the dormancy and activation of HBE stem cells is closely related to epigenetic modification.