Synthesis of C-Alkyl Glycosides from Alkyl Bromides and Glycosyl Carboxylic Acids via Ni/Photoredox Dual Catalysis.

C-Alkyl glycosides, an important class of C-glycosides, are widely found in various drugs and natural products. The synthesis of C-alkyl glycosides has attracted considerable attention. Herein, we developed a Ni/photoredox catalyzed decarboxylative C(sp3)-C(sp3) coupling reaction of stable glycosylcarboxylic acids with simple aliphatic bromides to generate C-alkyl glycosides. The method successfully linked several functional molecular fragments (natural products or drugs) to a sugar moiety, showing the extensive application prospects of this transformation. Controlled experiments and DFT calculations demonstrated that the reaction pathway contains a free radical process, and a possible mechanism is proposed.

Pharmacological effects of MT-1207 in bilateral renal artery stenosis hypertension and its hypotensive targets validation.

MT-1207 (MT) as a new antihypertensive drug is under clinical trial. However, its hypotensive mechanism has not been experimentally explored, and it is unknown whether MT can be used for bilateral renal artery stenosis hypertension. Using two-kidney two-clip (2K2C) to mimic bilateral renal artery stenosis in rats, a stroke-prone renovascular hypertension model, the present study further verified its antihypertensive effect, cardiovascular and renal protection, mortality reduction and lifespan prolongation, as well as demonstrated its two novel pharmacological effects for uric acid-lowering and cognition-improving. Notably, MT did not aggravate renal dysfunction; instead, it had beneficial effects on reducing serum uric acid level and maintaining serum K+ at a relatively stable level in 2K2C rats. In contrast, angiotensin receptor blocker losartan aggravated renal dysfunction in 2K2C rats. Mechanistically, MT hypotensive effect was dependent on its blockade of α1 and 5-HT2 receptors, since MT pretreatment abolished these receptor agonists-induced blood pressure elevations in vivo. Further evidence showed MT bound to and interacted with these receptor subtypes including α1A, α1B, α1D, 5-HT2A, 5-HT2B, and 5-HT2C receptors known for control of blood pressure. In conclusion, MT may be used for treatment of bilateral renal artery stenosis hypertension, different from losartan that is prohibited for treatment of bilateral renal artery stenosis hypertension. Targets validation of MT hypotensive mechanism and beneficial effects of MT on uric acid and cognitive function provide new insights for this novel multitarget drug, deserving clinical trial attention.

Targeted-lung delivery of bardoxolone methyl using PECAM-1 antibody-conjugated nanostructure lipid carriers for the treatment of lung inflammation.

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

Chiral-Boron Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of 2'-Hydroxychalcones with N-2,2,2-Trifluoroethylisatin Ketimines.

A highly efficient asymmetric [3 + 2] cycloaddition reaction of 2'-hydroxychalcones with N-2,2,2-trifluoroethylisatin ketimines catalyzed by a (R)-3,3'-I2-BINOL-boron complex was developed. A broad range of 3,2'-pyrrolidinyl spirooxindole derivatives bearing a CF3-substituted pyrrolidine moiety with four contiguous stereocenters was prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and excellent stereocontrol.

Research Progress on the Pathogenesis and Treatment of Neoatherosclerosis.

Neoatherosclerosis (NA) within stents has become an important clinical problem after coronary artery stent implantation. In-stent restenosis and in-stent thrombosis are the two major complications following coronary stent placement and seriously affect patient prognosis. As the common pathological basis of these two complications, NA plaques, unlike native atherosclerotic plaques, often grow around residual oxidized lipids and stent struts. The main components are foam cells formed by vascular smooth muscle cells (VSMCs) engulfing oxidized lipids at lipid residue sites. Current research mainly focuses on optical coherence tomography (OCT) and intravascular ultrasound (IVUS), but the specific pathogenesis of NA is still unclear. A thorough understanding of the pathogenesis and pathological features of NA provides a theoretical basis for clinical treatment. This article reviews the previous research of our research group and the current situation of domestic and foreign research.

Regulating Local Electron Density of Cyano Sites in Graphitic Nitride Carbon by Giant Internal Electric Field for Efficient CO2 Photoreduction to Hydrocarbons.

Selective photocatalytic CO2 reduction to high-value hydrocarbons using graphitic carbon nitride (g-C3N4) polymer holds great practical significance. Herein, the cyano-functionalized g-C3N4 (CN-g-C3N4) with a high local electron density site is successfully constructed for selective CO2 photoreduction to CH4 and C2H4. Wherein the potent electron-withdrawing cyano group induces a giant internal electric field in CN-g-C3N4, significantly boosting the directional migration of photogenerated electrons and concentrating them nearby. Thereby, a high local electron density site around its cyano group is created. Moreover, this structure can also effectively promote the adsorption and activation of CO2 while firmly anchoring *CO intermediates, facilitating their subsequent hydrogenation and coupling reactions. Consequently, using H2O as a reducing agent, CN-g-C3N4 achieves efficient and selective photocatalytic CO2 reduction to CH4 and C2H4 activity, with maximum rates of 6.64 and 1.35 µmol g-1 h-1, respectively, 69.3 and 53.8 times higher than bulk g-C3N4 and g-C3N4 nanosheets. In short, this work illustrates the importance of constructing a reduction site with high local electron density for efficient and selective CO2 photoreduction to hydrocarbons.

Five commonly used traditional Chinese medicine formulas in the treatment of ulcerative colitis: A network meta-analysis.

BACKGROUND: Currently, traditional Chinese medicine (TCM) formulas are commonly being used as adjunctive therapy for ulcerative colitis in China. Network meta-analysis, a quantitative and comprehensive analytical method, can systematically compare the effects of different adjunctive treatment options for ulcerative colitis, providing scientific evidence for clinical decision-making. AIM: To evaluate the clinical efficacy and safety of commonly used TCM for the treatment of ulcerative colitis (UC) in clinical practice through a network meta-analysis. METHODS: Clinical randomized controlled trials of these TCM formulas used for the adjuvant treatment of UC were searched from the establishment of the databases to July 1, 2022. Studies that met the inclusion criteria were screened and evaluated for literature quality and risk of bias according to the Cochrane 5.1 standard. The methodological quality of the studies was assessed using ReviewManager (RevMan) 5.4, and a funnel plot was constructed to test for publication bias. ADDIS 1.16 statistical software was used to perform statistical analysis of the treatment measures and derive the network relationship and ranking diagrams of the various intervention measures. RESULTS: A total of 64 randomized controlled trials involving 5456 patients with UC were included in this study. The adjuvant treatment of UC using five TCM formulations was able to improve the clinical outcome of the patients. Adjuvant treatment with Baitouweng decoction (BTWT) showed a significant effect [mean difference = 36.22, 95% confidence interval (CI): 7.63 to 65.76]. For the reduction of tumor necrosis factor in patients with UC, adjunctive therapy with BTWT (mean difference = -9.55, 95%CI: -17.89 to -1.41), Shenlingbaizhu powder [SLBZS; odds ratio (OR) = 0.19, 95%CI: 0.08 to 0.39], and Shaoyao decoction (OR = -23.02, 95%CI: -33.64 to -13.14) was effective. Shaoyao decoction was more effective than BTWT (OR = 0.12, 95%CI: 0.03 to 0.39), SLBZS (OR = 0.19, 95%CI: 0.08 to 0. 39), and Xi Lei powder (OR = 0.34, 95%CI: 0.13 to 0.81) in reducing tumor necrosis factor and the recurrence rate of UC. CONCLUSION: TCM combined with mesalazine is more effective than mesalazine alone in the treatment of UC.

Structural basis for linker histone H5-nucleosome binding and chromatin fiber compaction.

The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.

Electrostatic Self-Assembly of CdS Quantum Dots with Co9S8 Hollow Nanotubes for Enhanced Visible Light Photocatalytic H2 Production.

CdS quantum dots (CdS QDs) are regarded as a promising photocatalyst due to their remarkable response to visible light and suitable placement of conduction bands and valence bands. However, the problem of photocorrosion severely restricts their application. Herein, the CdS QDs-Co9S8 hollow nanotube composite photocatalyst has been successfully prepared by loading Co9S8 nanotubes onto CdS QDs through an electrostatic self-assembly method. The experimental results show that the introduction of Co9S8 cocatalyst can form a stable structure with CdS QDs, and can effectively avoid the photocorrosion of CdS QDs. Compared with blank CdS QDs, the CdS QDs-Co9S8 composite exhibits obviously better photocatalytic hydrogen evolution performance. In particular, CdS QDs loaded with 30% Co9S8 (CdS QDs-30%Co9S8) demonstrate the best photocatalytic performance, and the H2 production rate reaches 9642.7 µmol·g-1·h-1, which is 60.3 times that of the blank CdS QDs. A series of characterizations confirm that the growth of CdS QDs on Co9S8 nanotubes effectively facilitates the separation and migration of photogenerated carriers, thereby improving the photocatalytic hydrogen production properties of the composite. We expect that this work will facilitate the rational design of CdS-based photocatalysts, thereby enabling the development of more low-cost, high-efficiency and high-stability composites for photocatalysis.

Wide-Dynamic-Range Control of Quantum-Electrodynamic Electron Transfer Reactions in the Weak Coupling Regime.

Catalyzing reactions effectively by vacuum fluctuations of electromagnetic fields is a significant challenge within the realm of chemistry. As opposed to most studies based on vibrational strong coupling, we introduce an innovative catalytic mechanism driven by weakly coupled polaritonic fields. Through the amalgamation of macroscopic quantum electrodynamics (QED) principles with Marcus electron transfer (ET) theory, we predict that ET reaction rates can be precisely modulated across a wide dynamic range by controlling the size and structure of nanocavities. Compared to QED-driven radiative ET rates in free space, plasmonic cavities induce substantial rate enhancements spanning the range from 103- to 10-fold. By contrast, Fabry-Perot cavities engender rate suppression spanning the range from 10-2- to 10-1-fold. This work overcomes the necessity of using strong light-matter interactions in QED chemistry, opening up a new era of manipulating QED-based chemical reactions in a wide dynamic range.

The Clinical Characteristics and Manifestation of Anxious Depression Among Patients With Major Depressive Disorders-Results From a Taiwan Multicenter Study.

OBJECTIVE: Anxious depression is a prevalent characteristic observed in Asian psychiatric patients diagnosed with major depressive disorder (MDD). This study aims to investigate the prevalence and clinical presentation of anxious depression in Taiwanese individuals diagnosed with MDD. METHODS: We recruited psychiatric outpatients aged over 18 who had been diagnosed with MDD through clinical interviews. This recruitment took place at five hospitals located in northern Taiwan. We gathered baseline clinical and demographic information from the participants. Anxious depression was identified using a threshold of an anxiety/somatization factor score ≥7 on the 21-item Hamilton Rating Scale for Depression (HAM-D). RESULTS: In our study of 399 patients (84.21% female), 64.16% met the criteria for anxious depression. They tended to be older, married, less educated, with more children, and an older age of onset. Anxious depression patients had higher HAM-D and Clinical Global Impression-Severity scale score, more panic disorder (without agoraphobia), and exhibited symptoms like agitation, irritability, concentration difficulties, psychological and somatic anxiety, somatic complaints, hypochondriasis, weight loss, and increased insight. Surprisingly, their suicide rates did not significantly differ from non-anxious depression patients. This highlights the importance of recognizing and addressing these unique characteristics. CONCLUSION: Our study findings unveiled that the prevalence of anxious depression among Taiwanese outpatients diagnosed with MDD was lower compared to inpatients but substantially higher than the reported rates in European countries and the United States. Furthermore, patients with anxious depression exhibited a greater occurrence of somatic symptoms.

Hope and its relationship with treatment/ physical related factors in lung cancer patients receiving immunotherapy.

BACKGROUNDPURPOSE: Immunotherapy is a new treatment option for patients with Lung Cancer (LC). However, relatively limited research has explored about patients' perception of hope and its associated factors during the process. This study aimed to examine level of perceived hope and the factors related to hope, with a particular focus on treatment and physically related factors, in LC patients receiving immunotherapy. METHODS: A cross-sectional study was conducted and patients who had already received at least one immunotherapy cycle were recruited from two hospitals in northern Taiwan. The questionnaire included a background information form, the Herth's Hope Index, and the Symptom Severity Scale. Stepwise regression was applied to identify the most robust factors related to level of hope in the participants. RESULTS: A total of 130 patients were recruited. Overall, patients reported moderate to high levels of hope and mild symptoms. Fatigue, weakness, appearance changes, pruritus, and shortness of breath were identified as the most severe symptoms. Further regression analysis showed that patients with poor performance status, less immunotherapy cycles, higher level of fatigue, and more severe pruritus reported to have lower level of hope which explained 47% of the variances. CONCLUSIONS: This study revealed that lung cancer patients undergoing immunotherapy had moderate level of hope. Patients' performance status, selected symptoms and times of receiving immunotherapy were the robust factors related to hope. Systematic assessment of patients' symptoms and the development of appropriate interventions to reduce distress and enhance hope are strongly recommended for both clinical care and research.

Complex heterozygous mutations in hereditary spherocytosis: A case report.

BACKGROUND: The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis (HS) in children. We also hope to promote the application of gene detection technology in children with HS, with the goals of identifying more related gene mutations, supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children, and providing important guidance for the diagnosis, treatment, and prevention of HS in children. CASE SUMMARY: A 1-year and 5-month-old patient presented jaundice during the neonatal period, mild anemia 8 months later, splenic enlargement at 1 year and 5 months, and brittle red blood cell permeability. Genetic testing was performed on the patient, their parents, and sister. Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1. Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother. Combined with the clinical symptoms of the children, it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause, providing important guidance for revealing the pathogenesis, diagnosis, treatment, and promotion of gene detection technology in children with HS. CONCLUSION: This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1, which provides a reference for exploring HS.

Assessment of hepatitis B virus relapse in cancer patients receiving chemotherapy with prophylactic nucleos(t)ide analogues: Implications for overall mortality.

BACKGROUND AND AIMS: We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation. METHODS: From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors. RESULTS: We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy. CONCLUSIONS: The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients.

Podocyte programmed cell death in diabetic kidney disease: Molecular mechanisms and therapeutic prospects.

Diabetic kidney disease (DKD) is the primary cause of chronic kidney and end-stage renal disease. Glomerular podocyte loss and death are pathological hallmarks of DKD, and programmed cell death (PCD) in podocytes is crucial in DKD progression. PCD involves apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. During DKD, PCD in podocytes is severely impacted and primarily characterized by accelerated podocyte apoptosis and suppressed autophagy. These changes lead to a gradual decrease in podocyte numbers, impairing the glomerular filtration barrier function and accelerating DKD progression. However, research on the interactions between the different types of PCD in podocytes is lacking. This review focuses on the novel roles and mechanisms of PCD in the podocytes of patients with DKD. Additionally, we summarize clinical drugs capable of regulating podocyte PCD, present challenges and prospects faced in developing drugs related to podocyte PCD and suggest that future research should further explore the detailed mechanisms of podocyte PCD and interactions among different types of PCD.

Anti-aging effects of Lacticaseibacillus paracasei PS117 on cognitive and intestinal health in naturally-aged mice: A focus on senescence-related proteins and microbiota composition.

The rising global aging population underscores the urgency of maintaining the health and well-being of the elderly while reducing the healthcare burden. Anti-aging probiotics have emerged as a promising strategy. This study identified a novel anti-senescence probiotic, Lacticaseibacillus paracasei PS117 (PS117). The effects of PS117 and heat-treated PS117 (HT-PS117) supplementation on cognitive function of naturally-aged male mice were investigated. It was found that PS117 supplementation improved the cognitive performance of aged mice in the Y-maze test. Furthermore, the level of senescence-related protein p16INK4a (p16) were reduced, while anti-senescence protein sirtuin 1 (Sirt1) were increased in the hippocampus. In addition, there was an overall improvement in the intestinal function. Distinct changes in the gut microbiota were also identified, suggesting a potential contribution to the beneficial effects of PS117 supplementation. In conclusion, these results suggest that PS117 supplements could improve cognitive and intestinal functions in naturally-aged mice, while HT-117 improves only intestinal function, possibly by improving the gut microbiota composition.

Biological characteristics of tissue engineered-nerve grafts enhancing peripheral nerve regeneration.

BACKGROUND: A favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA). METHODS: In order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein-protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively. RESULTS: The results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1ß and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-ß, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences. CONCLUSIONS: This study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation.

3D organoid cultivation improves the maturation and functional differentiation of cholangiocytes from human pluripotent stem cells.

Idiopathic cholangiopathies are diseases that affect cholangiocytes, and they have unknown etiologies. Currently, orthotopic liver transplantation is the only treatment available for end-stage liver disease. Limited access to the bile duct makes it difficult to model cholangiocyte diseases. In this study, by mimicking the embryonic development of cholangiocytes and using a robust, feeder- and serum-free protocol, we first demonstrate the generation of unique functional 3D organoids consisting of small and large cholangiocytes derived from human pluripotent stem cells (PSCs), as opposed to traditional 2D culture systems. At day 28 of differentiation, the human PSC-derived cholangiocytes expressed markers of mature cholangiocytes, such as CK7, CK19, and cystic fibrosis transmembrane conductance regulator (CFTR). Compared with the 2D culture system-generated cholangiocytes, the 3D cholangiocyte organoids (COs) showed higher expression of the region-specific markers of intrahepatic cholangiocytes YAP1 and JAG1 and extrahepatic cholangiocytes AQP1 and MUC1. Furthermore, the COs had small-large tube-like structures and functional assays revealed that they exhibited characteristics of mature cholangiocytes, such as multidrug resistance protein 1 transporter function and CFTR channel activity. In addition to the extracellular matrix supports, the epidermal growth factor receptor (EGFR)-mediated signaling regulation might be involved in this cholangiocyte maturation and differentiation. These results indicated the successful generation of intrahepatic and extrahepatic cholangiocytes by using our 3D organoid protocol. The results highlight the advantages of our 3D culture system over the 2D culture system in promoting the functional differentiation and maturation of cholangiocytes. In summary, in advance of the previous works, our study provides a possible concept of small-large cholangiocyte transdifferentiation of human PSCs under cost-effective 3D culture conditions. The study findings have implications for the development of effective cell-based therapy using COs for patients with cholangiopathies.

Emotional differences based on comments on doctor-patient disputes with varying levels of severity.

BACKGROUND: The risks associated with negative doctor-patient relationships have seriously hindered the healthy development of medical and healthcare and aroused widespread concern in society. The number of public comments on doctor-patient relationship risk events reflects the degree to which the public pays attention to such events. AIM: To explore public emotional differences, the intensity of comments, and the positions represented at different levels of doctor-patient disputes. METHODS: Thirty incidents of doctor-patient disputes were collected from Weibo and TikTok, and 3655 related comments were extracted. The number of comment sentiment words was extracted, and the comment sentiment value was calculated. The Kruskal-Wallis H test was used to compare differences between each variable group at different levels of incidence. Spearman's correlation analysis was used to examine associations between variables. Regression analysis was used to explore factors influencing scores of comments on incidents. RESULTS: The study results showed that public comments on media reports of doctor-patient disputes at all levels are mainly dominated by "good" and "disgust" emotional states. There was a significant difference in the comment scores and the number of partial emotion words between comments on varying levels of severity of doctor-patient disputes. The comment score was positively correlated with the number of emotion words related to positive, good, and happy) and negatively correlated with the number of emotion words related to negative, anger, disgust, fear, and sadness. CONCLUSION: The number of emotion words related to negative, anger, disgust, fear, and sadness directly influences comment scores, and the severity of the incident level indirectly influences comment scores.

Clinical and Adverse Outcomes Associated With Concomitant Use of CYP2D6-Metabolized Opioids With Antidepressants in Older Nursing Home Residents : A Target Trial Emulation Study.

BACKGROUND: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents. OBJECTIVE: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs). DESIGN: Retrospective cohort study using a target trial emulation framework. SETTING: 100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021. PARTICIPANTS: Long-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use. INTERVENTION: Initiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more. MEASUREMENTS: Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting. RESULTS: Among 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose. LIMITATION: Findings are generalizable to NH populations only. CONCLUSION: Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents. PRIMARY FUNDING SOURCE: National Institute on Aging.