Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs.

Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. Interactions between bacterial products (MAMPs) and Toll-like receptors (TLRs) are known to be mandatory for IEC homeostasis, but how TLRs may time homeostatic functions with circadian changes is unknown. Our functional and molecular dissections of the IEC circadian clock demonstrate that its integrity is required for microbiota-IEC dialog. In IEC, the antiphasic expression of the RORα activator and RevErbα repressor clock output regulators generates a circadian rhythmic TLR expression that converts the temporally arrhythmic microbiota signaling into circadian rhythmic JNK and IKKß activities, which prevents RevErbα activation by PPARα that would disrupt the circadian clock. Moreover, through activation of AP1 and NF-κB, these activities, together with RORα and RevErbα, enable timing homeostatic functions of numerous genes with IEC circadian events. Interestingly, microbiota signaling deficiencies induce a prediabetic syndrome due to ileal corticosterone overproduction consequent to clock disruption.

Dihydrofolate reductase activity controls neurogenic transitions in the developing neocortex.

One-carbon/folate (1C) metabolism supplies methyl groups required for DNA and histone methylation, and is involved in the maintenance of self-renewal in stem cells. Dihydrofolate reductase (DHFR), a key enzyme in 1C metabolism, is highly expressed in human and mouse neural progenitors at the early stages of neocortical development. Here, we have investigated the role of DHFR in the developing neocortex and report that reducing its activity in human neural organoids and mouse embryonic neocortex accelerates indirect neurogenesis, thereby affecting neuronal composition of the neocortex. Furthermore, we show that decreasing DHFR activity in neural progenitors leads to a reduction in one-carbon/folate metabolites and correlates with modifications of H3K4me3 levels. Our findings reveal an unanticipated role for DHFR in controlling specific steps of neocortex development and indicate that variations in 1C metabolic cues impact cell fate transitions.

Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor.

The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex "negative" GREs (nGREs) has been reported. However, GR-mediated transrepression was generally ascribed to indirect "tethered" interaction with other DNA-bound factors. We report that GC-induces direct transrepression via the binding of GR to simple DBS (IR nGREs) unrelated to (+)GRE. These DBS act on agonist-liganded GR, promoting the assembly of cis-acting GR-SMRT/NCoR repressing complexes. IR nGREs are present in over 1000 mouse/human ortholog genes, which are repressed by GC in vivo. Thus variations in the levels of a single ligand can coordinately turn genes on or off depending in their response element DBS, allowing an additional level of regulation in GR signaling. This mechanism suits GR signaling remarkably well, given that adrenal secretion of GC fluctuates in a circadian and stress-related fashion.

The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene.

We demonstrate that there is a tight functional relationship between two highly evolutionary conserved cell processes, i.e., the circadian clock (CC) and the circadian DNA demethylation-methylation of cognate deoxyCpG-rich islands. We have discovered that every circadian clock-controlled output gene (CCG), but not the core clock nor its immediate-output genes, contains a single cognate intronic deoxyCpG-rich island, the demethylation-methylation of which is controlled by the CC. During the transcriptional activation period, these intronic islands are demethylated and, upon dimerization of two YY1 protein binding sites located upstream to the transcriptional enhancer and downstream from the deoxyCpG-rich island, store activating components initially assembled on a cognate active enhancer (a RORE, a D-box or an E-box), in keeping with the generation of a transcriptionally active condensate that boosts the initiation of transcription of their cognate pre-mRNAs. We report how these single intronic deoxyCpG-rich islands are instrumental in such a circadian activation/repression transcriptional process.

Cockayne's Syndrome A and B Proteins Regulate Transcription Arrest after Genotoxic Stress by Promoting ATF3 Degradation.

Cockayne syndrome (CS) is caused by mutations in CSA and CSB. The CSA and CSB proteins have been linked to both promoting transcription-coupled repair and restoring transcription following DNA damage. We show that UV stress arrests transcription of approximately 70% of genes in CSA- or CSB-deficient cells due to the constitutive presence of ATF3 at CRE/ATF sites. We found that CSB, CSA/DDB1/CUL4A, and MDM2 were essential for ATF3 ubiquitination and degradation by the proteasome. ATF3 removal was concomitant with the recruitment of RNA polymerase II and the restart of transcription. Preventing ATF3 ubiquitination by mutating target lysines prevented recovery of transcription and increased cell death following UV treatment. Our data suggest that the coordinate action of CSA and CSB, as part of the ubiquitin/proteasome machinery, regulates the recruitment timing of DNA-binding factors and provide explanations about the mechanism of transcription arrest following genotoxic stress.

Dynamically Reconfigurable on-Chip Polarimeters Based on Nanoantenna Enabled Polarization Dependent Optoelectronic Computing.

On-chip polarization detectors have attracted extensive research interest due to their filterless and ultracompact architecture. However, their polarization-dependent photoresponses cannot be dynamically adjusted, hindering the development toward intelligence. Here, we propose dynamically reconfigurable polarimetry based on in-sensor differentiation of two self-powered photoresponses with orthogonal polarization dependences and tunable responsivities. Such a device can be electrostatically configured in an ultrahigh polarization extinction ratio (PER) mode, where the PER tends to infinity, a Stokes parameter direct sensing mode, where the photoresponse is proportional to S1 or S2 with high accuracy (RMSES1 = 1.5%, RMSES2 = 2.0%), or a background suppressing mode, where the target-background polarization contrast is singularly enhanced. Moreover, the device achieves a polarization angle sensitivity of 0.51 mA·W-1·degree-1 and a specific polarization angle detectivity of 2.8 × 105 cm·Hz1/2·W·degree-1. This scheme is demonstrated throughout the near-to-long-wavelength infrared range, and it will bring a leap for next-generation on-chip polarimeters.

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL.

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph- B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10-4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

Insulin resistance, coronary artery lesion complexity and adverse cardiovascular outcomes in patients with acute coronary syndrome.

BACKGROUND: Insulin resistance (IR) is linked to both the complexity of coronary artery lesions and the prognosis of acute coronary syndrome (ACS). However, the precise extent of this correlation and its impact on adverse cardiovascular outcomes in ACS patients remain unclear. Therefore, this study aims to investigate the intricate relationship between IR, coronary artery lesion complexity, and the prognosis of ACS through a cohort design analysis. METHOD: A total of 986 patients with ACS who underwent percutaneous coronary intervention (PCI) were included in this analysis. IR was assessed using the triglyceride-glucose (TyG) index, while coronary artery lesion complexity was evaluated using the SYNTAX score. Pearson's correlation coefficients were utilized to analyze the correlations between variables. The association of the TyG index and SYNTAX score with major adverse cardiovascular events (MACEs) in ACS was investigated using the Kaplan-Meier method, restricted cubic splines (RCS), and adjusted Cox regression. Additionally, a novel 2-stage regression method for survival data was employed in mediation analysis to explore the mediating impact of the SYNTAX score on the association between the TyG index and adverse cardiovascular outcomes, including MACEs and unplanned revascularization. RESULTS: During a median follow-up of 30.72 months, 167 cases of MACEs were documented, including 66 all-cause deaths (6.69%), 26 nonfatal myocardial infarctions (MIs) (2.64%), and 99 unplanned revascularizations (10.04%). The incidence of MACEs, all-cause death, and unplanned revascularization increased with elevated TyG index and SYNTAX score. Both the TyG index (non-linear, P = 0.119) and SYNTAX score (non-linear, P = 0.004) displayed a positive dose-response relationship with MACEs, as illustrated by the RCS curve. Following adjustment for multiple factors, both the TyG index and SYNTAX score emerged as significant predictors of MACEs across the total population and various subgroups. Mediation analysis indicated that the SYNTAX score mediated 25.03%, 18.00%, 14.93%, and 11.53% of the correlation between the TyG index and MACEs in different adjusted models, respectively. Similar mediating effects were observed when endpoint was defined as unplanned revascularization. CONCLUSION: Elevated baseline TyG index and SYNTAX score were associated with a higher risk of MACEs in ACS. Furthermore, the SYNTAX score partially mediated the relationship between the TyG index and adverse cardiovascular outcomes.

Microbiota-microglia crosstalk between Blautia producta and neuroinflammation of Parkinson's disease: A bench-to-bedside translational approach.

Parkinson's disease (PD) is intricately linked to abnormal gut microbiota, yet the specific microbiota influencing clinical outcomes remain poorly understood. Our study identified a deficiency in the microbiota genus Blautia and a reduction in fecal short-chain fatty acid (SCFA) butyrate level in PD patients compared to healthy controls. The abundance of Blautia correlated with the clinical severity of PD. Supplementation with butyrate-producing bacterium B. producta demonstrated neuroprotective effects, attenuating neuroinflammation and dopaminergic neuronal death in mice, consequently ameliorating motor dysfunction. A pivotal inflammatory signaling pathway, the RAS-related pathway, modulated by butyrate, emerged as a key mechanism inhibiting microglial activation in PD. The change of RAS-NF-κB pathway in PD patients was observed. Furthermore, B. producta-derived butyrate demonstrated the inhibition of microglial activation in PD through regulation of the RAS-NF-κB pathway. These findings elucidate the causal relationship between specific gut microbiota and PD, presenting a novel microbiota-based treatment perspective for PD.

A case report of sepsis associated coagulopathy after percutaneous nephrostomy.

BACKGROUND: Hemorrhage is a common complication of nephrostomy and percutaneous nephrolithotripsy, and it is caused by surgical factors. Here we report a rare case of hemorrhage caused by sepsis-related coagulation dysfunction. CASE PRESENTATION: A 72-years-old male patient with bilateral ureteral calculi accompanied by hydronephrosis and renal insufficiency developed sepsis and hemorrhage on the third day after bilateral nephrostomy. After vascular injury was excluded by DSA, the hemorrhage was considered to be sepsis-associated coagulopathy(SAC/SIC), finally the patient recovered well after active symptomatic treatment. CONCLUSIONS: In patients with sepsis and hemorrhage, SAC/SIC cannot be excluded even if coagulation function is slightly abnormal after surgical factors are excluded. For urologists who may encounter similar cases in their general urology practice, it is important to be aware of these unusual causes of hemorrhage.

Waves of sumoylation support transcription dynamics during adipocyte differentiation.

Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, the mechanisms that orchestrate the global and dramatic transcriptional changes leading to adipocyte differentiation remain to be fully unraveled. We investigated the regulation of nascent transcription by the sumoylation pathway during adipocyte differentiation using SLAMseq and ChIPseq. We discovered that the sumoylation pathway has a dual function in differentiation; it supports the initial downregulation of pre-adipocyte-specific genes, while it promotes the establishment of the mature adipocyte transcriptional program. By characterizing endogenous sumoylome dynamics in differentiating adipocytes by mass spectrometry, we found that sumoylation of specific transcription factors like PPARγ/RXR and their co-factors are associated with the transcription of adipogenic genes. Finally, using RXR as a model, we found that sumoylation may regulate adipogenic transcription by supporting the chromatin occurrence of transcription factors. Our data demonstrate that the sumoylation pathway supports the rewiring of transcriptional networks required for formation of functional adipocytes. This study also provides the scientists in the field of cellular differentiation and development with an in-depth resource of the dynamics of the SUMO-chromatin landscape, SUMO-regulated transcription and endogenous sumoylation sites during adipocyte differentiation.

CD4+ T cells require Ikaros to inhibit their differentiation toward a pathogenic cell fate.

The production of proinflammatory cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), by pathogenic CD4+ T cells is central for mediating tissue injury in inflammatory and autoimmune diseases. However, the factors regulating the T cell pathogenic gene expression program remain unclear. Here, we investigated how the Ikaros transcription factor regulates the global gene expression and chromatin accessibility changes in murine T cells during Th17 polarization and after activation via the T cell receptor (TCR) and CD28. We found that, in both conditions, Ikaros represses the expression of genes from the pathogenic signature, particularly Csf2, which encodes GM-CSF. We show that, in TCR/CD28-activated T cells, Ikaros binds a critical enhancer downstream of Csf2 and is required to regulate chromatin accessibility at multiple regions across this locus. Genome-wide Ikaros binding is associated with more compact chromatin, notably at multiple sites containing NFκB or STAT5 target motifs, and STAT5 or NFκB inhibition prevents GM-CSF production in Ikaros-deficient cells. Importantly, Ikaros also limits GM-CSF production in TCR/CD28-activated human T cells. Our data therefore highlight a critical conserved transcriptional mechanism that antagonizes GM-CSF expression in T cells.

Decreased expression of ATP-binding cassette protein G1 promotes abnormal adipogenesis of condylar chondrocytes in temporomandibular joint osteoarthritis.

BACKGROUND: Abnormal lipid metabolism is involved in the development of osteoarthritis (OA). ATP-binding cassette protein G1 (ABCG1) is crucial in mediating the outflow of cholesterol, phosphatidylcholine and sphingomyelin and reducing intracellular lipid accumulation. OBJECTIVE: This study aimed to evaluate whether ABCG1 participates in the abnormal adipogenesis of chondrocytes in osteoarthritic cartilage of temporomandibular joint. METHODS: Eight-week-old female rats were subjected to unilateral anterior crossbite (UAC) to induce OA in the temporomandibular joint (TMJ). Histochemical staining, immunohistochemical (IHC) staining, and qRT-PCR were performed. Primary condylar chondrocytes of rats were transfected with ABCG1 shRNA or overexpression lentivirus and then stimulated with fluid flow shear stress (FFSS). Cells were collected for oil red O staining, immunofluorescence staining, and qRT-PCR analysis. RESULTS: Abnormal adipogenesis, characterized by increased expression of Adiponectin, CCAAT/enhancer-binding protein α (Cebpα), fatty acid binding protein 4 (Fabp4) and Perilipin1, was enhanced in the degenerative cartilage of TMJ OA in rats with UAC, accompanied by decreased expression of ABCG1. After FFSS stimulation, we observed lipid droplets in the cytoplasm of cultured cells with increased expression of Adiponectin, Cebpα, Fabp4 and Perilipin1 and decreased expression of ABCG1. Knockdown of Abcg1 induced abnormal adipogenesis and differentiation of condylar chondrocytes. Overexpression of ABCG1 alleviated the abnormal adipogenesis and differentiation of condylar chondrocytes induced by FFSS. CONCLUSIONS: Abnormal adipogenesis of chondrocytes and decreased ABCG1 expression were observed in degenerative cartilage of TMJ OA. ABCG1 overexpression effectively inhibits the adipogenesis of chondrocytes and thus alleviates TMJ condylar cartilage degeneration.

Hormone Regulation in Testicular Development and Function.

The testes serve as the primary source of androgens and the site of spermatogenesis, with their development and function governed by hormonal actions via endocrine and paracrine pathways. Male fertility hinges on the availability of testosterone, a cornerstone of spermatogenesis, while follicle-stimulating hormone (FSH) signaling is indispensable for the proliferation, differentiation, and proper functioning of Sertoli and germ cells. This review covers the research on how androgens, FSH, and other hormones support processes crucial for male fertility in the testis and reproductive tract. These hormones are regulated by the hypothalamic-pituitary-gonad (HPG) axis, which is either quiescent or activated at different stages of the life course, and the regulation of the axis is crucial for the development and normal function of the male reproductive system. Hormonal imbalances, whether due to genetic predispositions or environmental influences, leading to hypogonadism or hypergonadism, can precipitate reproductive disorders. Investigating the regulatory network and molecular mechanisms involved in testicular development and spermatogenesis is instrumental in developing new therapeutic methods, drugs, and male hormonal contraceptives.

Total Synthesis of Incarnatapeptins A and B.

The first total synthesis of incarnatapeptins A and B, two novel marine natural products, was accomplished from readily available (S)-1-benzyloxycarbonylhexahydropyridazine-3-carboxylic acid. This route, whose longest linear sequence was 12 steps, provided the incarnatapeptins A and B in yields of 26.5 % and 19.7 %, respectively, and enabled the structure and stereochemistry of both natural products to be unambiguously confirmed. Highlights of our synthesis include the photoredox-mediated decarboxylative 1,4-addition reaction and a novel and practical N-acylation paradigm promoted by silver carbonate. The unusual facile atropisomerism of some linear peptidic intermediates was also observed by TLC analysis in the course of this work.

Extrasynaptic NMDA Receptors Bidirectionally Modulate Intrinsic Excitability of Inhibitory Neurons.

The NMDA subtype glutamate receptors (NMDARs) play important roles in both physiological and pathologic processes in the brain. Compared with their critical roles in synaptic modifications and excitotoxicity in excitatory neurons, much less is understood about the functional contributions of NMDARs to the inhibitory GABAergic neurons. By using selective NMDAR inhibitors and potentiators, we here show that NMDARs bidirectionally modulate the intrinsic excitability (defined as spontaneous/evoked spiking activity and EPSP-spike coupling) in inhibitory GABAergic neurons in adult male and female mice. This modulation depends on GluN2C/2D- but not GluN2A/2B-containing NMDARs. We further show that NMDAR modulator EU1794-4 mostly enhances extrasynaptic NMDAR activity, and by using it we demonstrate a significant contribution of extrasynaptic NMDARs to the modulation of intrinsic excitability in inhibitory neurons. Together, this bidirectional modulation of intrinsic excitability reveals a previously less appreciated importance of NMDARs in the second-to-second functioning of inhibitory GABAergic neurons.SIGNIFICANCE STATEMENT NMDA subtype of glutamate receptors (NMDARs) have important roles in brain functions, including both physiological and pathologic ones. The role of NMDARs in inhibitory neurons has been less elucidated compared with that in excitatory neurons. Our results demonstrate the importance of GluN2C/GluN2D-containing but not GluN2A/GluN2B-containing extrasynaptic NMDARs in modulating the intrinsic excitability of inhibitory neurons. These results further suggest distinct contributions of subsynaptic locations and subunit compositions of NMDARs to their functions in excitatory and inhibitory neurons. The above findings have implications for better understanding of brain diseases, such as schizophrenia.

Identification of new candidate drugs for primary Sjögren's syndrome using a drug repurposing transcriptomic approach.

OBJECTIVES: To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes. METHODS: Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database. RESULTS: We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated. CONCLUSION: This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium-glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated. METHODS: Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-ß1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs). RESULTS: Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT. CONCLUSIONS: Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.

Triglyceride-glucose index is associated with recurrent revascularization in patients with type 2 diabetes mellitus after percutaneous coronary intervention.

BACKGROUND: The Triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, is independently associated with the severity of coronary artery lesions and the prognosis of coronary heart disease. The investigation aimed to explore the relationship between the TyG index and recurrent revascularization in individuals with type 2 diabetes mellitus (T2DM) resulting from the progression of lesions or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). METHOD: A total of 633 patients who met the inclusion and exclusion criteria were enrolled and divided into three groups based on the tertiles of the TyG index. The primary endpoint was recurrent revascularization resulting from the progression of lesions or ISR. All-cause death was considered as the competing risk event. Competing risk analysis and Cox regression analysis for predicting recurrent revascularization after PCI were conducted stepwise. Variables were standardized to make the hazard ratio (HR), subdistribution hazard ratio (SHR) and corresponding 95% CI more consistent prior to being used for fitting the multivariate risk model. The predictive ability of the TyG index was evaluated using several measures, including the ROC curve, likelihood ratio test, Akaike's information criteria, category-free continuous net reclassification improvement (cNRI > 0), and integrated discrimination improvement (IDI). Internal validation was conducted through bootstrapping with 1000 resamples. RESULTS: During a median follow-up period of 18.33 months, a total of 64 (10.11%) patients experienced recurrent revascularization, including 55 cases of lesion progression and 9 cases of in-stent restenosis. After controlling for competitive risk events, the TyG index was independently associated with a higher risk of recurrent revascularization [SHR:1.4345, (95% CI 1.1458-1.7959), P = 0.002]. The likelihood ratio test and Akaike's information criteria showed that the TyG index significantly improves the prognostic ability. Additionally, adding the TyG index improved the ability of the established risk model in predicting recurrent revascularization, indicated by a C-index of 0.759 (95% CI 0.724-0.792, P < 0.01), with a cNRI > 0 of 0.170 (95% CI 0.023-0.287, P < 0.05), and an IDI of 0.024 (95% CI 0.009-0.039, P = 0.002). These results remained consistent when the models containing TyG index were confirmed using an internal bootstrap validation method. CONCLUSION: The findings highlight the potential of the TyG index as a predictor of recurrent revascularization. Lesion progression emerged as the primary contributor to recurrent revascularization instead of in-stent restenosis. The incorporation of the TyG index into risk prediction models is likely to be beneficial for accurate risk stratification in order to improve prognosis.

Morphological Evolution of Calcite Grown in Zwitterionic Hydrogels: Charge Effects Enhanced by Gel-Incorporation.

The incorporation of charged biomacromolecules is widely found in biomineralization. To investigate the significance of this biological strategy for mineralization control, gelatin-incorporated calcite crystals grown from gelatin hydrogels with different charge concentrations along the gel networks are examined. It is found that the bound charged groups on gelatin networks (amino cations, gelatin-NH3 + and carboxylic anions, gelatin-COO- ) play crucial roles in controlling the single-crystallinity and the crystal morphology. And the charge effects are greatly enhanced by the gel-incorporation because the incorporated gel networks force the bound charged groups on them to attach to crystallization fronts. In contrast, ammonium ions (NH4 + ) and acetate ions (Ac- ) dissolve in the crystallization media do not exhibit the similar charge effects because the balance of attachment/detachment make them more difficult to be incorporated. Employing the revealed charge effects, the calcite crystal composites with different morphologies can be flexibly prepared.