Metabolic health and genetic predisposition in inflammatory bowel disease: Insights from a prospective cohort study.

BACKGROUND: Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. METHOD: This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. RESULTS: During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. CONCLUSION: Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.

Chelation-activated ultralong room-temperature phosphorescence and thermo-/excitation-dependent persistent luminescence.

Multidentate chelation effect can be used to activate the ultralong room-temperature phosphorescence and stabilize the triplet excitons. The as-synthesized cadmium(II) based complexes further exhibit thermo- and excitation-dependent persistent luminescence as potential for optical logic gate.

Integrated Evaluation Method of the Health-Related Physical Environment in Urbanizing Areas: A Case Study From a University Campus in China.

Environmental deterioration in urbanizing areas increases the risks of sudden death as well as chronic, infectious, and psychological diseases. Quantifying health-related physical environment can assess the health risk of urban residents. This study uses an integrated evaluation method to simulate the health-related physical environment in the four dimensions of acoustic, wind, thermal, and landscape. According to the case study of one university campus in an urbanizing area in China, results show that (1) areas with unqualified equivalent A sound levels are generally the sports area, green square 1 and laboratory areas, and residents who stay in these areas for a long time suffer the risks of hearing loss and mental stress. (2) The windless area ratio of teaching area 1 and dormitory area 4 is larger than 20%, and respiratory health risks increase because these areas relate to relatively wind discomfort. (3) The high-temperature zone ratio of sports area and green square 2 is larger than 50%, and heatstroke risks increase since these areas relate with low thermal comfort. (4) The overall landscape perception level of dormitories and dining areas is lower than that of the teaching area, and it can cause anxiety and irritability. (5) The sports area has the lowest average overall score of the health-related physical environment among all functional areas, followed by laboratory areas. These findings indicate that the proposed model and method can be valuable tools for the pre-evaluation and optimization of urban planning. It can reduce the health risks of residents in urbanizing areas and can benefit residents' health and urban sustainable development.

Gender-specific association between the regular use of statins and the risk of irritable bowel syndrome: A population-based prospective cohort study.

Introduction: In addition to lipid-lowering effects, statins might modulate the gut microbiome and alleviate systematic inflammation, which in turn, may have a protective effect against irritable bowel syndrome (IBS). The aim of our study was to evaluate the gender-specific association between statin exposure and the risk of IBS. Method: We undertook a prospective analysis based on the United Kingdom Biobank, a large ongoing cohort including 477,293 participants aged 37-73 years. We included participants based on information on their personal statin use and also those free of IBS and cancer at the baseline. We evaluated the gender-specific hazard ratio (HR) and 95% confidence interval (CI) with Cox proportional hazards regression, adjusting for demographic factors, lifestyle factors, comorbidities, and statin indications. Result: A total of 438,805 participants (206,499 males and 232,306 females) were included in the analysis. Among male participants, the regular use of statins was associated with a decreased risk of IBS (HR: 0.77; 95% CI: 0.61-0.97). This association persists across multiple sensitivity and subgroup analyses and did not show clear evidence of variance among the major types of statins. We did not find sufficient evidence of the association between the statin use and IBS risk in females (HR: 0.98; 95% CI: 0.82-1.16). Conclusion: Our study found that the regular use of statins was associated with a decreased risk of IBS in male participants. Further studies are required to confirm the beneficial effect of statins.

Low-Dimensional Organic Metal Halide Hybrids with Excitation-Dependent Optical Waveguides from Visible to Near-Infrared Emission.

Molecular luminescent materials with optical waveguide properties have wide application prospects in the fields of sensors, filters, and modulators. However, designing and synthesizing optical waveguide materials with unique morphology, high emissive efficiency, and tunable optical properties in the same solid-state system remains an open challenge. In this work, we report new types of morphological one-dimensional (1D) organic metal halide hybrid micro/nanotubes and micro/nanorods, which exhibit excitation-dependent optical waveguide properties from visible to near-infrared (NIR) regions with low-loss coefficient and high emissive efficiency during the propagation process. Strong intermolecular interactions within the hybrid systems could effectively reduce the nonradiative transition and improve quantum efficiency. Photophysical studies and theoretical calculations demonstrate that the color-tunable emission can be attributed to the coexistence of locally excited states and charge-transfer states. Utilizing excitation-dependent optical waveguide emission ranging from visible to NIR regions, we fabricate an optical wavelength converter to transfer short-wavelength into long-wavelength emission with multichannels. Furthermore, an optical logic gate system was designed based on the tunable emission properties of the 1D metal halide micro/nanotubes. Therefore, this work provides not only a facile process to synthesize 1D organic metal halide hybrids with excitation-dependent optical waveguide properties but also a new way to advance photofunctional logic computation at the micro/nanoscale.

Research Progress in Organic Synthesis by Means of Photoelectrocatalysis.

The rapid development of radical chemistry has spurred several innovative strategies for organic synthesis. The novel approaches for organic synthesis play a critical role in promoting and regulating the single-electron redox activity. Among them, photoelectrocatalysis (PEC) has attained considerable attention as the most promising strategy to convert organic compounds into fine chemicals. This review highlights the current progress in organic synthesis through PEC, including various catalytic reactions, catalyst systems and practical applications. The numerous catalytic reactions suffer the high overpotential and poor conversion efficiency, depending on the design of electrolyzers and the reaction mechanisms. We also considered the recent developments with special emphasis on scientific problems and efficient solutions, which enhance accessibility to utilize and further develop the photoelectrocatalytic technology for the specific chemical bonds formation and the fabrication of numerous catalytic systems.

Efficient passage of human pluripotent stem cells on spider silk matrices under xeno-free conditions.

Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine and pharmaceutical development. Such applications require cell culture methods and reagents that are chemically defined, xeno-free, scalable, and low-cost. Herein, we describe non-mechanical passaging of hPSCs on spider silk films under chemically defined and xeno-free conditions. The cells were dissociated into single cells or small aggregates using Accutase or enzyme-free dissociation buffer and then passaged to spider silk films, where they expanded in monolayers until they covered the surface. Cells cultured over 10 passages on spider silk film remained karyotypically normal and pluripotent. In conclusion, a novel method for passaging dissociated hPSCs under conditions that are compatible with clinical applications is presented. The method is cost-efficient and may be useful for both research and clinical applications.

Spider silk for xeno-free long-term self-renewal and differentiation of human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) can undergo unlimited self-renewal and have the capacity to differentiate into all somatic cell types, and are therefore an ideal source for the generation of cells and tissues for research and therapy. To realize this potential, defined cell culture systems that allow expansion of hPSCs and subsequent controlled differentiation, ideally in an implantable three-dimensional (3D) matrix, are required. Here we mimic spider silk - Nature's high performance material - for the design of chemically defined 2D and 3D matrices for cell culture. The silk matrices do not only allow xeno-free long-term expansion of hPSCs but also differentiation in both 2D and 3D. These results show that biomimetic spider silk matrices enable hPSC culture in a manner that can be applied for experimental and clinical purposes.

Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation.

The MYC and RAS oncogenes are frequently activated in cancer and, together, are sufficient to transform rodent cells. The basis for this cooperativity remains unclear. We found that although Ras interfered with Myc-induced apoptosis, Myc repressed Ras-induced senescence, together abrogating two main barriers of tumorigenesis. Inhibition of cellular senescence required phosphorylation of Myc at Ser-62 by cyclin E/cyclin-dependent kinase (Cdk) 2. Cdk2 interacted with Myc at promoters, where it affected Myc-dependent regulation of genes, including Bmi-1, p16, p21, and hTERT, which encode proteins known to control senescence. Repression of senescence by Myc was abrogated by the Cdk inhibitor p27Kip1, which is induced by antiproliferative signals like IFN-gamma or by pharmacological inhibitors of Cdk2 but not by inhibitors of other Cdks. In contrast, a phospho-mimicking Myc-S62D mutant was resistant to these manipulations. Inhibition of cyclin E/Cdk2 reversed the senescence-associated gene expression pattern imposed by Myc/cyclin E/Cdk2. This indicates a role of Cdk2 as a transcriptional cofactor and activator of the antisenescence function of Myc and provides mechanistic insight into the Myc-p27Kip1 antagonism. Finally, our findings highlight that pharmacological inhibition of Cdk2 activity is a potential therapeutical principle for cancer therapy, in particular for tumors with activated Myc or Ras.

TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity.

Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.

Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells.

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)-induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastoma cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heterodimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Mad1/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA+IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.

c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription.

The c-Myc oncoprotein regulates transcription of genes that are associated with cell growth, proliferation and apoptosis. c-Myc levels are modulated by ubiquitin/proteasome-mediated degradation. Proteasome inhibition leads to c-Myc accumulation within nucleoli, indicating that c-Myc might have a nucleolar function. Here we show that the proteins c-Myc and Max interact in nucleoli and are associated with ribosomal DNA. This association is increased upon activation of quiescent cells and is followed by recruitment of the Myc cofactor TRRAP, enhanced histone acetylation, recruitment of RNA polymerase I (Pol I), and activation of rDNA transcription. Using small interfering RNAs (siRNAs) against c-Myc and an inhibitor of Myc-Max interactions, we demonstrate that c-Myc is required for activating rDNA transcription in response to mitogenic signals. Furthermore, using the ligand-activated MycER (ER, oestrogen receptor) system, we show that c-Myc can activate Pol I transcription in the absence of Pol II transcription. These results suggest that c-Myc coordinates the activity of all three nuclear RNA polymerases, and thereby plays a key role in regulating ribosome biogenesis and cell growth.

Mad 1 inhibits cell growth and proliferation but does not promote differentiation or overall survival in human U-937 monoblasts.

The Mad family proteins are transcriptional repressors belonging to the basic region/helix-loop-helix/leucine zipper family. They share a common obligatory dimerization partner, Max, with the oncoprotein c-Myc and antagonize the function of Myc to activate transcription. The Myc/Max/Mad network has therefore been suggested to function as a molecular switch that regulates cell growth and differentiation by controlling a common set of genes. To study the biological consequences of Mad1 expression for hematopoietic cell growth and differentiation, we used the U-937 monocytic differentiation model to generate cells with inducible Mad1 expression using the reversed tetracycline-controlled transactivator system. The elevated expression of Mad1 in these cells resulted in increased Mad1/Max heterodimer formation correlating with reduced expression of the Myc/Mad target gene ODC. Mad1-expressing U-937 cells in suspension culture proliferated slower and exhibited an increased number of cells in the G1 phase of the cell cycle. Further, growth in semisolid medium was almost completely inhibited. Mad1-expression, however, neither enforced spontaneous differentiation nor enhanced differentiation induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, retinoic acid (RA), or vitamin D3 but rather led to delayed RA-stimulated differentiation. Mad1-expressing cells were further found to be reduced in cell size in all phases of the cells cycle and particularly in response to RA-induced differentiation. Unexpectedly, whereas Fas-induced apoptosis was slightly attenuated in Mad1-expressing U-937 cells, Mad1 sensitized the cells to tumor necrosis factor-alpha-induced apoptosis. These results suggest that Mad1 primarily regulates cell growth and proliferation in these cells, whereas its role in cellular differentiation and survival seems to be more complex.

The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription.

The transcription regulatory oncoprotein c-Myc controls genes involved in cell growth, apoptosis, and oncogenesis. c-Myc is turned over very quickly through the ubiquitin/proteasome pathway. The proteins involved in this process are still unknown. We have found that Skp2 interacts with c-Myc and participates in its ubiquitylation and degradation. The interaction between Skp2 and c-Myc occurs during the G1 to S phase transition of the cell cycle in normal lymphocytes. Surprisingly, Skp2 enhances c-Myc-induced S phase transition and activates c-Myc target genes in a Myc-dependent manner. Further, Myc-induced transcription was shown to be Skp2 dependent, suggesting interdependence between c-Myc and Skp2 in activation of transcription. Moreover, Myc-dependent association of Skp2, ubiquitylated proteins, and subunits of the proteasome to a c-Myc target promoter was demonstrated in vivo. The results suggest that Skp2 is a transcriptional cofactor for c-Myc and indicates a close relationship between transcription activation and transcription factor ubiquitination.

Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter.

Inhibition of cellular differentiation is one of the well-known biological activities of c-Myc-family proteins. We show here that Myc represses differentiation-induced expression of the cyclin-dependent kinase (CDK) inhibitor p21CIP1 (CDKN1A, p21), known to play an important role in cell fate decisions during growth and differentiation, in hematopoietic cells. Our results demonstrate that the c-Myc-responsive region is situated in the p21 core promoter. c-Myc binds to this region in vitro and in vivo through interaction with the initiator-binding Zn-finger transcription factor Miz-1, which associates directly with the promoter. Association of Myc with the promoter in vivo correlates inversely with p21 expression. Using mutants of c-Myc with impaired binding to Miz-1, our results further show that repression of p21 promoter/reporters as well as the endogenous p21 gene by Myc depends on interaction with Miz-1. Expression of Miz-1 increases during hematopoietic differentiation and Miz-1 activates the p21 promoter under conditions of low Myc levels, indicating a positive role for free Miz-1 in this process. In conclusion, repression of differentiation-induced p21 expression through Miz-1 may be an important mechanism by which Myc blocks differentiation.