A binary 2D perovskite passivation for efficient and stable perovskite/silicon tandem solar cells.

To achieve high power conversion efficiency in perovskite/silicon tandem solar cells, it is necessary to develop a promising wide-bandgap perovskite absorber and processing techniques in relevance. To date, the performance of devices based on wide-bandgap perovskite is still limited mainly by carrier recombination at their electron extraction interface. Here, we demonstrate assembling a binary two-dimensional perovskite by both alternating-cation-interlayer phase and Ruddlesden-Popper phase to passivate perovskite/C60 interface. The binary two-dimensional strategy takes effects not only at the interface but also in the bulk, which enables efficient charge transport in a wide-bandgap perovskite solar cell with a stabilized efficiency of 20.79% (1 cm2). Based on this absorber, a monolithic perovskite/silicon tandem solar cell is fabricated with a steady-state efficiency of 30.65% assessed by a third party. Moreover, the tandem devices retain 96% of their initial efficiency after 527 h of operation under full spectral continuous illumination, and 98% after 1000 h of damp-heat testing (85 °C with 85% relative humidity).

Nuclei engineering for even halide distribution in stable perovskite/silicon tandem solar cells.

Wide-bandgap (WBG) absorbers in tandem configurations suffer from poor crystallinity and weak texture, which leads to severe mixed halide-cation ion migration and phase segregation during practical operation. We control WBG film growth insensitive to compositions by nucleating the 3C phase before any formation of bromine-rich aggregates and 2H phases. The resultant WBG absorbers show improved crystallinity and strong texture with suppressed nonradiative recombination and enhanced resistance to various aging stresses. Perovskite/silicon tandem solar cells achieve power conversion efficiencies of 29.4% (28.8% assessed by a third party) in a 25-square centimeter active area and 32.5% in a 1-square centimeter active area. These solar cells retained 98.3 and 90% of the original efficiency after 1301 and 800 hours of operation at 25° and 50°C, respectively, at the maximum power point (AM 1.5G illumination, full spectrum, 1-sun) when encapsulated.

The ß-d-manno-heptoses are immune agonists across kingdoms.

Bacterial small molecule metabolites such as adenosine-diphosphate-d-glycero-ß-d-manno-heptose (ADP-heptose) and their derivatives act as effective innate immune agonists in mammals. We show that functional nucleotide-diphosphate-heptose biosynthetic enzymes (HBEs) are distributed widely in bacteria, archaea, eukaryotes, and viruses. We identified a conserved STTR5 motif as a hallmark of heptose nucleotidyltransferases that can synthesize not only ADP-heptose but also cytidine-diphosphate (CDP)- and uridine-diphosphate (UDP)-heptose. Both CDP- and UDP-heptoses are agonists that trigger stronger alpha-protein kinase 1 (ALPK1)-dependent immune responses than ADP-heptose in human and mouse cells and mice. We also produced ADP-heptose in archaea and verified its innate immune agonist functions. Hence, the ß-d-manno-heptoses are cross-kingdom, small-molecule, pathogen-associated molecular patterns that activate the ALPK1-dependent innate immune signaling cascade.

A Simple and Effective Strategy for the Development of Robust Promoter-Centric Gene Expression Tools.

Promoter-centric genetic tools play a crucial role in controlling gene expression for various applications, such as strain engineering and synthetic biology studies. Hence, a critical need persists for the development of robust gene expression tools. Streptomyces are well-known prolific producers of natural products and exceptional surrogate hosts for the production of high-value chemical compounds and enzymes. In this study, we reported a straightforward and effective strategy for the creation of potent gene expression tools. This was primarily achieved by introducing an additional -35-like motif upstream of the original -35 region of the promoter, coupled with the integration of a palindromic cis-element into the 5'-UTR region. This approach has generated a collection of robust constitutive and inducible gene expression tools tailored for Streptomyces. Of particular note, the fully activated oxytetracycline-inducible gene expression system containing an engineered kasOp* promoter (OK) exhibited nearly an order of magnitude greater activity compared to the well-established high-strength promoter kasOp* under the tested conditions, establishing itself as a powerful gene expression system for Streptomyces. This strategy is expected to be applicable in modifying various other promoters to acquire robust gene expression tools, as evidenced by the enhancement observed in the other two promoters, PL and P21 in this study. Moreover, the effectiveness of these tools has been demonstrated through the augmented production of transglutaminase and daptomycin. The gene expression tools established in this study, alongside those anticipated in forthcoming research, are positioned to markedly advance pathway engineering and synthetic biology investigations in Streptomyces and other microbial strains.

Astrocytes in the Ventral Hippocampus Bidirectionally Regulate Innate and Stress-Induced Anxiety-Like Behaviors in Male Mice.

The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch-clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety-like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3-d subacute restraint stress (SRS), a well-validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS-induced anxiety-related behaviors, whereas hM3Dq-mediated chemogenetic or SRS-induced activation of vHPC astrocytes enhances anxiety-like behaviors, which are reversed by intra-vHPC application of the ionotropic glutamate N-methyl-d-aspartate receptor antagonists. Furthermore, intra-vHPC or systemic application of the N-methyl-d-aspartate receptor antagonist memantine, a U.S. FDA-approved drug for Alzheimer's disease, fully rescues SRS-induced anxiety-like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety-related disorders.

Efficient degradation of haloacetic acids by vacuum ultraviolet-activated peroxymonosulfate: Kinetics, mechanisms and theoretical calculations.

Efficient degradation of haloacetic acids (HAAs) is crucial due to their potential risks. This study firstly proposed vacuum ultraviolet - activated peroxymonosulfate (VUV/PMS) to remove HAAs (i.e., monochloroacetic acid (MCAA), monobromoacetic acid (MBAA), dichloroacetic acid (DCAA), etc). VUV/PMS achieved 99.51 % MCAA and 63.29 % TOC removal within 10 min. Electron paramagnetic resonance (EPR), quenching and probe experiments demonstrated that •OH was responsible for MCAA degradation. MCAA degradation followed pathways of dehalogenation (major) and decarboxylation (minor). VUV/PMS showed application potential under various reaction parameters. Broad spectrum of VUV/PMS on various HAAs was further explored. Chlorinated HAAs (Cl-HAAs) were primarily degraded by oxidation reactions, while brominated HAAs (Br-HAAs) by direct VUV photolysis. The density functional theory-based calculations (DFT) revealed that reaction rates of HAAs correlated with the highest occupied molecular orbital (HOMO) and energy gap (ΔE), indicating that HAAs degradation depends on their chemical structures. The Fukui function (f0 values) and bond length showed vulnerability of the halogen atom in Cl-HAAs and C-Br bond in Br-HAAs. Overall, this study provides an in-depth perspective on the oxidation performance and mechanism of HAAs using VUV/PMS. It not only demonstrates a green and efficient method but also inspires new strategies for HAAs remediation.

Association between parental well-being and preschooler stress measured as hair cortisol concentration: A prospective cohort study.

Hair cortisol concentration (HCC) is a valuable biomarker for evaluating chronic stress in preschoolers. However, few studies have explored early life HCC and its associated factors. This prospective cohort study analysed the HCC in children aged 6-48 months and its associations with parental HCC as well as positive and negative parental mental health outcomes. We used data from the ongoing Longitudinal Examination Across Prenatal and Postpartum Health in Taiwan (LEAPP-HIT) project, conducted in Taipei between 2020 and 2024. Hair samples were collected from both parents and children in 177 families (91 samples obtained during pregnancy and 86 during the postpartum period). The parents also completed self-reported questionnaires. Multiple linear regression was conducted to analyse the data. We observed a significant positive correlation between parents' and preschoolers' HCC. Furthermore, maternal depression (adjusted beta coefficient [aß] = 0.09, 95% confidence interval [CI] = 0.02, 0.16) and perceived stress (aß = 0.15, 95% CI = 0.02, 0.26) were positively associated with preschoolers' HCC. By contrast, higher maternal eudaimonia was associated with lower HCC in preschoolers (aß = -0.11, 95% CI = -0.20, -0.01). For parents, maternal depression, anxiety, and perceived stress were independently associated with an increased HCC during the postnatal period, whereas maternal eudaimonia was negatively associated with HCC. Our results indicate that both mothers and fathers affect children's responses to stress. Assessment of cortisol stress hormone concentrations through hair samples can be a key means of detecting preschoolers' stress levels and enabling early intervention.

A crystal capping layer for formation of black-phase FAPbI3 perovskite in humid air.

Black-phase formamidinium lead iodide (α-FAPbI3) perovskites are the desired phase for photovoltaic applications, but water can trigger formation of photoinactive impurity phases such as δ-FAPbI3. We show that the classic solvent system for perovskite fabrication exacerbates this reproducibility challenge. The conventional coordinative solvent dimethyl sulfoxide (DMSO) promoted δ-FAPbI3 formation under high relative humidity (RH) conditions because of its hygroscopic nature. We introduced chlorine-containing organic molecules to form a capping layer that blocked moisture penetration while preserving DMSO-based complexes to regulate crystal growth. We report power conversion efficiencies of >24.5% for perovskite solar cells fabricated across an RH range of 20 to 60%, and 23.4% at 80% RH. The unencapsulated device retained 96% of its initial performance in air (with 40 to 60% RH) after 500-hour maximum power point operation.

Reprogramming of the Aurantinin Polyketide Assembly Line to Synthesize Auritriacids by Excising an Atypical Enoyl-CoA Hydratase Domain.

Modular polyketide synthases (PKSs) are capable of synthesizing diverse natural products with fascinating bioactivities. Canonical enoyl-CoA hydratases (ECHs) are components of the ß-branching cassette that modifies the polyketide chain by adding a ß-methyl branch. Herein, it is demonstrated that the deletion of an atypical ECHQ domain (featuring a Q280 residue) of Art21, a didomain protein contains an ECHQ domain and a thioesterase (TE) domain, reprograms the polyketide assembly line from synthesizing tetracyclic aurantinins (ARTs) to bicyclic auritriacids (ATAs) with much lower antibacterial activities. Genes encoding the ECHQ-TE didomain proteins distribute in many PKS gene clusters from different bacteria. Significantly, the ART PKS machinery can be directed to make ARTs, ATAs, or both of them by employing appropriate ECHQ-TE proteins, implying a great potential for using this reprogramming strategy in polyketide structure diversification.

A cross-sectional analysis of gender and psychological well-being among older Taiwanese adults.

Background: Psychological well-being (PWB) facilitates good health. Few studies have taken into consideration gender and how it can affect PWB within a sociocultural context. This study aims to determine if relationships between social, health, behavioral, and socioeconomic factors on PWB among older Taiwanese adults are affected by gender. Methods: Data were obtained from the 2016 Taiwan Mental Health Survey. A representative sample, of 2,286 individuals, was created using multistage proportional probability. Participants were interviewed at their homes using a structured questionnaire. Inclusion criteria were Taiwanese citizenship, age ≥ 55 years, and the ability to provide informed consent. Participants 65 years and above were selected for the study sample n = 1,533. An 18-item version of Ryff's PWB scale was used to determine PWB. The median value was used to categorize low and high PWB. Logistic regression analyses were used to examine predictors of PWB stratified by gender. Results: Chronic disease, unemployment, and financial dependence negatively impacted men's PWB. Satisfaction with living environment and family relationships positively impacted women's PWB. Unique characteristics of older men, women, and culture account for this. Conclusion: Gender-specific interventions aimed at promoting PWB in older adults are needed. Recommendations include educational programs, social support workshops, and community engagement initiatives.

A Soldering Flux Tackles Complex Defects Chemistry in Sn-Pb Perovskite Solar Cells.

Developing tin-lead (Sn-Pb) narrow-bandgap perovskites is crucial for the deployment of all-perovskite tandem solar cells, which can help to exceed the limits of single-junction photovoltaics. However, the Sn-Pb perovskite suffers from a large number of bulk traps and interfacial nonradiative recombination centers, with unsatisfactory open-circuit voltage and the consequent device efficiency. Herein, for the first time, it is shown that abietic acid (AA), a commonly used flux for metal soldering, effectively tackles complex defects chemistry in Sn-Pb perovskites. The conjugated double bond within AA molecule plays a key role for self-elimination of Sn4+-Pb0 defects pair, via a redox process. In addition, C═O group is able to coordinate with Sn2+, leading to the improved antioxidative stability of Sn-Pb perovskites. Consequently, a ten-times longer carrier lifetime is observed, and the defects-associated dual-peak emission feature at low temperature is significantly inhibited. The resultant device achieves a power conversion efficiency improvement from 22.28% (Ref) to 23.42% with respectable stability under operational and illumination situations.

Latent profiles of narrative competence and professional identity among nursing students: A cross-sectional analytic study based on the Ring theory of personhood.

AIM: To identify latent profiles of narrative competence in nursing students and examine the association between the potential competence profiles and professional identity from a person-centred perspective. BACKGROUND: According to the Ring theory of personhood, nursing students can develop their professional identities from individual, relational and social aspects through interaction with patients, as well as listening to, understanding and responding to patients' disease narratives. However, few studies have examined the relationship between narrative competence and professional identity through the quantitative method. DESIGN: A cross-sectional analytic study. METHODS: A total of 472 nursing students responded to the survey between March and May 2023. The Professional Identity Questionnaire for Nurse Students and the Narrative Competence Scale were given to participants. Latent profile analysis was conducted to identify narrative competence profiles. The Bolck-Croon-Hagenaars method was used to analyse whether these latent profiles for narrative competence affected nursing students' general, individual, interpersonal and social professional identities. RESULTS: Latent profiles were identified as "low narrative competence" (12.1 %), "relatively low narrative competence" (39.9 %), "moderate narrative competence" (40.1 %) and "high narrative competence" (7.9 %). The profiles only show level differences rather than combinations of competence areas. These profiles had varying effects on the nursing students' general professional identities, as well as their individual, relational and social professional identities. CONCLUSION: This study highlights the significance of providing tailored guidance and support to nursing students, taking into account their unique narrative competency profile, to promote the formation of professional identity from individual, relational and social aspects. Nursing educators should effectively distinguish nursing students with inadequate narrative competence and value patients' disease narratives to promote narrative competence and professional identity.

A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

Non-small cell lung cancer and metabolism research from 2013 to 2023: a visual analysis and bibliometric study.

Background: As one of the most prevalent primary lung tumors, non-small cell lung cancer (NSCLC) has garnered considerable research interest due to its high metastasis rates and poor prognosis outcomes. Across different cancer types, metabolic processes are required for tumors progression and growth, thus interfering with such processes in NSCLC may therapeutically viable for limiting/halting disease progression. Therefore, comprehending how metabolic processes contribute to growth and survival mechanisms in cancers, including NSCLC, may elucidate key functions underpinning tumor cell metabolism. However, no bibliometric analyses have been published in this field, therefore we address this knowledge gap here. Methods: Between 2013 and 2023 (December 28th), articles related to the NSCLC and metabolism (NSCLC-Met) field were retrieved from the Web of Science Core Collection (WoSCC). To fully dissect NSCLC-Met research directions and articles, we used the Bibliometrix package in R, VOSviewer and CiteSpace software to visually represent global trends and hotspots. Results: Between 2013 and 2023, 2,246 NSCLC-Met articles were retrieved, with a continuous upward trend and rapid development observed year on year. Cancers published the most articles, with Cancer Research recording the highest average citation numbers. Zhang Li from China was the most prolific author, but the highest number of authors came from the USA. China, USA, and Italy were the top three countries with the highest number of published articles, with close cooperation identified between countries. Recent hotspots and research directions were reflected by "lung adenocarcinoma", "immunotherapy", "nivolumab", "checkpoint inhibitors", "blockade", and "pembrolizumab", while "gut microbiome", "egfr" and "dose painting" were important topics for researchers. Conclusion: From our analyses, scientists can now explore new hotspots and research directions in the NSCLC-Met field. Further in-depth research in this field will undoubtedly provide more new insights on disease diagnostics, treatment, and prognostics.

Nitro-functionalization on MIL-53(Fe) for PCMX degradation: Elevating Fenton-like catalytic propelled by abundant reaction sites and iron cycle.

To address the issue of excessive residues of 4-chloro-3,5-dimethylphenol (PCMX) in the water environment. In a one-step solvothermal process, iron-based metal-organic frameworks (Fe-MOFs) material MIL-53(Fe) undergoes a synthetic modification strategy. 2-Nitroterephthalic acid as an organic ligand reacted with Fe3+ in a solvothermal process lasting 18 h to yield the nitro-functionalized MIL-53(Fe)-NO2(18h). The objective was to augment the abundance of Fe central unsaturated coordination sites (Fe CUCs) and expedite the Fe(III)/Fe(II) redox cycle, thereby enhancing the heterogeneous Fenton-like treatment capability of pollutants. MIL-53(Fe)-NO2(18h) has excellent hydrogen peroxide (H2O2) catalytic activity and PCMX degradation across a broad pH spectrum (4.0∼8.0). Almost complete removal of PCMX was achieved within 30 min, while pseudo-first-order kinetic rate constants (kobs) increased 4.37 times over MIL-53(Fe). The confirmation of increased Fe CUCs abundance in MIL-53(Fe)-NO2(18h) was achieved through Lewis acidity, oxygen vacancies (OVs) signals, and Fe-O coordination characterization results. Density functional theory (DFT) calculations revealed that Fe CUCs in MIL-53(Fe)-NO2(18h) exhibits heightened affinity for H2O2 adsorption, showcasing stronger charge transfer and enhanced H2O2 dissociation ability. The Fe(III)/Fe(II) redox cycle, a driving force of Fenton-like reactions, was notably improved in the nitro-modified materials. These enhancements significantly expedited the Fenton-like process, resulting in the generation of increased amounts of reactive oxygen species (ROSs), with hydroxyl radicals (OH·) being pivotal components in degradation. The MIL-53(Fe)-NO2(18h)/H2O2 system has demonstrated versatility in treating a variety of emerging contaminants, achieving removal efficiencies exceeding 99.7% for other antibiotics and endocrine disruptors within 60 min. Furthermore, MIL-53(Fe)-NO2(18h) demonstrated outstanding reusability and adaptability in actual water environments. This study introduces a straightforward and environmentally friendly strategy for remediating environmental pollution using Fe-MOF-catalysed heterogeneous Fenton-like technology.

Therapy-related myeloid neoplasms with single-hit TP53 mutations share the clinical, molecular, and survival characteristics of their multi-hit counterparts.

Recent updates in the classification of myeloid neoplasms (MNs) recognize the poor prognostic impact of TP53 mutations, with particular emphasis on the TP53 allele status. Studies on the effect of TP53 allele status exclusively in therapy-related MNs (t-MNs) are lacking. We compared the clinicopathologic and survival characteristics of t-MNs with single-hit (SH) and multi-hit (MH) TP53 mutations. A total of 71 TP53-mutated t-MNs were included, including 56 (78.9%) MH and 15 (21.1%) SH. Both groups showed comparable genetic profiles with an excess of high-risk karyotypes and a paucity of other co-mutated genes. TP53 was the sole detectable mutation in 73.3% of SH and 75.0% of MH cases. The overall survival (OS) of SH TP53-mutated t-MNs was not significantly different from MH cases (median survival: 233 vs.273 days, p = 0.70). Our findings suggest that t-MNs with SH TP53 mutations share the poor prognostic and biologic profile of their MH counterparts.

CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia.

CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.

The importance of mother-child interaction on smart device usage and behavior outcomes among toddlers: a longitudinal study.

BACKGROUND: In recent years, smart devices have become an integral part of daily life. However, longitudinal studies, particularly those regarding the relationship between toddlers' smart device usage and behavioral outcomes, are limited. Understanding the impact of parent-child interactions on this relationship is crucial for enhancing toddlers' developmental outcomes. Accordingly, this study examined the influence of early screen time and media content exposure on toddlers' behaviors, as well as the positive effects of mother-child interactions on this influence. METHODS: We used relevant data related to 277 children born between November 2016 and July 2020 and who were part of an ongoing prospective follow-up study conducted across five hospitals in Taipei City, Taiwan. We analyzed (1) data from maternal reports regarding children's behavior by using the Child Behavior Checklist (for ages 11/2-5 years), (2) assessments of mother-child interactions by using the Brigance Parent-Child Interactions Scale, and (3) self-reported parental data covering the first 3 postpartum years. Statistical analyses involved group-based trajectory modeling and multiple linear regression. RESULTS: A considerable increase in screen time between the ages of 1 and 3 years was associated with less favorable behavioral outcomes at age 3. These outcomes included somatic complaints [adjusted beta coefficient (aß) = 2.17, 95% confidence interval (CI) = 0.39-3.95, p-value = 0.01], withdrawal (aß = 2.42, 95% CI = 0.15-4.69, p-value = 0.04), and aggressive behavior (aß = 6.53, 95% CI = 0.25-12.81, p-value = 0.04). This association was particularly evident among children with lower levels of mother-child interaction. Nevertheless, positive mother-child interactions mitigated most of the adverse effects. Additionally, increased exposure to games and cartoons was associated with poorer behavioral outcomes in all children except for those experiencing positive mother-child interactions. CONCLUSION: Early mother-child interactions play a crucial role in mitigating the risk of behavioral problems in toddlers who spend prolonged periods looking at screens and who are frequently exposed to game and cartoon content.

Update on the development of TGR5 agonists for human diseases.

The G protein-coupled bile acid receptor 1 (GPBAR1) or TGR5 is widely distributed across organs, including the small intestine, stomach, liver, spleen, and gallbladder. Many studies have established strong correlations between TGR5 and glucose homeostasis, energy metabolism, immune-inflammatory responses, and gastrointestinal functions. These results indicate that TGR5 has a significant impact on the progression of tumor development and metabolic disorders such as diabetes mellitus and obesity. Targeting TGR5 represents an encouraging therapeutic approach for treating associated human ailments. Notably, the GLP-1 receptor has shown exceptional efficacy in clinical settings for diabetes management and weight loss promotion. Currently, numerous TGR5 agonists have been identified through natural product-based approaches and virtual screening methods, with some successfully progressing to clinical trials. This review summarizes the intricate relationships between TGR5 and various diseases emphasizing recent advancements in research on TGR5 agonists, including their structural characteristics, design tactics, and biological activities. We anticipate that this meticulous review could facilitate the expedited discovery and optimization of novel TGR5 agonists.

Discovery of an efficacious KDM5B PROTAC degrader GT-653 up-regulating IFN response genes in prostate cancer.

Epigenetic alterations promote cancer development by regulating the expression of various oncogenes and anti-oncogenes. Histone methylation modification represents a pivotal area in epigenetic research and numerous publications have demonstrated that aberrant histone methylation is highly correlated with tumorigenesis and development. As a key histone demethylase, lysine-specific demethylase 5B (KDM5B) demethylates lysine 4 of histone 3 (H3K4) and serves as a transcriptional repressor of certain tumor suppressor genes. Meanwhile, KDM5B inhibits STING-induced intrinsic immune response of tumor cells or recruits SETDB1 through non-enzymatic function to silence reverse transcription elements to promote immune escape. The conventional small molecule inhibitors can only inhibit the enzymatic function of KDM5B with no effect on the non-enzymatic function. In the article, we present the development of the first series of KDM5B degraders based on CPI-455 to inhibit the non-enzymatic function. Among them, GT-653 showed optimal KDM5B degradation efficiency in a ubiquitin proteasome-dependent manner. GT-653 efficiently reduced KDM5B protein levels without affecting KDM5B transcription. Interestingly, GT-653 increased H3K4me3 levels and activated the type-I interferon signaling pathway in 22RV1 cells without significant phenotypic response on cell proliferation.