Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα.

Pioneer transcription factors are vital for cell fate changes. PU.1 and C/EBPα work together to regulate hematopoietic stem cell differentiation. However, how they recognize in vivo nucleosomal DNA targets remains elusive. Here we report the structures of the nucleosome containing the mouse genomic CX3CR1 enhancer DNA and its complexes with PU.1 alone and with both PU.1 and the C/EBPα DNA binding domain. Our structures reveal that PU.1 binds the DNA motif at the exit linker, shifting 17 bp of DNA into the core region through interactions with H2A, unwrapping ~20 bp of nucleosomal DNA. C/EBPα binding, aided by PU.1's repositioning, unwraps ~25 bp of entry DNA. The PU.1 Q218H mutation, linked to acute myeloid leukemia, disrupts PU.1-H2A interactions. PU.1 and C/EBPα jointly displace linker histone H1 and open the H1-condensed nucleosome array. Our study unveils how two pioneer factors can work cooperatively to open closed chromatin by altering DNA positioning in the nucleosome.

Evaluation and comparison of efficacy and safety of tirzepatide and semaglutide in patients with type 2 diabetes mellitus: A Bayesian network meta-analysis.

BACKGROUND: As new antidiabetic drugs, tirzepatide (Tir) and semaglutide (Sem) are progressively applied in clinical practice. However, their efficacy and safety profiles have not been comprehensively assessed. Therefore, a Bayesian network meta-analysis was used to evaluate and compare the efficacy and safety of Tir and Sem in treating type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were systematically searched from inception to April 3rd, 2023. Randomized clinical trials (RCTs) comparing the efficacy and safety of Tir and Sem with placebo or the other antidiabetic drugs in treating T2DM were included. The efficacy outcomes included changes in glycated hemoglobin (HbA1c), body weight (BW), body mass index (BMI), and the proportion of participants with HbA1c< 7 %. The safety outcome was the proportion of participants experiencing gastrointestinal adverse events (GIAEs). RESULTS: A total of 38 studies involving 34,166 participants were included. Compared to 1 mg of subcutaneous Sem (Sem SC), 5 mg, 10 mg and 15 mg of Tir demonstrated superior efficacy in reducing HbA1c (mean difference (MD), [95 % CI], -0.22 [-0.40, -0.03] %, -0.42 [-0.60, -0.24] % and -0.53 [-0.71, -0.35] %, respectively) and BW (MD [95 % CI], -1.48 [-2.53, -0.43] kg, -4.00 [-5.05, -2.95] kg and -5.71 [-6.73, -4.68] kg, respectively). Conversely, 7 mg and 14 mg of oral Sem (Sem PO) displayed inferior efficacy in reducing HbA1c (MD [95 % CI], 0.47 [0.26, 0.68] % and 0.35 [0.16, 0.54] %, respectively) and BW (MD [95 % CI], 2.36 [1.24, 3.48] kg and 1.11 [0.10, 2.13] kg). However, 20 mg and 40 mg of Sem PO were non-inferior in reducing HbA1c (MD [95 % CI], 0.13 [-0.29, 0.55] % and 0.01 [-0.38, 0.40] %, respectively) and BW (MD [95 % CI], -0.41 [-2.71, 1.90] kg and -1.32 [-3.58, 0.92] kg). In terms of safety, compared to 1 mg of Sem SC, 5 mg, 10 mg and 15 mg of Tir did not significantly increase the incidence of GIAEs (odd ratio (OR) [95 % CI], 0.70 [0.42, 1.10], 0.87 [0.52, 1.36] and 0.99 [0.60, 1.54], respectively), while 7 mg of Sem PO showed a lower incidence of GIAEs (OR [95 % CI], 0.48 [0.25, 0.83]). Compared to insulin, 0.5 mg of Sem SC, 1 mg of Sem SC, 5 mg of Tir, 10 mg of Tir and 15 mg of Tir displayed better efficacy in lowering HbA1c (MD [95 % CI], -0.40 [-0.63, -0.18] %, -0.69 [-0.90, -0.48] %, -0.91 [-1.10, -0.72] %, -1.11 [-1.30, -0.92] % and -1.22 [-1.41, -1.03] %, respectively) and BW (MD [95 % CI], -5.34[-6.60, -4.09] kg, -6.70 [-7.90,-5.51] kg, -8.18 [-9.27, -7.10] kg, -10.70 [-11.79, -9.61] kg and -12.41 [-13.49,-11.33] kg, respectively). According to the surface under the cumulative ranking curve (SUCRA) value, among all the included interventions, 15 mg of Tir exhibited the most potent effect in reducing HbA1c (99.81 %) and BW (99.98 %), followed by 10 mg of Tir (96.83 % and 95.72 %), 5 mg of Tir (92.88 % and 86.04 %), 1 mg of Sem SC (85.85 % and 74.97 %), 40 mg of Sem PO (83.66 % and 84.31 %), 20 mg of Sem PO (76.98 % and 77.12 %), 300 mg of Can (49.93 % and 60.89 %), insulin (36.38 % and 0.22 %) and 100 mg of Sit (12.28 % and 18.51 %) respectively. Meanwhile, 5 mg, 10 mg, and 15 mg of Tir (48.32 %, 30.96 %, and 21.07 %, respectively), 0.5 mg and 1 mg of Sem SC (33.54 % and 24.77 %, respectively) significantly increased the incidence of GIAEs. CONCLUSION: Both Tir and Sem demonstrated favorable antidiabetic effects and were particularly suitable for T2DM patients who were obese or overweight. Despite a high incidence of GIAEs, their safety profile was deemed acceptable. Tir was the best option among all the included interventions.

Prediction of pediatric dose of tirzepatide from the reference adult dose using physiologically based pharmacokinetic modelling.

Tirzepatide is an emerging hypoglycemic agent that has been increasing used in adults, yet its pharmacokinetic (PK) behavior and dosing regimen in pediatric population remain unclear. This study aimed to employ the physiologically based pharmacokinetic (PBPK) model to predict changes of tirzepatide exposure in pediatric population and to provide recommendations for its dose adjustments. A PBPK model of tirzepatide in adults was developed and verified by comparing the simulated plasma exposure with the observed data using PK-Sim&MoBi software. This model was then extrapolated to three specific age subgroups, i.e., children (10-12 years), early adolescents (12-15 years), and adolescents (15-18 years). Each subgroup included healthy and obese population, respectively. All known age-related physiological changes were incorporated into the pediatric model. To identify an appropriate dosing regimen that yielded PK parameters which were comparable to those in adults, the PK parameters for each aforementioned subgroup were predicted at pediatric doses corresponding to 87.5%, 75%, 62.5%, and 50% of the adult reference dose. According to the results of simulation, dose adjustments of tirzepatide are necessary for the individuals aged 10-12 years, as well as those aged 12-15 years with healthy body weights. In conclusion, the adult PBPK model of tirzepatide was successfully developed and validated for the first time, and the extrapolated pediatric model could be used to predict pediatric dosing regimen of tirzepatide, which will provide invaluable references for the design of future clinical trials and its rational use in the pediatric population.

Cardiovascular benefits and safety of sotagliflozin in type 2 diabetes mellitus patients with heart failure or cardiovascular risk factors: a bayesian network meta-analysis.

Background: As an antidiabetic agent, sotagliflozin was recently approved for heart failure (HF). However, its cardiovascular benefits in type 2 diabetic mellitus (T2DM) patients with HF or cardiovascular (CV) risk factors have not been systematically evaluated. The aim of this study is to evaluate the cardiovascular benefits and safety of sotagliflozin in T2DM patients with HF or CV risk factors using Bayesian network meta-analysis. Methods: Data were retrieved from PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Library from their inception to 16 August 2023. Randomized controlled trials (RCTs) comparing sotagliflozin with a placebo, dapagliflozin, and empagliflozin in adult T2DM patients with HF or CV risks for at least 12 weeks were included in the study. Data analysis was conducted using R 4.2.3 and Stata 17.0. Cardiovascular efficacy outcomes included HF events (hospitalization or urgent visits for HF), MACE (deaths from CV causes, hospitalizations for HF, nonfatal myocardial infarctions, and strokes), cardiovascular death, the decrease in SBP, and weight loss. Safety outcomes are urinary tract infection, diarrhea, and diabetic ketoacidosis. Results: Eleven studies with 30,952 patients were included. Compared to dapagliflozin and empagliflozin, 200 mg of sotagliflozin showed the best effect in reducing HF events [OR (95% CI), 0.79 (0.66, 0.94) and 0.90 (0.63, 1.27)]. Compared to dapagliflozin, 200 mg of sotagliflozin [OR (95% CI), 0.76 (0.66, 0.87)] was superior in preventing MACE. Compared to empagliflozin, 200 mg of sotagliflozin [OR (95% CI), 1.46 (1.04, 2.05)] was inferior in preventing CV death. Sotagliflozin showed a poorer SBP decreasing effect than empagliflozin and dapagliflozin [MD (95% CI), 1.30 (0.03, 2.56) and 2.25 (0.35, 4.14), respectively]. There was no significant difference between sotagliflozin and other interventions in weight loss. Sotagliflozin exhibited no increased risk for diabetic ketoacidosis or urinary tract infection among all interventions, however, it showed a mild risk for diarrhea than placebo [OR (95% CI), 1.47 (1.28, 1.69)]. Conclusion: Sotagliflozin displayed moderate CV benefits and acceptable safety. Sotagliflozin can be one of the recommended options for T2DM patients with HF or CV risk factors, which will be important for evidence-based use of sotagliflozin as well as decision-making of T2DM medication.

The human LIN28B nucleosome is inherently pre-positioned for efficient binding of multiple OCT4s without H3 K27 acetylation.

Pioneer transcription factors possess the unique ability to access DNA within tightly packed chromatin structures, playing pivotal roles in cell differentiation and reprogramming. However, their precise mechanism for recognizing nucleosomes has remained mystery. Recent structural and biochemical investigations into the binding interactions between the human pioneer factor OCT4 and the LIN28B nucleosome by Sinha et al.1 and Guan et al.2 have yielded conflicting results regarding nucleosome positioning, nucleosomal DNA unwrapping, binding cooperativity, and the role of N-terminal tail of OCT4. In this study, we undertook a comparative analysis of these two research efforts and delved into the factors contributing to the observed discrepancies. Our investigation unveiled that the utilization of human and Xenopus laevis core histones, along with a discrete two-step salt dialysis method, led to distinct positioning of DNA within reconstituted LIN28B nucleosomes. Additionally, our reanalysis of the electrophoretic mobility shift assay data showed that H3 K27 acetylation did not increase OCT4 binding to the internal sites of the nucleosome when normalized to input; instead, it promoted sample aggregation. Thus, the available experimental data support the notion that the human LIN28B nucleosome is pre-positioned for efficient binding with multiple OCT4s, and there is no compelling evidence for its regulation by histone modifications.

Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα.

Pioneer transcription factors are vital for cell fate changes. PU.1 and C/EBPα work together to regulate hematopoietic stem cell differentiation. However, how they recognize in vivo nucleosomal DNA targets remain elusive. Here we report the structures of the nucleosome containing the mouse genomic CX3CR1 enhancer DNA and its complexes with PU.1 alone and with both PU.1 and the C/EBPα DNA binding domain. Our structures reveal that PU.1 binds the DNA motif at the exit linker, shifting 17 bp of DNA into the core region through interactions with H2A, unwrapping ~20 bp of nucleosomal DNA. C/EBPα binding, aided by PU.1's repositioning, unwraps ~25 bp entry DNA. The PU.1 Q218H mutation, linked to acute myeloid leukemia, disrupts PU.1-H2A interactions. PU.1 and C/EBPα jointly displace linker histone H1 and open the H1-condensed nucleosome array. Our study unveils how two pioneer factors can work cooperatively to open closed chromatin by altering DNA positioning in the nucleosome.

Structural mechanism of LIN28B nucleosome targeting by OCT4.

Pioneer transcription factors are essential for cell fate changes by targeting closed chromatin. OCT4 is a crucial pioneer factor that can induce cell reprogramming. However, the structural basis of how pioneer factors recognize the in vivo nucleosomal DNA targets is unknown. Here, we determine the high-resolution structures of the nucleosome containing human LIN28B DNA and its complexes with the OCT4 DNA binding region. Three OCT4s bind the pre-positioned nucleosome by recognizing non-canonical DNA sequences. Two use their POUS domains while the other uses the POUS-loop-POUHD region; POUHD serves as a wedge to unwrap ∼25 base pair DNA. Our analysis of previous genomic data and determination of the ESRRB-nucleosome-OCT4 structure confirmed the generality of these structural features. Moreover, biochemical studies suggest that multiple OCT4s cooperatively open the H1-condensed nucleosome array containing the LIN28B nucleosome. Thus, our study suggests a mechanism of how OCT4 can target the nucleosome and open closed chromatin.

Construction of a Chiral Fluorescent Probe for Tryptophan Enantiomers/Ascorbic Acid Identification.

Chiral recognition of amino acid enantiomers is critical in enhancing drug efficacy, detecting disease markers, and understanding physiological processes. Enantioselective fluorescent identification has gained attention among researchers due to its nontoxicity, easy synthesis, and biocompatibility. In this work, chiral fluorescent carbon dots (CCDs) were produced through a hydrothermal reaction followed by chiral modification. The fluorescent probe, Fe3+-CCDs (F-CCDs), was constructed by complexing Fe3+ with CCDs to differentiate between the enantiomers of tryptophan (Trp) and determine ascorbic acid (AA) through an "on-off-on" response. It is worth noting that l-Trp can greatly enhance the fluorescence of F-CCDs with a blue shift, whereas d-Trp does not have any effect on the fluorescence of F-CCDs. F-CCDs showed a low limit of detection (LOD) for l-Trp and l-AA, with an LOD of 3.98 and 6.28 µM, respectively. The chiral recognition mechanism of tryptophan enantiomers using F-CCDs was proposed based on the interaction force between the enantiomers and F-CCDs, as confirmed by UV-vis absorption spectroscopy and density functional theory calculations. The determination of l-AA by F-CCDs was also confirmed through the binding of l-AA to Fe3+ to release CCDs, as seen in UV-vis absorption spectra and time-resolved fluorescence decays. In addition, AND and OR gates were constructed based on the different responses of CCDs to Fe3+ and Fe3+-CCDs to l-Trp/d-Trp, demonstrating the significance of molecular-level logic gates in drug detection and clinical diagnosis.

Ratiometric fluorescent probe based on non-conjugated polymer dots for pH measurements in ordinary Portland cement-based materials.

An organic fluorescent probe, citric acid-1,3-Propanediamine-Rhodamine B (CPR) was synthesized to determine pH of ordinary Portland cement requiring only a small sample size (less than 500 µL cement leachate). The SEM, XRD, and FTIR investigations demonstrate that citric acid-1,3-Propanediamine are polymer dots with a fusiform structure. Ratio pH probe is constructed by rhodamine B with polymer dots, which exhibits a linear response in high alkaline range. A 6-fold increase in fluorescence intensity (455 nm) is achieved at pH from 12.00 to 13.25. Combined with measurements of the isothermal calorimeter, mineral composition, and microscopic morphology, variation of pH is used to evaluate the changes of components during hydration. Furthermore, CPR can be applied to measure pH of high-dose pulverized fuel ash blending systems, the non-pure cement with slightly lower alkalinity.

Liquid and solid-state tunable fluorescent carbon dots for trace water detection.

We synthesized a type of sulfur and nitrogen co-doped carbon dot, which can achieve tunable fluorescence both in solutions and solid matrices, that is dominated by the surface state. Moreover, it can be used to detect trace water in a variety of organic solvents, especially in acetone with a limit of detection as low as 0.042%.

Structural mechanism of LIN28B nucleosome targeting by OCT4 for pluripotency.

Pioneer transcription factors are essential for cell fate changes by targeting closed chromatin. OCT4 is a crucial pioneer factor that can induce cell reprogramming. However, the structural basis of how pioneer factors recognize the in vivo nucleosomal DNA targets is unknown. Here, we determine the high-resolution structures of the nucleosome containing human LIN28B DNA and its complexes with the OCT4 DNA binding region. Three OCT4s bind the pre-positioned nucleosome by recognizing non-canonical DNA motifs. Two use their POUS domains by forming extensive hydrogen bonds. The other uses the POUS-loop-POUHD region; POUHD serves as a wedge to unwrap ∻25 base pair DNA. Biochemical studies suggest that multiple OCT4s cooperatively open the H1-condensed nucleosome array containing the LIN28B nucleosome. Our study suggests a mechanism whereby OCT4s target the LIN28B nucleosome by forming multivalent interactions with nucleosomal motifs, unwrapping nucleosomal DNA, evicting H1, and cooperatively open closed chromatin to initiate cell reprogramming.

Bioinspired fluorescent molecules realize super bright blue luminescence under sunlight.

In recent years, non-aromatic fluorescent materials have attracted widespread attention, but achieving a high quantum yield (QY) in their dilute solutions still remains a challenge. In this work, inspired by the Clustering-triggered emission (CTE) phenomenon of non-aromatic amino acids and poly(amino acids), we successfully designed a bioinspired molecule with a dipeptide-like structure and active silanol groups. The as-prepared bioinspired molecule can be hydrolyzed by simple heating to obtain the hydrolysate h-PDs, which can emit strong blue fluorescence in dilute solution. And this was the first time to realize the emission behavior of non-aromatic fluorescent materials under sunlight. The QY of h-PDs in aqueous solution and solid state were as high as 98.2% and 96.3%, respectively, which were attributed to the condensation of active silanol groups at the end of the molecule, and the existence of hydrogen bonds and N â†’ Si coordination bonds that made small molecules cross-linked and aggregated into dense clusters. Finally, the application of h-PDs in the detection of intracellular and exogenous Hg2+ and Cys and luminescent films were also explored. Significantly, this work provides a design strategy for synthesizing high-fluorescence QY non-aromatic fluorescent materials, and verifies their potential application value in the fields of environment, biology and light-emitting devices.

Integration of pharmacodynamics, network pharmacology and metabolomics to elucidate effect and mechanism of Artemisia capillaris Thunb. in the treatment of jaundice.

ETHNOPHARMACOLOGICAL RELEVANCE: As one of the most commonly used herbs, Artemisia capillaris Thunb. (ACT) display favorable effect in the treatment of jaundice. However, mechanism of ACT in the treatment of jaundice remains unclear at present, which limits its development and application. AIM OF THE STUDY: To investigate effect and mechanism of Artemisia capillaris Thunb. (ACT) in the treatment of jaundice using pharmacodynamics, network pharmacology and metabolomics. METHODS: Effect of ACT in treating jaundice was evaluated by biochemical assays and pathological observation using the α-naphthyl isothiocyanate (ANIT)-induced mice. Jaundice-relieving mechanism of ACT was investigated by integration of network pharmacology and metabolomics. RESULTS: After the mice with jaundice were administrated ACT extract for 9 days, compared to that of the model group, serum D-BIL, T-BIL and ALP levels of the mice in the low, medium, high dose of ACT group decreased by 39.81%, 15.30% and 16.92%; 48.06%, 42.54% and 36.91%; 26.90%, 12.34% and 16.90%, respectively. The pathologic study indicated that ACT improved the symptoms of liver injury of the mice with jaundice. The network of herb (i.e., ACT)-components-targets-disease (i.e., jaundice) was established, which consisted of 17 components classified in flavonoids, chromones, organic acids, terpenoids, and 234 targets related to treatment of jaundice. Metabolomics analysis showed that, compared to that in the model group, level of 8 differential metabolites were upregulated and level of 29 differential metabolites were downregulated in the mice liver in the ACT group, respectively. The main metabolic pathways involved in treatment of jaundice by ACT were pantothenate and CoA biosynthesis, glutathione metabolism, biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis in the liver, respectively. The integrated analysis of network pharmacology and metabolomics showed that 3α,7α,12α a-Trihydroxy-5ß-cholanate, glycocholate, taurocholate, pantetheine 4'-phosphate, and d-4'-phosphopantothenate were the potential biomarkers for treatment of jaundice, and AKR1C4, ALDH2 and HSD11B were the potential drug targets in the treatment of jaundice by ACT. CONCLUSION: The study based on metabolomics and network pharmacology indicated that ACT can display favorable jaundice-relieving effect by its multiple components regulating multiple biomarkers, multiple targets and multiple pathways, and may be a rational therapy for the treatment of jaundice.

Efficacy and safety of teneligliptin in patients with type 2 diabetes mellitus: a Bayesian network meta-analysis.

Background: As a popular antidiabetic drug, teneligliptin has been used for over 10 years, but its efficacy and safety have rarely been systematically evaluated. Therefore, a Bayesian network meta-analysis was conducted to evaluate the efficacy and safety of teneligliptin in patients with type 2 diabetes mellitus (T2DM). Methods: We systematically searched PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Randomized controlled trials (RCTs) comparing teneligliptin with placebo or active comparators in T2DM patients for at least 12 weeks were included in the study. Data analysis was performed using R 4.2.3 and Stata 17.0 software. Each outcome was presented as a mean difference (MD) or an odds ratio (OR) along with 95% confidence interval (CI) and the surface under the cumulative ranking curve value (SUCRA). Results: A total of 18 RCTs with 3,290 participants with T2DM were included in this study. Generally, compared to placebo, sitagliptin, vildagliptin, metformin, and bromocriptine, 20 mg of teneligliptin showed better efficacy in reducing HbA1c (MD [95% CI], -0.78 [-0.86 to -0.70], -0.08 [-0.36 to 0.19], -0.04 [-0.72 to 0.60], -0.12 [-0.65 to 0.42], and -0.50 [-0.74 to -0.26], respectively) and fasting plasma glucose (FPG) (MD [95% CI], -18.02 [-20.64 to -15.13], 1.17 [-9.39 to 11.70], -8.06 [-30.95 to 14.35], -2.75 [-18.89 to 13.01], and -34.23 [-45.93 to -22.96], respectively), and 40 mg of teneligliptin also showed better efficacy in reducing HbA1c (MD [95% CI], -0.84 [-1.03 to -0.65], -0.15 [-0.49 to 0.19], -0.10 [-0.81 to 0.57], -0.18 [-0.76 to 0.39], and -0.56 [-0.88 to -0.26], respectively) and FPG (MD [95% CI], -20.40 [-26.07 to -14.57], -1.20 [-13.21 to 10.38], -10.43 [-34.16 to 12.65], -5.13 [-22.21 to 11.66], and -36.61 [-49.33 to -24.01], respectively). Compared to placebo, 20 mg of teneligliptin showed no significant difference in incidences of hypoglycemia and gastrointestinal adverse events (OR [95% CI], 1.30 [0.70 to 2.19] and 1.48 [0.78 to 2.98], respectively), and 40 mg of teneligliptin showed no significant difference in incidence of hypoglycemia (OR [95% CI], 2.63 [0.46 to 8.10]). Generally, antidiabetic effect and hypoglycemia risk of teneligliptin gradually increased as its dose increased from 5 mg to 40 mg. Compared to 20 mg of teneligliptin, 40 mg of teneligliptin showed superior efficacy and no-inferior safety, which was considered as the best option in reducing HbA1c, FPG, and 2h PPG and increasing proportion of the patients achieving HbA1c < 7% (SUCRA, 85.51%, 84.24%, 79.06%, and 85.81%, respectively) among all the included interventions. Conclusion: Compared to sitagliptin, vildagliptin, metformin, bromocriptine, and placebo, teneligliptin displayed favorable efficacy and acceptable safety in treating T2DM. Twenty milligrams or 40 mg per day was the optimal dosage regimen of teneligliptin. The results of this study will provide important evidence-based basis for rational use of teneligliptin and clinical decision-making of T2DM medication.

Efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus: A bayesian network meta-analysis.

Background: In light of clinical trials comparing different doses of tirzepatide with selective glucagon-like peptide-1 receptor agonist (GLP1-RA) or insulin analogue, a bayesian network meta-analysis was conducted to investigate the efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus (T2DM). Methods: We systematically searched PubMed, Embase, Web of science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to 2 May 2022. Final included studies met the eligibility criteria and methodological quality recommendations. Data analysis was performed using Stata 15.1 software. Each outcome was presented as a mean difference or an odds ratio, and the surface under the cumulative ranking curve value (SCURA). Results: Ultimately, eight eligible RCTs involving 7245 patients were included. Generally speaking, compared with basal insulin (glargine or degludec); selective GLP1-RA (dulaglutide or semaglutide once weekly), 10 and 15 mg of tirzepatide exhibited better antidiabetic and weight-loss effect, especially, 15 mg of tirzepatide was dominant on reducing glycated hemoglobin (SCURA probability: 93.5%), body weight (99.7%), and fasting serum glucose (86.6%). As for safety, insulin caused less gastrointestinal events (93.5%), and there was no statistical difference between GLP1-RA and tirzepatide. Conclusion: Compare with insulin and GLP1-RA, tirzepatide display favorable efficacy and acceptable safety for T2DM patients. More well-designed RCTs are needed to evaluate its clinical performance with higher doses of GLP1-RA and determine its potential cardiovascular benefits.

Fluorescent silicon nanoparticle-based quantitative hemin assay.

Hemin with functions such as oxygen carrying, oxygen storing, promoting redox, and performing electron transfer is important for the health of organisms. In this paper, green synthetic silicon nanoparticles (Si-NPs) were synthesized and used for free hemin detection in serum (a low limit of detection (LOD), 29.5 nM). The quenching mechanism was investigated by UV-vis absorption spectra, time-resolved luminescence decay curve, and circular dichroism (CD) spectra. It was confirmed that multiple redox centers of hemin led to intensified effective collision and increased the electron transfer rate, therefore enhancing the dynamic quenching, and it was undeniable that the inner filter effect (IFE) also played a role in the quenching.

Amide salt pyrolysis fabrication of graphene nanosheets with multi-excitation single color emission.

A novel and simple approach of using amide salt pyrolysis to produce photoluminescent (multi-excitation and single color emission) graphene nanosheets (GNs) with a thickness of <1 nm and a diameter of about 100-200 nm is described herein. It has characteristics of high water solubility, low toxicity, easy manufacturing, etc., and has potential application prospects in analytical chemistry and biomedicine.

A julolidine-chalcone-based fluorescent probe for detection of Al3+ in real water sample and cell imaging.

A fluorescent probe 1 based on julolidine-chalcone derivative, which can specifically recognize aluminum ion with high selectivity and anti-interference, was developed. Probe 1 has good fluorescence stability and can detect Al3+ with turn-on fluorescence in a wide pH range of 4.0-9.0. The probe has good repeatability for the detection of Al3+ and fluorescence turn-on and off can be repeated with the alternate Al3+ and EDTA. The sensing mechanism is speculated that Al3+ will coordinate with hydroxyl oxygen and carbonyl oxygen on the probe through in situ 1H NMR and HRMS combing with Job's plot. The probe can also detect Al3+ in actual water samples and applied to monitor Al3+ in biological system.

Silane-Functionalized Carbon Dots and Their Polymerized Hybrids: From Optoelectronics to Biotherapy.

Nanomaterials usually manifest unique properties in solutions but will be undermined in the solid state. It is necessary to incorporate them into substrates or hybrid them with other functional materials for multiple devices and applications. Though there are a variety of methods to inherit their intrinsic properties like fluorescent and mechanical performance, most nanohybrid materials would lose their transparency irreversibly when construct solid-state devices. As a hot topic of nanomaterials in recent years, scientific works found a type of carbon dots using silane coupling agents as precursors that can overcome the shortcoming. These carbon dots, called silane-functionalized carbon dots (SiCDs), are catching increasing interest due to their versatility. Silane coupling agents endow SiCDs with the ability to disperse in solvents or polymerize with matrices by blending or covalent bonds without loss of transparency and decline of performance. The distinguishing features make SiCDs an ideal high transmittance, high doping concentration nanomaterial. The synergistic effect of SiCDs and hybridized sol-gel solid structures can not only hold the optical features of CDs but also enhance their original physical and chemical performance. This highlight focuses on the connection between SiCDs and organosilanes. Plus, preparation methods, applications, and prospective of SiCDs are mentioned.

Mechanistic insights into central spindle assembly mediated by the centralspindlin complex.

The central spindle spatially and temporally regulates the formation of division plane during cytokinesis in animal cells. The heterotetrameric centralspindlin complex bundles microtubules to assemble the central spindle, the mechanism of which is poorly understood. Here, we determined the crystal structures of the molecular backbone of ZEN-4/CYK-4 centralspindlin from Caenorhabditis elegans, which revealed the detailed mechanism of complex formation. The molecular backbone of centralspindlin has the intrinsic propensity to undergo liquid-liquid phase separation. The condensation of centralspindlin requires two patches of basic residues at ZEN-4 and multiple acidic residues at the intrinsically disordered region of CYK-4, explaining the synergy of the two subunits for the function. These complementary charged residues were critical for the microtubule bundling activity of centralspindlin in vitro and for the assembly of the central spindle in vivo. Together, our findings provide insights into the mechanism of central spindle assembly mediated by centralspindlin through charge-driven macromolecular condensation.