Selective Adsorption of Dyes and Fe3+ Sensing via Tb3+ Incorporation in an Anionic Cadmium-Organic Framework.

A three-dimensional (3D) anionic cadmium-organic framework, namely [(CH3)2NH2][Cd1.5(DMTDC)2] ⋅ 2DMA ⋅ 0.5H2O (Cd-MOF; DMA=N,N-dimethylacetamide), was successfully synthesized under solvothermal conditions by using a linear thienothiophene-containing dicarboxylate ligand, 3,4-dimethylthieno [2,3-b]-thiophene-2,5-dicar-boxylic acid (H2DMTDC). Single-crystal X-ray diffraction analysis reveals that Cd-MOF exhibits a 3D anionic framework with pcu α-Po topology, featuring rectangle and rhombus-shaped channels along b- and c- axis direction. Cd-MOF demonstrates selective adsorption of cationic dyes over anionic and neutral dyes. Additionally, Tb3+-loaded Cd-MOF serves as a fast-response fluorescence sensor for the sensitive detection of Fe3+ ions with a low limit of detection (8.90×10-7 M) through fluorescence quenching.

[Preparation and performance evaluation of fast dissolving polymer microneedles piggybacked with sitagliptin].

The dramatic rise in the number of obese/overweight people is a global public health challenge that urgently requires novel and effective therapies. In this study, we designed a fast dissolving polymer microneedle array patch (SGN-PVP/PVA-MN) with sitagliptin as a model drug for treating obesity, focusing on the preparation process of the patch. We then characterized the morphology and dimensions of SGN-PVP/PVA-MN. Furthermore, we delved into the mechanical properties, solubility, skin-puncturing capability, and transdermal drug diffusion and release kinetics of SGN-PVP/PVA-MN. The results demonstrated that SGN-PVP/PVA-MN exhibited favorable morphology and mechanical properties, effectively penetrating the stratum corneum and creating microchannels for rapid transdermal drug diffusion. The in vitro transdermal diffusion assays revealed the release of 64.5% of the drug within 2 min and 95.7% within 10 min. With rapid dissolution and high drug diffusion efficiency, SGN-PVP/PVA-MN is poised to serve as an effective and safe treatment option for the individuals with obesity.

How Do the Position and Number of Methyl Substituents Affect the Photochemical Process of Criegee Intermediate? Trajectory Surface-Hopping Dynamics of Four-Carbon CIs.

Electronic-structure calculations combined with nonadiabatic trajectory surface-hopping (TSH) dynamic simulations were carried out on two alkenyl-substituted Criegee intermediates (CIs), i.e., propenyl-substituted CI (PCI) and 1-methyl-propenyl substituted CI (MPCI), in order to investigate the influence of the position and number of substituents on the photochemical process of CI in S1 states. It is found that they play critical roles in the reactivity, dominant product channel, and mechanism of the CIs. More specifically, introducing a methyl group on either C1 (α-C) or C3 (γ-C) position of a vinyl-substituted CI (VCI) skeleton facilitates the rotation of the C1═O1 bond and leads to the formation of a three-membered dioxirane ring; meanwhile, it evidently enhances the reactively of the S1-state molecule. Meanwhile, methyl substitution on the vinyl moiety [i.e., C2 (ß-C) and C3 (γ-C) positions] is beneficial for the rotation of the C2═C3 bond and thus facilitates the formation of the five-membered 1,2-dioxole ring, and the substitution on C2 site decreases the reactivity. The cosubstitution of C2 and C3 atoms by methyl groups well balances the features of VCI in the sense of high reactivity, consistently predominant channel, and possible dioxole side-product. The findings here not only deepen the knowledge on the photochemical processes of the CI but also inspire the rethinking of the "old" concept of substitution effect.

Manipulating heterointerface to boost formation and desorption of intermediates for highly efficient alkaline hydrogen evolution.

Promoting water dissociation and H intermediate desorption play a pivotal role in achieving highly efficient hydrogen evolution reaction (HER) in alkaline media but remain a great challenge. Herein, we rationally develop a unique W-doped NiSx/Ni heterointerface as a favorable HER electrocatalyst which was directly grown on the Cu nanowire foam substrate (W-NiSx/Ni@Cu) by the electrodeposition strategy. Benefiting from the rational design of the interfaces, the electronic coupling of the W-NiSx/Ni@Cu can be efficiently modulated to lower the HER kinetic barrier. The obtained W-NiSx/Ni@Cu exhibits an enhanced HER activity with a low overpotential of 38 mV at 10 mA cm-2 and a small Tafel value of 27.5 mV dec-1, and high stability during HER catalysis. In addition, in-situ Raman spectra reveal that the Ni2+ active sites preferentially adsorb OH intermediate. The theoretical calculation confirms that the water dissociation is accelerated by the construction of W-NiSx/Ni heterointerface and H intermediate desorption can be also promoted by H spillover from S active sites in W-NiSx to Ni active sites in metal Ni. This work offers a valuable reference for rational designing heterointerface of electrocatalysts and provides an available method to accelerate the HER kinetics for the ampere-level current density under low overpotential.

The association between serum methylmalonic acid, cobalamin-related biomarkers, and long-term mortality risk in cancer survivors: a prospective cohort study.

BACKGROUND: Elevated serum methylmalonic acid (MMA), a marker of cobalamin (vitamin B12) deficiency, has been linked to cancer progression. However, the impact of MMA or cobalamin on mortality risk in cancer survivors remains unknown. OBJECTIVES: To explore the relationship between MMA, serum, dietary, and supplement of cobalamin, MMA metabolism-related genes, and poor prognosis in adult cancer survivors. METHODS: We analyzed data from 1988 cancer survivors aged ≥20 y. Patients were selected from the National Health and Nutrition Examination Survey and followed up until December 31, 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for mortality risk assessment. Genomic analysis identified MMA metabolism-related genes linked to early death in a 33-cancer-type cohort from The Cancer Genome Atlas. RESULTS: Among 1988 participants, 872 deaths occurred over a 10-year follow-up. Higher serum MMA levels were significantly linked to increased long-term mortality risk (tertile 3 compared with tertile 1: adjusted HR: 1.37; 95% CI: 1.11, 1.70; P-trend < 0.001). No associations were found between serum, dietary, and supplement of cobalamin and cancer survivor mortality (each P-trend > 0.143). However, MMA-associated mortality was notable in patients without deficiency. When combining cobalamin and MMA categories, multivariate-adjusted HR (95% CI) for all-cause mortality was 2.06 (95% CI: 1.60, 2.65) in participants with >250 nmol/L and cobalamin >295.1 pmol/L compared with those with MMA ≤250 nmol/L and cobalamin >295.1 pmol/L. Moreover, reduced transcriptional levels of MMA metabolism-related genes, indicating decreased mitochondrial MMA metabolism capability, are linked to an unfavorable prognosis in certain cancer types. CONCLUSIONS: Serum MMA was associated with long-term mortality risk in adult cancer survivors, which was more significant among individuals with higher levels of serum cobalamin. These findings suggest that mortality related to MMA was attributed to the insufficient flux of MMA metabolism, not cobalamin deficiency.

Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy.

Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

Preliminary study of the homeostatic regulation of osseointegration by nanotube topology.

The ideal implant surface plays a substantial role in maintaining bone homeostasis by simultaneously promoting osteoblast differentiation and limiting overactive osteoclast activity to a certain extent, which leads to satisfactory dynamic osseointegration. However, the rational search for implant materials with an ideal surface structure is challenging and a hot research topic in the field of tissue engineering. In this study, we constructed titanium dioxide titanium nanotubes (TNTs) by anodic oxidation and found that this structure significantly promoted osteoblast differentiation and inhibited osteoclast formation and function while simultaneously inhibiting the total protein levels of proline-rich tyrosine kinase 2 (PYK2) and focal adhesion kinase (FAK). Knockdown of the PYK2 gene by siRNA significantly suppressed the number and osteoclastic differentiation activity of mouse bone marrow mononuclear cells (BMMs), while overexpression of PYK2 inhibited osteogenesis and increased osteoclastic activity. Surprisingly, we found for the first time that neither knockdown nor overexpression of the FAK gene alone caused changes in osteogenesis or osteoclastic function. More importantly, compared with deletion or overexpression of PYK2/FAK alone, coexpression or cosilencing of the two kinases accelerated the effects of TNTs on osteoclastic and osteogenic differentiation on the surface of cells. Furthermore, in vivo experiments revealed a significant increase in positiveexpression-PYK2 cells on the surface of TNTs, but no significant change in positiveexpression -FAK cells was observed. In summary, PYK2 is a key effector molecule by which osteoblasts sense nanotopological mechanical signals and maintain bone homeostasis around implants. These results provide a referable molecular mechanism for the future development and design of homeostasis-based regulatory implant biomaterials.

Mn-Based Artificial Mitochondrial Complex "VI" Acts as an Electron and Free Radical Conversion Factory to Suppress Macrophage Inflammatory Response.

Disturbance in the mitochondrial electron transport chain (ETC) is a key factor in the emerging discovery of immune cell activation in inflammatory diseases, yet specific regulation of ETC homeostasis is extremely challenging. In this paper, a mitochondrial complex biomimetic nanozyme (MCBN), which plays the role of an artificial "VI" complex and acts as an electron and free radical conversion factory to regulate ETC homeostasis is creatively developed. MCBN is composed of bovine serum albumin (BSA), polyethylene glycol (PEG), and triphenylphosphine (TPP) hierarchically encapsulating MnO2 polycrystalline particles. It has nanoscale size and biological properties like natural complexes. In vivo and in vitro experiments confirm that MCBN can target the mitochondrial complexes of inflammatory macrophages, absorb excess electrons in ETC, and convert the electrons to decompose H2O2. By reducing the ROS and ATP bursts and converting existing free radicals, inhibiting NLRP3 inflammatory vesicle activation and NF-κB signaling pathway, MCBN effectively suppresses macrophage M1 activation and inflammatory factor secretion. It also demonstrates good inflammation control and significantly alleviates alveolar bone loss in a mouse model of ligation-induced periodontitis. This is the first nanozyme that mimics the mitochondrial complex and regulates ETC, demonstrating the potential application of MCBN in immune diseases.

Disorder-Invariant Implicit Neural Representation.

Implicit neural representation (INR) characterizes the attributes of a signal as a function of corresponding coordinates which emerges as a sharp weapon for solving inverse problems. However, the expressive power of INR is limited by the spectral bias in the network training. In this paper, we find that such a frequency-related problem could be greatly solved by re-arranging the coordinates of the input signal, for which we propose the disorder-invariant implicit neural representation (DINER) by augmenting a hash-table to a traditional INR backbone. Given discrete signals sharing the same histogram of attributes and different arrangement orders, the hash-table could project the coordinates into the same distribution for which the mapped signal can be better modeled using the subsequent INR network, leading to significantly alleviated spectral bias. Furthermore, the expressive power of the DINER is determined by the width of the hash-table. Different width corresponds to different geometrical elements in the attribute space, e.g., 1D curve, 2D curved-plane and 3D curved-volume when the width is set as 1, 2 and 3, respectively. More covered areas of the geometrical elements result in stronger expressive power. Experiments not only reveal the generalization of the DINER for different INR backbones (MLP versus SIREN) and various tasks (image/video representation, phase retrieval, refractive index recovery, and neural radiance field optimization) but also show the superiority over the state-of-the-art algorithms both in quality and speed.

[Preparation and evaluation of chitosan-based light source-loaded soluble microneedles].

The combination of photodynamic therapy and drug delivery microneedle (MN) provides a safe and effective way to treat tumors. In this paper, we designed a controlled and sustained-release drug-loaded microneedle patch (LED-losartan-HEMA/CS-MN, LLH-CSMN) based on chitosan loaded with high-energy photons, investigated its preparation process, and characterized the morphology and size of the microneedle array with losartan as the model drug. The mechanical properties of LLH-CSMN, skin puncture properties, slow release properties and the photothermal properties of high energy photons under long-term operation were investigated. The experimental results showed that the chitosan-based microneedle patch loaded with high-energy photons can effectively open channels on the skin surface for drug delivery and photodynamic therapy. At the same time, the in vitro percutaneous diffusion experiment showed that the microneedles prepared with losartan as the model drug released about 30% of the drug within 1 h, about 60% of the drug in total within 1 d, followed by slow release, and finally released 93% of the drug after 6 d. LLH-CSMN has controllable slow-release characteristics and good long-term photoassisted therapy effect. It provides a new safe and effective way for tumor treatment.

What Happens to a Pyrrole Hemithioindigo Photoswitch Trapped in a Fluorescent Protein?

Artificial molecular photoswitches that can be reversibly controlled into different configurations by external light stimulation have broad application prospects in various fields, such as materials and chemical biology. Among them, the pyrrole hemithioindigo (PHT) photoswitch has a geometric structure similar to that of the fluorescent protein chromophore. What happens when the chromophore is replaced by PHT, and does it achieve similar functions to the original one? To answer these questions, we carried out ONIOM(QM/MM) and classical molecular dynamics studies on the photoisomerization mechanism and spectroscopic properties of PHT in the fluorescent protein. The results showed that in the protein environment, the fate of excited PHT is governed by the competition between fluorescence emission and hula-twist isomerization. Due to the strong steric hindrance effects caused by the interlacing residues in the protein that restrict the PHT conformation transformation, the cis-to-trans isomerization process of PHT needs to overcome a barrier of at least 4.9 kcal/mol; thus, fluorescence emission is more dominant in competition. It is also found that the intermolecular interaction between LYS67 and the carbonyl oxygen of PHT has a significant effect on the fluorescence emission. These results revealed the photochemical reaction mechanism of a light-driven molecular switch in the fluorescent protein and provided further theoretical support for the field of chemical biology.

Combination of Anti-PD-1 and Electroacupuncture Induces a Potent Antitumor Immune Response in Microsatellite-Stable Colorectal Cancer.

Programmed death receptor-1 (PD-1) inhibitors are ineffective against microsatellite-stable (MSS) colorectal cancer. Electroacupuncture (EA) has oncosuppressive and immunomodulatory properties. Here, we investigated the antitumor effects of EA and explored the feasibility of EA combined with anti-PD-1 in MSS colorectal cancer. Results showed that EA exerted its antitumor effect in an intensity-specific manner, and moderate-intensity EA (1.0 mA) induced maximal tumor inhibition. EA enhanced antitumor immune responses by increasing lymphocytes and granzyme B (GzmB) levels, as well as activating the stimulator of IFN genes (STING) pathway. EA combined with anti-PD-1 showed superior efficacy compared with either monotherapy in multiple MSS colorectal cancer mouse models. Single-cell RNA sequencing revealed that cotreatment reprogrammed the tumor immune microenvironment (TIME), as characterized by enhancement of cytotoxic functions. Mechanically, we found that the potentiated effect of EA was dependent upon the STING pathway. Collectively, EA reshapes the TIME of MSS colorectal cancer and sensitizes tumors to anti-PD-1 in a STING pathway-dependent manner. These results provide a mechanistic rationale for using EA as an immunomodulatory strategy to improve the clinical efficacy of anti-PD-1 in MSS colorectal cancer. EA is safe, well-tolerated, and feasible for clinical translation as a promising strategy for treating MSS colorectal cancer.

Association between composite dietary antioxidant index and coronary heart disease among US adults: a cross-sectional analysis.

BACKGROUND: The Composite Dietary Antioxidant Index (CDAI) is a dietary antioxidant score that plays a protective role in many diseases, including depression, osteoporosis, papillomavirus infection, etc. However, the association between CDAI and coronary heart disease (CHD) is currently unclear. We aim to explore the correlations between CDAI and the risk of CHD. METHODS: Eligible participants were obtained from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. All participants in this cross-sectional study are required to undergo two separate 24-h dietary recall interviews. Average daily intakes of dietary antioxidants were used to calculate CDAI. CHD status was determined through a questionnaire. Weighted multiple logistic regression models were used to evaluate the relationship between CDAI and CHD. Moreover, we also used restricted cubic spline to explore Non-linear correlations. Sensitivity analysis using unweighted logistic analysis and subgroup analysis were used to demonstrate the stability of the results. RESULTS: A total of 34,699 participants were eligible for analysis.Compared to the participants without CHD, the participants with CHD showed lower levels of CDAI. After adjusting confounding factors in the multivariate weighted logistic regression model, CDAI was inversely associated with CHD (Q4 vs. Q1, OR = 0.65 (0.51-0.82, P < 0.001). Restricted cubic spline showed that there was a negative non-linear correlation (L-shaped) between CDAI and CHD, suggesting a potential saturation effect at higher CDAI levels, with the inflection point of 0.16. Sensitivity analysis showed that the results were stable. No significant statistically interaction was showed in subgroup analysis. CONCLUSIONS: There was a negative non-linear correlation between CDAI and CHD in US adults. However, further prospective studies are still needed to reveal their relationship.

Sex-specific immune-inflammatory markers and lipoprotein profile in patients with anhedonia with unipolar and bipolar depression.

BACKGROUND: Anhedonia is a core symptom in patients with unipolar and bipolar depression. However, sex-specific markers reflecting biological heterogeneity are lacking. Emerging evidence suggests that sex differences in immune-inflammatory markers and lipoprotein profiles are associated with anhedonia. METHODS: The demographic and clinical data, immune-inflammatory markers (CD3, CD4, and CD8), and lipoprotein profiles [TC, TG, LDL-C, HDL-C, lipoprotein(a) Lp (a)] of 227 patients with unipolar and bipolar depression were collected. The Hamilton Depression Rating Scale (HAMD) and Snaith-Hamilton Pleasure Scale (SHAPS) were used to assess depression and anhedonia symptoms. Data were analyzed using ANOVA, logistic regression, and receiver operating characteristic curves. RESULTS: Male patients in the anhedonia group had higher levels of CD3, CD4, and CD8, and lower levels of Lp (a) than the non-anhedonia group, while no significant difference was identified in female patients with and without anhedonia. Logistic regression analysis showed that CD3, CD4, CD8, and Lp (a) levels were associated with anhedonia in male patients. Furthermore, the combination of CD3, CD4, CD8, and Lp (a) had the strongest predictive value for distinguishing anhedonia in male patients than individual parameters. CONCLUSIONS: We identified sex-specific associations between immune-inflammatory markers, lipoprotein profiles, and anhedonia in patients with unipolar and bipolar depression. The combination of CD3, CD4, CD8, and Lp (a) might be a possible biomarker for identifying anhedonia in male patients with unipolar and bipolar depression.

School-based Evaluation Advancing Response for Child Health (SEARCH): a mixed longitudinal cohort study from multifaceted perspectives in Jiangsu, China.

BACKGROUND: Schools play a crucial role in providing mental health services to children and adolescents. However, the vastness of the student population and mental health workforce shortage in China severely limit the capacity for adequate care access and delivery. OBJECTIVE: We propose a large, mixed longitudinal cohort study, 'School-based Evaluation Advancing Response for Child Health (SEARCH)', aimed at addressing the increasing demand from individuals seeking access to mental healthcare services. METHODS: SEARCH uses a digital platform and school-based protocol for comprehensive assessment of the mental well-being of Chinese students in grades 4-12 incorporating individual, caregiver and teacher input, including capture of facial and acoustic features and response times, as well as mental well-being assessments. FINDINGS: We completed first wave data collection from nearly 20 000 participants (students, caregivers and teachers) at 11 schools, grades 4-12, in 3 cities in Jiangsu province in Southeast China from September 2022 to February 2023. We intend to conduct follow-up assessments for grades 4 through 12 at the 11 school sites every 6 months for 5 years. CONCLUSIONS: SEARCH will provide important insight into the developmental trajectory of mental well-being in Chinese children and adolescents. The study protocol does not simply focus on student self-report and incorporates caregiver and teacher viewpoints as well. It also collects objective indicators that may facilitate development of screening tools. CLINICAL IMPLICATIONS: We believe future study findings will guide the development and implementation of school-based mental healthcare initiatives to improve the well-being of children and adolescents.

Synchronization of Time-Delay Coupled Neural Networks With Stabilizing Delayed Impulsive Control.

This brief studies the distributed synchronization of time-delay coupled neural networks (NNs) with impulsive pinning control involving stabilizing delays. A novel differential inequality is proposed, where the state's past information at impulsive time is effectively extracted and used to handle the synchronization of coupled NNs. Based on this inequality, the restriction that the size of impulsive delay is always limited by the system delay is removed, and the upper bound on the impulsive delay is relaxed, which is improved the existing related results. By using the methods of average impulsive interval (AII) and impulsive delay, some relaxed criteria for distributed synchronization of time-delay coupled NNs are obtained. The proposed synchronization conditions do not impose on the upper bound of two consecutive impulsive signals, and the lower bound is more flexible. Moreover, our results reveal that the impulsive delays may contribute to the synchronization of time-delay systems. Finally, typical networks are presented to illustrate the advantage of our delayed impulsive control method.

Theoretical Insights into Aggregation-Induced Emission with the Ionic π Fluorophore: The Importance of Choosing the Dimer QM Model in the ONIOM Study.

In understanding the mechanism of aggregation-induced emission (AIE), the multilevel ONIOM framework has been demonstrated as one of the efficient tools that can capture the essential mechanistic information by choosing a single fluorophore as the quantum mechanics (QM) model and putting all surrounding molecules in the low-level region. Recently, the ionic styryl-pyridine salt (namely, SPH) has been reported as a new class of AIEgen with a high fluorescence yield. In the SPH crystal, a pair of ionic SPH molecules are closely stacked with each other in an antiparallel, head-to-tail pattern, thus the choice of QM models (an individual or dimeric structure) becomes critical in the ONIOM study. Herein we report the AIE mechanism of the ionic SPH at the QM ((TD)-CAM-B3LYP) and ONIOM(QM:MM) levels. As usual, the fluorescence quenching of SPH in tetrahydrofuran (THF) solution is attributed to a nonradiative relaxation via the central C═C bond rotation, with a rather low barrier of 2.7 kcal/mol. In crystals, either with a monomer or dimer model, the fluorescence quenching channel is found to be restricted due to the obvious C═C rotation barriers. Compared with the monomer model, the dimer model, by treating the orbital interaction of the two SPH molecules at the QM level, provides significantly increased barriers and a red-shifted emission wavelength that better matches the experimental value. In addition, the calculated exciton coupling in the fluorescence emission state can be discovered only by a dimer model. The findings here emphasize not only the importance of choosing a proper model in the ONIOM study of AIE but also expanding our understanding of novel AIE systems.

Layer-Specific BTX-A Delivery to the Gastric Muscularis Achieves Effective Weight Control and Metabolic Improvement.

The rising incidence of health-endangering obesity constantly calls for more effective treatments. Gastric intramural injection of botulinum neurotoxin A (BTX-A) as a new modality carries great promise yet inconsistent therapeutic efficacy. A layer-specific delivery strategy enabled by dissolving microneedles is hence pioneered to investigate the working site of BTX-A and the resulting therapeutic effects. The drug-loaded tips of the layer-specific gastric paralysis microneedles (LGP-MN) rapidly release and achieve uniform distribution of BTX-A within the designated gastric wall layers. In an obesity rat model, the LGP-MNs not only prove safer than conventional injection, but also demonstrate consistently better therapeutic effects with muscular layer delivery, including 16.23% weight loss (3.06-fold enhancement from conventional injection), 55.20% slower gastric emptying rate, improved liver steatosis, lowered blood lipids, and healthier gut microbiota. Further hormonal study reveals that the elevated production of stomach-derived glucagon-like peptide-1 due to the muscularis-targeting LGP-MN treatment is an important contributor to its unique glucose tolerance-improving effect. This study provides clear indication of the gastric muscularis as the most favorable working site of BTX-A for weight loss and metabolic improvement purposes, and meanwhile suggests that the LGP-MNs could serve as a novel clinical approach to treat obesity and metabolic syndromes.

Three-Dimensional Matrix Stiffness Activates the Piezo1-AMPK-Autophagy Axis to Regulate the Cellular Osteogenic Differentiation.

Extracellular matrix (ECM) stiffness is a key stimulus affecting cellular differentiation, and osteoblasts are also in a three-dimensional (3D) stiff environment during the formation of bone tissues. However, it remains unclear how cells perceive matrix mechanical stiffness stimuli and translate them into intracellular signals to affect differentiation. Here, for the first time, we constructed a 3D culture environment by GelMA hydrogels with different amino substitution degrees and found that Piezo1 expression was significantly stimulated by the stiff matrix with high substitution; meanwhile, the expressions of osteogenic markers OSX, RUNX2, and ALP were also observably improved. Moreover, knockdown of Piezo1 in the stiff matrix revealed significant reduction of the abovementioned osteogenic markers. In addition, in this 3D biomimetic ECM, we also observed that Piezo1 can be activated by the static mechanical conditions of the stiff matrix, leading to the increase of the intracellular calcium content and accompanied with a continuous change in cellular energy levels as ATP was consumed during cellular differentiation. More surprisingly, we found that in the 3D stiff matrix, intracellular calcium as a second messenger promoted the activation of the AMP-activated protein kinase (AMPK) and unc-51-like autophagy-activated kinase 1 (ULK1) axis and modestly modulated the level of autophagy, bringing it more similar to differentiated osteoblasts, with increased ATP energy metabolism consumption. Our study innovatively clarifies the regulatory role of the mechanosensitive ion channel Piezo1 in a static mechanical environment on cellular differentiation and verifies the activation of the AMPK-ULK1 axis in the cellular ATP energy metabolism and autophagy level. Collectively, our research develops the understanding of the interaction mechanisms of biomimetic extracellular matrix biomaterials and cells from a novel perspective and provides a theoretical basis for bone regeneration biomaterials design and application.

The role of the core microorganisms in the microbial interactions in activated sludge.

In order to gain a deeper understanding of the microbial interactions in wastewater treatment plants (WWTPs) in China and clarify the role of the core community in the microbial interactions in activated sludge (AS), this study used a molecular ecological network approach based on random matrix theory to construct co-occurrence networks of the core microorganisms (CoreN), the whole AS community (WholeN) and the microbial communities without the core microorganisms (OtherN), respectively. It was shown that the WholeN had more complex and tighter connections compared with the OtherN, because of its higher total number of nodes, higher average clustering coefficient, and shorter average geodesic distance. The proportions of positive links in the CoreN, WholeN and OtherN were gradually decreased, indicating that the core microorganisms promoted cooperation between AS microorganisms. Moreover, higher robustness after random removal of 50% of the nodes of the WholeN (0.2836 ± 0.0311) was observed than the robustness of the OtherN (0.1152 ± 0.0263). In addition, the vulnerability of OtherN (0.0514) is significantly higher than WholeN (0.0225). Meanwhile, the average ratio of negative/positive cohesion, was significantly decreased when the core microorganisms were removed. These results demonstrated that core community could strengthen the stability of the ecological network in AS. By discerning the key factors affecting ecological network, AS temperature was observed to have a strong correlation with all three networks. Moreover, pollutants in wastewater shown stronger correlations with the CoreN and WholeN, supporting the point that core community play a critical role in pollutant removal in WWTPs to a certain extent.