Acidic biofilm microenvironment-responsive ROS generation via a protein nanoassembly with hypoxia-relieving and GSH-depleting capabilities for efficient elimination of biofilm bacteria.

Reactive oxygen species (ROS) are widely considered to the effective therapeutics for fighting bacterial infections especially those associated with biofilm. However, biofilm microenvironments including hypoxia, limited H2O2, and high glutathione (GSH) level seriously limit the therapeutic efficacy of ROS-based strategies. Herein, we have developed an acidic biofilm microenvironment-responsive antibacterial nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The three-in-one nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in a slightly acidic environment, where Cu2+ catalyzes the conversion of H2O2 into hydroxyl radical (•OH) and consumes the highly expressed GSH to disrupt the redox homeostasis. With the assistance of an 808 nm laser, the loaded ICG not only triggers the production of singlet oxygen (1O2) by a photodynamic process, but also provides photonic hyperpyrexia that further promotes the Fenton-like reaction for enhancing •OH production and induces thermal decomposition of CuO2 for the O2-self-supplying 1O2 generation. The CuO2/ICG@CBSA with laser irradiation demonstrates photothermal-augmented multi-mode synergistic bactericidal effect and is capable of inhibiting biofilm formation and eradicating the biofilm bacteria. Further in vivo experiments suggest that the CuO2/ICG@CBSA can effectively eliminate wound infections and accelerate wound healing. The proposed three-in-one nanotherapeutics with O2/H2O2-self-supplied ROS generating capability show great potential in treating biofilm-associated bacterial infections. STATEMENT OF SIGNIFICANCE: Here, we have developed an acidic biofilm microenvironment-responsive nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in an acidic environment, where Cu2+ catalyzes the conversion of H2O2 into •OH and consumes the overexpressed GSH to improve oxidative stress. With the aid of an 808 nm laser, ICG provides photonic hyperpyrexia for enhancing •OH production, and triggers O2-self-supplying 1O2 generation. CuO2/ICG@CBSA with laser irradiation displays photothermal-augmented multi-mode antibacterial and antibiofilm effect. Further in vivo experiments prove that CuO2/ICG@CBSA effectively eliminates wound infection and promotes wound healing. The proposed three-in-one nanotherapeutics show great potential in treating biofilm-associated bacterial infections.

SAFE-MIL: a statistically interpretable framework for screening potential targeted therapy patients based on risk estimation.

Patients with the target gene mutation frequently derive significant clinical benefits from target therapy. However, differences in the abundance level of mutations among patients resulted in varying survival benefits, even among patients with the same target gene mutations. Currently, there is a lack of rational and interpretable models to assess the risk of treatment failure. In this study, we investigated the underlying coupled factors contributing to variations in medication sensitivity and established a statistically interpretable framework, named SAFE-MIL, for risk estimation. We first constructed an effectiveness label for each patient from the perspective of exploring the optimal grouping of patients' positive judgment values and sampled patients into 600 and 1,000 groups, respectively, based on multi-instance learning (MIL). A novel and interpretable loss function was further designed based on the Hosmer-Lemeshow test for this framework. By integrating multi-instance learning with the Hosmer-Lemeshow test, SAFE-MIL is capable of accurately estimating the risk of drug treatment failure across diverse patient cohorts and providing the optimal threshold for assessing the risk stratification simultaneously. We conducted a comprehensive case study involving 457 non-small cell lung cancer patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors. Results demonstrate that SAFE-MIL outperforms traditional regression methods with higher accuracy and can accurately assess patients' risk stratification. This underscores its ability to accurately capture inter-patient variability in risk while providing statistical interpretability. SAFE-MIL is able to effectively guide clinical decision-making regarding the use of drugs in targeted therapy and provides an interpretable computational framework for other patient stratification problems. The SAFE-MIL framework has proven its effectiveness in capturing inter-patient variability in risk and providing statistical interpretability. It outperforms traditional regression methods and can effectively guide clinical decision-making in the use of drugs for targeted therapy. SAFE-MIL offers a valuable interpretable computational framework that can be applied to other patient stratification problems, enhancing the precision of risk assessment in personalized medicine. The source code for SAFE-MIL is available for further exploration and application at https://github.com/Nevermore233/SAFE-MIL.

Comparative effect of skeletal stem cells versus bone marrow mesenchymal stem cells on rotator cuff tendon-bone healing.

Background: Bone marrow mesenchymal stem cells (BMSCs) have immense potential in applications for the enhancement of tendon-bone (T-B) healing. Recently, it has been well-reported that skeletal stem cells (SSCs) could induce bone and cartilage regeneration. Therefore, SSCs represent a promising choice for cell-based therapies to improve T-B healing. In this study, we aimed to compare the therapeutic potential of SSCs and BMSCs for tendon-bone healing. Methods: SSCs and BMSCs were isolated by flow cytometry, and their proliferation ability was measured by CCK-8 assay. The osteogenic, chondrogenic, and adipogenic gene expression in cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). C57BL/6 mice underwent unilateral supraspinatus tendon detachment and repair, and the mice were then randomly allocated to 4 groups: control group (tendon-bone interface without any treatment), hydrogel group (administration of blank hydrogel into the tendon-bone interface), hydrogel + BMSCs group (administration of hydrogel with BMSCs into the tendon-bone interface), and hydrogel + SSCs group (administration of hydrogel with SSCs into the tendon-bone interface). Histological staining, Micro-computed tomography (Micro-CT) scanning, biomechanical testing, and qRT-PCR were performed to assay T-B healing at 4 and 8 weeks after surgery. Results: SSCs showed more cell proportion, exhibited stronger multiplication capacity, and expressed higher osteogenic and chondrogenic markers and lower adipogenic markers than BMSCs. In vivo assay, the SSCs group showed a better-maturated interface which was characterized by richer chondrocytes and more proteoglycan deposition, as well as more newly formed bone at the healing site and increased mechanical properties when compared to other there groups. qRT-PCR analysis revealed that the healing interface in the SSCs group expressed more transcription factors essential for osteogenesis and chondrogenesis than the interfaces in the other groups. Conclusions: Overall, the results demonstrated the superior therapeutic potential of SSCs over BMSCs in tendon-bone healing. The translational potential of this article: This current study provides valuable insights that SSCs may be a more effective cell therapy for enhancing T-B healing compared to BMSCs.

Associations Between Dietary Intake of Tomato and Lycopene with All-Cause and Cancer-Specific Mortality in US Adults with Diabetes: Results From a Cohort Study.

This study aimed to explore the association between dietary intake of tomatoes and lycopene with all-cause and cancer mortality among US adults with diabetes. We hypothesized that a higher intake of tomato and lycopene is related to a reduced risk of all-cause and cancer mortality among adults with diabetes. This prospective study was conducted among 9213 US adults with diabetes using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Data on dietary intake of tomatoes and lycopene were obtained from two 24-h dietary recalls. Multivariate Cox proportional hazard models determined the associations between tomato/lycopene intake and mortality. A higher intake of tomatoes and lycopene was significantly associated with a lower risk of all-cause mortality (tomato: Q5 vs. Q1: HR = 0.68, 95% CI = 0.54-0.86, p = 0.001, p for trend = 0.001; lycopene: Q5 vs. Q1: HR = 0.78, 95% CI = 0.64-0.95, p = 0.013, p for trend = 0.006) after adjusting for all covariates. Compared with the lowest quintile of tomato and lycopene intake, the highest quintile was associated with a lower risk of cancer mortality (tomato: HR = 0.58, 95% CI = 0.35-0.96, p = 0.035; lycopene: HR = 0.63, 95% CI = 0.40-0.98, p = 0.043). Our study demonstrated that dietary intake of tomatoes and lycopene was significantly associated with a lower risk of all-cause mortality in US adults with diabetes. High consumption of tomatoes and lycopene was also related to reduced cancer mortality in US adults with diabetes.

BeM(CO)3- (M = Co, Rh, Ir) and BeM(CO)3 (M = Ni, Pd, Pt): Triply bonded terminal beryllium in zero oxidation state.

We perform detailed potential energy surface explorations of BeM(CO)3- (M = Co, Rh, Ir) and BeM(CO)3 (M = Ni, Pd, Pt) using both single-reference and multireference-based methods. The present results at the CASPT2(12,12)/def2-QZVPD//M06-D3/def2-TZVPPD level reveal that the global minimum of BeM(CO)3- (M = Co, Rh, Ir) and BePt(CO)3 is a C3v symmetric structure with an 1A1 electronic state, where Be is located in a terminal position bonded to M along the center axis. For other cases, the C3v symmetric structure is a low-lying local minimum. Although the present complexes are isoelectronic with the recently reported BFe(CO)3- complex having a B-Fe quadruple bond, radial orbital-energy slope (ROS) analysis reveals that the highest occupied molecular orbital (HOMO) in the title complexes is slightly antibonding in nature, which bars a quadruple bonding assignment. Similar weak antibonding nature of HOMO in the previously reported BeM(CO)4 (M = Ru, Os) complexes is also noted in ROS analysis. The bonding analysis through energy decomposition analysis in combination with the natural orbital for chemical valence shows that the bonding between Be and M(CO)3q (q = -1 for M = Co, Rh, Ir and q = 0 for M = Ni, Pd, Pt) can be best described as Be in the ground state (1S) interacting with M(CO)30/- via dative bonds. The Be(spσ) → M(CO)3q σ-donation and the complementary Be(spσ) ← M(CO)3q σ-back donation make the overall σ bond, which is accompanied by two weak Be(pπ) ← M(CO)3q π-bonds. These complexes represent triply bonded terminal beryllium in an unusual zero oxidation state.

E3 Ubiquitin Ligase NEDD4L Negatively Regulates Skin Tumorigenesis by Inhibiting IL-6/GP130 Signaling Pathway.

IL-6 signaling plays a crucial role in the survival and metastasis of skin cancer. NEDD4L acts as a suppressor of IL-6 signaling by targeting GP130 degradation. However, the effects of the NEDD4L-regulated IL-6/GP130 signaling pathway on skin cancer remain unclear. In this study, protein expression levels of NEDD4L and GP130 were measured in tumor tissues from patients with cutaneous squamous cell carcinoma. Skin tumors were induced in wild-type and Nedd4l-knockout mice, and activation of the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway was detected. The results indicated a negative correlation between the protein expression levels of NEDD4L and GP130 in cutaneous squamous cell carcinoma tissues from patients. Nedd4l deficiency significantly promoted 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin tumorigenesis and benign-to-malignant conversion by activating the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway, which was abrogated by supplementation with the GP130 inhibitor SC144. Furthermore, our findings suggested that NEDD4L can interact with GP130 and promote its ubiquitination in skin tumors. In conclusion, our results indicate that NEDD4L could act as a tumor suppressor in skin cancer, and inhibition of GP130 could be a potential therapeutic method for treating this disease.

TMBstable: a variant caller controls performance variation across heterogeneous sequencing samples.

In cancer genomics, variant calling has advanced, but traditional mean accuracy evaluations are inadequate for biomarkers like tumor mutation burden, which vary significantly across samples, affecting immunotherapy patient selection and threshold settings. In this study, we introduce TMBstable, an innovative method that dynamically selects optimal variant calling strategies for specific genomic regions using a meta-learning framework, distinguishing it from traditional callers with uniform sample-wide strategies. The process begins with segmenting the sample into windows and extracting meta-features for clustering, followed by using a pre-trained meta-model to select suitable algorithms for each cluster, thereby addressing strategy-sample mismatches, reducing performance fluctuations and ensuring consistent performance across various samples. We evaluated TMBstable using both simulated and real non-small cell lung cancer and nasopharyngeal carcinoma samples, comparing it with advanced callers. The assessment, focusing on stability measures, such as the variance and coefficient of variation in false positive rate, false negative rate, precision and recall, involved 300 simulated and 106 real tumor samples. Benchmark results showed TMBstable's superior stability with the lowest variance and coefficient of variation across performance metrics, highlighting its effectiveness in analyzing the counting-based biomarker. The TMBstable algorithm can be accessed at https://github.com/hello-json/TMBstable for academic usage only.

Mitochondrial DNA Leakage and cGas/STING Pathway in Microglia: Crosstalk Between Neuroinflammation and Neurodegeneration.

Neurodegenerative diseases, characterized by abnormal deposition of misfolded proteins, often present with progressive loss of neurons. Chronic neuroinflammation is a striking hallmark of neurodegeneration. Microglia, as the primary immune cells in the brain, is the main type of cells that participate in the formation of inflammatory microenvironment. Cytoplasmic free mitochondrial DNA (mtDNA), a common component of damage-associated molecular patterns (DAMPs), can activate the cGas/stimulator of interferon genes (STING) signalling, which subsequently produces type I interferon and proinflammatory cytokines. There are various sources of free mtDNA in microglial cytoplasm, but mitochondrial oxidative stress accumulation plays the vital role. The upregulation of cGas/STING pathway in microglia contributes to the abnormal and persistent microglial activation, accompanied by excessive secretion of neurotoxic inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which exacerbates the damage of neurons and promotes the development of neurodegeneration. Currently, novel therapeutic approaches need to be found to delay the progression of neurodegenerative disorders, and regulation of the cGas/STING signaling in microglia may be a potential target.

Preparation and functional properties of rice bran globulin-chitooligosaccharide-quercetin-resveratrol covalent complex.

BACKGROUND: As the major protein (approximately 36%) in rice bran, globulin exhibits excellent foaming and emulsifying properties, endowing its useful application as a foaming and emulsifying agent in the food industry. However, the low water solubility restricts its commercial potential in industrial applications. The present study aimed to improve this protein's processing and functional properties. RESULTS: A novel covalent complex was fabricated by a combination of the Maillard reaction and alkaline oxidation using rice bran globulin (RBG), chitooligosaccharide (C), quercetin (Que) and resveratrol (Res). The Maillard reaction improved the solubility, emulsifying and foaming properties of RBG. The resultant glycosylated protein was covalently bonded with quercetin and resveratrol to form a (RBG-C)-Que-Res complex. (RBG-C)-Que-Res exhibited higher thermal stability and antioxidant ability than the native protein, binary globulin-chitooligosaccharide or ternary globulin-chitooligosaccharide-polyphenol (only containing quercetin or resveratrol) conjugates. (RBG-C)-Que-Res exerted better cytoprotection against the generation of malondialdehyde and reactive oxygen species in HepG2 cells, which was associated with increased activities of antioxidative enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) through upregulated genes SOD1, CAT, GPX1 (i.e. gene for glutathione peroxidase-1), GCLM (i.e. gene for glutamate cysteine ligase modifier subunit), SLC1A11 (i.e. gene for solute carrier family 7, member 11) and SRXN1 (i.e. gene for sulfiredoxin-1). The anti-apoptotic effect of (RBG-C)-Que-Res was confirmed by the downregulation of caspase-3 and p53 and the upregulation of B-cell lymphoma-2 gene expression. CONCLUSION: The present study highlights the potential of (RBG-C)-Que-Res conjugates as functional ingredients in healthy foods. © 2024 Society of Chemical Industry.

Recent Advances in Functional Cellulose-based Films with Antimicrobial and Antioxidant Properties for Food Packaging.

The packaging of food plays a crucial role in food preservation worldwide. However, traditional packaging systems are passive layers with weak efficiency in protecting the food quality. Therefore, packaged foods are gradually spoiled due to the oxidation and growth of microorganisms. Additionally, most of the commercial packaging films are made of petroleum-based materials which raise environmental concerns. Accordingly, the development of eco-friendly natural-derived active packaging systems has increased the attention of scientists. Cellulose as the most abundant polysaccharide on earth with high biocompatibility, no toxicity, and high biodegradability has extensively been applied for the fabrication of packaging films. However, neat cellulose-based films lack antioxidant and antimicrobial activities. Therefore, neat cellulose-based films are passive films with weak food preservation performance. Active films have been developed by incorporating antioxidants and antimicrobial agents into the films. In this review, we have explored the latest research on the fabrication of antimicrobial/antioxidant cellulose-based active packaging films by incorporating natural extracts, natural polyphenols, nanoparticles, and microparticles into the cellulose-based film formulations. We categorized these types of packaging films into two main groups: (i) blend films which are obtained by mixing solutions of cellulose with other soluble antimicrobial/antioxidant agents such as natural extracts and polyphenols; and (ii) composite films which are fabricated by dispersing antimicrobial/antioxidant nano- or microfillers into the cellulose solution. The effect of these additives on the antioxidant and antimicrobial properties of the films has been explained. Additionally, the changes in the other properties of the films such as hydrophilicity, water evaporation rate, and mechanical properties have also been briefly addressed.

Clusters and bulky Lewis acid protected complexes with planar hexacoordinate beryllium and magnesium.

Planar hexacoordination (ph) is only rarely reported in the literature. So far, only a few neutral and cationic molecules possessing phE (E = C, Si, B, Al, Ga) in the most stable isomer are predicted theoretically. Present electronic structure calculations report hitherto unknown anionic planar hexcoordinate beryllium and magnesium, phBe/Mg, as the most stable isomer. Global minimum searches show that the lowest energy structure of BeC6M3- (M = Al, Ga) and MgC6M3- (M = Ga, In, Tl) is the D3h symmetric phBe/Mg clusters, where beryllium/magnesium is covalently bonded with six carbon centers and M is located in a bridging position between two carbon centers. These global minimum phBe/Mg clusters are highly kinetically stable against isomerization, facilitating the experimental confirmation by photoelectron spectroscopy. Noteworthy is the fact that the phBe/Mg center is linked with carbon centers through three 7c-2e delocalized σ bonds and three 7c-2e π bonds, making the cluster double aromatic (σ + π) in nature. The bonding between the Be/Mg and outer ring moiety can be best expressed as an electron-sharing σ-bond between the s orbital of Be+/Mg+ and C6M32- followed by three dative interactions involving empty pπ and two in-plane p orbitals of Be/Mg. Furthermore, Lewis basic M centers of the title clusters can be passivated through the complexation with bulky Lewis acid, 9-boratriptycene, lowering the overall reactivity of the cluster, which can eventually open up the possibility of their large-scale syntheses.

What makes TMB an ambivalent biomarker for immunotherapy? A subtle mismatch between the sample-based design of variant callers and real clinical cohort.

Tumor mutation burden (TMB) is a widely recognized biomarker for predicting the efficacy of immunotherapy. However, its use still remains highly controversial. In this study, we examine the underlying causes of this controversy based on clinical needs. By tracing the source of the TMB errors and analyzing the design philosophy behind variant callers, we identify the conflict between the incompleteness of biostatistics rules and the variety of clinical samples as the critical issue that renders TMB an ambivalent biomarker. A series of experiments were conducted to illustrate the challenges of mutation detection in clinical practice. Additionally, we also discuss potential strategies for overcoming these conflict issues to enable the application of TMB in guiding decision-making in real clinical settings.

B7 Be6 B7 : A Boron-Beryllium Sandwich Complex.

Planar boron clusters have often been regarded as "π-analogous" to aromatic arenes because of their similar delocalized π-bonding. However, unlike arenes such as C5 H5 - and C6 H6 , boron clusters have not previously shown the ability to form sandwich complexes. In this study, we present the first sandwich complex involving beryllium and boron, B7 Be6 B7 . The global minimum of this combination adopts a unique architecture having a D6h geometry, featuring an unprecedented monocyclic Be6 ring sandwiched between two quasi-planar B7 motifs. The thermochemical and kinetic stability of B7 Be6 B7 can be attributed to strong electrostatic and covalent interactions between the fragments. Chemical bonding analysis shows that B7 Be6 B7 can be considered as a [B7 ]3- [Be6 ]6+ [B7 ]3- complex. Moreover, there is a significant electron delocalization within this cluster, supported by the local diatropic contributions of the B7 and Be6 fragments.

TMBserval: a statistical explainable learning model reveals weighted tumor mutation burden better categorizing therapeutic benefits.

A high tumor mutation burden (TMB) is known to drive the response to immune checkpoint inhibitors (ICI) and is associated with favorable prognoses. However, because it is a one-dimensional numerical representation of non-synonymous genetic alterations, TMB suffers from clinical challenges due to its equal quantification. Since not all mutations elicit the same antitumor rejection, the effect on immunity of neoantigens encoded by different types or locations of somatic mutations may vary. In addition, other typical genomic features, including complex structural variants, are not captured by the conventional TMB metric. Given the diversity of cancer subtypes and the complexity of treatment regimens, this paper proposes that tumor mutations capable of causing various degrees of immunogenicity should be calculated separately. TMB should therefore, be segmented into more exact, higher dimensional feature vectors to exhaustively measure the foreignness of tumors. We systematically reviewed patients' multifaceted efficacy based on a refined TMB metric, investigated the association between multidimensional mutations and integrative immunotherapy outcomes, and developed a convergent categorical decision-making framework, TMBserval (Statistical Explainable machine learning with Regression-based VALidation). TMBserval integrates a multiple-instance learning concept with statistics to create a statistically interpretable model that addresses the broad interdependencies between multidimensional mutation burdens and decision endpoints. TMBserval is a pan-cancer-oriented many-to-many nonlinear regression model with discrimination and calibration power. Simulations and experimental analyses using data from 137 actual patients both demonstrated that our method could discriminate between patient groups in a high-dimensional feature space, thereby rationally expanding the beneficiary population of immunotherapy.

Optimization of a silver-nanoprism conjugated with 3,3',5,5'-tetramethylbenzidine towards easy-to-make colorimetric analysis of acetaldehyde: a new platform towards rapid analysis of carcinogenic agents and environmental technology.

Acetaldehyde acts as an important mediator in the metabolism of plants and animals; however, its abnormal level can cause problems in biological processes. Although acetaldehyde is found naturally in many organisms, exposure to high concentrations can have effects on the eyes, respiratory system, etc. Due to the importance of detecting acetaldehyde in environmental samples and biofluids, determination of its concentration is highly demanded. There are some reports showing exposure to high concentrations of acetaldehyde for a long time can increase the risk of cancer by reacting with DNA. In this work, we presented a novel colorimetric method for rapid and sensitive detection of acetaldehyde with high reproducibility using different AgNPs with various morphologies. The redox reaction between AgNPs, 3,3',5,5'-tetramethylbenzidine (TMB) solution, and analytes endows a color change in 15 minutes that is detectable by the naked eye. UV spectrophotometry was further used for quantitative analysis. An iron mold with a hexagonal pattern and liquid paraffin were also used to prepare the paper-based microfluidic substrate, as a low cost, accessible, and rapid detection tool. Different types of AgNPs showed different lower limits of quantification (LLOQ). The AgNPs-Cit and AgNPrs could identify acetaldehyde with linear range of 10-7 to 10 M and an LLOQ of 10-7 M. The AgNWs showed the best color change activity with a linear range 10-5 to 10 M and the lowest diagnostic limit is 10-5 M. Finally, analysis of human biofluids as real samples were successfully performed using this system.

Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist.

Cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) signaling stimulators, an essential innate immunity component, monitor invading pathogen DNA and damaged self-DNA, making them an appealing target for drug development. The natural STING agonist, 2'3'-cGAMP, mounts and stabilizes the STING homodimer to trigger an antiviral or antitumor immune responses. However, cyclic-dinucleotide-based STING agonists show limited clinical effects owing to their short half-lives. To explore whether STING-dimer stabilizers could trigger STING signaling instead of cyclic dinucleotide-based molecules, we analyzed the structural characteristics of STING to design and synthesize a series of compounds based on the covalent STING inhibitor C-170, three of which were 23, 26, and 27, exhibited STING-dependent immune activation, both in vitro and in vivo. Compound 23 could act synergistically with cGAMP and other STING agonists as a promising moderate STING agonist. This indicates that promoting STING dimerization is a promising strategy for designing next-generation STING agonists.

Bonding situations in tricoordinated beryllium phenyl complexes.

The bonding situation in the tricoordinated beryllium phenyl complexes [BePh3 ]- , [(pyridine)BePh2 ] and [(trimethylsilyl-N-heterocyclic imine)BePh2 ] is investigated experimentally and computationally. Comparison of the NMR spectroscopic properties of these complexes and of their structural parameters, which were determined by single crystal X-ray diffraction experiments, indicates the presence of π-interactions. Topology analysis of the electron density reveals elliptical electron density distributions at the bond critical points and the double bond character of the beryllium-element bonds is verified by energy decomposition analysis with the combination of natural orbital for chemical valence. The present beryllium-element bonds are highly polarized and the ligands around the central atom have a strong influence on the degree of π-delocalization. These results are compared to related triarylboranes.

Mechanical stimulation improves rotator cuff tendon-bone healing via activating IL-4/JAK/STAT signaling pathway mediated macrophage M2 polarization.

Background: It is well known that appropriate mechanical stimulation benefits tendon-bone (T-B) healing, however, the mechanisms behind this are still uncovered completely. Here, we aimed to explore whether the IL-4/JAK/STAT signaling pathway mediated macrophage polarization was involved in mechanical stimulation induced T-B healing. Method: C57BL/6 mice rotator cuff (RC) repair model was established, and the mice were randomly allocated to the following group. 1. Mice were allowed for free cage activities after surgery (FC group); 2. Mice received treadmill running initiated on postoperative day 7 (TR group); 3. Mice only received a local injection of hydrogel containing IL-4 neutralizing antibody without postoperative intervention (FC â€‹+ â€‹AF-404-SP group); 4. Mice received a local injection of hydrogel containing IL-4 neutralizing antibody and postoperative treadmill running (TR â€‹+ â€‹AF-404-SP group). The expression of IL-4 within supraspinatus tendon (SST) enthesis was measured by Enzyme-linked immunosorbent assay (ELISA). In addition, the activation of JAK/STAT signaling pathway in macrophages and identification of macrophage phenotype at the RC insertion site was detected by Flow cytometry and qRT-PCR. T-B healing quality in this RC repair model was evaluated by histological staining, Micro-computed tomography (Micro-CT) scanning, and biomechanical testing. Result: In this study, using the RC repair model, we confirmed that generation of IL-4, activation of the JAK/STAT signaling pathway in macrophages, the ability of macrophages to polarize towards M2 subtype, and T-B healing quality were significantly enhanced in TR group compared to FC group. When comparing FC â€‹+ â€‹AF-404-SP group with TR â€‹+ â€‹AF-404-SP group, it was found that the mechanical stimulation induced this effect was depleted following the blockade of the IL-4/JAK/STAT signaling pathway. Conclusion: Our finding suggested that mechanical stimulation could accelerate T-B healing via activating the IL-4/JAK/STAT signaling pathway that modulates macrophages to polarize towards M2 subtype. The translational potential of this article: This is the first study to reveal a significant role of mechanical stimulation in the IL-4/JAK/STAT signaling pathway activation and macrophage polarization during RC T-B healing, which highlights the IL-4/JAK/STAT signaling pathway as a potential target to mediate macrophage M2 polarization and improves T-B healing for RC repair.

TMBcat: A multi-endpoint p-value criterion on different discrepancy metrics for superiorly inferring tumor mutation burden thresholds.

Tumor mutation burden (TMB) is a widely recognized stratification biomarker for predicting the efficacy of immunotherapy; however, the number and universal definition of the categorizing thresholds remain debatable due to the multifaceted nature of efficacy and the imprecision of TMB measurements. We proposed a minimal joint p-value criterion from the perspective of differentiating the comprehensive therapeutic advantages, termed TMBcat, optimized TMB categorization across distinct cancer cohorts and surpassed known benchmarks. The statistical framework applies to multidimensional endpoints and is fault-tolerant to TMB measurement errors. To explore the association between TMB and various immunotherapy outcomes, we performed a retrospective analysis on 78 patients with non-small cell lung cancer and 64 patients with nasopharyngeal carcinomas who underwent anti-PD-(L)1 therapy. The stratification results of TMBcat confirmed that the relationship between TMB and immunotherapy is non-linear, i.e., treatment gains do not inherently increase with higher TMB, and the pattern varies across carcinomas. Thus, multiple TMB classification thresholds could distinguish patient prognosis flexibly. These findings were further validated in an assembled cohort of 943 patients obtained from 11 published studies. In conclusion, our work presents a general criterion and an accessible software package; together, they enable optimal TMB subgrouping. Our study has the potential to yield innovative insights into therapeutic selection and treatment strategies for patients.