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Abstract: Fragmentation pathways of eight nitrogen-containing bisphosphonates (BPs), including Pamidronate, Alendronate, and five corresponding acylated derivatives, and Risedronate, were investigated by electrospray ionization mass spectrometry (ESI-MS) in conjunction with tandem mass spectrometry in negative ion mode. Characteristic fragment ions involved were formed by successive loss of water molecules, including α, β-unsaturated product ions formed by dehydration of the α-hydroxyl group and β-hydrogen, cyclic ions with P–O–P four-membered rings formed by dehydration of the two –OH groups attached to two phosphorus atoms, and cyclic phosphoramide ions with five- or six-membered rings formed by loss of water via an intramolecular nucleophilic substitution reaction, in which –NH2 (or –NH–) group on γ or δ carbon acted as the nucleophile to attack phosphorus atom of Pt the initial stage. Another notable characteristic product ion [HP2O5]− at m/z 143, shown by all eight ESI-MS2 spectra, is a diagnostic ion of bisphosphonate group, formed from the four-membered ring ion containing P–O–P. Some additional fragmentation ions were produced from chloroacetyl Alendronate, chloroacetyl Pamidronate, and Risedronate containing triple bond ions, formed by loss of water from the corresponding enol anions. The hydrogen/deuterium (H/D) exchange experiment, theoretical calculations, and the high-resolution mass spectrometry were appropriately employed to rationalize the proposed fragmentation pathways. [ABSTRACT FROM AUTHOR]

Designing adhesive hydrogel wound dressings with inherent antibacterial and antioxidant properties is desirable to treat cutaneous full-thickness injuries in clinical care. Herein, a series of photo-induced Schiff base crosslinking-based adhesive hydrogels with promising traits are designed and prepared through Diels-Alder (DA) reactions between functional groups-grafted carboxymethyl chitosan (CMCS) and a photo-responsive polyethylene glycol (PEG) crosslinker. The quaternary ammonium and phenol groups in modified CMCS endows hydrogels excellent antibacterial and antioxidant properties. Upon UV (365 nm) irradiation, the generated o -nitrosobenzaldehyde from the photo-isomerization of o -nitrobenzyl in PEG derivative can subsequently crosslink with amino groups on tissue interfaces via Schiff base, endowing the hydrogel with well adhesiveness. Additionally, the hydrogel exhibits good BSA adsorption capacity, cytocompatibility and hemostatic property. The in vivo full-thickness skin defect study on mice indicates that the multi-functional hydrogel with considerable collagen deposition and vascularization capacities can be an effective and promising adhesive dressing for improving wound healing. [Display omitted] • A series of photo-induced Schiff base crosslinking-based adhesive hydrogels • Carboxymethyl chitosan and polyethylene glycol crosslinker construct gel networks. • Functional groups endow hydrogels inherent antibacterial and antioxidant properties. • Hydrogels promote wound healing by collagen deposition and regulating factors • expression [ABSTRACT FROM AUTHOR]

BTK (Bruton's tyrosine kinase) inhibitors are the most promising drugs for the treatment of hematological tumors. A high selectivity of BTK inhibitors ensures reduced side effects from off-targeting. Accordingly, here, based on Zanubrutinib, we designed and synthesized a new range of imidazopyrazole-3-carboxamide derivatives as novel BTK inhibitors that retained the amide group for improved selectivity. These compounds revealed potent inhibitory activity against BTK in vitro. Remarkably, compounds 12a (IC 50 5.2 nM) and 18a (IC 50 4.9 nM) possessed the highest kinase selectivity. Both of these effectively inhibited the auto-phosphorylation of BTK, blocked the cell cycle in G0/G1 phase, and induced apoptosis in the TMD8 cells. In a TMD8 cells xenograft model, a twice-daily dose of compound 12a at 25 mg/kg and a thrice-daily dose of compound 18a at 15 mg/kg significantly suppressed the tumor growth without obvious toxicity. Collectively, 12a and 18a are the potential selective BTK inhibitors that can be developed further. [Display omitted] • A series of imidazopyrazole-3-carboxamide-containing BTK inhibitors were synthesized. • 12a and 18a exhibited potent BTK inhibitory activity and good selectivity. • 12a and 18a showed a significant in vivo anti-tumor activity. [ABSTRACT FROM AUTHOR]

The direct carboxylation of aldehydes with CO 2 is rare due to the polarity mismatch between these two electrophilic substrates. To address this challenge, we propose a sequential approach for synthesizing α-ketoacids from commercially available aldehydes by integrating umpolung and CO 2 shuttling strategies. This transition metal-free shuttle carboxylation method enables the transfer of CO 2 from triphenylacetic acid potassium salt to thioacetal, eliminating the need for handling pressurized CO 2 gas or using specialized equipment, while also enhancing the reaction's functional group tolerance. Furthermore, the use of stoichiometric or slightly excess amounts of triphenylacetic acid potassium salt as a formal CO 2 donor makes it suitable for complete 1 3 C labeling of α-ketoacids.

The sustainable construction of spirocyclic compounds is important to the scientific community and the pharmaceutical industries. Herein, we demonstrate a carbamoyl radical-initiated intramolecular dearomative spirocyclization to access the spiro-cyclohexadiene oxindoles under visible light irradiation, which constitutes the first example of accessing the I-substituted derivatives that facilitate diversified transformations. Additionally, the scalability, late-stage modification of drugs, and significant antitumor activity of the products demonstrate the novel spirocyclic synthesis platform for expediting drug development.

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMB high CNA high , as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer., (© 2024 Wiley Periodicals LLC.)

2,1,3-Benzothiadiazole is widely used as a privileged scaffold in pharmaceuticals and organic functional materials. Nonetheless, many current methods for the functionalization of 2,1,3-benzothiadiazole rely on preactivation, transition metal catalysts/promoters, or an elevated reaction temperature. Herein we disclose a transition-metal-free visible-light-induced photocatalytic method for the direct C-H alkylation of 2,1,3-benzothiadiazole using readily accessible carboxylic acid derivatives, i.e., N -hydroxyphthalimide esters (NHPEs), as alkylating reagents under room temperature. This mild and scalable method is highlighted by the late-stage installation of the benzothiadiazole scaffold in drugs and natural products.

Herein, we present an efficient synthesis of 1,7-fused indolines tethered with a spiroindolinonyl moiety through the cascade reaction of indolin-1-yl(aryl)methanimines with diazo oxindoles. To the best of our knowledge, this is the first example in which 1,7-fused indoline skeleton was constructed along with the simultaneous introduction of a spiro element initiated by the C-H bond activation of indoline. In forming the title product, the indoline substrate and the diazo coupling partner demonstrated an unprecedented reaction pattern in which the latter acts as a C1 synthon to participate in the construction of the spirocyclic scaffold through the reductive elimination of a key seven-membered Ru(II) species by using air as an effective and sustainable oxidant to regenerate the active catalyst. Moreover, studies on the cytotoxicity of selected products against several human cancer cell lines demonstrated their potential as lead compounds for the development of anticancer drugs. With notable features such as simple and economical substrates, pharmaceutically valuable products with sophisticated spirocyclic skeleton, mild reaction conditions, cost-free and sustainable oxidants, high efficiency, excellent compatibility with diverse functional groups, and scalability, this method is expected to find wide applications in related areas.

The study compared and analyzed the quality of loquat jam with different cooking times through physicochemical parameters, headspace-gas chromatography-ion migration spectroscopy (HS-GC-IMS) and intelligent senses. The results showed that with the prolongation of the cooking time, the color of loquat jam slowly deepened, the energy significantly increased, the adhesiveness, gumminess, hardness and chewiness enhanced, the free amino acid content increased from 22.40 to 65.18 mg/g. The organic acid content increased from 1.64 to 9.82 mg/g. Forty-seven volatile flavor compounds were identified in five types of loquat jam using HS-GC-IMS, among which the relative content of aldehydes was sharply higher than that of other chemical substances, playing an important role in the flavor formation of loquat jam. LJ0, LJ1 and LJ2 had higher aldehyde content, followed by LJ3 and LJ4 had the lowest aldehyde content. The orthogonal partial least squares-discriminant analysis (OPLS-DA) screened 15 marker compounds that could distinguish five types of loquat jam. The E-nose results showed a significant difference in olfactory sense between loquat jam cooked for 100 and 120 min. The E-tongue results corroborated the results of free amino acids (FAAs) and organic acids, indicating that the gustatory sense of loquat jam changed significantly when the cooking time reached 120 min. The results provided a basis for further research on the relationship between the cooking process and quality characteristics of loquat jam.

Adjustment difficulties of school students are common and their school adjustment has gained wide concern in recent years. Negative life events (NLEs) hope, and gratitude have been associated with school adjustment. However, the potential effect of NLEs on hope and gratitude and whether hope and gratitude mediate the association between NLEs and school adjustment among high students have not been studied. Thus, this study aims to investigate the association between NLEs, hope and gratitude, and school adjustment in high school students in China. Additionally, the study aims to examine the mediating role of hope and gratitude in the association between NLEs and school adjustment. A total of 700 junior high school students in Guangxi Province (336 boys, 364 girls, M age = 15 years) completed the questionnaire. The results indicated significant mediating effects of hope and gratitude in the sequential positive association between NLEs and school adjustment. Furthermore, this study unraveled the complexity of the link between NLEs and school adjustment with the combination of hope and gratitude. The findings emphasized the importance of fostering hope and gratitude in left-behind adolescents to combat the negative consequences of NLEs. The study is also one of the first to investigate a serial mediation model to determine which NLEs influence Chinese left-behind adolescents' school adjustment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Dual-atom catalysts (DAC) are deemed as promising electrocatalysts due to the abundant active sites and adjustable electronic structure, but the fabrication of well-defined DAC is still full of challenges. Herein, bonded Fe dual-atom catalysts (Fe 2 DAC) with Fe 2 N 6 C 8 O 2 configuration were developed through one-step carbonization of a preorganized covalent organic framework with bimetallic Fe chelation sites (Fe 2 COF). The transition from Fe 2 COF to Fe 2 DAC involved the dissociation of the nanoparticles and the capture of atoms by carbon defects. Benefitting from the optimized d-band center and enhanced adsorption of OOH* intermediates, Fe 2 DAC exhibited outstanding oxygen reduction activity with a half-wave potential of 0.898 V vs. RHE. This work will guide more fabrication of dual-atom and even cluster catalysts from preorganized COF in the future., (© 2023 Wiley-VCH GmbH.)

Photonic disinfection, particularly near-infrared (NIR) light triggered antibacterial, has emerged as a highly promising solution for combating pathogenic microbes due to its spatiotemporal operability, safety, and low cost of apparatus. However, it remains challenging to construct NIR-responsive antibacterial agents with high light-converting efficacy and elucidate synergistic mechanisms. In this work, ultrathin two-dimensional (2D) BiOCl-Bi 2 S 3 -Cu 2 S ternary heterostructures that can efficiently kill drug-resistant bacteria were synthesized by doping 0D Bi 2 S 3 and Cu 2 S nanoparticles in the 2D BiOCl nanosheets via a facile one-pot hydrothermal method. Notably, the incorporation of Cu 2 S nanoparticles bestows strong NIR light-harvesting capability to the composite nanosheets due to their localized surface plasmon resonance (LSPR). Upon NIR light illumination, the BiOCl-Bi 2 S 3 -Cu 2 S nanosheets can achieve enhanced photonic hyperthermia and reaction oxygen species (ROS) generation, serving as single light-activated bi-functional photothermal/photodynamic therapeutics. High-speed hot electrons and large local electronic fields caused by LSPR might play an important role in thermal vibrations and effective carrier separations, respectively. Benefiting from the unique ternary heterostructures, both the photothermal conversion and ROS generation efficacy of BiOCl-Bi 2 S 3 -Cu 2 S nanosheets are significantly improved compared to the binary BiOCl-Cu 2 S or BiOCl-Bi 2 S 3 nanosheets. Accordingly, the ternary composite nanosheets can effectively kill bacteria via the NIR-driven photonic disinfection mechanism. This work presents a new type of 2D composite nanosheets with ternary heterostructures for NIR photonic disinfection., (© 2023 Wiley-VCH GmbH.)

The design and facile preparation of the smart hydrogel wound dressings with inherent excellent antioxidant and antibacterial capacity to effectively promote wound healing processes is highly desirable in clinical applications. Herein, a series of multifunctional hydrogels were prepared by the dynamic Schiff base and boronate ester crosslinking among phenylboronic acid (PBA) grafted carboxymethyl chitosan (CMCS), polyphenols and Cu 2+ -crosslinked polyphenol nanoparticles (CuNPs). The dynamic crosslinking bonds endowed hydrogels with excellent self-healing and degradable properties. Three polyphenols including tannic acid (TA), oligomeric proanthocyanidins (OPC) and (-)-epigallocatechin-3-O-gallate (EGCG) contributed to the outstanding antibacterial and antioxidant abilities of these hydrogels. The tissue adhesive capacity of hydrogels gave them good hemostatic effect. Through a full-thickness skin defect model of mice, these biocompatible hydrogels could accelerate wound healing processes by promoting granulation tissue formation, collagen deposition, M2 macrophage polarization and cytokine secretion, demonstrating that these natural-derived hydrogels with inherent physiological properties and low-cost preparation approaches could be promising dressing materials., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Atmospheric moisture is a sustainable clean water source that can solve the shortage of fresh water in arid areas. Herein a 2D covalent organic framework (COF-ok) was reported as a promising porous sorbent for solar-driven atmospheric water harvesting. COF-ok with ortho-ketoenamine linkage was extremely stable in harsh environment, including in boiling water, strong acids and bases. Because of the balanced hydrophilic and hydrophobic sites in channels, COF-ok showed a high water uptake of 0.33 g g -1 at a low relative humidity of 34 % featuring a characteristic S-shaped water sorption isotherm with low regeneration temperature (∼45 °C) and excellent cyclic stability. A laboratory-scale water harvesting system could collect water of 161 g kg -1 under sunlight., (© 2022 Wiley-VCH GmbH.)

We reported a general transition metal-free transformation to access C3-carbamoylated 2 H -indazoles via visible light-induced oxidative decarboxylation coupling, in the presence of oxamic acids as the coupling sources, 4CzIPN as the photocatalyst, and Cs 2 CO 3 as the base. The great application potential of this mild condition is highlighted by the late-stage modification of drugs, N-terminal modification of peptides, and the good antitumor activity of the novel desired product., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the author QL., (Copyright © 2022 Ma, Shang, Zhao, He, Lv, Zhang and Jiang.)

The greener synthesis of N-substituted isonicotinamides is of high importance and remains a significant challenge to the chemistry community. Herein we delineated a visible-light-driven, transition-metal-free, external-oxidant-free radical-radical cross-coupling reaction to access the N-substituted isonicotinamides via consecutive photoinduced electron transfer (ConPET). The utility of this protocol is highlighted through the N-terminal modification of peptides and late-stage modification of drugs.

A model of the influence of cultural differences on English learning from the perspective of the linguistic and cultural community based on data feature decomposition and fusion clustering is proposed. The new knowledge and the old knowledge are connected through the optimal control of the learning model. By decomposing relevant data through data features and fusion clustering algorithm, the impact of cultural differences on English learning can be modeled and analyzed from the perspective of language and cultural community. The simulation results show that the data fusion performance of the impact model of this method on English learning is good, and the quantitative analysis results are accurate and reliable. According to the results of visual data, targeted interventions were carried out for teachers, learners, and teaching managers., Competing Interests: The authors declared that they have no conflicts of interest regarding this work., (Copyright © 2022 Bin Tang et al.)

Orphans and vulnerable children fall under the category of children who are at risk of exposure to more stressful circumstances and receive less social assistance compared to other children. This study aims to investigate the impact of group counseling based on social intervention and psychological therapy (SSGPC) on social support and the perceived stress growth of orphans and vulnerable children. In one special educational needs school in Nanning, China, the SSGPC was developed and implemented. Using the social support and post-stress growth scales, the researchers investigated the effects of SSGPC on orphans and vulnerable children. Twenty-seven orphans and vulnerable children between the ages of nine and 12 were arbitrarily assigned to the experimental and control groups. A pre-test post-test method of quasi-experimental design was applied, with 13 participants in the experimental group and 14 in the control group. The results revealed that the intervention group had significantly higher scores for social support and post-stress growth than the control group. The SSGPC had significantly improved the levels of social support for orphans. The findings indicated that the SSGPC provided an effective way to improve social support and post-stress growth of orphans and vulnerable children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Wu, Roslan, Zaremohzzabieh, Chen and Jiang.)

A visible-light-promoted transition-metal-free perfluoroalkylation/cyclization reaction was developed with 9-mesityl-10-methylacridinium perchlorate (Acr + -Mes·ClO 4 - ) as the photocatalyst, by which various perfluoroalkyl-substituted heterocycles including thioflavones, oxindoles, and quinoline-2,4(1 H ,3 H )-diones were prepared at room temperature. Moreover, the potential of this sustainable method is demonstrated by the excellent in vitro anti-lymphoma and cervical carcinoma activity of the novel 3-perfluoroalkylated thioflavone 3m ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ma, Meng, He, Jiang and Yu.)

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1 H -imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo , which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1 H -imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

Presented herein is an effective preparation of succinimide spiro-fused sultams through the coupling reaction of N -(phenylsulfonyl)acetamides with maleimides. It is deduced that this reaction should proceed through a cascade process including Rh(III)-catalyzed C(sp 2 )-H bond cleavage of N -(phenylsulfonyl)acetamide, maleimide double bond insertion into the C-Rh bond, β-hydride elimination, reductive elimination, and intramolecular aza-Michael addition. Notably, this cascade procedure features simultaneous annulation and spirocyclization through traceless fusion of the directing group into target product by using air as an economical oxidant to assist the regeneration of the active Rh(III) catalyst. This new method has several advantages including readily accessible starting materials with broad scope, significantly reduced synthetic steps, redox-neutral conditions, high atom-economy, and sustainability.

Background: Human movement is one of the forces that drive the spatial spread of infectious diseases. To date, reducing and tracking human movement during the COVID-19 pandemic has proven effective in limiting the spread of the virus. Existing methods for monitoring and modeling the spatial spread of infectious diseases rely on various data sources as proxies of human movement, such as airline travel data, mobile phone data, and banknote tracking. However, intrinsic limitations of these data sources prevent us from systematic monitoring and analyses of human movement on different spatial scales (from local to global)., Objective: Big data from social media such as geotagged tweets have been widely used in human mobility studies, yet more research is needed to validate the capabilities and limitations of using such data for studying human movement at different geographic scales (eg, from local to global) in the context of global infectious disease transmission. This study aims to develop a novel data-driven public health approach using big data from Twitter coupled with other human mobility data sources and artificial intelligence to monitor and analyze human movement at different spatial scales (from global to regional to local)., Methods: We will first develop a database with optimized spatiotemporal indexing to store and manage the multisource data sets collected in this project. This database will be connected to our in-house Hadoop computing cluster for efficient big data computing and analytics. We will then develop innovative data models, predictive models, and computing algorithms to effectively extract and analyze human movement patterns using geotagged big data from Twitter and other human mobility data sources, with the goal of enhancing situational awareness and risk prediction in public health emergency response and disease surveillance systems., Results: This project was funded as of May 2020. We have started the data collection, processing, and analysis for the project., Conclusions: Research findings can help government officials, public health managers, emergency responders, and researchers answer critical questions during the pandemic regarding the current and future infectious risk of a state, county, or community and the effectiveness of social/physical distancing practices in curtailing the spread of the virus., International Registered Report Identifier (irrid): DERR1-10.2196/24432., (©Zhenlong Li, Xiaoming Li, Dwayne Porter, Jiajia Zhang, Yuqin Jiang, Bankole Olatosi, Sharon Weissman. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 18.12.2020.)

Background: The prevalence of chronic kidney disease (CKD) has been rapidly increasing and has become one of the most concerned global health problems. It is of good importance to improve therapeutic efficiency of CKD and delay disease progression to end stage renal disease (ESRD). Traditional Chinese Medicine (TCM) is a widely used complementary therapy for patients with CKD. The aim of this study is to evaluate whether basic treatment combined with Chinese herbs mixture Qi Gui Yi Shen decoction could achieve better therapeutic effect on CKD patients., Methods: To determine whether traditional Chinese medicine Qi Gui Yi Shen decoction could achieve better therapeutic effect, we will conduct a randomized controlled trial. A total of 100 CKD patients that meet the inclusion criteria will be enrolled and divided into 2 groups: Qi Gui Yi Shen group (QGYS group) and placebo group. Each group will receive 6-monthly basic treatment in combination with TCM or placebo 3 times per day. Efficacy of Qi Gui Yi Shen decoction is evaluated by analyzing renal function and TCM symptoms, other efficacy assessments include serum level of PAI-I, expression of transforming growth factor beta1 (TGF-beta1). Routine blood count, plasma albumin (ALB), and alanine transaminase (ALT) are evaluated as side effect and safety profile., Discussion: The results from the clinical trial will provide evidence for the effectiveness and safety of Qi Gui Yi Shen Decoction as a treatment for CKD patients. Furthermore, this will propose a new theory and method for CKD treatment., Trial Registration: Registered with Chinese Clinical Trials Registry at www.chictr.org. (Registration number: ChiCTR1900021622) on 1 March 2019.

In the title compound, Na(+)·4C(7)H(5)N(6) (+)·5BF(4) (-), the Na(+) ion lies on a fourfold rotation axis and one of the tetra-fluoridoborate ions lies on a site of symmetry . Each Na(+) ion is surrounded by four symmetry-related tetra-fluoridoborate ions, and is eight-coordinated by F atoms, the Na⋯F separation being 2.3956 (15) or 2.4347 (17) Å. The hexa-azaphenalenium ring system is essentially planar. In the crystal structure, the cations and anions are linked into a three-dimensional network by N-H⋯N and C-H⋯F hydrogen bonds.

Nitration of 2,7-di-tert-butyl-naphthalene 1,8-disulfide with fuming nitric acid in 1:3 molar ratio gives the title compound, C(14)H(11)N(3)O(6)S(2). A tape motif is formed by weak head-to-tail inter-actions (3.131 Å) between S and NO(2) O atoms of a symmetry-related mol-ecule.