Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Design of amidobenzimidazole STING receptor agonists with systemic activity.

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire in patients with advanced lung cancer.

Lung cancer is one of the greatest threats to human health, and is initially detected and attacked by the immune system through tumor-reactive T cells. The aim of this study was to determine the basic characteristics and clinical significance of the peripheral blood T-cell receptor (TCR) repertoire in patients with advanced lung cancer. To comprehensively profile the TCR repertoire, high-throughput sequencing was used to identify hypervariable rearrangements of complementarity determining region 3 (CDR3) of the TCR ß chain in peripheral blood samples from 64 advanced lung cancer patients and 31 healthy controls. We found that the TCR repertoire differed substantially between lung cancer patients and healthy controls in terms of CDR3 clonotype, diversity, V/J segment usage, and sequence. Specifically, baseline diversity correlated with several clinical characteristics, and high diversity reflected a better immune status. Dynamic detection of the TCR repertoire during anticancer treatment was useful for prognosis. Both increased diversity and high overlap rate between the pre- and post-treatment TCR repertoires indicated clinical benefit. Combination of the diversity and overlap rate was used to categorize patients into immune improved or immune worsened groups and demonstrated enhanced prognostic significance. In conclusion, TCR repertoire analysis served as a useful indicator of disease development and prognosis in advanced lung cancer and may be utilized to direct future immunotherapy.

Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction.

Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.

Long-Range Inhibitor-Induced Conformational Regulation of Human IRE1α Endoribonuclease Activity.

Activation of the inositol-requiring enzyme-1 alpha (IRE1α) protein caused by endoplasmic reticulum stress results in the homodimerization of the N-terminal endoplasmic reticulum luminal domains, autophosphorylation of the cytoplasmic kinase domains, and conformational changes to the cytoplasmic endoribonuclease (RNase) domains, which render them functional and can lead to the splicing of X-box binding protein 1 (XBP 1) mRNA. Herein, we report the first crystal structures of the cytoplasmic portion of a human phosphorylated IRE1α dimer in complex with (R)-2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2,7-diazaspiro(4.5)decane-7-carboxamide, a novel, IRE1α-selective kinase inhibitor, and staurosporine, a broad spectrum kinase inhibitor. (R)-2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2,7-diazaspiro(4.5)decane-7-carboxamide inhibits both the kinase and RNase activities of IRE1α. The inhibitor interacts with the catalytic residues Lys599 and Glu612 and displaces the kinase activation loop to the DFG-out conformation. Inactivation of IRE1α RNase activity appears to be caused by a conformational change, whereby the αC helix is displaced, resulting in the rearrangement of the kinase domain-dimer interface and a rotation of the RNase domains away from each other. In contrast, staurosporine binds at the ATP-binding site of IRE1α, resulting in a dimer consistent with RNase active yeast Ire1 dimers. Activation of IRE1α RNase activity appears to be promoted by a network of hydrogen bond interactions between highly conserved residues across the RNase dimer interface that place key catalytic residues poised for reaction. These data implicate that the intermolecular interactions between conserved residues in the RNase domain are required for activity, and that the disruption of these interactions can be achieved pharmacologically by small molecule kinase domain inhibitors.

Structure-guided optimization of small molecule c-Abl activators.

c-Abl kinase is maintained in its normal inactive state in the cell through an assembled, compact conformation. We describe two chemical series that bind to the myristoyl site of the c-Abl kinase domain and stimulate c-Abl activation. We hypothesize that these molecules activate c-Abl either by blocking the C-terminal helix from adopting a bent conformation that is critical for the formation of the autoinhibited conformation or by simply providing no stabilizing interactions to the bent conformation of this helix. Structure-based molecular modeling guided the optimization of binding and activation of c-Abl of these two chemical series and led to the discovery of c-Abl activators with nanomolar potency. The small molecule c-Abl activators reported herein could be used as molecular tools to investigate the biological functions of c-Abl and therapeutic implications of its activation.

Examining the Use and Application of the WHO Integrated People-Centred Health Services Framework in Research Globally - a Systematic Scoping Review.

Introduction: The World Health Organisation (WHO) accepted the Integrated People-centred Health Services (IPCHS) framework in 2016 as an essential component for achieving universal health coverage in fragmented health systems. We aimed to examine the empirical applications of the WHO IPCHS framework to guide its use in strengthening health-service research. Methods: Academic databases and the IPCHS website were searched for relevant articles published between 2016 and July 2023. Two reviewers independently screened and extracted data on the study design, setting, IPCHS framework components, and facilitators and barriers to implementing the IPCHS strategies. Descriptive and content analyses were conducted. Results: Six studies were identified using the IPCHS framework. Studies have examined a combination of the five IPCHS strategies. All studies reported building strong primary care-based systems and coordinating care for individuals. Continued relationships and trust, co-production of health programmes, diversity of health care team, and technology were major facilitators, while low health literacy, lack of primary setting capacity and healthcare workforce were principal barriers to IPCHS implementation. Conclusion: This scoping review offers an overview of IPCHS strategies employed in healthcare research. Generally, the IPCHS framework remains underutilised in primary research. These results offer guidance for future research to support effective healthcare delivery.

Understanding Gaps in the Hypertension and Diabetes Care Cascade: Systematic Scoping Review.

BACKGROUND: Hypertension and diabetes are global health challenges requiring effective management to mitigate their considerable burden. The successful management of hypertension and diabetes requires the completion of a sequence of stages, which are collectively termed the care cascade. OBJECTIVE: This scoping review aimed to describe the characteristics of studies on the hypertension and diabetes care cascade and identify potential interventions as well as factors that impact each stage of the care cascade. METHODS: The method of this scoping review has been guided by the framework by Arksey and O'Malley. We systematically searched MEDLINE, Embase, and Web of Science using terms pertinent to hypertension, diabetes, and specific stages of the care cascade. Articles published after 2011 were considered, and we included all studies that described the completion of at least one stage of the care cascade of hypertension and diabetes. Study selection was independently performed by 2 paired authors. Descriptive statistics were used to elucidate key patterns and trends. Inductive content analysis was performed to generate themes regarding the barriers and facilitators for improving the care cascade in hypertension and diabetes management. RESULTS: A total of 128 studies were included, with 42.2% (54/128) conducted in high-income countries. Of them, 47 (36.7%) focused on hypertension care, 63 (49.2%) focused on diabetes care, and only 18 (14.1%) reported on the care of both diseases. The majority (96/128, 75.0%) were observational in design. Cascade stages documented in the literature were awareness, screening, diagnosis, linkage to care, treatment, adherence to medication, and control. Most studies focused on the stages of treatment and control, while a relative paucity of studies examined the stages before treatment initiation (76/128, 59.4% vs 52/128, 40.6%). There was a wide spectrum of interventions aimed at enhancing the hypertension and diabetes care cascade. The analysis unveiled a multitude of individual-level and system-level factors influencing the successful completion of cascade sequences in both high-income and low- and middle-income settings. CONCLUSIONS: This review offers a comprehensive understanding of hypertension and diabetes management, emphasizing the pivotal factors that impact each stage of care. Future research should focus on upstream cascade stages and context-specific interventions to optimize patient retention and care outcomes.

Biochar and hydrochar application influence soil ammonia volatilization and the dissolved organic matter in salt-affected soils.

Biochar, which including pyrochar (PBC) and hydrochar (HBC), has been tested as a soil enhancer to improve saline soils. However, the effects of PBC and HBC application on ammonia (NH3) volatilization and dissolved organic matter (DOM) in saline paddy soils are poorly understood. In this research, marsh moss-derived PBC and HBC biochar types were applied to paddy saline soils at 0.5 % (w/w) and 1.5 % (w/w) rates to assess their impact on soil NH3 volatilization and DOM using a soil column experiment. The results revealed that soil NH3 volatilization significantly increased by 56.1 % in the treatment with 1.5 % (w/w) HBC compared to the control without PBC or HBC. Conversely, PBC and the lower application rate of HBC led to decrease in NH3 volatilization ranging from 2.4 % to 12.1 %. Floodwater EC is a dominant factor in NH3 emission. Furthermore, the fluorescence intensities of the four fractions (all humic substances) were found to be significantly higher in the 1.5 % (w/w) HBC treatment applied compared to the other treatments, as indicated by parallel factor analysis modeling. This study highlights the potential for soil NH3 losses and DOM leaching in saline paddy soils due to the high application rate of HBC. These findings offer valuable insights into the effects of PBC and HBC on rice paddy saline soil ecosystems.

Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.

Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summarize mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involved in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing details on the design of mitochondria-targeted delivery systems and the limitations regarding the various technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.

Iodine(III)-Mediated Trifluoroacetylation of a C(sp2)-H or C(sp)-H Bond with Masked Trifluoroacyl Reagents.

A novel strategy for incorporating a trifluoroacetyl functionality into a range of structurally varied unsaturated bonds was developed by using PhI(OCOMe)2 as an oxidant with a masked trifluoroacyl reagent as a trifluoroacetyl radical precursor. The oxidative decarboxylation of the masked trifluoroacyl precursor followed by a tandem radical process provides versatile access to 5-exo-trig cyclization of N-arylacrylamides, direct C(sp2)-H trifluoroacetylation of quinolines, isoquinoline, 2H-indazole, and quinoxalin-2(1H)-ones, and C(sp)-H trifluoroacetylation of alkynes. This protocol is characterized by mild reaction conditions, operational simplicity, and broad functional group compatibility.

Coordinative Management of Soil Resources and Agricultural Farmland Environment for Food Security and Sustainable Development in China.

Major problems in China's pursuit of sustainable agricultural development include inadequate, low-quality soil and water resources, imbalanced regional allocation and unreasonable utilization of resources. In some regions, overexploitation of soil resources and excessive use of chemicals triggered a web of unforeseen consequences, including insufficient use of agricultural resources, agricultural non-point source pollution and land degradation. In the past decade, China has changed its path of agricultural development from an output-oriented one to a modern, sustainable one with agricultural ecological civilization as its goal. First, the government has formulated and improved its laws and regulations on soil resources and the environment. Second, the government has conducted serious actions to ensure food safety and coordinated management of agricultural resources. Third, the government has planned to establish national agricultural high-tech industry demonstration zones based on regional features to strengthen the connection among the government, agri-businesses, scientific community and the farming community. As the next step, the government should improve the system for ecological and environmental regulation and set up a feasible eco-incentive mechanism. At the same time, the scientific community should strengthen the innovation of bottleneck technologies and the development of whole solutions for sustainable management in ecologically fragile regions. This will enhance the alignment between policy mechanisms and technology modes and effectively promote the sustainable development of agriculture in China.

Salinity-dependent potential soil fungal decomposers under straw amendment.

Soil salinization is a severe environmental problem that restricts plant productivity and ecosystem functioning. Straw amendment could increase the fertility of saline soils by improving microbial activity and carbon sequestration, however, the adaptation and ecological preference of potential fungal decomposers after straw addition under varied soil salinities remains elusive. Here, a soil microcosm study was conducted by incorporating wheat and maize straws into soils with a range of salinities, respectively. We showed that the amendment of straws increased MBC, SOC, DOC and NH4+-N contents by 75.0 %, 17.2 %, 88.3 % and 230.9 %, respectively, but decreased NO3--N content by 79.0 %, irrespective of soil salinity, with intensified connections among these parameters after straw addition. Although soil salinity had a more profound effect on both fungal α- and ß-diversity, straw amendment also significantly reduced fungal Shannon diversity and changed community composition, especially for severe saline soil. Complexity of the fungal co-occurrence network was specifically strengthened after straw addition, with average degree increasing from 11.9 in the control to 22.0 and 22.7 in wheat and maize straw treatments, respectively. Intriguingly, there was very little overlap among the straw-enriched ASVs (Amplicon Sequence Variants) in each saline soil, indicating the soil-specific involvement of potential fungal decomposers. Particularly, fungal species belonging to Cephalotrichum and unclassified Sordariales were the most responsive to straw addition in severe saline soil, whereas light saline soil supported the enrichment of Coprinus and Schizothecium species after straw addition. Together, our study provides a new insight on the common and specific responses of soil chemical and biological characteristics at different salinity levels under straw management, which will help guide precise microbial-based strategies to boost straw decomposition in future agricultural practice and environmental management of saline-alkali lands.

Visible-Light-Induced, Catalyst-Free Monofluoromethyl Sulfonylation of Alkenes with Iodine(III) Reagent and DABSO.

A visible-light-induced radical relay strategy to access heterocycles bearing a monofluoromethylsufonyl moiety is reported, with PhI(OCOCH2F)2 as the CH2F radical precursor and DABSO as the SO2 source. A range of oxindoles, containing a CH2FSO2CH2- group at the C3 position, were synthesized from N-arylacrylamides in up to 97% yields. The protocol features catalyst-free photochemical tandem, mild reaction conditions, broad functional group compatibility, and good to excellent yields.

Analysis on Recycling Channel Selection of Construction and Demolition Waste in China from the Perspective of Supply Chain.

Although construction and demolition waste (C&D waste) recycling has been widely regarded as an effective way to save resources, its selection of recycling channels has received little attention. In order to improve the recycling efficiency of C&D waste and promote the process of C&D waste management, we innovatively propose a dual-channel recycling problem of C&D waste from the perspective of supply-chain operation, aiming to study the impact of the selection of recycling channels and the government's economic intervention on pricing decisions. Specifically, we build in this paper a three-echelon construction material supply chain including a construction contractor, a professional recycling agency, and a building materials manufacturer, considering two modes: the construction contractor does the recycling job alone (as the direct channel) and the construction contractor entrusts the recycling job to the professional recycling agency (as the indirect channel). We use game theory to analyze the optimal decision strategies of the members with or without governmental intervention and the equilibrium strategies are obtained. At the same time, taking Chongqing city as an example, we apply the model to carry out numerical simulation, and the results reveal that greater recycling costs of C&D waste leads to lower profits for the members. When the market capacity of first-class renewable building materials increases, the recycler's recycling cost of C&D waste decreases, and the remanufacturing cost of recycled materials processed into first-class renewable building materials decreases, the supply-chain members will choose the indirect channel to perform the recycling job. In the case when government intervention exists, the recycling quantity of C&D waste increases, the price of the final products decreases, and both the total profit of the system and the profit of the supply-chain members increase; there is a positive correlation with the government subsidies. The study provides some insights on managerial significance to C&D waste recycling management.

Study on strain sensing property of fiber Bragg grating based on surface strain measurement of mechanical structure.

Strain monitoring is of great significance to identify the failure of key mechanical components and ensure the good operation of mechanical equipment. In terms of the common issue of the low sensitivity of fiber Bragg grating (FBG) strain sensor in strain measurement on the mechanical structure surface, this paper describes a flexible hinge strain sensor with the FBG as the sensitive element. A theoretical analysis of the sensitivity of the sensor is performed, a copper alloy material with a large elastic modulus is selected, the simulation analysis and optimization design for the structural parameters of the sensor are carried out by using ANSYS and Solidworks software, then the object of the sensor is developed according to the simulation results, and finally, the performance of the sensor is tested. The results show that the maximum deformation the sensor can measure is 0.5299 µÎµ, the sensitivity of the sensor is ∼1.8870 pm/µÎµ, which is approximately twice that of the bare FBG sensor, the linearity is greater than 99%, and the relative standard deviation of the repeatability is 0.9%. The results of the study provide a reference for developing the optical fiber strain sensor and further improving its sensitivity.

Biochar Addition Inhibits Nitrification by Shifting Community Structure of Ammonia-Oxidizing Microorganisms in Salt-Affected Irrigation-Silting Soil.

Biochar has been widely recognized as an effective and eco-friendly ameliorant for saline soils, but information about the mechanism of how biochar influences nitrification in salt-affected agroecosystem remains fragmented. An incubation experiment was performed on the salt-affected soil collected from a three-consecutive-year experiment at biochar application gradients of 7.5 t⋅ha-1, 15 t⋅ha-1 and 30⋅t ha-1 and under nitrogen (N) fertilization. Responses of the nitrification rate (NR), numbers of ammonia monooxygenase (amoA) gene copies, and community structures of ammonia-oxidizing bacteria (AOB) and archaea (AOA) to biochar application were investigated. The results indicated that, under N fertilization, the NR and numbers of amoA-AOB and amoA-AOA gene copies negatively responded to biochar addition. Biochar application increased the community diversity of AOB but decreased that of AOA. Biochar addition and N fertilization shifted the AOB community from Nitrosospira-dominated to Nitrosospira and Nitrosomonas-dominated, and altered the AOA community from Nitrososphaera-dominated to Nitrososphaera and Nitrosopumilus-dominated. The relative abundance of Nitrosospira, Nitrosomonas and Nitrosopumilus decreased, and that of Nitrosovibrio and Nitrososphaera increased with biochar application rate. Soil SOC, pH and NO3--N explained 87.1% of the variation in the AOB community, and 78.1% of the variation in the AOA community was explanatory by soil pH and SOC. The SOC and NO3--N influenced NR through Nitrosovibrio, Nitrosomonas, Norank_c_environmental_samples_p_Crenarchaeota and amoA-AOB and amoA-AOA gene abundance. Therefore, biochar addition inhibited nitrification in salt-affected irrigation-silting soil by shifting the community structures of AOB and AOA and reducing the relative abundance of dominant functional ammonia-oxidizers, such as Nitrosospira, Nitrosomonas and Nitrosopumilus.

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Understanding the nitrification capacity of coastal saline farmland soils and its main drivers is of great significance to regulate soil nitrification and improve the utilization efficiency of nitrogen fertilization in farmland. Using a combination of field investigations and laboratory analyses, we examined farmland soil nitrification potential and soil physical, chemical, and biological properties in the coastal muddy tidal flat saline soil area (Dongying and Dongtai). We established the correlation between soil properties and soil nitrification potential with multiple stepwise regression analyses and structural equation modeling (SEM). The results showed that soil pH value was relatively stable and other soil properties and soil nitrification potential varied in coastal saline farmland. The soil nitrification potential ranged from 0.04 to 10.42 mg·kg-1·d-1 and decreased with the increases of soil salinization level. Soil nitrification potential had the strongest correlation with soil organic matter, cation exchange capacity, and Cl-, with the correlation coefficient being 0.409, 0.397 and -0.337, respectively. The results of multiple stepwise regression analysis showed that Na+, silt, cation exchange capacity, and CO32-+HCO3- were the main influencing factors of soil nitrification potential. The results from the SEM analysis suggested that Na+, silt, cation exchange capacity, and CO32-+HCO3- directly affected soil nitrification potential, and soil organic matter, clay, Cl- and SO42- had indirect effects. In all, soil Na+ and cation exchange capacity were the two main factors affecting nitrification. Adjusting soil NaCl content and cation exchange capacity was an effective means of regulating soil nitrification.

Effect of Adjuvant Radiation Dose on Survival in Patients with Esophageal Squamous Cell Carcinoma.

Background: For patients with esophageal squamous cell carcinoma (ESCC) treated with surgery alone, the incidence of local-regional recurrence remains unfavorable. Postoperative radiotherapy (PORT) has been associated with increased local-regional recurrence-free survival (LRFS), although its application is limited by concerns of PORT-related toxicities. Methods: Among 3591 patients with ESCC analyzed in this study, 2765 patients with T3-4N0 and T1-4N1-3 lesions and specific local-regional status information were analyzed in a subsequent analysis of adjuvant radiation dose (aRTD) effect. Application of the restricted cubic spline regression model revealed a non-linear relationship between aRTD and survival/radiotoxicity. Linear regression analysis (LRA) was performed to evaluate correlations between LRFS and overall survival (OS)/ disease-free survival (DFS). Results: For patients staged T1−2N0, T1−2N1−3, T3−4N0, and T3−4N1−3, 5-year OS in PORT and non-PORT groups were 77.38% vs. 72.91%, p = 0.919, 52.35% vs. 46.60%, p = 0.032, 73.41% vs. 61.19%, p = 0.005 and 38.30% vs. 25.97%, p < 0.001. With aRTD escalation, hazard ratios (HRs) of OS/DFS declined until aRTD exceeded 50Gy, then increased, whereas that of LRFS declined until aRTD exceeded 50 Gy, then remained steady. HR of treatment-related mortality was stable until aRTD exceeded 50 Gy, then increased. LRA revealed strong correlations between LRFS and OS/DFS (r = 0.984 and r = 0.952, respectively). An absolute 1% advancement in LRFS resulted in 0.32% and 0.34% improvements in OS and DFS. Conclusions: An aRTD of 50Gy was well-tolerated, with favorable survival resulting from PORT-related LRFS improvement in patients staged T3−4N0 or T1-4N1−3. Further stratification analyses based on tumor burden would help determine potential PORT-beneficiaries.