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Background: To evaluate the prevalence and characteristics of taurodontism in northern China by using cone-beam computed tomography (CBCT) and assisting the treatment., Methods: The study involved CBCT scans of 8112 teeth from 507 participants of northern China, comprising 217 males and 290 females aged 18 to 60. Analysis was conducted using Shifman and Chanannel's criteria to assess the prevalence and attributes of taurodontism, examining differences based on tooth position (maxilla and mandible) as well as gender (P < 0.05). Specific morphology including C-shaped canal was recorded. The curvature of the canals was measured using a modified Schneider method. Moreover, we reported two failure cases with taurodontism referred to a retreatment., Results: Taurodontism was observed in 113 participants, affecting 23.50% of the males and 21.38% of the females in at least one tooth (P > 0.05). The prevalence was significant higher in maxilla (P < 0.05). The highest incidence of taurodontism was detected in premolars, 9.86% in the maxillary first premolars, and in molars, with 3.94% in the maxillary first molars. Regarding canal curvature, a higher incidence of curved canal could be found in maxillary and mandibular molars of taurodontism (47.50-66.67%), alongside an elevated prevalence of C-shaped taurodontism in mandibular second molars (71.43%). After follow-up, the healing response was satisfactory in both cases., Conclusion: The study highlighted a higher incidence of taurodontism in maxilla, indicating a significant association between taurodontism, C-shaped characteristics, and canal curvature. Dentists are advised to carefully consider the presence of special morphologies during taurodontism treatment., Competing Interests: Declarations. Ethics approval and consent to participate: The CBCT images used in this study were obtained from Beijing stomatological hospital, Capital medical university. All methods have been approved by Institutional Review Board of Beijing Stomatological Hospital, Capital Medical University with the approval number CMUSH-IRB-KJ-PJ-2024-08). Informed consent was obtained from all subjects and/or their legal guardian(s). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The potential risk posed by infectious agents (IAs) associated with netpen aquaculture to wild fishes is determined based on the "release" of IAs from netpens into the environment, the "exposure" of the wild fish to those released agents, and the "consequence" for wild fish experiencing infection by those agents. Information available to characterize these three factors is often lacking, and the occurrence of transmission from aquaculture to wild fish as well as potential consequences of such transmission are difficult to observe. In this study, we utilized environmental DNA (eDNA) to characterize the release of dozens of IAs from, and exposure of Pacific salmon to, Atlantic salmon aquaculture. We combined these factors with the consequence of infection, as determined by the literature, to identify IAs that may pose a risk to wild salmon exposed to aquaculture in British Columbia, Canada. Over an 18-month period, eDNA samples were collected from seven active and four inactive netpen aquaculture sites in the Broughton Archipelago, BC. A meta-analytical mean across 22 IAs showed that the odds of IA detection at active sites was 4.3 (95% confidence interval = 2.3:8.1) times higher than at inactive sites, with 11 IAs in particular demonstrating a pattern consistent with elevated release. Oncorhynchus tshawytscha was the only Pacific salmon species presenting eDNA detections more likely to occur around and within active netpens relative to inactive sites. After considering the evidence of negative consequences of infection (from previous literature) in tandem with release model results, we determined that Tenacibaculum maritimum, Tenacibaculum finnmarkense, Ichthyobodo spp., and Piscine orthoreovirus are potential risks to Pacific salmon exposed to marine netpen aquaculture. These IAs, and others demonstrating patterns consistent with release but with insufficient prior research to evaluate the consequences of infection, require further studies that identify the factors influencing the intensity of release, the spatial extent of release around netpens, and the prevalence of infection in wild fish within known distances from netpens., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. Crown.)

Aquatic species are increasingly confronted with environmental stressors because of climate change. Although molecular technologies have advanced our understanding of how organisms respond to stressors in laboratory settings, the ability to detect physiological responses to specific stressors under complex field conditions remains underdeveloped. This research applied multi-stressor challenge trials on coho salmon, employing the "Salmon Fit-Chips" genomic tool and a random forest-based classification model to develop classifiers predictive for chronic thermal and hypoxic stress, as well as salinity acclimation, smolt stage and morbidity status. The study also examined how smolts and de-smolts (smolts not having entered SW during the smolt window) responded transcriptionally to exposure to saltwater. Using RF classifiers optimized with 4 to 12 biomarkers, we identified transcriptional signatures that accurately predicted the presence of each stressor and physiological state, achieving prediction accuracy rates between 86.8 % and 100 %, regardless of other background stressors present. Stressor recovery time was established by placing fish back into non-stressor conditions after stress exposure, providing important context to stressor detections in field applications. Recovery from thermal and hypoxic stress requires about 3 and 2 days, respectively, with >3 days needed for re-acclimation to freshwater for seawater acclimated fish. The study also found non-additive (synergistic) effects of multiple stressors on mortality risk. Importantly, osmotic stress associated with de-smolts was the most important predictor of mortality. In saltwater, de-smolts exposed to salinity, high temperature, and hypoxia experienced a 9-fold increase in mortality compared to those only exposed to saltwater, suggesting a synergistic response to multiple stressors. These findings suggest that delays in hatchery releases to support release of larger fish need to be carefully scrutinized to ensure fish are not being released as de-smolts, which are highly susceptible to additional climate-induced stressors like rising temperatures and reduced dissolved oxygen levels in the marine environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

In this study, using chiral L-lysine as the molecular skeleton, three kinds of L-lysine-derived gelators (G BLB , G BLF and G FLF ) were synthesized and then bonded to the surface of silica matrix (5 μm) by amide condensation to prepare a series of multifunctional chromatography stationary phases (G BLB -SiO 2 , G BLF -SiO 2 , and G FLF -SiO 2) were prepared. The L-lysine-derived gelators not only possess chiral recognition ability, but also can spontaneously form oriented and ordered network structures in liquid medium through the interaction of non-covalent bonding forces such as hydrogen bonding, π-π stacking, and van der Waals forces. The comprehensive effect of multiple weak interaction sites enhances the molecular recognition ability and further improves the separation diversity of different types of compounds on stationary phases. The separation and evaluation of chiral compounds showed that benzoin, 1-phenyl-ethanol, 1-phenyl-propanol and 6-hydroxyflavanone could be separated in normal phase mode (NPLC). The separation of different types of non-chiral compounds, such as sulfonamides, nucleosides, nucleobases, polycyclic aromatic hydrocarbons (PAHs), anilines, and aromatic acids, were achieved in hydrophilic interaction/reversed-phase/ion-exchange mode (HILIC/RPLC/IEC), and the separation of polarized compounds could be performed under the condition of ultrapure water as the mobile phase, which has the typical retention characteristics of per aqueous liquid chromatography (PALC). The effects of organic solvent content, temperature, pH value, and buffer salt concentration on the retention and separation performance of the column were investigated. Comparison of the three prepared columns showed that the separation performance (such as aromatic selectivity) could be improved by increasing the types of functional groups on the surface of the stationary phase and the number of aromatic groups. In a word, the prepared stationary phase have multiple retention properties, can simultaneously separate chiral compounds and various types of achiral compounds. This work provides an idea for developing multifunctional liquid chromatography stationary phase materials, and further expands the application of gelators in separation science., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC)., Objectives: To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC., Design: A multicenter, open-label, phase Ib trial., Methods: Patients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1-2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3-5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety., Results: A total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%-93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%-87.5% for lower doses; grade 4, 46.7% and 4.2%-20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%-54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5-82.6) and patients progressing after ET (53.3%; 95% CI 26.6-78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9-46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9-24.1) with fulvestrant., Conclusion: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg., Trial Registration: ClinicalTrials.gov identifier: NCT03481998., Competing Interests: S.L., G.X., and X.Z. were employees of Hengrui Pharmaceuticals at the time of study. All other authors have no conflicts to declare., (© The Author(s), 2024.)

Background: Molecular shape selectivity, based on the size and shape parameters of the molecule, such as length and planarity, is a separation process that can be used for compounds with restricted shapes, such as isomers. The separation of geometric isomers is challenging because these compounds have similar physicochemical properties but differ slightly in molecular shape. The ability to separate and quantify these isomers is important in high performance liquid chromatography (HPLC), which is one of the most widely used techniques in separation science today, because the shape of the molecule has a strong influence on biological processes., Results: We prepared symmetrical discoidal dendrimeric organomolecule gelators (G SDM ) and o-phenylenediamine-derived low-molecular-weight dendrimeric organomolecule gelators (G1) and bonded them to silica surfaces. The dendritic organic compound-grafted silica (SiO 2 @G SDM and SiO 2 @G1) was used as HPLC stationary phases for the separation of shape-restricted isomers of polycyclic aromatic hydrocarbons (PAHs), carotenoids and tocopherols. The two phases exhibit a very high molecular shape selectivity compared to the commercially available alkyl phases. There are differences in molecular shape selectivity between the two stationary phases. Changes in the chemical structure of dendritic organic compounds can alter the orientation of the molecules, as well as changes in the molecular recognition ability. It was found that SiO 2 @G SDM has high molecular linear selectivity for PAHs at different temperatures, even at 50 °C. The planar selectivity of SiO 2 @G SDM was better for triphenylene and o-terphenyl benzenes compared to SiO 2 @G1., Significance: This separation behavior may be attributed to the combined effect of weak interaction centers, which allowed the effective separation of bioactive and shape-restricted isomers through multiple interactions. Furthermore, SiO 2 @G SDM showed better separation of tocopherols and carotenoids, suggesting that the backbone and ordered structure of organic molecular gelators is an effective way to improve the shape selectivity of the molecules, whereas the molecular orientation of the functional groups influences the separation mechanism of the shape-restricted isomers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Context: Two-dimensional materials are a new and promising research field in materials science. This is mainly attributed to their unique photoelectric and chemical properties. In addition to possessing unique optoelectronic and chemical properties, two-dimensional materials also have important application prospects in the field of field-effect devices. Based on density functional theory, the effects of uniaxial strain and equibiaxial strain on the mechanical properties, electronic structure, and optical properties of monolayer h-BN were studied using first principles. The results indicate that compressive strain has a significant impact on the stability of monolayer h-BN. The band gap width of monolayer h-BN decreases with increasing strain, and the optical properties of monolayer h-BN exhibit a relative trend under tensile and compressive strains. The influence of biaxial strain on the mechanical properties, electronic structure, and optical properties of monolayer h-BN is greater than that of uniaxial strain., Methods: All the calculations were done by the VASP software based on density functional theory. The interaction between atomic nuclei and electrons is described by the projected added wave pseudopotential (PAW), using the generalized gradient approximation (GGA) to exchange the Perdew-Burke-Ernzerhof (PBE) of the functional. To avoid interlayer interactions, a 15-Å vacuum layer was set up. The Brillouin zone selects the Monkhorst-Pack method to generate 9 × 9 × 1 of k-point grid, the cut off energy is set to 500 eV, the energy convergence standard of the system is 1 × 10 -5  eV, and the interaction force between atoms is 0.01 eV/Å., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The contamination of bone defects is a serious therapeutic problem. The treatment of infected bone defects involves rigorous infection control followed by bone reconstruction. Considering these two processes, the development of biomaterials possessing antibacterial and osteogenic properties offers a promising approach for the treatment of infected bone defects. In this study, a dual-functional, thermosensitive, and injectable hydrogel composed of chitosan (CS), quaternized CS (QCS), and nano-hydroxyapatite (nHA) was designed, and the ratio of CS to QCS in the hydrogel was optimized to enhance the antibacterial efficacy of CS while reducing the cytotoxicity of QCS. In vitro studies demonstrated that the hydrogel with an 85 %:15 % ratio of CS to QCS exhibited excellent biocompatibility and antibacterial properties while also possessing suitable mechanical characteristics and degradability. The incorporation of nHA into the hydrogel enhanced MC3T3-E1 proliferation and osteogenic differentiation. Moreover, this hydrogel demonstrated superior in vivo therapeutic effectiveness in a rabbit model of infected bone defect. In summary, this study provides a promising material design and a comprehensive one-step treatment strategy for infected bone defects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The treatment of bone defects is a difficult problem in orthopedics. The excessive destruction of local bone tissue at defect sites destroys blood supply and renders bone regeneration insufficient, which further leads to delayed union or even nonunion. To solve this problem, in this study, we incorporated icariin into alginate/mineralized collagen (AMC) hydrogel and then placed the drug-loaded hydrogel into the pores of a 3D-printed porous titanium alloy (AMCI/PTi) scaffold to prepare a bioactive scaffold with the dual functions of promoting angiogenesis and bone regeneration. The experimental results showed that the ACMI/PTi scaffold had suitable mechanical properties, sustained drug release function, and excellent biocompatibility. The released icariin and mineralized collagen (MC) synergistically promoted angiogenesis and osteogenic differentiation in vitro . After implantation into a rabbit radius defect, the composite scaffold showed a satisfactory effect in promoting bone repair. Therefore, this composite dual-functional scaffold could meet the requirements of bone defect treatment and provide a promising strategy for the repair of large segmental bone defects in clinic., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: Apatinib combined with gefitinib was proven to benefit advanced EGFR-mutant NSCLC patients in first-line treatment. This study aimed to evaluate the drug-drug interaction of gefitinib and apatinib when coadministered in EGFR-mutated NSCLC patients., Methods: In this phase 1b, multi-center, open-label, fixed-sequence study, the drug-drug interaction of gefitinib and apatinib was evaluated when coadministered in EGFR-mutated NSCLC patients. Patients received single-agent apatinib 500 mg QD on days 1-4. Gefitinib 250 mg QD was given on days 5-15 and combined with apatinib 500 mg QD on days 12-15. Serial blood samples were drawn on days 4 and 15. The plasma concentrations and other pharmacokinetics parameters were measured for apatinib with and without gefitinib., Results: The study enrolled 22 patients and 20 were analyzed for pharmacokinetics. There were no distinct differences in apatinib C max and AUC 0-τ with versus without gefitinib (geometric LSM ratio, 0.96 [90% CI 0.84-1.10] for C max and 1.12 [90% CI 0.96-1.30] for AUC 0-τ ). Similar PFS and grade of treatment-emergent adverse events (TEAEs) were found between different C max and AUC 0-τ of apatinib and gefitinib at 500 mg apatinib and 250 mg gefitinib dose levels., Conclusions: Apatinib pharmacokinetics parameters were not significantly changed when coadministered with gefitinib. All TEAEs were manageable, and there was no need to change the dose level when combining apatinib and gefitinib (ClinicalTrials.gov identifier: NCT04390984, May 18, 2020)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The decellularized bone matrix (DCB) provides a promising bone substitute for the treatment of bone defects because of its similar biochemical, biophysical, and mechanical properties to normal bone tissue. However, the decellularized procedure also greatly reduced its osteogenic induction activity. In this study, peptides derived from the knuckle epitope of bone morphogenetic protein-2 were incorporated into the thermo-sensitive hydrogel poloxamer 407, and the peptide-loaded hydrogel was then filled into the pores of DCB to construct a functionalized scaffold with enhanced osteogenesis. In vitro studies have shown that the functionalized DCB scaffold possessed appropriate mechanical properties and biocompatibility and exhibited a sustained release profile of osteogenic peptide. These performances critically facilitated cell proliferation and cell spreading of bone marrow mesenchymal stem cells and upregulated the expression of osteogenic-related genes by activating the Smad/Runx2 signaling pathway, thereby promoting osteogenic differentiation and extracellular matrix mineralization. Further in vivo studies demonstrated that the functionalized DCB scaffold accelerated the repair of critical radial defects in rabbits without inducing excessive graft-related inflammatory responses. These results suggest a clinically meaningful strategy for the treatment of large segmental bone defects, and the prepared osteogenic peptide modified composite DCB scaffold has great application potential for bone regeneration.

Beijing-Tianjin-Hebei and its surrounding areas (hereinafter referred to as "2+26" cities) are one of the most severe air pollution areas in China. The fine particulate matter (PM 2.5 ) and surface ozone (O 3 ) pollution have aroused a significant concern on the national scale. In this study, we analyzed the pollution characteristics of PM 2.5 and O 3 in "2+26" cities, and then estimated the health burden and economic loss before and after the implementation of the joint PM 2.5 -O 3 control policy. During 2017-2019, PM 2.5 concentration reduced by 19% while the maximum daily 8 hr average (MDA8) O 3 stayed stable in "2+26" cities. Spatially, PM 2.5 pollution in the south-central area and O 3 pollution in the central region were more severe than anywhere else. With the reduction in PM 2.5 concentration, premature deaths from PM 2.5 decreased by 18% from 2017 to 2019. In contrast, premature deaths from O 3 increased by 5%. Noticeably, the huge potential health benefits can be gained after the implementation of a joint PM 2.5 -O 3 control policy. The premature deaths attributed to PM 2.5 and O 3 would be reduced by 91.6% and 89.1%, and the avoidable economic loss would be 60.8 billion Chinese Yuan (CNY), and 68.4 billion CNY in 2035 compared with that in 2019, respectively. Therefore, it is of significance to implement the joint PM 2.5 -O 3 control policy for improving public health and economic development., (Copyright © 2022. Published by Elsevier B.V.)

Background: Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody., Objectives: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802., Design: A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors., Methods: Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D., Results: Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%-53.5%). The median progression-free survival was 2.0 months (95% CI 1.2-6.1)., Conclusions: SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application., Registration Clinicaltrialsgov: NCT04414150., Competing Interests: Y Li, S Li, P Xiu, and S Wang are employees of Jiangsu Hengrui Pharmaceuticals. The other authors declare no conflicts of interest., (© The Author(s), 2023.)

Famitinib is a tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. Here, a 3-period crossover trial investigated the effect of high-fat or low-fat food intake on the single-dose pharmacokinetic properties of oral famitinib. Twenty-four healthy Chinese participants were enrolled and received a single 25-mg dose of famitinib malate capsule following a high-fat or low-fat breakfast before dosing. Blood samples were collected before dosing (0 hour) to 192 hours after dosing, and famitinib concentrations in plasma were determined with validated liquid chromatography-tandem mass spectrometry. Compared with the fasting condition, the geometric mean ratios for low-fat/fasting were 98.6%, 107.7%, and 107.5% for maximum plasma concentration, area under the plasma concentration-time curve (AUC) over the dosing interval, and AUC from time 0 to infinity, respectively. Those for high-fat/fasting were 84.4%, 105.0%, and 105.1% for maximum plasma concentration, AUC over the dosing interval, and AUC from time 0 to infinity, respectively. There was no significant difference in adverse events between fasting and fed conditions, and no serious adverse events occurred during the trial. In conclusion, oral famitinib bioavailability is not affected by food intake, implying that patients with cancer do not need to consider dietary status when using famitinib. This is considered important for convenience and treatment compliance., (© 2023, The American College of Clinical Pharmacology.)

The early marine life of Pacific salmon is believed to be a critical period limiting population-level survival. Recent evidence suggests that some infectious agents are associated with survival but linkages with underlying physiological mechanisms are lacking. While challenge studies can demonstrate cause and effect relationships between infection and pathological change or mortality, in some cases pathological change may only manifest in the presence of environmental stressors; thus, it is important to gain context from field observations. Herein, we examined physiological correlates with infectious agent loads in Chinook salmon during their first ocean year. We measured physiology at the molecular (gene expression), metabolic (plasma chemistry) and cellular (histopathology) levels. Of 46 assayed infectious agents, 27 were detected, including viruses, bacteria and parasites. This exploratory study identified., a strong molecular response to viral disease and pathological change consistent with jaundice/anemia associated with Piscine orthoreovirus,strong molecular signals of gill inflammation and immune response associated with gill agents ` Candidatus Branchiomonas cysticola' and Parvicapsula pseudobranchicola, a general downregulation of gill immune response associated with Parvicapsula minibicornis complementary to that of P. pseudobranchicola .Importantly, our study provides the first evidence that the molecular activation of viral disease response and the lesions observed during the development of the PRV-related disease jaundice/anemia in farmed Chinook salmon are also observed in wild juvenile Chinook salmon., Competing Interests: The authors have no conflicts to declare., (© The Author(s) 2023. Published by Oxford University Press and the Society for Experimental Biology.)

Bacterial bone infection in open fractures is an urgent problem to solve in orthopedics. Antimicrobial peptides (AMPs), as a part of innate immune defense, have good biocompatibility. Their antibacterial mechanism and therapeutic application against bacteria have been widely studied. Compared with traditional antibiotics, AMPs do not easily cause bacterial resistance and can be a reliable substitute for antibiotics in the future. Therefore, various physical and chemical strategies have been developed for the combined application of AMPs and bioactive materials to infected sites, which are conducive to maintaining the local stability of AMPs, reducing many complications, and facilitating bone infection resolution. This review explored the molecular structure, function, and direct and indirect antibacterial mechanisms of AMPs, introduced two important AMPs (LL-37 and β-defensins) in bone tissues, and reviewed advanced AMP loading strategies and different bioactive materials. Finally, the latest progress and future development of AMPs-loaded bioactive materials for the promotion of bone infection repair were discussed. This study provided a theoretical basis and application strategy for the treatment of bone infection with AMP-loaded bioactive materials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Inorganic nitrate is an indispensable nutrient that has been used in experimental studies for the prevention and treatment of several diseases. However, the short half-life of nitrate limits its clinical application. To increase the usability of nitrate and overcome the challenges of traditional combination drug discovery through large-scale high-throughput biological experiments, we developed a swarm learning-based combination drug prediction system that identified vitamin C as the drug of choice to be combined with nitrate. Employing microencapsulation technology, we used vitamin C, sodium nitrate, and chitosan 3000 as the core materials to prepare a nitrate nanoparticle, which we named Nanonitrator. The long-circulating delivery ability of nitrate by Nanonitrator significantly increased the efficacy and effect duration of nitrate in irradiation-induced salivary gland injury, without compromising safety. Nanonitrator at the same dose could better maintain intracellular homeostasis than nitrate (with or without vitamin C), emphasizing its potential for clinical use. More importantly, our work provides a method for incorporating inorganic compounds into sustained-release nanoparticles., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2023 Science China Press. Published by Elsevier B.V. All rights reserved.)

To address the issues of not accurately identifying ice types and thickness in current fiber-optic ice sensors, in this paper, we design a novel fiber-optic ice sensor based on the reflected light intensity modulation method and total reflection principle. The performance of the fiber-optic ice sensor was simulated by ray tracing. The low-temperature icing tests validated the performance of the fiber-optic ice sensor. It is shown that the ice sensor can detect different ice types and the thickness from 0.5 to 5 mm at temperatures of -5 °C, -20 °C, and -40 °C. The maximum measurement error is 0.283 mm. The proposed ice sensor provides promising applications in aircraft and wind turbine icing detection.

Although infectious agents can act as strong population regulators, knowledge of their spatial distributions in wild Pacific salmon is limited, especially in the marine environment. Characterizing pathogen distributions during early marine residence, a period considered a survival bottleneck for Pacific salmon, may reveal where salmon populations are exposed to potentially detrimental pathogens. Using high-throughput qPCR, we determined the prevalence of 56 infectious agents in 5719 Chinook, 2032 Coho and 4062 Sockeye salmon, sampled between 2008 and 2018, in their first year of marine residence along coastal Western Canada. We identified high prevalence clusters, which often shifted geographically with season, for most of the 41 detected agents. A high density of infection clusters was found in the Salish Sea along the east coast of Vancouver Island, an important migration route and residence area for many salmon populations, some experiencing chronically poor marine survival. Maps for each infectious agent taxa showing clusters across all host species are provided. Our novel documentation of salmon pathogen distributions in the marine environment contributes to the ecological knowledge regarding some lesser known pathogens, identifies salmon populations potentially impacted by specific pathogens, and pinpoints priority locations for future research and remediation., (© 2023. The Author(s).)

SHR6390 (dalpiciclib) is a selective and effective cyclin-dependent kinase (CDK) 4/6 inhibitor and an effective cancer therapeutic agent. On 31 December 2021, the new drug application was approved by National Medical Product Administration (NMPA). The metabolism, mass balance, and pharmacokinetics of SHR6390 in 6 healthy Chinese male subjects after a single oral dose of 150 mg [ 14 C]SHR6390 (150 µCi) in this research. The Tmax of SHR6390 was 3.00 h. In plasma, the t 1/2 of SHR6390 and its relative components was approximately 17.50 h. The radioactivity B/P (blood-to-plasma) AUC 0-t ratio was 1.81, indicating the preferential distribution of drug-related substances in blood cells. At 312 h after administration, the average cumulative excretion of radioactivity was 94.63% of the dose, including 22.69% in urine and 71.93% in stool. Thirteen metabolites were identified. In plasma, because of the low level of radioactivity, only SHR6390 was detected in pooled AUC 0-24 h plasma. Stool SHR6390 was the main component in urine and stool. Five metabolites were identified in urine, and 12 metabolites were identified in stool. Overall, faecal clearance is the main method of excretion., Competing Interests: Authors SL and GL were employed by Jiangsu Hengrui Medicine Co., Ltd. The remaining 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 © 2023 Zhang, Yan, Zhan, Ma, Bian, Li, Tian, Li, Zhong, Diao and Miao.)

The purpose of this study was to determine the pharmacokinetic characteristics and safety of dalpiciclib at 100-, 125-, and 150-mg doses after process modification in healthy Chinese volunteers. This single-center, randomized, open-label, three-dose, phase I clinical study was conducted in healthy Chinese adults. Thirty-six volunteers were randomized to three groups, including groups administered 100, 125, and 150 mg of dalpiciclib, and each group contained an equal number of males and females. A single oral dose of dalpiciclib was administered to each group, and plasma concentrations were measured by a validated liquid chromatography-tandem mass spectrometry method. The oral formulation of dalpiciclib was well absorbed, the plasma concentration reached the maximum concentration (C max ) in 4-6 hours, and it was eliminated from plasma with a mean terminal half-life of 42.9-45.5 hours after 100-150 mg was administered. Dalpiciclib exhibited safety and favorable pharmacokinetic profiles, supporting further investigations in phase II studies. The plasma exposure of dalpiciclib was dose-dependent, with increasing doses in the range of 100-150 mg., (© 2022, The American College of Clinical Pharmacology.)

Dendritic organic molecular gels are a promising class of three-dimensional network compounds. Here, we have synthesized a new type of dendritic organic molecular gel stationary phase (SiO 2 -G3) by using benzyl alcohol as raw material and dimethyl 5-hydroxyisophthalate as growth unit to synthesize a third-generation organic molecular gel G3, which grafted onto the silica surface by cyanogen chloride (CC). The developed stationary phase not only exhibits high molecular shape selectivity but also has a RPLC/HILIC/IEC mixed-mode characteristic for HPLC due to the ordered structure, the multiple strong π-π stacking interactions and the introduction of a hydrophilic triazine fraction during the grafting process. Compared with a commercial C 18 column, the developed column exhibited flexible selectivity, enhanced separation performance and excellent separation of monosubstituted benzene, polycyclic aromatic hydrocarbons (PAHs), positional isomers, nucleosides and nucleobases, benzoic acid and aniline compounds. In addition, the new column provided baseline separation of polycyclic aromatic hydrocarbon contaminants in Yellow River water, verifying its potential for application in the analysis of real samples., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

The treatment of bone defects is an important problem in clinical practice. The rapid development of bone tissue engineering (BTE) may provide a new method for bone defect treatment. Metal ions have been widely studied in BTE and demonstrated a significant effect in promoting bone tissue growth. Different metal ions can be used to treat bone defects according to specific conditions, including promoting osteogenic activity, inhibiting osteoclast activity, promoting vascular growth, and exerting certain antibacterial effects. Multiple studies have confirmed that metal ions-modified composite scaffolds can effectively promote bone defect healing. By studying current extensive research on metal ions in the treatment of bone defects, this paper reviews the mechanism of metal ions in promoting bone tissue growth, analyzes the loading mode of metal ions, and lists some specific applications of metal ions in different types of bone defects. Finally, this paper summarizes the advantages and disadvantages of metal ions and analyzes the future research trend of metal ions in BTE. This article can provide some new strategies and methods for future research and applications of metal ions in the treatment of bone defects.

Background: Strategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC., Methods: This phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT)., Results: A total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9-22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3-79.3). The median progression-free survival was 5.2 months (95% CI, 3.6-7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0-88.8)., Conclusions: Combination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC., Trial Registration: ClinicalTrials.gov NCT03945604 (May 10, 2019)., (© 2022. The Author(s).)

The large incidence of bone defects in clinical practice increases not only the demand for advanced bone transplantation techniques but also the development of bone substitute materials. A variety of emerging bone tissue engineering materials with osteogenic induction ability are promising strategies for the design of bone substitutes. MicroRNAs (miRNAs) are a class of non-coding RNAs that regulate intracellular protein expression by targeting the non-coding region of mRNA3'-UTR to play an important role in osteogenic differentiation. Several miRNA preparations have been used to promote the osteogenic differentiation of stem cells. Therefore, multiple functional bone tissue engineering materials using miRNA as an osteogenic factor have been developed and confirmed to have critical efficacy in promoting bone repair. In this review, osteogenic intracellular signaling pathways mediated by miRNAs are introduced in detail to provide a clear understanding for future clinical treatment. We summarized the biomaterials loaded with exogenous cells engineered by miRNAs and biomaterials directly carrying miRNAs acting on endogenous stem cells and discussed their advantages and disadvantages, providing a feasible method for promoting bone regeneration. Finally, we summarized the current research deficiencies and future research directions of the miRNA-functionalized scaffold. This review provides a summary of a variety of advanced miRNA delivery system design strategies that enhance bone regeneration., 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 Wang, Cui, Liu, Li, Sun, Xu, Peng, Wang and Wu.)

The treatment of infected bone defects is an intractable problem in orthopedics. It comprises two critical parts, namely that of infection control and bone defect repair. According to these two core tasks during treatment, the ideal approach of simultaneously controlling infection and repairing bone defects is promising treatment strategy. Several engineered biomaterials and drug delivery systems with dual functions of anti-bacterial action and ostogenesis-promotion have been developed and demonstrated excellent therapeutic effects. Compared with the conventional treatment method, the dual-functional composite scaffold can provide one-stage treatment avoiding multiple surgeries, thereby remarkably simplifying the treatment process and reducing the treatment time, overcoming the disadvantages of conventional bone transplantation. In this review, the impaired bone repair ability and its specific mechanisms in the microenvironment of pathogen infection and excessive inflammation were analyzed, providing a theoretical basis for the treatment of infectious bone defects. Furthermore, we discussed the composite dual-functional scaffold composed of a combination of antibacterial and osteogenic material. Finally, a series of advanced drug delivery systems with antibacterial and bone-promoting capabilities were summarized and discussed. This review provides a comprehensive understanding for the microenvironment of infectious bone defects and leading-edge design strategies for the antibacterial and bone-promoting dual-function scaffold, thus providing clinically significant treatment methods for infectious bone defects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Aim: This trial (NCT04013048) investigated the metabolite profiles, mass balance and pharmacokinetics of fuzuloparib, a novel poly (ADP-ribose) polymerase inhibitor, in subjects with advanced solid cancers., Methods: A single dose of 150 mg [ 14 C]fuzuloparib was administered to five subjects with advanced solid cancers. Blood, urine and faecal samples were collected, analysed for radioactivity and unchanged fuzuloparib, and profiled for metabolites. The safety of the medicine was assessed during the study., Results: The maximum concentrations (C max ) of the total radioactivity (TRA) and unchanged fuzuloparib in plasma were 5.39 μg eq./mL and 4.19 μg/mL, respectively, at approximately 4 hours post dose. The exposure (AUC 0-t ) of fuzuloparib accounted for 70.7% of the TRA in plasma, and no single metabolite was observed accounting for more than 10% of the plasma TRA. The recovery of TRA in excreta was 103.3 ± 3.8% in 288 hours, including 59.1 ± 9.9% in urine and 44.2 ± 10.8% in faeces. Sixteen metabolites of fuzuloparib were identified, including mono-oxidation (M1), hydrogenation (M2), di-oxidation (M3), trioxidation (M4), glucuronidation (M5, M7, M8) and de-ethylation (M6) products, and there was no specific binding between these metabolites and blood cells. Aliphatic hydroxylated fuzuloparib (M1-1) was the primary metabolite in the excreta, accounting for more than 40% of the dose for subjects. There were no serious adverse events observed in the study., Conclusion: Fuzuloparib was widely metabolized and excreted completely through urine and faeces in subjects with advanced solid cancer. Unchanged fuzuloparib was indicated to be the primary drug-related compound in circulation. [ 14 C]fuzuloparib was well-tolerated at the study dose., (© 2022 British Pharmacological Society.)

Hydrogen sulfide (H 2 S) sensors are in urgent demand in the field of hermetic environment detection and metabolic disease diagnosis. However, most of the reported room-temperature (RT) H 2 S sensors based on transition metal oxides/salts unavoidably suffer from the poisoning effect, resulting in the unrecoverable behavior to restrain their application. Herein, copper(II) chloride-doped polyaniline emeraldine salt (PANI-CuCl 2 ) was devised for RT-recoverable H 2 S detection, where the copper ion (Cu 2+ ) was designed as a partial substitution of protons (H + ) in PANI. The prepared gas sensor exhibited full recovery capability toward 0.25-10 ppm H 2 S, good repeatability, and long-term stability under 80% RH. Meanwhile, the changes of the PANI-CuCl 2 during the H 2 S sensing period were analyzed via multiple analytical methods to reveal the reversible sensing behavior. Results showed that doping of Cu 2+ not only promoted the PANI's response through the formation of conductive copper sulfide (CuS) and following H + redoping in the PANI but also facilitated the sensor's recovery behavior because of the Cu 2+ regeneration under the H + /oxygen environment. This work not only proves the changes of the interaction between the PANI and Cu 2+ during the H 2 S sensing period but also sheds light on designing recoverable H 2 S sensors based on transition metal salts.

Background: Second-line treatment options for small cell lung cancer (SCLC) are limited. Preclinical research shows that inhibition of poly (ADP-ribose) polymerase (PARP) could upregulate programmed death-ligand 1 (PD-L1), and thus render cancer cells more sensitive to immune checkpoint inhibitors. This study investigated the tolerability, safety, and preliminary antitumor activity of fuzuloparib (a PARP inhibitor) plus SHR-1316 (a PD-L1 inhibitor) for relapsed SCLC., Methods: Patients with SCLC who failed previous first-line platinum-based therapy were enrolled in this two-stage phase Ib trial. In stage 1, 2 dose levels were designed: fuzuloparib 100 mg or 150 mg twice daily plus SHR-1316 600 mg every 2 weeks, with 6 patients in each dose level. Based on the tolerability during the first 28-day cycle and the preliminary antitumor activity in stage 1, a recommended phase II dose (RP2D) was determined and introduced in the stage 2 expansion phase. The primary endpoints were safety and RP2D in stage 1 and objective response rate (ORR) in stage 2., Results: A total of 23 patients were enrolled, with 16 receiving fuzuloparib 100 mg plus SHR-1316 and 7 receiving fuzuloparib 150 mg plus SHR-1316. At data cutoff on April 23, 2021, the median follow-up duration was 6.4 months (IQR, 3.0-9.7 months). All patients discontinued study treatment. One patient receiving fuzuloparib 150 mg plus SHR-1316 had clinically significant toxicities, and fuzuloparib 100 mg plus SHR-1316 was considered as the RP2D. In the RP2D cohort, the confirmed ORR was 6.3% (95% CI: 0.2-30.2%), and the disease control rate was 37.5% (95% CI: 15.2-64.6%). The median progression-free survival was 1.4 months (95% CI: 1.3-2.8 months), and the median overall survival was 5.6 months (95% CI: 3.0-16.7 months). Grade ≥3 treatment-related adverse events (TRAE) occurred in 8 patients (34.8%). No treatment-related death occurred, and no patients discontinued treatment due to TRAEs., Conclusions: Fuzuloparib combined with SHR-1316 failed to improve the outcomes in unselected patients with relapsed SCLC. Future studies with biomarker analysis are warranted to select patients most likely to benefit from this combination treatment. Fuzuloparib 100 and 150 mg plus SHR-1316 were both tolerable with no new signals observed., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-356/coif). XM, WS, YS, and SL are employees of Jiangsu Hengrui Pharmaceuticals and Jiangsu Hengrui Pharmaceuticals provided all support for the present manuscript. YHK reports payment or honoraria from AstraZeneca, Chugai Pharmaceutical, and Eli Lilly Japan. TH has received personal fees from Chugai Pharmaceutical outside the submitted work. AA has received consulting fees from Amgen, Astrazeneca, Roche, Astellas, Takeda, BMS, MSD, Pfize, Merck and Novartis. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Hebei Province, located in the North China Plain (NCP) and encircling Beijing and Tianjin, has been suffering from severe air pollution. The monthly average fine particulate matter (PM 2.5 ) concentration was up to 276 μg/m 3 in Hebei Province, which adversely affects human health. However, few studies evaluated the coordinated health impact of exposure to PM (PM 2.5 and PM 10 ) and other key air pollutants (SO 2 , NO 2 , CO, and surface ozone (O 3 )). In this study, we systematically analyzed the health risks (both mortality and morbidity) due to multiple air pollutants exposures in Hebei Province. The economic loss associated with these health consequences was estimated using the value of statistical life (VSL) and cost of illness (COI) methods. Our results show the health burden and economic loss attributable to multiple ambient air pollutants exposures in Hebei Province is substantial. In 2017, the total premature mortality from multiple air pollutants exposures in Hebei Province was 69,833 (95% CI: 55,549-83,028), which was 2.9 times higher than that of the Pearl River Delta region (PRD). Most of the potential economic loss (79.65%) was attributable to premature mortality from air pollution. The total economic loss due to the health consequences of multiple air pollutants exposures was 175.16 (95% CI: 134.61-224.61) billion Chinese Yuan (CNY), which was 4.92% of Hebei Province's annual gross domestic product (GDP). Thus, the adverse health effects and economic loss caused by exposure to multiple air pollutants should be seriously taken into consideration. To alleviate these damages, Hebei's government ought to establish more stringent measures and regulations to better control air pollution., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

In the last decade, perovskite solar cells have made a quantum leap in performance with the efficiency increasing from 3.8% to 25%. However, commercial perovskite solar cells have faced a major impediment due to toxicity and stability issues. Therefore, lead-free inorganic perovskites have been investigated in order to find substitute perovskites which can provide a high efficiency similar to lead-based perovskites. In recent studies, as a kind of lead-free inorganic perovskite material, Cs 4 CuSb 2 Cl 12 has been demonstrated to possess impressive photoelectric properties and excellent environmental stability. Moreover, Cs 4 CuSb 2 Cl 12 nanocrystals have smaller effective photo-generated carrier masses than bulk Cs 4 CuSb 2 Cl 12 , which provides excellent carrier mobility. To date, there have been no reports about Cs 4 CuSb 2 Cl 12 nanocrystals used for making solar cells. To explore the potential of Cs 4 CuSb 2 Cl 12 nanocrystal solar cells, we propose a lead-free perovskite solar cell with the configuration of FTO/ETL/Cs 4 CuSb 2 Cl 12 nanocrystals/HTL/Au using a solar cell capacitance simulator. Moreover, we numerically investigate the factors that affect the performance of the Cs 4 CuSb 2 Cl 12 nanocrystal solar cell with the aim of enhancing its performance. By selecting the appropriate hole transport material, electron transport material, thickness of the absorber layer, doping densities, defect density in the absorber, interface defect densities, and working temperature point, we predict that the Cs 4 CuSb 2 Cl 12 nanocrystal solar cell with the FTO/TiO 2 /Cs 4 CuSb 2 Cl 12 nanocrystals/Cu 2 O/Au structure can attain a power conversion efficiency of 23.07% at 300 K. Our analysis indicates that Cs 4 CuSb 2 Cl 12 nanocrystals have great potential as an absorbing layer towards highly efficient lead-free all-inorganic perovskite solar cells.

Objectives: Hepatic ischemia-reperfusion injury (HIRI) is of common occurrence during liver surgery and liver transplantation and may cause hepatic impairment, resulting in acute liver dysfunction. Nitrate plays an important physiological regulatory role in the human body. Whether dietary nitrate could prevent HIRI is, however, unknown. Methods: A HIRI mouse model was established in that the blood supply to the median lobe and left lateral lobe was blocked for 60 min through the portal vein and related structures using an atraumatic clip. Sodium nitrate (4 mM) was administrated in advance through drinking water to compare the influence of sodium nitrate and normal water on HIRI. Results: Liver necrosis and injury aggravated after HIRI. The group treated with sodium nitrate showed the lowest activities of plasma aminotransferase and lactate dehydrogenase and improved outcomes in histological investigation and TUNEL assay. Mechanistically, sodium nitrate intake increased plasma and liver nitric oxide levels, upregulated nuclear factor erythroid 2-related factor 2 (NRF2)-related molecules to reduce malondialdehyde level, and increased the activities of antioxidant enzymes to modulate hepatic oxidative stress. Conclusions: Dietary inorganic nitrate could prevent HIRI, possibly by activating the NRF2 pathway and modulating oxidative stress. Our study provides a novel therapeutic compound that could potentially prevent HIRI during liver transplantation or hepatic surgery., 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 © 2021 Li, Jin, Sun, Zhang, Wang, Xu, Zhang and Wang.)

Global expansion of aquaculture and agriculture facilitates disease emergence and catalyzes transmission to sympatric wildlife populations. The health of wild salmon stocks critically concerns Indigenous peoples, commercial and recreational fishers, and the general public. Despite potential impact of viral pathogens such as Piscine orthoreovirus-1 (PRV-1) on endangered wild salmon populations, their epidemiology in wild fish populations remains obscure, as does the role of aquaculture in global and local spread. Our phylogeographic analyses of PRV-1 suggest that development of Atlantic salmon aquaculture facilitated spread from Europe to the North and South East Pacific. Phylogenetic analysis and reverse transcription polymerase chain reaction surveillance further illuminate the circumstances of emergence of PRV-1 in the North East Pacific and provide strong evidence for Atlantic salmon aquaculture as a source of infection in wild Pacific salmon. PRV-1 is now an important infectious agent in critically endangered wild Pacific salmon populations, fueled by aquacultural transmission., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Optical metalens has been attracting more and more attention in recent years. To date, it is still difficult to simultaneously achieve wide field and broadband imaging in the visible region, which is very important in many applications, such as cameras, microscopy, and other imaging devices. In this paper, we design a double-layer metalens to achieve achromatic imaging over a field of view (FOV) of 60° in the visible light range of 470 nm to 650 nm, and its performance is verified by numerical simulations. The numerical aperture (NA) of the metalens is 0.61 and the average focusing efficiency is > 50% at normal incidence. The metalens has an additional advantage of polarization insensitivity.

Predation risk for animal migrants can be impacted by physical condition. Although size- or condition-based selection is often observed, observing infection-based predation is rare due to the difficulties in assessing infectious agents in predated samples. We examined predation of outmigrating sockeye salmon ( Oncorhynchus nerka ) smolts by bull trout ( Salvelinus confluentus ) in south-central British Columbia, Canada. We used a high-throughput quantitative polymerase chain reaction (qPCR) platform to screen for the presence of 17 infectious agents found in salmon and assess 14 host genes associated with viral responses. In one (2014) of the two years assessed (2014 and 2015), the presence of infectious haematopoietic necrosis virus (IHNv) resulted in 15-26 times greater chance of predation; in 2015 IHNv was absent among all samples, predated or not. Thus, we provide further evidence that infection can impact predation risk in migrants. Some smolts with high IHNv loads also exhibited gene expression profiles consistent with a virus-induced disease state. Nine other infectious agents were observed between the two years, none of which were associated with increased selection by bull trout. In 2014, richness of infectious agents was also associated with greater predation risk. This is a rare demonstration of predator consumption resulting in selection for prey that carry infectious agents. The mechanism by which this selection occurs is not yet determined. By culling infectious agents from migrant populations, fish predators could provide an ecological benefit to prey., (© 2021 The Authors.)

Spring viremia of carp virus (SVCV) is a rhabdovirus of the Sprivivirus genus and the etiological agent of an internationally regulated aquatic animal disease in several fish species, including koi carp Cyprinus carpio L. The virus has a complex lifecycle with both acute and persistent stages of infection and can cause high mortality in affected populations. In this study, the diagnostic repeatability (within laboratory agreement) and reproducibility (between laboratory agreement) of 3 tests were investigated to assess their fitness as SVCV diagnostic tools. The tests, reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays targeting either the SVCV glycoprotein (Q1G) or nucleoprotein (Q2N) genes and virus isolation by cell culture (VI), were performed in a blinded study with four Canadian laboratories. Test panels consisted of duplicate sets of 100 tissue samples collected from 3 SVCV prevalence populations of koi: a low-prevalence negative reference population (n = 20 fish) as well as moderate- (n = 50 fish) and high-prevalence (n = 30 fish) populations of koi experimentally infected with SVCV. The Q1G and Q2N tests were performed with kidney tissue in 3 laboratories and with brain tissue in 1 laboratory whereas pools of kidney, spleen and gill tissues were tested with the VI assay in 2 laboratories. Agreement of binary results was evaluated using the observed proportion of agreement, Cohen's kappa and Gwet's agreement coefficient (AC1) whereas the concordance correlation coefficient (ccc) and Bland Altman's limit of agreement were used to evaluate agreement of the RT-qPCR continuous data. Gwet's AC1 provided a more stable estimate of agreement than Cohen's kappa. Overall, high repeatability (AC1, 0.78-0.90) and reproducibility (AC1, 0.74-0.89) were observed for the Q1G and Q2N tests when kidney tissue was used. Lower agreement estimates of repeatability (AC1, 0.54-0.77) and reproducibility (AC1, 0.50-0.80) were obtained for the VI test. RT-qPCR reproducibility was low with kidney-brain tissue pairs (AC1, 0.09-0.46) and high with inter-test pairs of brain (AC1, 0.76-0.86) or kidney tissue (0.75-0.86). Tissue-specific differences in virus load affected test precision and informed final tissue selection. Repeatability (ccc, 0.94-0.97) and reproducibility (ccc, 0.91-0.97) estimates of agreement for paired continuous data from the RT-qPCR assays were similarly high with kidney tissue and lower with paired brain (ccc, 0.15-0.83) and kidney-brain tissues (ccc, 0.01-0.55). The high precision of Q1G and Q2N with kidney tissue suggests that the tests are performing similarly and are suitable candidates for assessment of their diagnostic accuracy., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

The spread of infection from reservoir host populations is a key mechanism for disease emergence and extinction risk and is a management concern for salmon aquaculture and fisheries. Using a quantitative environmental DNA methodology, we assessed pathogen environmental DNA in relation to salmon farms in coastal British Columbia, Canada, by testing for 39 species of salmon pathogens (viral, bacterial, and eukaryotic) in 134 marine environmental samples at 58 salmon farm sites (both active and inactive) over 3 years. Environmental DNA from 22 pathogen species was detected 496 times and species varied in their occurrence among years and sites, likely reflecting variation in environmental factors, other native host species, and strength of association with domesticated Atlantic salmon. Overall, we found that the probability of detecting pathogen environmental DNA (eDNA) was 2.72 (95% CI: 1.48, 5.02) times higher at active versus inactive salmon farm sites and 1.76 (95% CI: 1.28, 2.42) times higher per standard deviation increase in domesticated Atlantic salmon eDNA concentration at a site. If the distribution of pathogen eDNA accurately reflects the distribution of viable pathogens, our findings suggest that salmon farms serve as a potential reservoir for a number of infectious agents; thereby elevating the risk of exposure for wild salmon and other fish species that share the marine environment.

The emergence of infectious agents poses a continual economic and environmental challenge to aquaculture production, yet the diversity, abundance, and epidemiology of aquatic viruses are poorly characterised. In this study, we applied salmon host transcriptional biomarkers to identify and select fish in a viral disease state, but only those that were negative for known viruses based on RT-PCR screening. These fish were selected for metatranscriptomic sequencing to discover potential viral pathogens of dead and dying farmed Atlantic ( Salmo salar ) and Chinook ( Oncorhynchus tshawytscha ) salmon in British Columbia (BC). We found that the application of the biomarker panel increased the probability of discovering viruses in aquaculture populations. We discovered two viruses that have not previously been characterised in Atlantic salmon farms in BC (Atlantic salmon calicivirus and Cutthroat trout virus-2), as well as partially sequenced three putative novel viruses. To determine the epidemiology of the newly discovered or emerging viruses, we conducted high-throughput reverse transcription polymerase chain reaction (RT-PCR) and screened over 9,000 farmed and wild salmon sampled over one decade. Atlantic salmon calicivirus and Cutthroat trout virus-2 were in more than half of the farmed Atlantic salmon we tested. Importantly we detected some of the viruses we first discovered in farmed Atlantic salmon in Chinook salmon, suggesting a broad host range. Finally, we applied in situ hybridisation to determine infection and found differing cell tropism for each virus tested. Our study demonstrates that continual discovery and surveillance of emerging viruses in these ecologically important salmon will be vital for management of both aquaculture and wild resources in the future., (© The Author(s) 2020. Published by Oxford University Press.)

Wild fish are confronting changing pathogen dynamics arising from anthropogenic disturbance and climate change. Pathogens can influence animal behaviour and life histories, yet there are little such data from fish in the high north where pathogen dynamics may differ from comparatively southern regions. We aimed to compare the pathogen communities of 160 wild anadromous brown trout in two fjords in northern Norway and to determine whether pathogens influenced area use or return to spawn. Application of high-throughput qPCR detected 11 of the 46 pathogens screened for; most frequently encountered were Ichthyobodo spp., Flavobacterium psychrophilum and Candidatus Branchiomonas cysticola. The rate of returning to freshwater during the spawning season was significantly lower for the Skjerstadfjord fish. Piscichlamydia salmonis and F. psychrophilum were indicator species for the Skjerstadfjord and pathogen communities in the two fjords differed according to perMANOVA. Individual length, Fulton's condition factor and the time between first and last detection of the fish were not related to the presence of pathogens ordinated using non-metric multidimensional scaling (NMDS). However, there was evidence that pathogen load was correlated with the expression of smoltification genes, which are upregulated by salmonids in freshwater. Correspondingly, percentage of time in freshwater after release was longer for fish with greater pathogen burdens., (© 2020 John Wiley & Sons Ltd.)

We examined cardiac pacemaker rate resetting in rainbow trout following a reciprocal temperature transfer. In the original experiment, performed in winter, 4°C-acclimated fish transferred to 12°C reset intrinsic heart rate after just 1 h (from 56.8±1.2 to 50.8±1.5 beats min -1 ); 12°C-acclimated fish transferred to 4°C reset intrinsic heart rate after 8 h (from 33.4±0.7 to 37.7±1.2 beats min -1 ). However, in a replicate experiment, performed in the summer using a different brood year, intrinsic heart rate was not reset, even after 10 weeks at a new temperature. Using this serendipitous opportunity, we compared mRNA expression changes of a suite of proteins in sinoatrial node (SAN), atrial and ventricular tissues after both 1 h and longer than 3 weeks for both experimental acclimation groups to identify those changes only associated with pacemaker rate resetting. Of the changes in mRNA expression occurring after more than 3 weeks of warm acclimation and associated with pacemaker rate resetting, we observed downregulation of NKA α1c in the atrium and ventricle, and upregulation of HCN1 in the ventricle. However, in the SAN there were no mRNA expression changes unique to the fish with pacemaker rate resetting after either 1 h or 3 weeks of warm acclimation. Thus, despite identifying changes in mRNA expression of contractile cardiac tissues, there was an absence of changes in mRNA expression directly involved with the initial, rapid pacemaker rate resetting with warm acclimation. Importantly, pacemaker rate resetting with thermal acclimation does not always occur in rainbow trout., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Early marine survival of juvenile salmon is intimately associated with their physiological condition during smoltification and ocean entry. Smoltification (parr-smolt transformation) is a developmental process that allows salmon to acquire seawater tolerance in preparation for marine living. Traditionally, this developmental process has been monitored using gill Na + /K + -ATPase (NKA) activity or plasma hormones, but gill gene expression offers the possibility of another method. Here, we describe the discovery of candidate genes from gill tissue for staging smoltification using comparisons of microarray studies with particular focus on the commonalities between anadromous Rainbow trout and Sockeye salmon datasets, as well as a literature comparison encompassing more species. A subset of 37 candidate genes mainly from the microarray analyses was used for TaqMan quantitative PCR assay design and their expression patterns were validated using gill samples from four groups, representing three species and two ecotypes: Coho salmon, Sockeye salmon, stream-type Chinook salmon and ocean-type Chinook salmon. The best smoltification biomarkers, as measured by consistent changes across these four groups, were genes involved in ion regulation, oxygen transport and immunity. Smoltification gene expression patterns (using the top 10 biomarkers) were confirmed by significant correlations with NKA activity and were associated with changes in body brightness, caudal fin darkness and caudal peduncle length. We incorporate gene expression patterns of pre-smolt, smolt and de-smolt trials from acute seawater transfers from a companion study to develop a preliminary seawater tolerance classification model for ocean-type Chinook salmon. This work demonstrates the potential of gene expression biomarkers to stage smoltification and classify juveniles as pre-smolt, smolt or de-smolt., (© The Author(s) 2019. Published by Oxford University Press and the Society for Experimental Biology.)

The collapse of iconic, keystone populations of sockeye ( Oncorhynchus nerka ) and Chinook ( Oncorhynchus tshawytscha ) salmon in the Northeast Pacific is of great concern. It is thought that infectious disease may contribute to declines, but little is known about viruses endemic to Pacific salmon. Metatranscriptomic sequencing and surveillance of dead and moribund cultured Chinook salmon revealed a novel arenavirus, reovirus and nidovirus. Sequencing revealed two different arenavirus variants which each infect wild Chinook and sockeye salmon. In situ hybridisation localised arenavirus mostly to blood cells. Population surveys of >6000 wild juvenile Chinook and sockeye salmon showed divergent distributions of viruses, implying different epidemiological processes. The discovery in dead and dying farmed salmon of previously unrecognised viruses that are also widely distributed in wild salmon, emphasizes the potential role that viral disease may play in the population dynamics of wild fish stocks, and the threat that these viruses may pose to aquaculture., Competing Interests: GM, KM, ED, AS, KK, TM, SL, AT, AT, DP, HF, CS No competing interests declared, (© 2019, Mordecai et al.)

Multiple stressors are commonly encountered by wild animals, but their cumulative effects are poorly understood, especially regarding infection development. We conducted a holding study with repeated gill and blood sampling to characterize the effects of cumulative stressors on infection development in adult coho salmon. Treatments included chronic thermal stress (15°C vs. 10°C) and acute gill net entanglement with an air exposure (simulating fisheries bycatch release). The potential loadings of 35 infectious agents and the expression of 17 host immune genes were quantified using high-throughput quantitative polymerase chain reaction, while host physiology was characterized with chemical analysis of blood. Temporal increases in infectious agent richness and loads were concurrent with decreased expression of immune genes in fish sampled in the river. In the laboratory, mortality was minimal in cool water regardless of fishery treatment (<15%). Elevated water temperature under laboratory conditions increased mortality of males and females (8% and 28% mortality, respectively, delayed by >1 wk) and enhanced mortality associated with handling and biopsy (∼40% both sexes). Experimental gillnetting at high temperature further enhanced female mortality (73%). Fish held at high temperature demonstrated heavier infectious agent loads, osmoregulatory impairment, suppressed female maturation, and upregulation of inflammatory and extracellular immune genes. At high temperature, heavy Parvicapsula minibicornis loads were associated with premature mortality. Females exhibited physiological impairment from both stressors after 1 wk, and infection burdens correlated poorly with immune gene regulation compared with males. Cumulative effects of multiple stressors on female mortality are likely a function of physiological impairment and enhanced infections at high temperature.

An organism's ability to respond effectively to environmental change is critical to its survival. Yet, life stage and overall condition can dictate tolerance thresholds to heightened environmental stressors, such that stress may not be equally felt across individuals and at all times. Also, the transcriptional responses induced by environmental changes can reflect both generalized responses as well as others that are highly specific to the type of change being experienced. Thus, if transcriptional biomarkers specific to a stressor, even under multi-stressor conditions, can be identified, the biomarkers could then be applied in natural environments to determine when and where an individual experiences such a stressor. Here, we experimentally challenged juvenile Chinook salmon ( Oncorhynchus tshawytscha ) to validate candidate gill gene expression biomarkers. A sophisticated experimental design manipulated salinity (freshwater, brackish water and seawater), temperature (10, 14 and 18°C) and dissolved oxygen (normoxia and hypoxia) in all 18 possible combinations for 6 days using separate trials for three smolt statuses (pre-smolt, smolt and de-smolt). In addition, changes in juvenile behaviour, plasma variables, gill Na + /K + -ATPase activity, body size, body morphology and skin pigmentation supplemented the gene expression responses. We identified biomarkers specific to salinity and temperature that transcended the multiple stressors, smolt status and mortality (live, dead and moribund). Similar biomarkers for dissolved oxygen were not identified. This work demonstrates the unique power of gene expression biomarkers to identify a specific stressor even under multi-stressor conditions, and we discuss our next steps for hypoxia biomarkers using an RNA-seq study., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Viral erythrocytic necrosis (VEN) affects over 20 species of marine and anadromous fishes in the North Atlantic and North Pacific Oceans. However, the distribution and strain variation of its viral causative agent, erythrocytic necrosis virus (ENV), has not been well characterized within Pacific salmon. Here, metatranscriptomic sequencing of Chinook salmon revealed that ENV infecting salmon was closely related to ENV from Pacific herring, with inferred amino-acid sequences from Chinook salmon being 99% identical to those reported for herring. Sequence analysis also revealed 89 protein-encoding sequences attributed to ENV, greatly expanding the amount of genetic information available for this virus. High-throughput PCR of over 19,000 fish showed that ENV is widely distributed in the NE Pacific Ocean and was detected in 12 of 16 tested species, including in 27% of herring, 38% of anchovy, 17% of pollock, and 13% of sand lance. Despite frequent detection in marine fish, ENV prevalence was significantly lower in fish from freshwater (0.03%), as assessed with a generalized linear mixed effects model ( p = 5.5 × 10 -8 ). Thus, marine fish are likely a reservoir for the virus. High genetic similarity between ENV obtained from salmon and herring also suggests that transmission between these hosts is likely.

Osimertinib (AZD9291) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated significant clinical benefits in patients with EGFR‑sensitizing mutations or the T790M mutation. However, the potential therapeutic effect of osimertinib combined with ionizing irradiation (IR) is not well understood. The present study investigated treatment with osimertinib combined with IR in EGFR T790M non‑small cell lung cancer (NCI‑H1975) in vitro and in vivo. The results revealed that osimertinib inhibited proliferation and clonogenic survival following irradiation, decreased G2/M phase arrest in irradiated cells, and delayed DNA damage repair in a concentration‑ and time‑dependent manner. Furthermore, osimertinib alone or in combination with IR, blocked the phosphorylation of EGFR (Tyr1068/Tyr1173), protein kinase B and extracellular signal‑regulated kinase. Osimertinib also enhanced the antitumor activity of IR in tumor‑bearing nude mice. The results of the present study indicated that osimertinib has therapeutic potential as a radiation‑sensitizer in lung cancer cells harboring the EGFR T790M mutation, providing a rationale for clinically combining osimertinib with irradiation in EGFR T790M non‑small cell lung cancer.

Background: Pacific salmon (Oncorhynchus spp.) serve as good biological indicators of the breadth of climate warming effects on fish because their anadromous life cycle exposes them to environmental challenges in both marine and freshwater environments. Our study sought to mine the extensive functional genomic studies in fishes to identify robust thermally-responsive biomarkers that could monitor molecular physiological signatures of chronic thermal stress in fish using non-lethal sampling of gill tissue., Results: Candidate thermal stress biomarkers for gill tissue were identified using comparisons among microarray datasets produced in the Molecular Genetics Laboratory, Pacific Biological Station, Nanaimo, BC, six external, published microarray studies on chronic and acute temperature stress in salmon, and a comparison of significant genes across published studies in multiple fishes using deep literature mining. Eighty-two microarray features related to 39 unique gene IDs were selected as candidate chronic thermal stress biomarkers. Most of these genes were identified both in the meta-analysis of salmon microarray data and in the literature mining for thermal stress markers in salmonids and other fishes. Quantitative reverse transcription PCR (qRT-PCR) assays for 32 unique genes with good efficiencies across salmon species were developed, and their activity in response to thermally challenged sockeye salmon (O. nerka) and Chinook salmon (O. tshawytscha) (cool, 13-14 °C and warm temperatures 18-19 °C) over 5-7 days was assessed. Eight genes, including two transcripts of each SERPINH1 and HSP90AA1, FKBP10, MAP3K14, SFRS2, and EEF2 showed strong and robust chronic temperature stress response consistently in the discovery analysis and both sockeye and Chinook salmon validation studies., Conclusions: The results of both discovery analysis and gene expression showed that a panel of genes involved in chaperoning and protein rescue, oxidative stress, and protein biosynthesis were differentially activated in gill tissue of Pacific salmon in response to elevated temperatures. While individually, some of these biomarkers may also respond to other stressors or biological processes, when expressed in concert, we argue that a biomarker panel comprised of some or all of these genes could provide a reliable means to specifically detect thermal stress in field-caught salmon.