Search

Sonodynamic therapy depending on ultrasound irradiation, which generates reactive species to kill cancer cells, has attracted considerable attention due to the deep tissue penetration depth. However, the insufficient separation of electron/hole pairs induces its limited therapeutic efficiency. Herein, we use oxygen vacancy and ZnO quantum dots decoration techniques to enhance electron/hole separation and reactive species production. In oxygen vacancy-engineered BaTiO 3 , the higher oxygen vacancy concentration leads to more efficient adsorption of activate O 2 and thus results in production of more radicals. In BaTiO 3 /ZnO heterostructures, the built-in electric field further improves separation of electron/hole pairs. The separated electron/hole react with O 2 /H 2 O to produce reactive species of •OH/∙O 2 - and kill cancer cells upon ultrasound irradiation. The work provides a guidance for sonosensitizers to tumor therapy., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The fraudulent adulteration of goat milk with cheaper and more available milk of other species such as cow milk is occurrence. The aims of the present study were to investigate the effect of goat milk adulteration with cow milk on the mid-infrared (MIR) spectrum and further evaluate the potential of MIR spectroscopy to identify and quantify the goat milk adulterated. Goat milk was adulterated with cow milk at 5 different levels including 10%, 20%, 30%, 40%, and 50%. Statistical analysis showed that the adulteration had significant effect on the majority of the spectral wavenumbers. Then, the spectrum was preprocessed with standard normal variate (SNV), multiplicative scattering correction (MSC), Savitzky-Golay smoothing (SG), SG plus SNV, and SG plus MSC, and partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLSR) were used to establish classification and regression models, respectively. PLS-DA models obtained good results with all the sensitivity and specificity over 0.96 in the cross-validation set. Regression models using raw spectrum obtained the best result, with coefficient of determination (R 2 ), root mean square error (RMSE), and the ratio of performance to deviation (RPD) of cross-validation set were 0.98, 2.01, and 8.49, respectively. The results preliminarily indicate that the MIR spectroscopy is an effective technique to detect the goat milk adulteration with cow milk. In future, milk samples from different origins and different breeds of goats and cows should be collected, and more sophisticated adulteration at low levels should be further studied to explore the potential and effectiveness of milk mid-infrared spectroscopy and chemometrics., 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.)

In humans, seasonal influenza viruses cause epidemics. Avian influenza viruses are of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against all influenza strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines, which promotes type I interferons' production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in mice for protective antibody responses. cGAMP MPs adjuvanted COBRA HA vaccines elicited robust antigen-specific antibodies following vaccination. Compared with COBRA HA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI activity elicited by COBRA HA vaccines. The HAI activity was not significantly different between cGAMP MPs adjuvanted monovalent or multivalent COBRA HA vaccines. The cGAMP MPs adjuvanted COBRA vaccine groups had higher antigen-specific IgG2a-binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated diseases caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains., Importance: Influenza viruses cause severe respiratory disease, particularly in the very young and the elderly. Next-generation influenza vaccines are needed to protect against new influenza variants. This report used a promising adjuvant, cyclic GMP-AMP (cGAMP), to enhance the elicited antibodies by an improved influenza hemagglutinin candidate and protect against influenza virus infection. Overall, adding adjuvants to influenza vaccines is an effective method to improve vaccines., Competing Interests: The authors declare no conflict of interest.

Background: Allii Macrostemonis Bulbus is also named Xiebai in China. It is an edible vegetable, and also a famous herb for treating coronary heart disease. Allium chinense G. Don (ACGD) and Allium macrostemon Bunge (AMB) are it botanical sources. The aim of this study was to explore the cardioprotective effects, and decipher the visual spatial distribution and absolute content of primary metabolites derived from these two herbs., Methods: H9c2 cells were used to perform the hypoxia-reoxygenation (H/R)-induced myocardial injury model. Their protective effects were evaluated by apoptosis levels. Furthermore, matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry imaging approach (MALDI-TOF MSI) was carried out to present the spatial location of primary metabolites including fatty acids, amino acids, carotenoids, and vitamins in these two Allium herbs. Multiple analytical methods were applied to perform quantitative analysis of these primary metabolites in AMB and ACGD bulbs by liquid chromatography tandem mass spectrometry (LC-MS)., Results: First, AMB and ACGD extracts both could increase the cell viability in H9c2 cells, and attenuate H/R-induced injury. They markedly decreased apoptosis, accompanied by activating the BCL-2/BAX pathway. Further, MALDI-TOF MSI-based relative quantification results showed several amino acids, fatty acids, carotenoids, and vitamins were largely rich in the tunics and outside scales of fresh bulbs, while some primary metabolites were abundant in their developing flower buds. Absolute quantification results displayed total contents of amino acids in ACGD bulbs were higher than those in AMB, while total contents of fatty acids and vitamins provides opposite trends in these two Allium herbs. The total contents of carotenoids and trace elements showed no significant differences between AMB and ACGD samples., Conclusions: This study would be helpful to understand the myocardial injury protection effects of these two Allium herbs, and the spatial accumulation and quantitative content levels of their main nutrients., (© 2024. The Author(s).)

The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.

Chlorogenic acid (CGA) has demonstrated anti-tumor effects across various cancers, but its role in cholangiocarcinoma (CCA) remains unclear. Our study revealed CGA's potent anti-tumor effects on CCA, significantly suppressing cell proliferation, migration, colony formation, and invasion while inhibiting the epithelial-mesenchymal transition. CGA induced apoptosis, modulated cell cycle progression, and exhibited a stable binding affinity to AKR1B10 in CCA. AKR1B10 was highly expressed in RBE cells, and CGA treatment reduced AKR1B10 expression. Knocking out AKR1B10 inhibited the proliferation of RBE cells, whereas the overexpression of AKR1B10 promoted their proliferation. Additionally, CGA suppressed the proliferation of RBE cells with AKR1B10 overexpression. Mechanistically, AKR1B10 activated AKT, and CGA exerted its inhibitory effect by reducing AKR1B10 levels, thereby suppressing AKT activation. Furthermore, CGA facilitated the polarization of tumor-associated macrophages towards an anti-tumor phenotype and enhanced T-cell cytotoxicity. These findings underscore CGA's potential as a promising therapeutic agent for CCA treatment.

This study aimed to investigate the structural characteristics, in vivo antiatherosclerosis activity, and in vitro myocardial injury protection effects of polysaccharides from Allium macrostemon Bunge and Allium chinense G. Don. Thus, crude polysaccharides of Allium macrostemon Bunge and Allium chinense G. Don significantly reduced serum lipid levels, improved cardiac myocyte morphology and arrangement, and relieved the development of myocardial fibrosis. Meanwhile, the lesion areas of the aorta and aortic valve had evident visual improvements. Furthermore, two main novel purified polysaccharides, namely, AMB-1 and ACGD-1, were isolated and characterized from crude Allium macrostemon Bunge and Allium chinense G. Don fractions, respectively. The purified polysaccharides mainly consisted of fructose and glucose and had molecular weights of 25.22 and 19.53 kDa, respectively. In addition, Fourier transform infrared spectroscopy, methylation, and nuclear magnetic resonance data revealed the primary structures of the AMB1 (or ACGD1) backbone with branched side chains. Scanning electron microscope analysis showed that the purified polysaccharides were both piled together in a lamellar or clastic form with a smooth surface along with linear or irregular bulges. Moreover, the purified polysaccharides both showed nontoxicity on H9c2 cells and effectively dropped hypoxia/reoxygenation-induced apoptosis by the BCL-2/BAX pathway. Overall, the characterization of the structural properties and in vivo and in vitro myocardial injury protection effects of Allium macrostemon Bunge and Allium chinense G. Don polysaccharides enriched our understanding of their nutritional and medicinal values. To the best of our knowledge, this is the first study on the structural characteristics and bioactivities of Allium chinense G. Don polysaccharides., Competing Interests: Declaration of competing interest The authors declare no competing financial interest. The experiment was performed and approved in accordance with the guidelines of Laboratory Animal Ethics Committee of Zhengzhou University, which comply with national and international scientific and ethical guidelines., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To gain an in-depth and comprehensive understanding of Chinese organ transplant recipients' perceptions, expectations, and suggestions of pharmacy services to hospital pharmacists., Methods: This qualitative study was conducted in central China, from February to December 2020. Participants were collected with a purposive and snowball sampling method. Focus group discussions were conducted with organ transplant recipients and content analysis was applied to identify themes and subthemes., Results: 21 recipients participated in the qualitative study. Four themes and thirteen subthemes were identified: (1) perceptions of clinical pharmacists and pharmacy services; (2) expectations for pharmacy service content; (3) expectations for pharmacy service form; and (4) difficulties as a special group., Conclusion: The pharmacy services provided by Chinese healthcare institutions are inadequate to meet the needs of organ transplant recipients. However, the acceptance and expectation of pharmacy services by transplant recipients are high. Therefore, China should learn from the experience of developed countries and focus on the actual needs of patients to establish a better pharmacy service system for organ transplantation., (© 2024. The Author(s).)

Xenotransplantation is emerging as a vital solution to the critical shortage of organs available for transplantation, significantly propelled by advancements in genetic engineering and the development of sophisticated immunosuppressive treatments. Specifically, the transplantation of kidneys from genetically engineered pigs into human patients has made significant progress, offering a potential clinical solution to the shortage of human kidney supply. Recent trials involving the transplantation of these modified porcine kidneys into deceased human bodies have underscored the practicality of this approach, advancing the field towards potential clinical applications. However, numerous challenges remain, especially in the domains of identifying suitable donor-recipient matches and formulating effective immunosuppressive protocols crucial for transplant success. Critical to advancing xenotransplantation into clinical settings are the nuanced considerations of anesthesia and surgical practices required for these complex procedures. The precise genetic modification of porcine kidneys marks a significant leap in addressing the biological and immunological hurdles that have traditionally challenged xenotransplantation. Yet, the success of these transplants hinges on the process of meticulously matching these organs with human recipients, which demands thorough understanding of immunological compatibility, the risk of organ rejection, and the prevention of zoonotic disease transmission. In parallel, the development and optimization of immunosuppressive protocols are imperative to mitigate rejection risks while minimizing side effects, necessitating innovative approaches in both pharmacology and clinical practices. Furthermore, the post-operative care of recipients, encompassing vigilant monitoring for signs of organ rejection, infectious disease surveillance, and psychological support, is crucial for ensuring post-transplant life quality. This comprehensive care highlights the importance of a multidisciplinary approach involving transplant surgeons, anesthesiologists, immunologists, infectiologists and psychiatrists. The integration of anesthesia and surgical expertise is particularly vital, ensuring the best possible outcomes of those patients undergoing these novel transplants, through safe procedural practices. As xenotransplantation moving closer to clinical reality, establishing consensus guidelines on various aspects, including donor-recipient selection, immunosuppression, as well as surgical and anesthetic management of these transplants, is essential. Addressing these challenges through rigorous research and collective collaboration will be the key, not only to navigate the ethical, medical, and logistical complexities of introducing kidney xenotransplantation into mainstream clinical practice, but also itself marks a new era in organ transplantation., 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 © 2024 Zhang, Wang, Xie, Zhang, Yang, Yuan, Cui, Song, Lv and Wang.)

Earthquakes pose substantial threats to communities worldwide. Understanding how people respond to the fast-changing environment during earthquakes is crucial for reducing risks and saving lives. This study aims to study people's protective action decision-making in earthquakes by leveraging explainable machine learning and video data. Specifically, this study first collected real-world CCTV footage and video postings from social media platforms, and then identified and annotated changes in the environment and people's behavioral responses during the M7.1 2018 Anchorage earthquake. By using the fully annotated video data, we applied XGBoost, a widely-used machine learning method, to model and forecast people's protective actions (e.g., drop and cover, hold on, and evacuate) during the earthquake. Then, explainable machine learning techniques were used to reveal the complex, nonlinear relationships between different factors and people's choices of protective actions. Modeling results confirm that social and environmental cues played critical roles in affecting the probability of different protective actions. Certain factors, such as the earthquake shaking intensity and number of people shown in the environment, displayed evident nonlinear relationships with the probability of choosing to evacuate. These findings can help emergency managers and policymakers design more effective protective action recommendations during earthquakes., (© 2024. The Author(s).)

Designing catalysts that can effectively make use of renewable energy benefits to solve the current challenges of environmental pollution and increasing energy demands. Piezo-photocatalysis that can utilize solar energy and natural vibration-energy has emerged as a "green" technique. In this work, we fabricated BiFeO 3 /C nano composites that can harvest solar and vibration energies and degrade organic pollutants. The incorporated carbon quantum dots bring about more efficient visible light absorbance and separation of photoinduced electron-hole pairs. The piezoelectric polarization further suppresses the recombination of photoinduced electron-hole pairs. The catalysts own higher reaction rates in piezo-photocatalysis and the BiFeO 3 /C-0.12 shows the highest degradation efficiency (k-value of 0.0835 min -1 )., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The role of the Hospital Pharmacy Preceptor (HPP) is pivotal in upholding the excellence of experiential training and fostering the professional growth of pharmacy interns. However, there is a lack of studies that provide an overview of pharmacy internships from the perspective of HPP. This study explores the experience and expectations of HPPs regarding existing problems and possible coping strategies in intern teaching., Methods: This is a qualitative study that was conducted through individual interviews and focus group discussions. HPPs were invited as participants from large-scale tertiary hospitals in representative provinces of mainland China. Interview and focus group discussion data were analyzed using thematic analysis to see emerging themes from the data. Nvivo 12 was utilized for data management and processing., Results: Eight individual interviews and two focus group discussions were conducted, involving 14 HPPs as participants. Upon the examination of the interviews and focus group data, four themes were summarized regarding HPPs' perceptions: 1) current presenting problems; 2) possible coping strategies; 3) something HPPs should do; 4) something interns should do., Conclusion: This study found that from the HPPs' perspective, the hospital-based pharmacy internship still has some problems from policy to practice, which need to be addressed by the joint efforts of the state, schools, internship bases, pharmacy preceptors, and students., (© 2024. The Author(s).)

Introduction: Anti-neuraminidase (NA) immunity correlates with the protection against influenza virus infection in both human and animal models. The aim of this review is to better understand the mechanism of anti-NA immunity, and also to evaluate the approaches on developing NA-based influenza vaccines or enhancing immune responses against NA for current influenza vaccines., Areas Covered: In this review, the structure of influenza neuraminidase, the contribution of anti-NA immunity to protection, as well as the efforts and challenges of targeting the immune responses to NA were discussed. We also listed some of the newly discovered anti-NA monoclonal antibodies and discussed their contribution in therapeutic as well as the antigen design of a broadly protective NA vaccine., Expert Opinion: Targeting the immune response to both HA and NA may be critical for achieving the optimal protection since there are different mechanisms of HA and NA elicited protective immunity. Monoclonal antibodies (mAbs) that target the conserved protective lateral face or catalytic sites are effective therapeutics. The epitope discovery using monoclonal antibodies may benefit NA-based vaccine elicited broadly reactive antibody responses. Therefore, the potential for a vaccine that elicits cross-reactive antibodies against neuraminidase is a high priority for next-generation influenza vaccines.

Objective: The study explores the psychological state and related influences of hospital pharmacists enclosed in extreme work environments in the post-epidemic era, and also explores potential measures to alleviate negative emotions., Methods: An embedded mixed research methodology was used. In the qualitative research phase, semi-structured interviews were carried out with 30 pharmacists consistently confined to their work environments. The data were managed and analyzed using NVivo12 software. In the quantitative research phase, 146 pharmacists with experience in extreme work environments were selected, and the data were collected through questionnaires (GAD-7 and CD-RISC-25) and self-administered questions generated during the qualitative phase. The Shapiro-Wilk test was utilized to assess data normality. Spearman correlation was conducted to evaluate correlations among self-designed questions, resilience, and anxiety., Results: The results from interviews with 30 pharmacists revealed four factors influencing the psychological state of pharmacists in the post-epidemic era: personal factors, interpersonal relationships, environmental factors, and policy and public opinion. Mitigation measures for negative emotions encompass material security, life adjustment, epidemic prevention policy, public opinion information, and organizational management. The results of a quantitative study of 146 pharmacists showed that only 1% had severe anxiety, but the psychological resilience scores were generally low, and 62% had poor psychological resilience, with scores below 73. Simultaneously, it was observed that, except religious beliefs, factors influencing psychological status in extreme work environments were significantly negatively correlated with personal anxiety levels and significantly positively correlated with psychological resilience., Conclusion: Our study holds significance in unraveling the psychological aspects of pharmacists as healthcare workers. It also offers insights into how healthcare organizations respond to the negative emotions experienced by healthcare workers in emergencies or extreme environments., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Yang et al.)

Background: Sequential embryo transfer has been recognized as a strategy to increase pregnancy rates in women undergoing in vitro fertilization and embryo transfer (IVF-ET). However, its impact on assisted reproductive outcomes remains to be substantiated by robust evidence. This systematic review aims to summarize and analyze the available evidence to investigate the effect of sequential embryo transfer on assisted reproductive outcomes., Methods: A comprehensive literature search was executed across the Pubmed, Cochrane Library, Web of Science, and Scopus databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were aggregated utilizing a random effects model, and the resultant outcomes were articulated as odds ratios (ORs) along with their 95% confidence intervals (CIs)., Results: The pooled results revealed a statistically significant enhancement in reproductive outcomes for infertile patients undergoing sequential embryo transfer as evidenced by elevated rates of chemical pregnancy (OR = 1.67, 95% CI = 1.23-2.27), clinical pregnancy (OR = 1.78, 95% CI = 1.43-2.21), and ongoing pregnancy (OR = 1.54, 95% CI = 1.03-2.31). Compared with cleavage-stage embryo transfer, sequential transfer yielded superior outcomes in terms of chemical pregnancy rate (OR = 2.08, 95% CI = 1.35-3.19) and clinical pregnancy rate (OR = 1.78, 95% CI = 1.37-2.31). Furthermore, among the repeated implantation failure (RIF) cohort, sequential embryo transfer surpassed blastocyst-stage transfer, delivering a heightened chemical pregnancy rate (OR = 1.66, 95% CI = 1.19-2.53) and clinical pregnancy rate (OR = 1.65, 95% CI = 1.19-2.27)., Conclusion: Our meta-analysis indicates that sequential transfer may enhance clinical pregnancy rate in a small subgroup of well-selected women. While promising, further evidence from prospective studies is needed., 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 © 2023 Teng, Xian, Wang, Wang, Meng, Zhang, Shan and Yi.)

Rapid advances in nanomedicine have enabled potential applications in cancer therapy. The enhanced permeability and retention (EPR) effect is the primary rationale for the passive targeting of nanoparticles in oncology. However, growing evidence indicates that the accumulation of nanomaterials via the EPR effect could be more efficient. Inspired by our clinical observation of the Gap Junction connecpion between folliculostellate cells and pituitary adenoma cells, we designed a novel drug delivery system that targets tumours by coating folliculostellate cell (FS) membranes onto PLGA nanoparticles (NPs). The resulting FSNPs, inheriting membrane proteins from the folliculostellate cell membrane, significantly enhanced the EPR effect compared to nanoparticles without cancer cell membranes. We further demonstrated that mitotane encapsulation improved the therapeutic efficacy of mitotane in both heterotopic and orthotopic pituitary adenoma models. Owing to its significant efficacy, our FS cell membrane-coated nanoplatforms has the potential to be translated into clinical applications for the treatment of invasive pituitary adenoma., 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., (© 2023 The Authors.)

Objectives: Intensive care unit (ICU) dying patients are the most important source of organ donation. This study explores the reasons affecting organ donation in the Chinese sociocultural context from the perspectives of coordinators and physicians, and further seeks countermeasures to alleviate the shortage of organs., Design and Setting: Semistructured interviews conducted in a large tertiary hospital in China., Participants and Method: 15 respondents (including 8 organ coordinators and 7 ICU physicians) were interviewed. Participants were invited to describe the factors that influence organ donation and the underlying reasons behind it. Bronfenbrenner's socioecological system model was used as theoretical support to construct a theoretical model of the factors influencing organ donation. Respondents participated in semistructured qualitative interviews that were audio-recorded and transcribed. The relevant data were analysed using thematic analysis., Results: Four themes that influenced organ donation were identified including the influence of the deceased person's attributes, immediate family members, surrounding people and the environment, and the social-level factors. In addition, we obtained four strategies from the interviews to improve the organ shortage to ameliorate the current supply-demand imbalance in organ donation. These include multilevel publicity, relevant policy support, increasing other forms of supply and reducing organ demand., Conclusions: Factors affecting organ donation after the death of a Chinese citizen include the personal characteristics of the donor, the decisions of family members such as immediate family members and the indirect influence of surrounding people such as collateral family members, in addition to factors related to the humanistic environment, religious beliefs and social opinion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The biosynthesis of functional sugars has gained significant attention due to their potential health benefits and increasing demand in the food industry. Enzymatic synthesis has emerged as a promising approach, offering high catalytic efficiency, chemoselectivity, and stereoselectivity. However, challenges such as poor thermostability, low catalytic efficiency, and food safety concerns have limited the commercial production of functional sugars. Protein engineering, including directed evolution and rational design, has shown promise in overcoming these barriers and improving biocatalysts for large-scale production. Furthermore, enzyme immobilization has proven effective in reducing costs and facilitating the production of functional sugars. To ensure food safety, the use of food-grade expression systems has been explored. However, downstream technologies, including separation, purification, and crystallization, still pose challenges in terms of efficiency and cost-effectiveness. Addressing these challenges is crucial to optimize the overall production process. Despite the obstacles, the future outlook for functional sugars is promising, driven by increasing awareness of their health benefits and continuous technological advancements. With further research and technological breakthroughs, industrial-scale production of functional sugars through biosynthesis will become a reality, leading to their widespread incorporation in various industries and products.

Lysine-specific histone demethylase 2 (Kdm2a) is a regulatory factor of histone modifications that participates in gametogenesis and embryonic development. The mis-regulation of Kdm2a can lead to aberrant gene expression, thereby contributing to abnormal cell proliferation, differentiation, apoptosis, and tumorigenesis. However, due to the potential confounding effects that are secondary to the loss of Kdm2a function from the soma in existing whole-animal mutants, the in vivo function of Kdm2a in spermatogenesis for male fertility remains unknown. Herein, we focus on exploring the spatiotemporal expression profile and biological functions of Kdm2a in the spermatogenesis and fertility of male mice. A testis-specific knockout Kdm2a model (Kdm2a cKO) was established by using the Stra8-Cre/loxP recombinase system to explore the roles of Kdm2a in male fertility. Our results showed that Kdm2a was ubiquitously expressed and dynamically distributed in multiple tissues and cell types in the testis of mice. Surprisingly, Kdm2a-deficient adult males were completely fertile and comparable with their control (Kdm2a flox/flox ) counterparts. Despite the significantly reduced total number of sperm and density of seminiferous tubules in Kdm2a cKO testis accompanied by the degeneration of spermatogenesis, the fertilization ability and embryonic developmental competence of the Kdm2a cKO were comparable with those of their control littermates, suggesting that Kdm2a disruption did not markedly affect male fertility, at least during younger ages. Furthermore, Kdm2a homozygous mutants exhibited a lower total number and motility of sperm than the control group and showed notably affected serum 17β-estradiol concentration. Interestingly, the transcriptome sequencing revealed that the loss of Kdm2a remarkably upregulated the expression level of Kdm2b. This effect, in turn, may induce compensative effects in the case of Kdm2a deficiency to maintain normal male reproduction. Together, our results reveal that Kdm2a shows spatiotemporal expression during testicular development and that its loss is insufficient to compromise the production of spermatozoa completely. The homologous Kdm2b gene might compensate for the loss of Kdm2a. Our work provides a novel Kdm2a cKO mouse allowing for the efficient deletion of Kdm2a in a testis-specific manner, and further investigated the biological function of Kdm2a and the compensatory effects of Kdm2b. Our study will advance our understanding of underlying mechanisms in spermatogenesis and male fertility., Competing Interests: Declaration of competing interest We state that the authors or author's institution have no financial or other relationship with other people or organizations that may inappropriately influence the author's work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Control of N-nitrosodimethylamine (NDMA) in drinking water could be achieved by removing its precursors as one practical way. Herein, superfine powdered activated carbons with a diameter of about 1 µm (SPACs) were successfully prepared by grinding powdered activated carbon (PAC, D 50 =24.3 µm) and applied to remove model NDMA precursors, i.e. ranitidine (RAN) and nizatidine (NIZ). Results from grain diameter experiments demonstrated that the absorption velocity increased dramatically with decreasing particle size, and the maximum increase in k 2 was 26.8-folds for RAN and 33.4-folds for NIZ. Moreover, kinetic experiments explained that rapid absorption could be attributed to the acceleration of intraparticle diffusion due to the shortening of the diffusion path. Furthermore, performance comparison experiments suggested that the removal of RAN and NIZ (C 0 =0.5 mg/L) could reach 61.3% and 60%, respectively, within 5 min, when the dosage of SAPC-1.1 (D 50 =1.1 µm) was merely 5 mg/L, while PAC-24.3 could only eliminate 17.5% and 18.6%. The adsorption isotherm was well defined by Langmuir isotherm model, indicating that the adsorption of RAN/NIZ was a monolayer coverage process. The adsorption of RAN or NIZ by SAPC-1.1 and PAC-24.3 was strongly pH dependent, and high adsorption capacity could be observed under the condition of pH > pk a +1. The coexistence of humic acid (HA) had no significant effect on the adsorption performance because RAN/NIZ may be coupled with HA and removed simultaneously. The coexistence of anions had little effect on the adsorption also. This study is expected to provide an alternative strategy for drinking water safety triggered by NDMA., 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 article., (Copyright © 2023. Published by Elsevier B.V.)

Background & Aims: Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripheral rhythms via diurnal nutritional signals. Here, we investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism., Methods: Transcriptomic analysis, metabolomics, metabolic assays, histology, quantitative (q)PCR, and immunoblotting were performed with Bmal1-intestine-specific knockout (iKO), Rev-erba-iKO, and control mice., Results: Bmal1 iKO caused large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, the liver clock was resistant to entrainment by inverted feeding and a high-fat diet. Importantly, Bmal1 iKO remodelled diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis during the dark phase, leading to elevated glucose production (hyperglycaemia) and insulin insensitivity. Conversely, Rev-erba iKO caused a diversion to lipogenesis from gluconeogenesis during the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcohol-related liver injury. These temporal diversions were attributed to disruption of hepatic SREBP-1c rhythmicity, which was maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of a local clock., Conclusions: Our findings establish a pivotal role for the intestinal clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health., Impact and Implications: Our findings establish the centrality of the intestinal clock among peripheral tissue clocks, and associate liver-related pathologies with its malfunction. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. Such knowledge will help clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Although hyperthermia-based photothermal therapy (PTT) has achieved great success in the battle against malignant tumors, various commonly used photothermal sensitizers still suffer from non-selective tumor accumulation, limited photothermal conversion efficiency, potential toxicity and side effects, as well as complex and low cost-effective preparation process. Therefore, novel photothermal sensitizers are urgently required. The well-organized self-assembling of natural bacteriochlorophylls with superior photothermal property may provide an interesting option for the engineering of ideal PTS., Methods: Inspired by the self-assembly peripheral light-harvesting antennas of natural bacteriochlorin in microorganisms, a biomimetic light-harvesting nanosystem (Nano-Bc) was developed via bacteriochlorophylls self-arranging in aqueous phase. The characterization of Nano-Bc were measured using DLS, TEM, UV-vis-near-infrared spectroscopy and preclinical PA imaging system. The cytotoxicity of Nano-Bc was quantitatively evaluated via a standard MTT assay using mouse breast cancer 4T1 cells, and the in vivo photothermal eradication of tumor was investigated in the 4T1 breast tumor-bearing mouse model., Results: The obtained bacteriochlorin nanoparticles (Nano-Bc) exhibited ultra-high photothermal performance within the biological transparent window, showing superior heating capacity compared to commonly used photothermal sensitizers of organic dye indocyanine green and inorganic gold nanorods. Guiding by the inherent photoacoustic imaging of Nano-Bc, complete tumor elimination in vitro and vivo was evidenced upon laser irradiation., Conclusion: The green and facile preparation, ultra-high photothermal effect in the transparent window, excellent photoacoustic imaging capacity, and great biosafety prompt, the bio-inspired Nano-Bc as a promising theranostic platform against cancer in the areas of healthcare., Competing Interests: Declaration of Competing Interest Please declare any financial or personal interests that might be potentially viewed to influence the work presented. Interests could include consultancies, honoraria, patent ownership or other. If there are none state ‘there are none’., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Long noncoding RNAs (lncRNAs) have been shown to contribute to tumorigenesis and cancer progression. However, neither the dysregulation nor the functions of anti-sense lncRNAs in papillary thyroid carcinoma (PTC) have been exhaustively studied. In this study, we accessed The Cancer Genome Atlas (TCGA) database and discovered that the natural antisense lncRNA SOCS2-AS1 is highly expressed in PTC and that patients with a higher level of SOCS2-AS1 had a poor prognosis. Furthermore, loss- and gain-function assays demonstrated that SOCS2-AS1 promotes PTC cell proliferation and growth both in vitro and in vivo. In addition, we demonstrated that SOCS2-AS1 regulates the rate of fatty acid oxidation (FAO) in PTC cells. Analysis of the mechanism revealed that SOCS2-AS1 binds to p53 and controls its stability in PTC cell lines. Overall, our findings showed that the natural antisense lncRNA SOCS2-AS1 stimulates the degradation of p53 and enhances PTC cell proliferation and the FAO rate., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Detao Yin reports financial support was provided by the Major Scientific Research Projects of Traditional Chinese Medicine in Henan Province. Detao Yin reports financial support was provided by the Cultivation of Young and Middle-aged Health Science and Technology Innovation Leading Talents in Henan Province., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tibetan chicken is one of the most common and widely distributed highland breeds, and is often used as a model organism for understanding genetic adaptation to extreme environments in Tibet. Despite its apparent geographical diversity and large variations in plumage patterns, the genetic differences within breed were not accounted for in most studies and have not been systematically investigated. In order to reveal and genetically differentiate the current existing TBC sub-populations that might have major implications for genomic research in TBCs, we systematically evaluated the population structure and demography of current TBC populations. Based on 344 whole-genome sequenced birds including 115 Tibetan chickens that were mostly sampled from family-farms across Tibet, we revealed a clear separation of Tibetan chickens into 4 sub-populations that broadly aligns with their geographical distribution. Moreover, population structure, population size dynamics, and the extent of admixture jointly suggest complex demographic histories of these sub-populations, including possible multiple origins, inbreeding, and introgressions. While most of the candidate selected regions found between the TBC sub-populations and Red Jungle fowls were nonoverlapping, 2 genes RYR2 and CAMK2D were revealed as strong selection candidates in all 4 sub-populations. These 2 previously identified high altitude associated genes indicated that the sub-populations responded to similar selection pressures in an independent but functionally similar fashion. Our results demonstrate robust population structure in Tibetan chickens that will help inform future genetic analyses on chickens and other domestic animals alike in Tibet, recommending thoughtful experimental design., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Pirfenidone is an antifibrotic agent that has been proven to slow down the progression of idiopathic pulmonary fibrosis (IPF). This study aimed to characterize the population pharmacokinetics (PK) and exposure-efficacy analysis of pirfenidone in patients with IPF., Methods: Data from 10 hospitals with 106 patients were used to develop a population PK model. The annual decline in forced vital capacity (FVC) over 52 weeks was integrated with pirfenidone plasma concentration to characterize the exposure-efficacy relationship., Results: A linear one-compartment model with first-order absorption and elimination processes and lag time best described the pirfenidone PK. The population estimates of clearance and central volume of distribution at steady-state were 13.37 L/h and 53.62 L, respectively. Bodyweight and food were statistically correlated with PK variability but had no significant influence on pirfenidone exposure. Annual decline in FVC with pirfenidone plasma concentration was described by a maximum drug effect (E max ) model. The typical EC 50 was 1.73 mg/L (1.18-2.31 mg/L) and the corresponding EC 80 was 2.18 mg/L (1.49-2.87 mg/L). Simulations showed that two dosing regimens of 500 and 600 mg three times daily were predicted to generate 80% of the E max ., Conclusions: In patients with IPF, covariates such as bodyweight and food might not be sufficient for dose adjustment, and a low dose of 1500 mg/day could also provide 80% of the E max , as the standard dose (1800 mg/day)., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Anlotinib, as a promising oral small-molecule antitumor drug, its role in glioma has been only reported in a small number of case reports. Therefore, anlotinib has been considered as a promising candidate in glioma. The aim of this study was to investigate the metabolic network of C6 cells after exposure to anlotinib and to identify anti-glioma mechanism from the perspective of metabolic reprogramming. Firstly, CCK8 method was used to evaluate the effects of anlotinib on cell proliferation and apoptosis. Secondly, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS)-based metabolomic and lipidomic were developed to characterize the metabolite and lipid changes in cell and cell culture medium (CCM) caused by anlotinib in the treatment of glioma. As a result, anlotinib had concentration-dependent inhibitory effect with the concentration range. In total, twenty-four and twenty-three disturbed metabolites in cell and CCM responsible for the intervention effect of anlotinib were screened and annotated using UHPLC-HRMS. Altogether, seventeen differential lipids in cell were identified between anlotinib exposure and untreated groups. Metabolic pathways, including amino acid metabolism, energy metabolism, ceramide metabolism, and glycerophospholipid metabolism, were modulated by anlotinib in glioma cell. Overall, anlotinib has an effective treatment against the development and progression of glioma, and these remarkable pathways can generate the key molecular events in cells treated with anlotinib. Future research into the mechanisms underlying the metabolic changes is expected to provide new strategies for treating glioma., (© 2023. The Author(s).)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Background: RNA 5-methylcytosine (m 5 C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m 5 C modification in tumor drug resistance remain unclear., Methods: The correlation between RNA m 5 C methylation, m 5 C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m 5 C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays., Results: RNA m 5 C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m 5 C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m 5 C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m 5 C reader Y-box binding protein 1 (YBX1)., Conclusions: Our study reveals a critical function of aberrant RNA m 5 C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC., (© 2023. The Author(s).)

Rationale: The role of circadian clock in pituitary tumorigenesis remains elusive. Here we investigate whether and how circadian clock modulates the development of pituitary adenomas. Methods and Results: We found altered expression of pituitary clock genes in patients with pituitary adenomas. In particular, PER2 is prominently upregulated. Further, jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor. Conversely, loss of Per2 protects mice against developing estrogen-induced pituitary adenoma. Similar antitumor effect is observed for SR8278, a chemical that can decrease pituitary PER2 expression. RNA-seq analysis suggests involvement of cell cycle disturbance in PER2 regulation of pituitary adenoma. Subsequent in vivo and cell-based experiments validate that PER2 induces pituitary expression of Ccnb2 , Cdc20 and Espl1 (three cell cycle genes) to facilitate cell cycle progression and inhibit apoptosis, thereby promoting pituitary tumorigenesis. Mechanistically, PER2 regulates the transcription of Ccnb2 , Cdc20 and Espl1 through enhancing the transcriptional activity of HIF-1α. HIF-1α trans-activates Ccnb2 , Cdc20 and Espl1 via direct binding to its specific response element in the gene promoters. Conclusion: PER2 integrates circadian disruption and pituitary tumorigenesis. These findings advance our understanding of crosstalk between circadian clock and pituitary adenomas and highlight the relevance of clock-based approaches in disease management., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

This study investigated the effect of frequently used analgesics in cancer pain management (flurbiprofen (FLU), tramadol (TRA), and morphine (MOR)) and a novel α2-adrenergic agonist (dexmedetomidine, DEX) on temozolomide (TMZ) sensitivity in glioma cells. Cell counting kit-8 and colony-formation assays were performed to analyze the viability of U87 and SHG-44 cell lines. A high and low cell density of colony method, pharmacological methods, and connexin43 mimetic peptide GAP27 were used to manipulate the function of gap junctions; "Parachute" dye coupling and western blot were employed to determine junctional channel transfer ability and connexin expression. The results showed that DEX (in the concentration range of 0.1 to 5.0 ng/ml) and TRA (in the concentration range of 1.0 to 10.0 µg/ml) reduced the TMZ cytotoxicity in a concentration-dependent manner but was only observed with high cell density (having formed gap junction). The cell viability percentage was 71.3 to 86.8% when DEX was applied at 5.0 ng/ml, while tramadol showed 69.6 to 83.7% viability at 5.0 μg/ml in U87 cells. Similarly, 5.0 ng/ml of DEX resulted in 62.6 to 80.5%, and 5.0 μg/ml TRA showed 63.5 to 77.3% viability in SHG-44 cells. Further investigating the impact of analgesics on gap junctions, only DEX and TRA were found to decrease channel dye transfer through connexin phosphorylation and ERK pathway, while no such effect was observed for FLU and MOR. Analgesics that can affect junctional communication may compromise the effectiveness of TMZ when used simultaneously., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To determine the effects of neoadjuvant chemotherapy combined with breast-conserving surgery (BCS) on the breast cancer (BC) condition and immune and inflammatory indexes of patients with BC., Methods: A total of 114 patients with BC admitted to the First People's Hospital of Shangqiu from March 2018 to March 2020 were retrospectively enrolled in this study. Fifty-four patients who underwent radical mastectomy alone were enrolled into the control group (Con group), and the other 60 patients who received neoadjuvant chemotherapy combined with BCS were assigned to the observation group (Obs group). The two groups were compared in terms of surgical indexes, therapeutic effects, immune indexes including immunoglobulin IgG, IgA, IgM, and inflammatory indexes. Cox regression analysis was conducted to analyze the independent prognostic factors of overall survival (OS) and disease-free survival (DFS)., Results: After therapy, the Obs group yielded a significantly higher effective therapy rate than the Con group and experienced notably shorter hospital stay and operation time than the Con group. In addition, the Obs group showed significantly higher levels of IgG, IgA and IgM and significantly lower levels of TNF-α and IL-6 than the Con group after therapy. According to Cox regression analysis, clinical stage and HER2 were independent prognostic factors impacting patients' OS and DFS., Conclusion: Neoadjuvant chemotherapy combined with BCS can substantially alleviate the disease condition, effectively improve the immune ability, and lower the inflammation level of BC patients, without impacting their 2-year OS and DFS., Competing Interests: None., (AJTR Copyright © 2023.)

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently., (© 2022 UICC.)

Objective: As lifelong learners, hospital pharmacists must continually improve their self-directed learning skills. Reasonable learning strategies have been proven to enhance self-directed learning (SDL) significantly. Therefore, this study aims to investigate the SDL strategies used by hospital pharmacists in depth to provide them with a reference for the development of their SDL skills., Setting: The study was conducted in three tertiary hospitals in Henan, China., Design and Participants: This study employed a multicentre qualitative design and lasted 12 months. One-on-one interviews and focus group discussions were used to collect data. All interviews were transcribed verbatim, and the interview data were analysed using the thematic analysis method. Purposive sampling was used to select interviewees (n=17) from three tertiary hospitals in Henan province in central China., Results: After conducting data analysis, we summarised 12 learning strategies related to SDL, which were grouped into four themes: use of information resources, application of cognitive strategies, development of learning plans and use of learning platforms., Conclusion: The findings suggest that classic learning strategies, such as cognitive strategies and the development of learning plans, remain the cornerstones of hospital pharmacists' SDL abilities, while contemporary advances in information technology and changes in learning concepts have enriched the learning resources and learning platforms that are available to hospital pharmacists and have confronted contemporary hospital pharmacists with certain challenges., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4‑nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFR Del19 -based PROTAC 8. The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFR Del19 in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia. Moreover, nitroreductase reductive activation assay indicated that prodrugs 9 and 10 could successfully release the active compound 8. This study confirmed the feasibility to develop ha-PROTACs to enhance the selectivity of PROTACs by caging CRBN E3 ligase ligand., 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 Ltd. All rights reserved.)

Iron release from pipe scale is an important reason for water quality deterioration in drinking water distribution systems (DWDS) globally. Disruption of pipe scale, release and transformation of iron compounds are hot topics in the field of water supply. The aim of this study is to determine whether and how ferric components in pipe scale be reduced under anoxic condition. In this study, new investigation approaches were applied, which include simplifying the complex scale into electrode pairs, developing novel simulating reactors and conducting tailored electrochemical assays. A galvanic cell reactor with anode of metallic iron (Fe 0 ) and various cathode made of certain iron oxide (FeO x ) was firstly developed to simulate the complex niche and components of pipe scale. Electrochemical methods were used to study the reduction characteristics of scale. The results proved that reduction of iron oxide scale did occur under anoxic condition. Electromotive forces between various electrodes match the Nernst Equation quite well. As main components in pipe scale, lepidocrocite (γ-FeOOH) was found to be the most reducible iron oxide but at low rate, while goethite (α-FeOOH) has weak reducibility but can be quickly reduced. As a result of electrochemical reactions, goethite in pipe scale was transformed into magnetite (Fe 3 O 4 ). By these means, electrochemical reaction mechanisms of pipe scale disruption were revealed, which is helpful to restrain pipe corrosion and water deterioration in DWDS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chao Chen has patent Working electrode for electrochemical study of pipe scale, its preparation method and electrochemical device pending to Chao Chen, Lvtong Zhao and other authors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: To learn about the effect and mechanism of total glucosides of white peony capsule (TGP), on experimental autoimmune encephalomyelitis (EAE), an acknowledged animal model of multiple sclerosis (MS)., Methods: The rat model of EAE was induced by subcutaneous injection with guinea pig spinal cord homogenate. The severity of the disease model was assessed by clinical score, hematoxylin and eosin (H&E) and luxol fast blue (LFB). Immunohistochemical assay was used to observe the types of inflammatory cells and adhesive molecule expression. Enzyme-linked immunosorbent assay (ELISA) was applied to detect content of the stem cell growth factor / mast cell growth factor (scf/MGF), interleukin-6 (IL-6) and IL-2. Immunofluorescence assay was applied to observe the expression of connexin43 (Cx43), glial fibrillary acidic protein (GFAP), connexin47 (Cx47) and the monoclonal antibody anti-adenomatous polyposis coli (APC) clone CC1., Results: Compare with the animals in EAE model group, TGP treated rats (particularly those treated with high doses) showed a significant decrease in morbidity, clinical scores, CNS infiltration of inflammatory cells (including mononuclear macrophages, CD4 + and CD8 + T cells) and demyelination. The key adhesion molecule ICAM-1, cytokines IL-2、IL-6 and scf/MGF were significantly decreased with TGP treatment. Oppositely, PD-1, connexin47 in oligodendrocytes and connexin43 in astrocytes were elevated with TGP treatment., Conclusion: To sum up, TGP exhibited a significantly prevention and treatment effect on EAE rat model, and this improvement was achieved through a combination way composed of glial and inflammatory cells, junction proteins, various factors including adhesion factors, interleukins and scf/MGF., 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 © 2022 Elsevier GmbH. All rights reserved.)

Understanding the genetic mechanism of highland adaptation is of great importance for breeding improvement of Tibetan chickens (TBC). Some studies of TBC have identified some candidate genes and pathways from multiple subgroups, but the related genetic mechanisms remain largely unknown. Different genetic backgrounds and the independent genetic basis of highland adaptation make it difficult to identity the selective region of highland adaptation with all TBC samples. In this study, we conducted pre-analysis in a large-scale population to select a TBC subgroup with the purest and highest level of highland-specific lineage for the further analysis. Finally, the 37 samples from a TBC subgroup and 19 Lahsa White chickens were used to represent the highland group for further analysis with 80 samples from five Chinese local lowland breeds as controls. Population structure analysis revealed that highland adaptation significantly affected population stratification in Chinese local chicken breeds. Genome-wide selection signal analysis identified 201 candidate genes associated with highland adaptation of TBC, and these genes were significantly enriched in calcium signaling, vascular smooth muscle contraction and the cellular response to oxidative stress pathways. Additionally, we identified a narrow 1.76 kb region containing an overlapping region between HBZ and an active enhancer, and our identified region showed a highly significant signal. The highland group selected the haplotype with high activity to improve the oxygen-carrying capacity, thus being adapted to a hypoxic environment. We also found that STX2 was significantly selected in the highland group, thus potentially reducing the oxidative stress caused by hypoxia, and that STX2 exhibited the opposite effects on highland adaptation and reproductive traits. Our findings advance our understanding of extreme environment adaptation of highland chickens, and provide some variants and genes beneficial to TBC genetic breeding improvement., (© 2022 Stichting International Foundation for Animal Genetics.)

The ergosterol biosynthesis pathway plays an important role in model pathogenic bacteria Saccharomyces cerevisiae, but little is known about the biosynthesis of ergosterol in the pathogenic fungus Verticillium dahliae. In this study, we identified the VdERG2 gene encoding sterol C-8 isomerase from V. dahliae and investigated its function in virulence by generating gene deletion mutants (ΔVdERG2) and complemented mutants (C-ΔVdERG2). Knockout of VdERG2 reduced ergosterol content. The conidial germination rate and conidial yield of ΔVdERG2 significantly decreased and abnormal conidia were produced. In spite of VdERG2 did not affect the utilization of carbon sources by V. dahliae, but the melanin production of ΔVdERG2 was decreased in cellulose and pectin were used as the sole carbon sources. Furthermore, the ΔVdERG2 mutants produced less microsclerotia and melanin with a significant decrease in the expression of microsclerotia and melanin-related genes VaflM, Vayg1, VDH1, VdLAC, VdSCD and VT4HR. In addition, mutants ΔVdERG2 were very sensitive to congo red (CR), sodium dodecyl sulfate (SDS) and hydrogen peroxide (H 2 O 2 ) stresses, indicating that VdERG2 was involved in the cell wall and oxidative stress response. The absence of VdERG2 weakened the penetration ability of mycelium on cellophane and affected the growth of mycelium. Although ΔVdERG2 could infect cotton, its pathogenicity was significantly impaired. These phenotypic defects in ΔVdERG2 could be complemented by the reintroduction of a full-length VdERG2 gene. In summary, as a single conservative secretory protein, VdERG2 played a crucial role in ergosterol biosynthesis, nutritional differentiation and virulence in V. dahliae., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Allium macrostemon Bge. (AMB) and Allium chinense G. Don (ACGD) are both edible Allium vegetables and named officinal Xiebai (or Allii Macrostemonis Bulbus) in East Asia. Their medicinal qualities involve in lipid lowering and anti-atherosclerosis effects. And steroidal saponins, nitrogenous compounds and sulfur compounds are like the beneficial components responsible for medicinal functions. Sulfur compounds are the recognized main components both in the volatile oils of AMB and ACGD. Besides, few researches were reported about their holistic chemical profiles of volatile organic compounds (VOCs) and pharmacodynamic effects., Methods: In this study, we first investigated the lipid-lowering and anti-atherosclerotic effects of volatile oils derived from AMB and ACGD in ApoE -/- mice with high fat and high cholesterol diets., Results: The results showed the volatile oils of AMB and ACGD both could markedly reduce serum levels of TG, TC, and LDL-C ( p < 0.05), and had no alterations of HDL-C, ALT, and AST levels ( p > 0.05). Pathological results displayed they both could obviously improve the morphology of cardiomyocytes and the degree of myocardial fibrosis in model mice. Meanwhile, oil red O staining results also proved they could apparently decrease the lesion areas of plaques in the aortic intima ( p < 0.05). Furthermore, head space solid phase microextraction coupled with gas chromatography tandem mass spectrometry combined with metabolomics analysis was performed to characterize the VOCs profiles of AMB and ACGD, and screen their differential VOCs. A total of 121 and 115 VOCs were identified or tentatively characterized in the volatile oils of AMB and ACGD, respectively. Relative-quantification results also confirmed sulfur compounds, aldehydes, and heterocyclic compounds accounted for about 85.6% in AMB bulbs, while approximately 86.6% in ACGD bulbs were attributed to sulfur compounds, ketones, and heterocyclic compounds. Multivariate statistical analysis showed 62 differentially expressed VOCs were observed between AMB and ACGD, of which 17 sulfur compounds were found to be closely associated with the garlic flavor and efficacy., Discussion: Taken together, this study was the first analysis of holistic chemical profiles and anti-atherosclerosis effects of AMB and ACGD volatile oils, and would benefit the understanding of effective components in AMB and ACGD., 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 © 2023 Qin, Duan, Li, Li, Xing, Yao, Zhang, Yao and Yang.)

The influenza neuraminidase (NA) is a promising target for next-generation vaccines. Protection induced by vaccination with the computationally optimized broadly reactive NA antigen (N1-I COBRA NA) was characterized in both influenza serologically naive and pre-immune ferret models following H1N1 (A/California/07/2009, CA/09) or H5N1 (A/Vietnam/1203/2004, Viet/04) influenza challenges. The N1-I COBRA NA vaccine elicited antibodies with neutralizing ELLA activity against both seasonal and pandemic H1N1 influenza, as well as the H5N1 influenza virus. In both models, N1-I COBRA NA-vaccinated ferrets that were challenged with CA/09 virus had similar morbidity (weight loss and clinical symptoms) as ferrets vaccinated with the CA/09 HA control vaccine. There were significantly reduced viral titers compared to the mock-vaccinated control animals. Ferrets vaccinated with N1-I COBRA NA or Viet/04 NA vaccines were protected against the H5N1 virus infection with minimal clinical symptoms and negligible weight loss. In contrast, ferrets vaccinated with the CA/09 NA vaccine lost ~10% of their original body weight with 25% mortality. Vaccination with either HA or NA vaccines did not inhibit contact transmission of CA/09 virus to naïve cage mates. Overall, the N1-I COBRA vaccine elicited protective immune responses against both H1N1 and H5N1 infections and partially mitigated disease in contact-transmission receiving ferrets. These results indicate that the N1-I COBRA NA performed similarly to the CA/09 HA and NA positive controls. Therefore, the N1-I COBRA NA alone induces protection against viruses from both H5N1 and H1N1 subtypes, indicating its value as a vaccine component in broadly protective influenza vaccines.

DEK is associated with DNA replication and break repair, mRNA splicing, and transcriptional regulation, which had been studied in humans and mammals. The function of DEK in plants was poorly understood. In this study, GhDEK 2D was identified in Gossypium hirsutum by genome-wide and post-translational modifications. GhDEK2D had been phosphorylated, acetylated and ubiquitylated under Verticillium dahliae ( Vd ) challenge. The GhDEK2D -silenced cotton decreased resistance against Vd . In GhDEK2D -silenced cotton plants, the reactive oxygen species was activated, the callose, xylogen, hypersensitive reaction (HR) and expression levels of defense-related genes were reduced. Homozygous overexpressing-GhDEK2D transgenic Arabidopsis lines were more resistant to Verticillium wilt (Vw). We propose that GhDEK2D was a potential molecular target for improving resistance to Vw in cotton.

Mai-Luo-Shu-Tong pill is an effective traditional Chinese medicine formula for the treatment of superficial thrombophlebitis, but it was insufficiently chemically scrutinized. In this study, the mass spectral data of Mai-Luo-Shu-Tong pill were acquired by ultra-high performance liquid chromatography coupled with Q Exactive hybrid Quadrupole-Orbitrap high resolution mass spectrometry. Then, a data mining strategy combining multiple data processing methods was used to identify chemical constituents in Mai-Luo-Shu-Tong pill by constructing a database of precursor ions and summarizing the mass spectral fragmentation behaviors. As a result, a total of 211 compounds including 70 flavonoids, 56 terpenoids, 37 phenolic acids and 48 others were identified in positive and negative ion modes. Among them, 66 compounds have passed comparison verification with reference standards, 145 compounds were identified based on the data mining strategy combining the characteristic cleavage behaviour of homologous compounds and fragment ions and 4 compounds were potentially new compounds. This study provides a database for quality evaluation and further study of Mai-Luo-Shu-Tong pill in vivo . Moreover, it provides a reference for the characterization of the chemical constituents of other traditional Chinese medicine formulae.

The high incidence and mortality of idiopathic pulmonary fibrosis (IPF) have led to the widespread use of antifibrotic drugs such as pirfenidone; however, the associated adverse reactions greatly vary among individuals and the dose is not fixed. To date, no reliable blood concentration range of pirfenidone is available to monitor adverse reactions and clinical efficacy. This real study assessed the efficacy and safety of different plasma concentrations of pirfenidone in patients with IPF. The study included 99 patients with IPF orally treated with pirfenidone capsules for at least 52 weeks. Ultra-performance liquid chromatography-mass spectrometry was used to analyze drug plasma concentrations. The annual rate of forced vital capacity (FVC) decline, assessed at week 52, was set as the primary end point. Secondary end points were the change from the baseline in the 6-min walk distance (6 MWD) and the time to the first acute exacerbation of IPF, both of which evaluated over 52 weeks. In the total population, the annual FVC decline in the high-concentration group was -90.0 ml per year versus -260.0 ml per year in the low-concentration group, for a between-group difference of 190.3 ml per year. The proportion of patients treated with high plasma concentrations of pirfenidone who showed an absolute decline of ≥10% in FVC% predicted, with a 6 MWD reduction of ≥50 m, or died, was lower than that of patients treated with low plasma concentrations of pirfenidone. High concentrations of pirfenidone reduced the risk of acute exacerbation in patients with IPF. Considerable differences were not observed for the total St. George's Respiratory Questionnaire score or the rates of death between the high- and low-concentration groups. Mild to moderate adverse events, mainly involving the gastrointestinal system and the skin, were more common in the high-concentration group than in the low-concentration group but did not lead to termination of treatment in most cases. Our results suggest that treatment of IPF with high blood concentration of pirfenidone is both safe and effective. In the case of tolerable adverse reactions, patients with IPF may benefit from high concentrations of pirfenidone., 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 Li, Yang, Chen, Wang, Yu, Zhou, Zhang and Zhang.)

Aims: The risk of ticagrelor-related bleeding events remains a major clinical concern, especially in East Asian populations. Previous studies have reported higher ticagrelor exposure in Asian patients than in Caucasians. This prompted us to investigate the correlation between ticagrelor concentrations and bleeding events., Methods: Patients diagnosed with acute coronary syndrome and receiving dual antiplatelet therapy (aspirin and ticagrelor) were enrolled and followed up for 12 months. Trough plasma concentrations of ticagrelor and a major active metabolite were assayed, and 10 single nucleotide polymorphisms associated with ticagrelor pharmacokinetics and safety were also identified., Results: A total of 631 patients were included and 133 patients had bleeding academic research consortium type 1 or 2 bleeding event. The median ticagrelor concentration (interquartile range) was significantly higher in patients with bleeding events than that in patients without bleeding events (322.6 ng/mL [196.2-458.0 ng/mL] vs. 222.1 ng/mL [140.4-341.9 ng/mL], P < .001). According to the receiver operating characteristic curve, the cut-off value for ticagrelor levels predicting bleeding events was 363.3 ng/mL (area under the curve = 0.65; P < .001, 95% Cl: 0.595-0.700). Pharmacogenomics results showed that P2Y12 (rs6787801, P = .024) and P2Y12 (rs6785930, P = .048) were statistically associated with ticagrelor levels and bleeding events, respectively., Conclusion: Ticagrelor plasma concentrations were associated with bleeding events in Chinese patients with acute coronary syndrome., (© 2022 British Pharmacological Society.)

There are limited data on the pharmacokinetics (PK) and pharmacodynamics (PD) of polymyxin B in the elderly population. The objective of this study was to develop a population PK model of polymyxin B in elderly patients, determine factors that affect its PK parameters, and propose alternative dosing regimens. Critically ill elderly patients (age ≥65 years) who received intravenous polymyxin B for multi-drug-resistant Gram-negative bacterial infections were enrolled. A population PK model was developed using Phoenix NLME software. Monte Carlo simulations were performed to optimize regimens attaining the PK/PD target of AUC 24h /MIC >50 and target exposure of 50-100 mg‧h/L. Clinical efficacy and nephrotoxicity of polymyxin B treatment were also assessed. A total of 142 polymyxin B concentrations from 23 patients were available. A two-compartment model with first-order elimination was developed, and albumin was the significant covariate of PK parameters. However, albumin had only a slight effect on polymyxin B exposure. Simulation results indicated that two fixed regimens of 50 mg and 75 mg would be sufficient to reach the PK/PD targets when the minimum inhibitory concentrations was ≤0.5 mg/L. With the exception of 1.25 mg/kg for 58 kg, other weight-based regimens (1.25-1.5 mg/kg for 70 kg and 80 kg; twice daily) may result in at least 40% of predicted AUC ss,24h >100 mg‧h/L. In conclusion, fixed maintenance dosing of 50 mg and 75 mg for polymyxin B may maximize efficacy while balancing nephrotoxicity concerns for elderly patients., (Copyright © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration-time curve across 24 h at steady state (AUC ss,24 h ) threshold are still limited. This study aimed to examine exposure-response/toxicity relationship for polymyxin B to establish an AUC ss,24 h threshold in a real-world cohort of patients., Methods: Using a validated Bayesian approach to estimate AUC ss,24 h from two samples, AUC ss,24 h threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis., Results: A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUC ss,24 h thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUC ss,24 h of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16-30.25, P < 0.001) and AUC ss,24 h of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56-7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2-2.8 mg/L) with outcomes was similar to AUC ss,24 h ., Conclusions: For critically ill patients, AUC ss,24 h threshold of 50-100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing., (© 2022. The Author(s).)

Subtype H7 avian influenza A viruses (IAVs) are enzootic in wild aquatic birds and have caused sporadic spillovers into domestic poultry and humans. Here, we determined the distribution of fucosylated α2,3 sialoglycan (i.e., sialyl Lewis X [SLe X ]) in chickens and five common dabbling duck species and the association between SLe X and cell/tissue/host tropisms of H7 IAVs. Receptor binding analyses showed that H7 IAVs bind to both α2,3-linked (SA2,3Gal) and α2,6-linked sialic acids (SA2,6Gal), but with a higher preference for SLe X ; H7 IAVs replicated more efficiently in SLe X -overexpressed than SLe X -deficient MDCK cells. While chickens and all tested dabbling ducks expressed abundant SA2,3Gal and SA2,6Gal, SLe X was detected in both respiratory and gastrointestinal tissues of chickens and mallard ducks and in only the respiratory tissues of gadwall, green-wing teal, and northern shoveler but not in wood ducks. Viral-tissue binding assays showed that H7 IAVs bind to chicken colon crypt cells that express SLe X but fewer bind to mallard colon crypt cells, which do not express SLe X ; H7 IAVs bind efficiently to epithelial cells of all tissues expressing SA2,3Gal. High viral replication was identified in both chickens and mallards infected with an H7 virus, regardless of SLe X expression, and viruses were detected in all cells to the same degree as viruses detected in the viral-tissue binding assays. In summary, this study suggests that SLe X facilitates infection of H7 viruses, but other types of SA2,3Gal glycan receptors shape the tissue/host tropisms of H7 IAVs. IMPORTANCE In addition to causing outbreaks in domestic poultry, subtype H7 IAVs can cause sporadic spillover infections in lower mammals and humans. In this study, we showed that SLe X expression varies among wild dabbling ducks. Although it facilitated virus binding and affected infection of H7 IAV in cells, SLe X expression is not the only determinant of viral replication at either the tissue or host level. This study suggested that access to heterologous SA2,3Gal glycan receptors, including fucosylated α2,3-linked sialoglycans, shape tissue and host tropism of H7 IAVs in aquatic wild birds.