Bismuth-based mesoporous nanoball carrying sorafenib for synergistic photothermal and molecularly-targeted therapy in an orthotopic hepatocellular carcinoma xenograft mouse model.

Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), has limited clinical application due to severe side effects and drug resistance. To overcome these challenges, we developed a bismuth-based nanomaterial (BOS) for thermal injury-assisted continuous targeted therapy in HCC. Initially, the mesoporous nanomaterial was loaded with SOR, forming the BOS@SOR nano-carrier system for drug delivery and controlled release. Notably, compared to targeted or photothermal therapy alone, the combination therapy using this nano-carrier system significantly impaired cell proliferation and increased apoptosis. In vivo efficacy evaluations demonstrated that BOS@SOR exhibited excellent biocompatibility, confirmed through hemolysis and biochemical analyses. Additionally, BOS@SOR enhanced contrast in computed tomography, aiding in the precise identification of HCC size and location. The photothermal therapeutic properties of bismuth further contributed to the synergistic anti-tumor activity of BOS@SOR, significantly reducing tumor growth in an orthotopic xenograft HCC model. Taken together, encapsulating SOR within a bismuth-based mesoporous nanomaterial creates a multifunctional and environmentally stable nanocomposite (BOS@SOR), enhancing the therapeutic effect of SOR and presenting an effective strategy for HCC treatment.

Establishment of goat mammary organoid cultures modeling the mammary gland development and lactation.

BACKGROUND: Although several cell culture systems have been developed to investigate the function of the mammary gland in dairy livestock, they have potential limitations, such as the loss of alveolar structure or genetic and phenotypic differences from their native counterparts. Overcoming these challenges is crucial for lactation research. Development of protocols to establish lactating organoid of livestock represents a promising goal for the future. In this study, we developed a protocol to establish a culture system for mammary organoids in dairy goats to model the mammary gland development and lactation process. RESULTS: The organoids cultured within an extracellular matrix gel maintained a bilayer structure that closely resembled the native architecture of mammary tissue. The expansion of mammary organoids was significantly promoted by growth factors containing epidermal growth factor and fibroblast growth factor 2 whereas the proliferative index of the organoids was significantly inhibited by the treatment with WNT inhibitors. Upon stimulation with a lactogenic medium containing prolactin, the mammary organoids exhibited efficient lactation, characterized by the accumulation of lipid droplets in the lumen space. The lactation could be sustained for more than 3 weeks. Importantly, the expression patterns of genes related to fatty acid synthesis and milk proteins in lactating organoids closely mirrored those observed in mammary tissues. These observations were confirmed by data from proteomic analysis that the bulk of milk proteins was produced in the lactating organoids. CONCLUSION: This study is the first to establish a mammary organoid culture system modeling the mammary gland development and lactation process in ruminants. The efficient induction of lactation in ruminant mammary organoids holds promises for advancing the field of cell-based milk bio-manufacture in the food industry.

High sensitivity distinguishing detection of fluoroquinolones with a cage-based lanthanide metal-organic framework in food.

Sensitive and selective detection of fluoroquinolones, especially from different sources, is challenging. This study reported an uncommon three-cage lanthanide metal-organic framework (1-Eu) with a Eu3+ cluster as its structural primitive using a C2-symmetric 5,5-(Pyrazine-2,6-diyl) diisophthalic acid ligand. The 1-Eu probe effectively detected four fluoroquinolones through distinct color changes and spectral emission bands, demonstrating excellent performance with low detection limits: moxifloxacin (LOD: 9.3 nM), danofloxacin (LOD: 33.7 nM), gatifloxacin (LOD: 67.9 nM), and ofloxacin (LOD: 238.6 nM). Mechanistic studies revealed that internal filtration and photoinduced electron transfer (a-PET) effects were key factors. Furthermore, 1-Eu was successfully used to detect fluoroquinolones in food samples. Additionally, portable paper-based sensors were developed to quickly semi-quantify analyte concentrations using a smartphone color recognition app, underscoring the practical potential of this probe. This study introduces a novel methodology for the identification and detection of fluoroquinolones to enhance food safety.

Functional Bidirectionality of ERV-Derived Long Non-Coding RNAs in Humans.

Human endogenous retroviruses (HERVs) are widely recognized as the result of exogenous retroviruses infecting the ancestral germline, stabilizing integration and vertical transmission during human genetic evolution. To date, endogenous retroviruses (ERVs) appear to have been selected for human physiological functions with the loss of retrotransposable capabilities. ERV elements were previously regarded as junk DNA for a long time. Since then, the aberrant activation and expression of ERVs have been observed in the development of many kinds of human diseases, and their role has been explored in a variety of human disorders such as cancer. The results show that specific ERV elements play respective crucial roles. Among them, long non-coding RNAs (lncRNAs) transcribed from specific long-terminal repeat regions of ERVs are often key factors. lncRNAs are over 200 nucleotides in size and typically bind to DNA, RNA, and proteins to perform biological functions. Dysregulated lncRNAs have been implicated in a variety of diseases. In particular, studies have shown that the aberrant expression of some ERV-derived lncRNAs has a tumor-suppressive or oncogenic effect, displaying significant functional bidirectionality. Therefore, theses lncRNAs have a promising future as novel biomarkers and therapeutic targets to explore the concise relationship between ERVs and cancers. In this review, we first summarize the role of ERV-derived lncRNAs in physiological regulation, mainly including immunomodulation, the maintenance of pluripotency, and erythropoiesis. In addition, pathological regulation examples of their aberrant activation and expression leading to carcinogenesis are highlighted, and specific mechanisms of occurrence are discussed.

Liquid Metal-Based Elastomer Composite with Selective Switchable Adhesion to Solids.

Selective switchable adhesion has recently attracted much attention due to its wide applications in transfer printing, information transfer, and flexible electronics. However, selective adhesive materials often have a complex adhesion or preparation process, which limits their use. To overcome this problem, this study prepares a composite of liquid metal foam and polydimethylsiloxane (PDMS) with selective photocontrolled adhesion, which can directly adhere to solids at room temperature. Utilizing the photoinduced phase transition of liquid metals, solid adhesion can be regulated by changing the backing layer modulus of the adhesive layer. Since the phase transition process is gradually completed by heat transfer from the illuminated side to the backlight side that adheres to the solid, the melting area on the backlight side can be regulated by controlling the light time, which determines the adhesion regulation area. Therefore, the accuracy of the adhesion regulation can reach less than 0.9 mm without relying on the accuracy of the infrared light. Moreover, based on the selective switchable adhesion, the selective transfer of solids with different scales can be achieved at room temperature. The findings of this study may provide strategies for the simple preparation of selective adhesive materials and the improvement of control accuracy.

Impacts of government social media on public engagement in low-carbon practices focusing on Japan.

This study investigates the role of Government Social Media (GSM) in enhancing public engagement with Low-Carbon Practices (LCP) in Japan. Motivated by the need to foster sustainable development and mitigate climate change impacts, this research utilizes negative binomial regression model analyzing 1022 posts from nine Japanese government social media accounts. Our findings reveal that increased media richness negatively correlates with engagement, suggesting that content depth over visual appeal is more effective for LCP-related communication. Surprisingly, the dialogic loop reduces engagement, indicating complex public reactions to governmental initiatives. Content themes related to governmental actions and LCP information significantly enhance engagement, while emotional valence shows minimal impact. The study introduces 'social media capital' as a moderating factor, which mitigates the negative effects of dialogic loops and media richness on engagement, and influences the impact of content themes. These insights provide a foundation for future research and guide the development of effective public engagement strategies in environmental policy. The study highlights the need for nuanced GSM strategies that prioritize information quality and relevance to increase public participation in low-carbon initiatives.

Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment.

Cereblon (CRBN) has been successfully co-opted to affect the targeted degradation of "undruggable" proteins with immunomodulatory imide drugs (IMiDs). IMiDs act as molecule glues that facilitate ternary complex formation between CRBN and a target protein, leading to ubiquitination and proteasomal degradation. Subtle structural modifications often cause profound and sometimes unpredictable changes in the degradation selectivity. Herein, we successfully utilize enantioselective cyclopropanation and cyclopropenation on intact glutarimides to enable the preparation of stereochemically and regiochemically matched molecular pairs for structure-activity relationship (SAR) analysis across several classical CRBN neosubstrates. The resulting glutarimide analogs were found to reside in unique chemical space when compared to other IMiDs in the public domain. SAR studies revealed that, in addition to the more precedented impacts of regiochemistry, stereochemical modifications far from the glutarimide can lead to divergent neosubstrate selectivity. These findings emphasize the importance of enabling enantioselective methods for glutarimide-containing compounds to tune the degradation selectivity.

Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives.

Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1-2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15-20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10-40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.

Association Between Proton Pump Inhibitor Use and Overactive Bladder Risk in Adults: A Cross-sectional Study.

OBJECTIVE: To investigate the association between the use of proton pump inhibitors (PPIs) and overactive bladder (OAB) in adults. METHODS: This study adopts a cross-sectional approach to scrutinize data derived from the National Health and Nutrition Examination Survey (NHANES), spanning from 2007 to 2018. It employs multivariable logistic regression along with restricted cubic splines (RCS) to investigate the relationship between the use of PPI and the incidence of OAB. Additionally, through interaction and stratification analyses, the study delves into how specific factors may influence this correlation. RESULTS: A total of 24,458 adults participated in this study. Individuals using PPIs exhibited higher rates of nocturia, urge incontinence, and OAB compared to non-users. After full adjustment, PPI users had a significantly increased risk of developing OAB (OR=1.36, 95%CI: 1.17-1.60). Moreover, with each year of continued PPI usage, the frequency of OAB symptoms escalated by 3% (P = .01). Further examinations within various subgroups maintained a uniform direction in these effect estimates. CONCLUSION: The findings of this research highlight a noteworthy positive link between the use of PPIs and the emergence of OAB among adults. Moreover, it was observed that an extended period of using PPIs correlates with a heightened likelihood of encountering OAB.

Caring through uncertainty: a qualitative exploration of older colorectal cancer caregivers' experiences during palliative chemotherapy.

PURPOSE: Despite the increasing research on cancer patient caregivers, there is still a lack of detailed understanding about the experiences of spouses caring for elderly colorectal cancer patients. This study aimed to fill this gap by examining the caregiving experiences of spouses during palliative chemotherapy for elderly Chinese colorectal cancer patients. METHODS: Using a qualitative descriptive design, we recruited spousal caregivers of elderly colorectal cancer patients undergoing palliative chemotherapy. Semistructured interviews were conducted, and thematic analysis was employed to analyse the data. RESULTS: Sixteen caregivers aged 60 to 82 years participated in the interviews. The analysis revealed three main themes: ambivalence, multiple role adaptation to conflicts, and the coexistence of hope and pressure. These themes shed light on the behaviors of older caregivers and the challenges they face, including physical and psychosocial issues associated with aging. CONCLUSION: This study highlights the significant stress and challenges experienced by older caregivers, characterized by intertwined emotions such as anxiety about their spouses' health deterioration, exhaustion from long-term care responsibilities, and anticipation of treatment outcomes.

Rotavirus outbreaks in China, 1982-2021: a systematic review.

Background: Rotavirus is globally recognized as an important cause of acute gastroenteritis in young children. Whereas previous studies focused more on sporadic diarrhea, the epidemiological characteristics of rotavirus outbreaks have not been systematically understood. Methods: This systematic review was carried out according to the Preferred Reporting Items for Systematic Review and Meta-Analysis standards, WANFANG, China National Knowledge Infrastructure (CNKI), PubMed, and Web of Science databases were searched from database inception to February 20, 2022. We used SPSS 21.0 statistical software for data analysis, RStudio1.4.1717, and ArcGIS trial version for plotting bar graphs and maps. Results: Among 1,596 articles, 78 were included, with 92 rotavirus outbreaks and 96,128 cases. Most outbreaks (67.39%, 62/92) occurred in winter and spring. The number of rotavirus outbreaks reported in the eastern region was more than that in the western region. Outbreaks were most commonly reported in villages (33/92, 35.87%), followed by hospitals (19, 20.65%). The outbreak duration was longer in factories and workers' living places, and villages, while it was shorter in hospitals. Waterborne transmission was the main transmission mode, with the longest duration and the largest number of cases. Rotavirus groups were identified in 66 outbreaks, with 40 outbreaks (60.61%) caused by Group B rotaviruses and 26 outbreaks (39.39%) caused by Group A rotaviruses. Significant differences were found in duration, number of cases, settings, population distribution, and transmission modes between Groups A and B rotavirus outbreaks. Conclusion: Rotavirus is an important cause of acute gastroenteritis outbreaks in China. It should also be considered in the investigation of acute gastroenteritis outbreaks, especially norovirus-negative outbreaks.

Risk Factors for Norovirus Outbreaks in Schools and Kindergartens - Beijing Municipality, China, July 2017-June 2022.

What is already known on this topic?: Norovirus is the leading cause of global acute gastroenteritis outbreaks. Norovirus outbreaks mainly occur in schools and kindergartens in China, always causing public health issues. What is added by this report?: Conditional logistic regression method was used to analyze the risk factors for norovirus outbreaks in schools and kindergartens, and found that students vomiting at school or kindergarten, case activity in public areas, and the first case's classroom less than 5 meters from toilets were risk factors. What are the implications for public health practice?: Effective measures to address these factors can help reduce the risk of norovirus outbreaks in schools and kindergartens.

Manipulation of host phagocytosis by fungal pathogens and therapeutic opportunities.

An important host defence mechanism against pathogens is intracellular killing, which is achieved through phagocytosis, a cellular process for engulfing and neutralizing extracellular particles. Phagocytosis results in the formation of matured phagolysosomes, which are specialized compartments that provide a hostile environment and are considered the end point of the degradative pathway. However, all fungal pathogens studied to date have developed strategies to manipulate phagosomal function directly and also indirectly by redirecting phagosomes from the degradative pathway to a non-degradative pathway with the expulsion and even transfer of pathogens between cells. Here, using the major human fungal pathogens Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum as examples, we discuss the processes involved in host phagosome-fungal pathogen interactions, with a focus on fungal evasion strategies. We also discuss recent approaches to targeting intraphagosomal pathogens, including the redirection of phagosomes towards degradative pathways for fungal pathogen eradication.

Application of Mechanistic Multiparameter Optimization and Large-Scale In Vitro to In Vivo Pharmacokinetics Correlations to Small-Molecule Therapeutic Projects.

Computational chemistry and machine learning are used in drug discovery to predict the target-specific and pharmacokinetic properties of molecules. Multiparameter optimization (MPO) functions are used to summarize multiple properties into a single score, aiding compound prioritization. However, over-reliance on subjective MPO functions risks reinforcing human bias. Mechanistic modeling approaches based on physiological relevance can be adapted to meet different potential key objectives of the project (e.g., minimizing dose, maximizing safety margins, and/or minimizing drug-drug interaction risk) while retaining the same underlying model structure. The current work incorporates recent approaches to predict in vivo pharmacokinetic (PK) properties and validates in vitro to in vivo correlation analysis to support mechanistic PK MPO. Examples of use and impact in small-molecule drug discovery projects are provided. Overall, the mechanistic MPO identifies 83% of the compounds considered as short-listed for clinical experiments in the top second percentile, and 100% in the top 10th percentile, resulting in an area under the receiver operating characteristic curve (AUCROC) > 0.95. In addition, the MPO score successfully recapitulates the chronological progression of the optimization process across different scaffolds. Finally, the MPO scores for compounds characterized in pharmacokinetics experiments are markedly higher compared with the rest of the compounds being synthesized, highlighting the potential of this tool to reduce the reliance on in vivo testing for compound screening.

Recent progress in lanthanide-based fluorescent nanomaterials for tetracycline detection and removal.

Tetracycline (TC) has been widely used in clinical medicine and animal growth promotion due to its broad-spectrum antibacterial properties and affordable prices. Unfortunately, the high toxicity and difficult degradation rate of TC molecules make them easy to accumulate in the environment, which breaks the ecological balance and seriously threatens human health. Rapid and accurate detection of TC residue levels is important for ensuring water quality and food safety. Recently, fluorescence detection technology of TC residues has developed rapidly. Lanthanide nanomaterials, based on the high luminescence properties of lanthanide ions and the high matching with TC energy levels, are favored in the real-time trace detection of TC due to their advantages of high sensitivity, rapidity, and high selectivity. Therefore, they are considered potential substitutes for traditional detection methods. This review summarizes the synthesis strategy, TC response mechanism, removal mechanism, and applications in intelligent sensing. Finally, the development of lanthanide nanomaterials for TC fluorescence detection and removal is reasonably summarized and prospected. This review provides a reference for the establishment of a method for the accurate determination of TC content in complex food matrices.

Identification of novel covalent JAK3 inhibitors through consensus scoring virtual screening: integration of common feature pharmacophore and covalent docking.

Accumulated research strongly indicates that Janus kinase 3 (JAK3) is intricately involved in the initiation and advancement of a diverse range of human diseases, underscoring JAK3 as a promising target for therapeutic intervention. However, JAK3 shows significant homology with other JAK family isoforms, posing substantial challenges in the development of JAK3 inhibitors. To address these limitations, one strategy is to design selective covalent JAK3 inhibitors. Therefore, this study introduces a virtual screening approach that combines common feature pharmacophore modeling, covalent docking, and consensus scoring to identify novel inhibitors for JAK3. First, common feature pharmacophore models were constructed based on a selection of representative covalent JAK3 inhibitors. The optimal qualitative pharmacophore model proved highly effective in distinguishing active and inactive compounds. Second, 14 crystal structures of the JAK3-covalent inhibitor complex were chosen for the covalent docking studies. Following validation of the screening performance, 5TTU was identified as the most suitable candidate for screening potential JAK3 inhibitors due to its higher predictive accuracy. Finally, a virtual screening protocol based on consensus scoring was conducted, integrating pharmacophore mapping and covalent docking. This approach resulted in the discovery of multiple compounds with notable potential as effective JAK3 inhibitors. We hope that the developed virtual screening strategy will provide valuable guidance in the discovery of novel covalent JAK3 inhibitors.

A Palladium-Containing Polyoxotungstate with Anisotropic Proton Conductivity.

Here, a case of bilayer heterojunction Pd-containing polyoxotungstate (POW), connecting a Te3Pd3 ring and an Anderson-like TeW6 cluster, has been synthesized. The Anderson-like cluster is the first example in POW. The coordination of Pd in the ring with the S atom on the sulfo group breaks the traditional coordination configuration of Pd and O in polyoxometalates (POMs), enriching the structural types of Pd-containing POMs. In addition, the hybrid bilayer heterojunction structure at the molecular level not only provides high thermal stability but also results in spatial arrangement anisotropy, leading to up to five times the anisotropic proton conductivity.

Estimating the contribution of setting-specific contacts to SARS-CoV-2 transmission using digital contact tracing data.

While many countries employed digital contact tracing to contain the spread of SARS-CoV-2, the contribution of cospace-time interaction (i.e., individuals who shared the same space and time) to transmission and to super-spreading in the real world has seldom been systematically studied due to the lack of systematic sampling and testing of contacts. To address this issue, we utilized data from 2230 cases and 220,878 contacts with detailed epidemiological information during the Omicron outbreak in Beijing in 2022. We observed that contact number per day of tracing for individuals in dwelling, workplace, cospace-time interactions, and community settings could be described by gamma distribution with distinct parameters. Our findings revealed that 38% of traced transmissions occurred through cospace-time interactions whilst control measures were in place. However, using a mathematical model to incorporate contacts in different locations, we found that without control measures, cospace-time interactions contributed to only 11% (95%CI: 10%-12%) of transmissions and the super-spreading risk for this setting was 4% (95%CI: 3%-5%), both the lowest among all settings studied. These results suggest that public health measures should be optimized to achieve a balance between the benefits of digital contact tracing for cospace-time interactions and the challenges posed by contact tracing within the same setting.

Adherence with oral nutritional supplements and influencing factors in postoperative patients with digestive tract tumors: a cross-sectional study.

OBJECTIVE: This study aims to use structural equation modeling to explore the pathways and effect sizes of factors influencing the adherence of postoperative patients with digestive tract tumor to oral nutritional supplements, providing a theoretical basis for future nursing intervention measures. METHODS: A total of 300 postoperative patients with digestive tract tumor within 30 days after surgery were conveniently sampled. Surveys were conducted using a General Information Questionnaire, Morisky Medication Adherence Scale, Digestive System Tumor Patient Nutrition Knowledge-Attitude-Behavior Questionnaire, Multidimensional Social Perception Scale, Beliefs about Medical Questionnaire, and General Self-Efficacy Scale. Structural equation modeling was employed to analyze the factors and pathways affecting adherence with oral nutritional supplements. RESULTS: The adherence score of postoperative patients with digestive tract tumor to oral nutritional supplements was 1.61 ± 1.38. The structural equation model had a good fit (χ2/df = 2.685, GFI = 0.930, CFI = 0.913, AGFI = 0.887, IFI = 0.915, and RMSEA = 0.075). Nutrition knowledge, social support, medication beliefs, and self-efficacy were found to be factors influencing adherence with oral nutritional supplements in postoperative patients with digestive tract tumor, with total effects of 0.539, 0.264, 0.215, and 0.180, respectively. Nutrition knowledge indirectly affected adherence through self-efficacy and medication beliefs, while social support indirectly affected adherence through self-efficacy. CONCLUSION: Adherence with oral nutritional supplements in postoperative patients with digestive tract tumor is at a low level. Improving social support, enhancing patients nutrition knowledge, increasing self-efficacy, and strengthening medication beliefs are effective ways to improve patient adherence.