Bile acids promote the caveolae-associated entry of swine acute diarrhea syndrome coronavirus in porcine intestinal enteroids.

Intestinal microbial metabolites have been increasingly recognized as important regulators of enteric viral infection. However, very little information is available about which specific microbiota-derived metabolites are crucial for swine enteric coronavirus (SECoV) infection in vivo. Using swine acute diarrhea syndrome (SADS)-CoV as a model, we were able to identify a greatly altered bile acid (BA) profile in the small intestine of infected piglets by untargeted metabolomic analysis. Using a newly established ex vivo model-the stem cell-derived porcine intestinal enteroid (PIE) culture-we demonstrated that certain BAs, cholic acid (CA) in particular, enhance SADS-CoV replication by acting on PIEs at the early phase of infection. We ruled out the possibility that CA exerts an augmenting effect on viral replication through classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling, innate immune suppression or viral attachment. BA induced multiple cellular responses including rapid changes in caveolae-mediated endocytosis, endosomal acidification and dynamics of the endosomal/lysosomal system that are critical for SADS-CoV replication. Thus, our findings shed light on how SECoVs exploit microbiome-derived metabolite BAs to swiftly establish viral infection and accelerate replication within the intestinal microenvironment.

Estimating rainfall interception loss of three dominant shrub species in an oasis-desert ecotone using in situ measurements and the revised Gash analytical model.

Canopy interception loss affects the local water budget by removing a non-negligible proportion of rainfall from the terrestrial surface. Thus, quantifying interception loss is essential for thoroughly understanding the role of vegetation in the local hydrological cycle, especially in dryland ecosystems. However, sparse shrubs in dryland ecosystems have not been sufficiently studied, owing to time- and labor-intensive field experiments and challenging model parameterization. In this work, 4-year growing season field experiments on rainfall partitioning were conducted for three dominant shrub species (Haloxylon ammodendron, Nitraria sphaerocarpa, and Calligonum mongolicum) in an oasis-desert ecotone in northwestern China. The revised Gash analytical model was well parameterized, which reliably simulated the cumulative interception loss for sparse shrubs, and the validated model performed better for H. ammodendron, followed by C. mongolicum and N. sphaerocarpa, with relative errors of 8.4%, 15.4%, and 23.9%, respectively. The mean individual interception loss percentage for H. ammodendron (28.4%) was significantly higher than that for C. mongolicum (11.0%) and N. sphaerocarpa (10.9%) (p < 0.05), which could be ascribed to the higher canopy storage capacity and wet-canopy evaporation rate of H. ammodendron. For all shrub species, the majority proportion of interception loss occurred during canopy saturation and drying-out periods, accounting for approximately 79-85% of the cumulative interception loss. Overall, the mean local interception loss of three dominant shrub species in the ecotone removed nearly 17% of the corresponding cumulative rainfall during the growing season. These results not only provide methodological references for estimating the interception loss of sparse vegetation in dryland ecosystems, but also provide scientific insights for water resource management and ecosystem restoration in water-limited regions similar to the experimental site.

Transient Receptor Potential Melastatin 2 Thermosensitive Neurons in the Preoptic Area Involved in Menopausal Hot Flashes in Ovariectomized Mice.

INTRODUCTION: Menopausal hot flashes are related to hypothalamic preoptic area (POA) dysfunction. Thermosensitive transient receptor potential channels (ThermoTRPs) are involved in temperature sensing and regulation of thermosensitive neurons (TSNs) in the POA. Whether ThermoTRP-TSNs in the POA, particularly the non-noxious thermoreceptor, transient receptor potential melastatin 2 (TRPM2), are involved in the occurrence of hot flashes is still unclear. METHODS: Twenty wild-type and 50 Trpm2-Cre adult female mice were randomly divided into sham (SHAM) and ovariectomy (OVX) groups. In the POA, ERα, ERß, GPR30, TRPA1, TRPM8, TRPM2, and TRPV1 expression was detected by Western blot or/and quantitative real-time polymerase chain reaction and the number of TSNs expressing TRPM2 (TRPM2-TSNs) by immunofluorescence. Before and after TRPM2-TSN activation/inhibition, back (BST) and tail skin temperature (TST) and the proportion of glutamatergic and GABAergic neurons among TRPM2-TSNs were recorded. RESULTS: Compared with SHAM, the expression of ERα, ERß, TRPM2, and TRPM8 in the POA of the OVX group decreased, with a significantly larger change range for TRPM2 than TRPM8. In addition, the number of TRPM2-TSNs showing TRPA1, TRPM8, and TRPV1 expression in the OVX group decreased, and the proportion of glutamatergic and GABAergic neurons in TRPM2-TSNs decreased and increased, respectively. Meanwhile, BST and TST increased. After activating or inhibiting TRPM2-TSNs, the proportions of glutamatergic and GABAergic neurons in TRPM2-TSNs changed, along with the BST and TST. CONCLUSION: In menopause, the abnormal quantity and function of TRPM2-TSNs in the POA is key for the development of hot flashes, characterized by an imbalance in heat dissipation and production due to the corresponding imbalance in glutamatergic and GABAergic neurons.

Borneol in cardio-cerebrovascular diseases: Pharmacological actions, mechanisms, and therapeutics.

With the coming acceleration of global population aging, the incidence rate of cardio-cerebrovascular diseases (CVDs) is increasing. It has become the leading cause of human mortality. As a natural drug, borneol (BO) not only has anti-inflammatory, anti-oxidant, anti-apoptotic, anti-coagulant activities and improves energy metabolism but can also promote drugs to enter the target organs or tissues through various physiological barriers, such as the blood-brain barrier (BBB), mucous membrane, skin. Thus, it has a significant therapeutic effect on various CVDs, which has been confirmed in a large number of studies. However, the pharmacological actions and mechanisms of BO on CVDs have not been fully investigated. Hence, this review summarizes the pharmacological actions and possible mechanisms of BO, which provides novel ideas for the treatment of CVDs.

Are the shoreline and eutrophication of desert lakes related to desert development?

Desert lakes are unique ecosystems found in oases within desert landscapes. Despite the numerous studies on oases, there are no reports regarding the spatiotemporal distribution and causes of eutrophication in the desert lakes that are located at the edge of the Linze Oasis in northwestern China. In this study, the seasonal shoreline and eutrophication of a desert lake were monitored using an unmanned aerial vehicle (UAV) and water sampling during three crop growth stages. The spatial extents of the shoreline and algal blooms and the chromophoric dissolved organic matter (CDOM) absorption coefficient were derived through UAV images. The desert lake shoreline declined during the crop growing stage, which exhibited the largest water demand and began to expand after this stage. The estimated CDOM absorption coefficient measurements and classified algal bloom area showed seasonal variations that increased from spring to late summer and then decreased in autumn. The first two crop growth stages accounted for most of the water and fertilizer requirements of the entire growth period, which may have contributed to large amounts of groundwater consumption and pollution and resulted in peak eutrophication of the lake in the second growth stage. However, the CDOM absorption coefficient of the third stage was not well correlated with that of the first two stages, suggesting that the lake may be affected by the dual effects of groundwater and precipitation recharge in the third stage. These results indicate that the water quality of desert lakes may be affected by agricultural cultivation. The agricultural demands for water and fertilizer may change the spatiotemporal changes in water quality in the lake, especially in the middle and early stages of crop growth.

Nose to brain drug delivery - A promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion.

Cerebral ischemia reperfusion injury (CIRI), one of the major causes of death from stroke in the world, not only causes tremendous damage to human health, but also brings heavy economic burden to society. Current available treatments for CIRI, including mechanical therapies and drug therapies, are often accompanied by significant side-effects. Therefore, it is necessary to discovery new strategies for treating CIRI. Many studies have confirmed that the herbal medicine has the advantages of abundant resources, good curative effect and little side effects, which can be used as potential drug for treatment of CIRI through multiple targets. It's known that oral administration commonly has low bioavailability, and injection administration is inconvenient and unsafe. Many drugs can't delivery to brain through routine pathways due to the blood-brain-barrier (BBB). Interestingly, increasing evidences have suggested the nasal administration is a potential direct route to transport drug into brain avoiding the BBB and has the characteristics of high bioavailability for treating brain diseases. Therefore, intranasal administration can be treated as an alternative way to treat brain diseases. In the present review, effective methods to treat CIRI by using active ingredients derived from herbal medicine through nose to brain drug delivery (NBDD) are updated and discussed, and some related pharmacological mechanisms have also been emphasized. Our present study would be beneficial for the further drug development of natural agents from herbal medicines via NBDD.

The imbalance in the aortic ceramide/sphingosine-1-phosphate rheostat in ovariectomized rats and the preventive effect of estrogen.

BACKGROUND: The prevalence of hypertension in young women is lower than that in age-matched men while the prevalence of hypertension in women is significantly increased after the age of 50 (menopause) and is greater than that in men. It is already known that sphingosine-1-phosphate (S1P) and ceramide regulate vascular tone with opposing effects. This study aimed to explore the effects of ovariectomy and estrogen supplementation on the ceramide/S1P rheostat of the aorta in rats, and to explore a potential mechanism for perimenopausal hypertension and a brand-new target for menopausal hormone therapy to protect vessels. METHODS: In total, 30 female adult SD rats were randomly divided into three groups: The sham operation group (SHAM), ovariectomy group (OVX) and ovariectomy plus estrogen group (OVX + E). After 4 weeks of treatment, the blood pressure (BP) of the rats was monitored by a noninvasive system; the sphingolipid content (e.g., ceramide and S1P) was detected by liquid chromatography-mass spectrometry (LC-MS); the expression of the key enzymes involved in ceramide anabolism and catabolism was measured by real-time fluorescence quantitative polymerase chain reaction (qPCR); and the expression of key enzymes and proteins in the sphingosine kinase 1/2 (SphK1/2)-S1P-S1P receptor 1/2/3 (S1P1/2/3) signaling pathway was detected by qPCR and western blotting. RESULTS: In the OVX group compared with the SHAM group, the systolic BP (SBP), diastolic BP (DBP) and pulse pressure (PP) increased significantly, especially the SBP and PP (P < 0.001). For aortic ceramide metabolism, the mRNA level of key enzymes involved in anabolism and catabolism decreased in parallel 2-3 times, while the contents of total ceramide and certain long-chain subtypes increased significantly (P < 0.05). As for the S1P signaling pathway, SphK1/2, the key enzymes involved in S1P synthesis, decreased significantly, and the content of S1P decreased accordingly (P < 0.01). The S1P receptors showed various trends: S1P1 was significantly down-regulated, S1P2 was significantly up-regulated, and S1P3 showed no significant difference. No significant difference existed between the SHAM and OVX + E groups for most of the above parameters (P > 0.05). CONCLUSIONS: Ovariectomy resulted in the imbalance of the aortic ceramide/S1P rheostat in rats, which may be a potential mechanism underlying the increase in SBP and PP among perimenopausal women. Besides, the ceramide/S1P rheostat may be a novel mechanism by which estrogen protects vessels.

Baicalin Liposome Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice via Inhibiting TLR4/JNK/ERK/NF-κB Pathway.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are challenging diseases with the high mortality in a clinical setting. Baicalin (BA) is the main effective constituent isolated from the Chinese medical herb Scutellaria baicalensis Georgi, and studies have proved that it has a protective effect on ALI induced by lipopolysaccharide (LPS) due to the anti-inflammatory efficacy. However, BA has low solubility which may limit its clinical application. Hence, we prepared a novel drug delivery system-Baicalin liposome (BA-LP) in previous research-which can improve some physical properties of BA. Therefore, we aimed to explore the effect of BA-LP on ALI mice induced by LPS. In pharmacokinetics study, the values of t 1/2 and AUC0- t in the BA-LP group were significantly higher than that of the BA group in normal mice, indicating that BA-LP could prolong the duration time in vivo of BA. The BA-LP group also showed a higher concentration in lung tissues than the BA group. Pharmacodynamics studies showed that BA-LP had a better effect than the BA group at the same dosage on reducing the W/D ratio, alleviating the lung injury score, and decreasing the proinflammatory factors (TNF-α, IL-1ß) and total proteins in bronchoalveolar lavage fluids (BALF). In addition, the therapeutic effects of BA-LP showed a dose-dependent manner. Western blot analysis indicated that the anti-inflammatory action of BA could be attributed to the inhibition of the TLR4-NFκBp65 and JNK-ERK signaling pathways. These results suggest that BA-LP could be a valuable therapeutic candidate in the treatment of ALI.

Furan formation from ingredient interactions and furan mitigation by sugar alcohols and antioxidants of bamboo leaves in milk beverage model systems.

BACKGROUND: Furan is a potential carcinogen that can be formed in various heat-treated foods, including milk beverages. Studies on the formation and mitigation of furan in milk beverages are rare. In the present study, the effects of ingredients on furan formation and the reduction of furan by sugar alcohols and antioxidants of bamboo leaves (AOB) were investigated in a milk beverage model system. RESULTS: The results obtained demonstrated that the Maillard reaction is the major pathway for furan formation in a milk beverage model system, and the type of sugar has a great influence on furan formation. High fructose corn syrup (HFCS 55) was more favorable for furan formation than sucrose. Thermal oxidation of ascorbic acid and lipids significantly enhanced furan generation. Xylitol, sorbitol and mannitol inhibited furan formation in model systems by replacing sucrose or HFCS. The maximum inhibition percentage of furan formation was observed when sucrose/HFCS was substituted completely by xylitol and the inhibition rate was 78.28% and 88.64% separately for the sucrose/HFCS-containing system. AOB significantly inhibited furan formation and the inhibition rate reached 32.13% and 28.52% separately for the sucrose/HFCS-containing system. CONCLUSION: The present study demonstrates that the use of sugar alcohols and AOB could be a feasible way of reducing furan formation in thermally processed milk beverages. © 2019 Society of Chemical Industry.

Extensive investigation of the sap flow of maize plants in an oasis farmland in the middle reach of the Heihe River, Northwest China.

A better understanding of the sap flow characteristics of maize plants is critical for improving irrigation water-use efficiency, especially for regions facing water resource shortages. In this study, sap flow rates, related soil-physics and plant-growth parameters, and meteorological factors, were simultaneously monitored in a maize field in two consecutive years, 2011 and 2012, and the sap flow rates of the maize plants were extensively analyzed based on the monitored data. Seasonal and daily variational characteristics were identified at different growth stages and under different weather conditions, respectively. The analyses on the relationships between sap flow rate and reference evapotranspiration (ET0), as well as several plant-growth parameters, indicate that the irrigation schedule can exert an influence on sap flow, and can consequently affect crop yield. The ranking of the main meteorological factors affecting the sap flow rate was: net radiation > air temperature > vapor pressure deficit > wind speed. For a quick estimation of sap flow rates, an empirical formula based on the two top influencing factors was put forward and verified to be reliable. The sap flow rate appeared to show little response to irrigation when the water content was relatively high, implying that some of the irrigation in recent years may have been wasted. These results may help to reveal the bio-physical processes of maize plants related to plant transpiration, which could be beneficial for establishing an efficient irrigation management system in this region and also for providing a reference for other maize-planting regions.

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review.

Fibroblast-like synoviocytes (FLS) are important components of the synovial membrane. They can contribute to joint damage through crosstalk with inflammatory cells and direct actions on tissue damage pathways in rheumatoid arthritis (RA). Recent evidence suggests that, compared with FLS in normal synovial tissue, FLS in RA synovial tissue exhibits significant differences in metabolism. Recent metabolomic studies have demonstrated that metabolic changes, including those in glucose, lipid, and amino acid metabolism, exist before synovitis onset. These changes may be a result of increased biosynthesis and energy requirements during the early phases of the disease. Activated T cells and some cytokines contribute to the conversion of FLS into cells with metabolic abnormalities and pro-inflammatory phenotypes. This conversion may be one of the potential mechanisms behind altered FLS metabolism. Targeting metabolism can inhibit FLS proliferation, providing relief to patients with RA. In this review, we aimed to summarize the evidence of metabolic changes in FLS in RA, analyze the mechanisms of these metabolic alterations, and assess their effect on RA phenotype. Finally, we aimed to summarize the advances and challenges faced in targeting FLS metabolism as a promising therapeutic strategy for RA in the future.

Improving water resistance and mechanical properties of starch-based films by incorporating microcrystalline cellulose in a dynamic network structure.

The widespread use of starch-based films is hindered by inadequate tensile strength and high water sensitivity. To address these limitations, a novel starch film with a dynamic network structure was produced via the dehydration-condensation reaction of N, N'-methylene diacrylamide (MBA) and microcrystalline cellulose (MCC). The improvement in mechanical properties was enhanced by the incorporation of MCC, which was achieved through intermolecular hydrogen bonding and chemical crosslinking. To verify the interactions among MCC, MBA, and starch, x-ray photoelectron spectroscopy (XPS), fourier transform infrared spectroscopy (FTIR), and x-ray diffraction (XRD) were conducted. The results established the predicted interactions. The dynamic network structure of the film reduced the water absorption capacity (WAC) of starch and MCC hydroxyl groups, as confirmed by differential scanning calorimeter (DSC) and dynamic mechanical thermal analysis (DMTA). These analyses showed a restriction in the mobility of starch chains, resulting in a higher glass transition temperature (Tg) of 69.26 °C. The modified starch films exhibited excellent potential for packaging applications, demonstrating a higher contact angle (CA) of 89.63°, the lowest WAC of 4.73 g/g, and the lowest water vapor transmission rate (WVTR) of 13.13 g/m2/d, along with improved mechanical properties and identical light transmittance compared to pure starch films.

Single-atom Mn-embedded carbon nitride as highly efficient peroxymonosulfate catalyst for the harmful algal blooms control.

In recent years, water quality deterioration caused by harmful algal blooms (HABs) has become one of the global drinking water safety issues, and sulfate radical driven heterogeneous advanced oxidation technology has been widely used for algae removal. However, the shortages of low active site exposure, metal leaching, and secondary contamination limit its further application. Therefore, the single-atom Mn anchored on inorganic carbon nitride was constructed to enhance the oxidation and coagulation of algal cells while maintaining cell integrity in this study. The removal efficiency of Microcystis aeruginosa was as high as 100 % within 30 min under the optimal conditions of 400 mg/L single-atom Mn-embedded g-C3N4 (SA-MCN) and 0.32 mM peroxymonosulfate (PMS). Importantly, the K+ release, malondialdehyde concentration, floccules morphology and variation of algal organic matters further showed that the algal cells still maintained high integrity without severe rupture during the catalytic reaction. Furthermore, the catalytic mechanisms of algae removal by moderate oxidation and simultaneous coagulation in this system were explored by quenching experiments, EPR analysis, theoretical calculation, and Zeta potential. In brief, this study highlighted the single-atom heterogeneous catalyst with high-efficiency and environmental-friendliness in harmful algal blooms control.

RPA-CRISPR-Cas13a-assisted detection method of transmissible gastroenteritis virus.

Background and aim: Transmissible gastroenteritis virus (TGEV) is a highly contagious gastrointestinal virus that causes diarrhea, vomiting, anorexia, dehydration, and weight loss in piglets. In clinical practice, it often occurs in mixed infections with other pathogens, and is therefore difficult to diagnose and prevent. It mainly harms piglets of about 2 weeks old, causing huge losses on farms. The clinical confirmation of TGEV usually requires a laboratory diagnosis, but traditional PCR and immunofluorescence assays have some limitations. Moreover, most farms in China are ill-equipped to accurately diagnose the disease. Therefore, a new detection method with high sensitivity and specificity and less dependence on instrumentation is required. Methods: We used recombinase polymerase amplification (RPA), combined with the nuclease characteristics of the activated Cas13a protein to establish a visual CRISPR-Cas13a-assisted detection method for TGEV by adding a reporter RNA with fluorescent and quenching moieties to the system. Result: We selected the optimal RPA primer and best CRISPR RNA (crRNA). The reaction system was optimized and its repeatability, specificity, and sensitivity verified. The TGEV detection system did not cross-react with other common diarrhea viruses, and its detection limit was 101 copies, which is similar with the sensitivity of qPCR. We successfully established an RPA-CRISPR-Cas13a-assisted detection method, and used this detection system to analyze 123 pig blood samples. qPCR was used as the gold standard method. The sensitivity, specificity, positive coincidence rate, and negative coincidence rate of the new method were 100, 98.93, 96.66, and 100%, respectively.

Progress of nanopreparation technology applied to volatile oil drug delivery systems.

Traditional Chinese medicine volatile oil has a long history and possesses extensive pharmacological activity. However, volatile oils have characteristics such as strong volatility, poor water solubility, low bioavailability, and poor targeting, which limit their application. The use of volatile oil nano drug delivery systems can effectively improve the drawbacks of volatile oils, enhance their bioavailability and chemical stability, and reduce their volatility and toxicity. This article first introduces the limitations of the components of traditional Chinese medicine volatile oils, discusses the main classifications and latest developments of volatile oil nano formulations, and briefly describes the preparation methods of traditional Chinese medicine volatile oil nano formulations. Secondly, the limitations of nano formulation technology are discussed, along with future challenges and prospects. A deeper understanding of the role of nanotechnology in traditional Chinese medicine volatile oils will contribute to the modernization of volatile oils and broaden their application value.

A simple method for microwave-assisted preparation of tire samples.

Heavy metals content in tires affects the safety of soil and agricultural products. The digestion method is a pretreatment for determining heavy metals in tire samples, and will affect the efficiency and accuracy of the heavy metal determination. The microwave digestion process and reagents for tire samples are not currently standardized. Therefore, this study attempts to provide an appropriate method of resolution for scholars. All digestion processes were performed in Mars One. We tested 15 different acid mixtures to determine the best reagent type and dose and then investigated the effect of maximum temperature, holding time, and sample grams on the degree of digestion. In summary, the best condition to digest the tire sample was a mixture of 3 ml HNO3 and 7 ml H2SO4, taking 0.1 (± 0.0005) g tire sample, at the maximum digestion temperature of 220 °C for 25 min. The experimental conclusion will provide a reliable experimental method for scientists using MARS One to study heavy metals in tires. At the same time, researchers using the MARS series can also find valuable references in this paper.

Construction of cubic CaTiO3 perovskite modified by highly-dispersed cobalt for efficient catalytic degradation of psychoactive pharmaceuticals.

Sulfate radical mediated advanced oxidation processes (SR-AOPs) have emerged as a promising alternative for emerging contaminants degradation. However, high activity and great stability are commonly difficult to juggle, and the structure-activity correlations are still ambiguous. This study constructed the cubic CaTiO3 perovskite modified by highly-dispersed cobalt for peroxymonosulfate (PMS) activation to improve the specific lattice plane exposure and reduce the metal leaching simultaneously. 98% of amitriptyline (AMT) degradation was achieved within 60 min under the condition of 200 mg/L Co0.1-CTO and 100 mg/L PMS. The results indicated that surface Co2+/Co3+ redox couple and lattice oxygen were responsible for PMS activation, and the evolution of ·OH, SO4·- and 1O2 were revealed. According to density functional theory (DFT) calculations, the highly-dispersed Co on cubic surface effectively captured PMS and promoted electron transfer for the generation of ·OH and SO4·-, while more oxygen atoms exposed on Co0.1-CTO(200) surface facilitated the generation of 1O2. Briefly, this study provides a novel strategy of catalyst synthesis in PMS activation for water treatment.

NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common malignancy globally and ranks third in terms of both mortality and incidence rates. Surgical resection holds potential as a curative approach for HCC. However, the residual disease contributes to a high 5-year recurrence rate of 70%. Due to their excellent specificity and optical properties, fluorescence-targeted probes are deemed effective auxiliary tools for addressing residual lesions, enabling precise surgical diagnosis and treatment. Research indicates histone deacetylase 6 (HDAC6) overexpression in HCC cells, making it a potential imaging biomarker. This study designed a targeted small-molecule fluorescent probe, SeCF3-IRDye800cw (SeCF3-IRD800), operating within the Second near-infrared window (NIR-II, 1000-1700 nm). The study confirms the biocompatibility of SeCF3-IRD800 and proceeds to demonstrate its applications in imaging in vivo, fluorescence-guided surgery (FGS) for liver cancer, liver fibrosis imaging, and clinical samples incubation, thereby preliminarily validating its utility in liver cancer. METHODS: SeCF3-IRD800 was synthesized by combining the near-infrared fluorescent dye IRDye800cw-NHS with an improved HDAC6 inhibitor. Initially, a HepG2-Luc subcutaneous tumor model (n = 12) was constructed to investigate the metabolic differences between SeCF3-IRD800 and ICG in vivo. Subsequently, HepG2-Luc (n = 12) and HCCLM3-Luc (n = 6) subcutaneous xenograft mouse models were used to assess in vivo targeting by SeCF3-IRD800. The HepG2-Luc orthotopic liver cancer model (n = 6) was employed to showcase the application of SeCF3-IRD800 in FGS. Liver fibrosis (n = 6) and HepG2-Luc orthotopic (n = 6) model imaging results were used to evaluate the impact of different pathological backgrounds on SeCF3-IRD800 imaging. Three groups of fresh HCC and normal liver samples from patients with liver cancer were utilized for SeCF3-IRD800 incubation ex vivo, while preclinical experiments illustrated its potential for clinical application. FINDINGS: The HDAC6 inhibitor 6 (SeCF3) modified with trifluoromethyl was labeled with IRDy800CW-NHS to synthesize the small-molecule targeted probe SeCF3-IRD800, with NIR-II fluorescence signals. SeCF3-IRD800 was rapidly metabolized by the kidneys and exhibited excellent biocompatibility. In vivo validation demonstrated that SeCF3-IRD800 achieved optimal imaging within 8 h, displaying high tumor fluorescence intensity (7658.41 ± 933.34) and high tumor-to-background ratio (5.20 ± 1.04). Imaging experiments with various expression levels revealed its capacity for HDAC6-specific targeting across multiple HCC tumor models, suitable for NIR-II intraoperative imaging. Fluorescence-guided surgery experiments were found feasible and capable of detecting sub-visible 2 mm tumor lesions under white light, aiding surgical decision-making. Further imaging of liver fibrosis mice showed that SeCF3-IRD800's imaging efficacy remained unaffected by liver pathological conditions. Correlations were observed between HDAC6 expression levels and corresponding fluorescence intensity (R2 = 0.8124) among normal liver, liver fibrosis, and HCC tissues. SeCF3-IRD800 identified HDAC6-positive samples from patients with HCC, holding advantages for perspective intraoperative identification in liver cancer. Thus, the rapidly metabolized HDAC6-targeted small-molecule NIR-II fluorescence probe SeCF3-IRD800 holds significant clinical translational value. INTERPRETATION: The successful application of NIR-II fluorescence-guided surgery in liver cancer indicates that SeCF3-IRD800 has great potential to improve the clinical diagnosis and treatment of liver cancer, and could be used as an auxiliary tool for surgical treatment of liver cancer without being affected by liver pathology. FUNDING: This paper is supported by the National Natural Science Foundation of China (NSFC) (92,059,207, 62,027,901, 81,930,053, 81,227,901, 82,272,105, U21A20386 and 81,971,773), CAS Youth Interdisciplinary Team (JCTD-2021-08), the Zhuhai High-level Health Personnel Team Project (Zhuhai HLHPTP201703), and Guangdong Basic and Applied Basic Research Foundation under Grant No. 2022A1515011244.

An International Investigation of Molar Incisor Hypomineralisation (iMIH) and Its Association with Dental Anomalies: Development of a Protocol.

BACKGROUND: Molar incisor hypomineralisation (MIH) is a common disorder of tooth development, which has recently been found to be associated with a higher prevalence of hypodontia. The aim of this international multicentre study is to determine the association between MIH and other developmental anomalies in different populations. METHODS: Investigators were trained and calibrated for the assessment of MIH and dental anomalies and ethical approvals obtained in each participating country. The study aimed to recruit 584 children with MIH and 584 children without MIH. Patients aged 7-16 years who attend specialist clinics will be invited to participate. Children will undergo a clinical examination to determine the presence and severity of MIH, using an established index. The presence of any other anomalies, affecting tooth number, morphology, or position, will be documented. Panoramic radiographs will be assessed for dental anomalies and the presence of third permanent molars. Statistical analysis, using a chi squared test and regression analysis, will be performed to determine any differences in dental anomaly prevalence between the MIH and non-MIH group and to determine any association between dental anomalies and patient characteristics. CONCLUSION: This large-scale study has the potential to improve understanding about MIH with benefits for patient management.

Identification of CKS1B as a prognostic indicator and a predictive marker for immunotherapy in pancreatic cancer.

As a regulatory subunit of cyclin kinase, CKS1B promotes cancer development and is associated with poor prognosis in multiple cancer patients. However, the intrinsic role of CKS1B in pancreatic cancer remains elusive. In our research, CKS1B expression in pancreatic tumor tissue was higher than that in normal tissue by TCGA, Oncomine and CPTAC databases analysis. Similar result was verified in our center tissues by qRT-PCR. CKS1B expression was closely relevant to histologic grading, prognosis, and TMB. GSEA showed that CKS1B mainly participated in the regulation of autophagy and T cell receptor signaling pathway. Furthermore, CIBERSORT analysis showed that there was a strong correlation between CKS1B expression and tumor immune cells infiltration. Drug sensitivity analysis showed that patients with high CKS1B expression appeared to be more sensitive to gemcitabine, 5-fluorouracil, and paclitaxel. We then investigated cell viability and migratory ability by CCK8 and transwell assay, respectively. Results indicated that CKS1B knockdown by short hairpin RNA significantly reduced pancreatic cancer cell viability and invasion via regulating PD-L1 expression. In conclusion, our research further demonstrates the role of CKS1B in pancreatic cancer and the signaling pathways involved. The association of CKS1B with immune infiltration and immune checkpoint may provide a new direction for immunotherapy of pancreatic cancer.