Assessing the impact of different contact patterns on disease transmission: Taking COVID-19 as a case.

Human-to-human contact plays a leading role in the transmission of infectious diseases, and the contact pattern between individuals has an important influence on the intensity and trend of disease transmission. In this paper, we define regular contacts and random contacts. Then, taking the COVID-19 outbreak in Yangzhou City, China as an example, we consider age heterogeneity, household structure and two contact patterns to establish discrete dynamic models with switching between daytime and nighttime to depict the transmission mechanism of COVID-19 in population. We studied the changes in the reproduction number with different age groups and household sizes at different stages. The effects of the proportion of two contacts patterns on reproduction number were also studied. Furthermore, taking the final size, the peak value of infected individuals in community and the peak value of quarantine infected individuals and nucleic acid test positive individuals as indicators, we evaluate the impact of the number of random contacts, the duration of the free transmission stage and summer vacation on the spread of the disease. The results show that a series of prevention and control measures taken by the Chinese government in response to the epidemic situation are reasonable and effective, and the young and middle-aged adults (aged 18-59) with household size of 6 have the strongest transmission ability. In addition, the results also indicate that increasing the proportion of random contact is beneficial to the control of the infectious disease in the phase with interventions. This work enriches the content of infectious disease modeling and provides theoretical guidance for the prevention and control of follow-up major infectious diseases.

Claudin18.2 expression and its clinicopathological feature in adenocarcinoma from various parts.

AIMS: To clarify claudin18.2 expression and its clinicopathological features in various cancers, especially in lung adenocarcinoma. METHODS: Immunohistochemistry staining and fluorescence in situ hybridisation (FISH) were performed to detect claudin18.2 expression and CLDN18 gene rearrangement in adenocarcinoma from different organs. RESULTS: The results showed that claudin18.2 expression was found in 68% (27 of 40) of lung mucinous adenocarcinoma, 52% (16 of 31) of cholangiocarcinoma, 2% (10 of 423) of colorectal adenocarcinoma tissue microarray, 27% (6 of 22) of colorectal mucinous adenocarcinoma and 30% (3 of 10) of cervical adenocarcinoma, but not in all 39 cases of invasive breast adenocarcinoma by immunohistochemistry staining. There was significantly positive correlation between ratio of claudin18.2-positive carcinoma cells and staining intensity in lung mucinous adenocarcinoma and cholangiocarcinoma. Claudin18.2 expression was much more in female patients than male patients with lung mucinous adenocarcinoma. In addition, cholangiocarcinoma with claudin18.2 expression was more aggressive and had perineural invasion. Intraductal papillary neoplasm of the bile duct and epithelial dysplasia of the adjacent bile in cholangiocarcinoma also showed claudin18.2 expression. All three cases of cervical adenocarcinoma with claudin18.2 expression were moderately differentiated adenocarcinoma including one human papillomavirus (HPV)-associated carcinoma, two non-HPV-associated and gastric-type carcinoma. CLDN18 gene rearrangement was not found in all 22 cases with high claudin18.2 expression by FISH. CONCLUSIONS: Our results suggest claudin18.2 might be a potential biomarker for targeted therapy on lung mucinous adenocarcinoma, cholangiocarcinoma, colorectal mucinous adenocarcinoma and gastric-type cervical adenocarcinoma.

[Analysis of the current quality of life status and influencing factors of sepsis survivors in intensive care unit].

OBJECTIVE: To explore the current situation and influencing factors of quality of life of septic patients in intensive care unit (ICU) after discharge, and to provide theoretical basis for clinical early psychological intervention and continuity of care. METHODS: A prospective observational study was conducted. The septic patients who were hospitalized in the department of critical care medicine of the Affiliated Hospital of Jining Medical University and discharged with improvement from January 1 to December 31, 2022 were selected as the research objects. The demographic information, basic diseases, infection site, vital signs at ICU admission, severity scores of the condition within 24 hours after ICU admission, various biochemical indexes, treatment process, and prognostic indexes of all the patients were recorded. All patients were assessed by questionnaire at 3 months of discharge using the 36-item short-form health survey scale (SF-36 scale), the activities of daily living scale (ADL scale), and the Montreal cognitive assessment scale (MoCA scale). Multiple linear regression was used to analyze the factors influencing the quality of life of septic patients after discharge from the hospital. RESULTS: A total of 200 septic patients were discharged with improvement and followed up at 3 months of discharge, of which 150 completed the questionnaire. Of the 150 patients, 57 had sepsis and 93 had septic shock. The total SF-36 scale score of septic patients at 3 months of discharge was 81.4±23.0, and the scores of dimensions were, in descending order, role-emotional (83.4±23.0), mental health (82.9±23.6), bodily pain (82.8±23.3), vitality (81.6±23.2), physical function (81.4±23.5), general health (81.1±23.3), role-physical (79.5±27.0), and social function (78.8±25.2). There was no statistically significant difference in the total SF-36 scale score between the patients with sepsis and septic shock (82.6±22.0 vs. 80.7±23.6, P > 0.05). Incorporating the statistically significant indicators from linear univariate analysis into multiple linear regression analysis, and the results showed that the factors influencing the quality of life of septic patients at 3 months after discharge included ADL scale score at 3 months after discharge [ß= 0.741, 95% confidence interval (95%CI) was 0.606 to 0.791, P < 0.001], length of ICU stay (ß= -0.209, 95%CI was -0.733 to -0.208, P = 0.001), duration of mechanical ventilation (ß= 0.147, 95%CI was 0.122 to 0.978, P = 0.012), total dosage of norepinephrine (ß= -0.111, 95%CI was -0.044 to -0.002, P = 0.028), mean arterial pressure (MAP) at ICU admission (ß= -0.102, 95%CI was -0.203 to -0.007, P = 0.036) and body weight (ß= 0.097, 95%CI was 0.005 to 0.345, P = 0.044). CONCLUSIONS: The quality of life of patients with sepsis at 3 months after discharge is at a moderately high level. The influencing factors of the quality of life of patients with sepsis at 3 months after discharge include the ADL scale score at 3 months after discharge, the length of ICU stay, the duration of mechanical ventilation, the total dosage of norepinephrine, MAP at ICU admission and body weight, and healthcare professionals should enhance the treatment and care of the patients during their hospitalization based on the above influencing factors, and pay attention to early psychological intervention and continued care for such patients.

Co-fermentation of titanium-flocculated-sludge with food waste towards simultaneous water purification and resource recovery.

Recovery of resources from domestic sewage and food waste has always been an international-thorny problem. Titanium-based flocculation can achieve high-efficient destabilization, quick concentration and separation of organic matter from sewage to sludge. This study proposed co-fermentation of the titanium-flocculated sludge (Ti-loaded sludge) and food waste towards resource recovery by converting organic matter to value-added volatile fatty acids (VFAs) and inorganic matter to struvite and TiO2 nanoparticles. When Ti-loaded sludge and food waste were co-fermented at a mass ratio of 3:1, the VFAs yield reached 3725.2 mg-COD/L (VFAs/SCOD 91.0%), which was more than 4 times higher than the case of the sludge alone. The 48-day semicontinuous co-fermentation demonstrated stable long-term operation, yielding VFAs at 2529.0 mg-COD/L (VFAs/SCOD 89.8%) and achieving a high CODVFAs/NNH4 of 58.9. Food waste provided sufficient organic substrate, enriching plenty of acid-producing fermentation bacteria (such as Prevotella 7 about 21.0% and Bacteroides about 9.4%). Moreover, metagenomic sequencing analysis evidenced the significant increase of the relative gene abundance corresponding to enzymes in pathways, such as extracellular hydrolysis, substrates metabolism, and VFAs biosynthesis. After fermentation, the precious element P (≥ 99.0%) and extra-added element Ti (≥99.0%) retained in fermented residues, without releasing to VFAs supernatant, which facilitated the direct re-use of VFAs as resource. Through simple and commonly used calcination and acid leaching methodologies, 80.9% of element P and 82.1% of element Ti could be successfully recovered as struvite and TiO2 nanoparticles, respectively. This research provides a strategy for the co-utilization of domestic sludge and food waste, which can realize both reduction of sludge and recovery of resources.

Bibliometric study and review of Klotho research: global characteristics and trends from 2000 to 2023.

BACKGROUND: Although Klotho-related research has seen a significant upsurge, the field lacks comprehensive analytical representation and in-depth exploration of pertinent areas such as prevailing research trends and key focus areas. METHOD: This review presents a bibliometric analysis of literature data gathered from the Web of Science Core Collection databases from January 1, 2000, to April 30, 2023. Parameters such as co-authorship, co-citation, co-occurrence, and the emergence of publications, countries, categories, references, and keywords were scrutinized predominantly using Citespace software. RESULTS: Our investigation amassed a total of 3548 papers, with the United States leading in the quantity of publications (1175, accounting for 33.12%), followed by China (867, representing 24.44%), and Japan (439, accounting for 12.37%). While the United States is preeminent in the overall volume of publications, Scotland holds prominence in terms of centrality. Out of a total of 96 subject categories, urology and nephrology (573), and endocrinology and metabolism (542) were the two leading domains of Klotho-related publications. The 2011 paper titled "FGF23 induces left ventricular hypertrophy" by Faul C et al. holds the distinction of being the most frequently cited. The keywords "fibroblast growth factor 23," "phosphate homeostasis," and "functional variants" demonstrated the highest intensity, underscoring the potential of these research areas. CONCLUSION: As the volume of literature grows, the role of Klotho in disease management and its applicability as a marker in disease progression warrant vigilant tracking and study.

Forecast of peak infection and estimate of excess deaths in COVID-19 transmission and prevalence in Taiyuan City, 2022 to 2023.

In this paper, with the method of epidemic dynamics, we assess the spread and prevalence of COVID-19 after the policy adjustment of prevention and control measure in December 2022 in Taiyuan City in China, and estimate the excess population deaths caused by COVID-19. Based on the transmission mechanism of COVID-19 among individuals, a dynamic model with heterogeneous contacts is established to describe the change of control measures and the population's social behavior in Taiyuan city. The model is verified and simulated by basing on reported case data from November 8th to December 5th, 2022 in Taiyuan city and the statistical data of the questionnaire survey from December 1st to 23rd, 2022 in Neijiang city. Combining with reported numbers of permanent residents and deaths from 2017 to 2021 in Taiyuan city, we apply the dynamic model to estimate theoretical population of 2022 under the assumption that there is no effect of COVID-19. In addition, we carry out sensitivity analysis to determine the propagation character of the Omicron strain and the effect of the control measures. As a result of the study, it is concluded that after adjusting the epidemic policy on December 6th, 2022, three peaks of infection in Taiyuan are estimated to be from December 22nd to 31st, 2022, from May 10th to June 1st, 2023, and from September 5th to October 13th, 2023, and the corresponding daily peaks of new cases can reach 400 000, 44 000 and 22 000, respectively. By the end of 2022, excess deaths can range from 887 to 4887, and excess mortality rate can range from 3.06% to 14.82%. The threshold of the infectivity of the COVID-19 variant is estimated 0.0353, that is if the strain infectivity is above it, the epidemic cannot be control with the previous normalization measures.

Anthropogenic As pollution mediated by submarine groundwater discharge in a marine ranch.

Arsenic (As) pollution, is a global problem, threatening human health and ecological security, especially in the bay environment with dense population and human activities. Among potential pathways of As into the bay, submarine groundwater discharge (SGD) has not received adequate attention due to its invisibility. We determined As and 222Rn activity concentrations in different water mass. Spatial variation of dissolved As concentration in the groundwater was large and attributed to the adjacent local industries. By combining 222Rn mass balance modeling with As concentrations measured, the SGD-derived As fluxes was conservatively estimated to be 1310 kg As d-1 and 5880 kg As d-1 in the dry and wet seasons, respectively. The migration of arsenic may be enhanced by rainfall and dissolved carbon. The amount of SGD derived As input to the bay was greater than the total combined As input from river discharge, atmosphere, sewage drainage, and diffusion from sediment.

Achieving health-oriented air pollution control requires integrating unequal toxicities of industrial particles.

Protecting human health from fine particulate matter (PM) pollution is the ambitious goal of clean air actions, but current control strategies  largely ignore the role of source-specific PM toxicity. Here, we proposed health-oriented control strategies by integrating the unequal toxic potencies of the most polluting industrial PMs. Iron and steel industry (ISI)-emitted PM2.5 exhibit about one order of magnitude higher toxic potency than those of cement and power industries. Compared with the current mass-based control strategy (prioritizing implementation of ultralow emission standards in the power sector), the proposed health-oriented control strategy (priority control of the ISI sector) could generate 5.4 times higher reduction in population-weighted toxic potency-adjusted PM2.5 exposure among polluting industries in China. Furthermore, the marginal abatement cost per unit of toxic potency-adjusted mass of ISI-emitted PM2.5 is only a quarter of that of the other two sectors under ultralow emission scenarios. We highlight that a health-oriented air pollution control strategy is urgently required to achieve cost-effective reductions in particulate exposure risks.

Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway.

RNA binding proteins (RBPs) contributes to cancer progression, but the underlying mechanism reminds unclear. Here, we find that DDX21, a representative RBP, is highly expressed in colorectal cancer (CRC), which leads to CRC cell migration and invasion in vitro, and CRC to liver metastasis and lung metastasis in vivo. This effect of DDX21 on CRC metastasis is correlated to the activation of Epithelial-mesenchymal transition (EMT) pathway. Moreover, we reveal that DDX21 protein is phase separated in vitro and in CRC cells, which controls CRC metastasis. Phase-separated DDX21 highly binds on MCM5 gene locus, which is markedly reduced when phase separation is disrupted by mutations on its intrinsically disordered region (IDR). The impaired metastatic ability of CRC upon DDX21 loss is restored by ectopic expression of MCM5, indicating MCM5 is a key downstream target of DDX21 for CRC metastasis. Furthermore, co-higher expressions of DDX21 and MCM5 is significantly correlated with poor survival outcomes of stage III and IV CRC patients, indicating the importance of this mechanism in CRC late and metastatic stage. Altogether, our results elucidate a new model of DDX21 in regulating CRC metastasis via phase separation.

Microbial necromass carbon in estuarine tidal wetlands of China: Influencing factors and environmental implication.

Microbial necromass is an important component of the stable soil organic carbon (SOC) pool. However, little is known about the spatial and seasonal patterns of soil microbial necromass and their influencing environmental factors in estuarine tidal wetlands. In the present study, amino sugars (ASs) as biomarkers of microbial necromass were investigated along the estuarine tidal wetlands of China. Microbial necromass carbon (C) contents were in the range of 1.2-6.7 mg g-1 (3.6 ± 2.2 mg g-1, n = 41) and 0.5-4.4 mg g-1 (2.3 ± 1.5 mg g-1, n = 41), which accounted for 17.3-66.5 % (44.8 % ± 16.8 %) and 8.9-45.0 % (31.0 % ± 13.7 %) of the SOC pool in the dry (March to April) and wet (August to September) seasons, respectively. At all sampling sites, fungal necromass C predominated over bacterial necromass C as a component of microbial necromass C. Compared to bacterial necromass C, fungal necromass C showed a stronger connection with ferrous oxides (Fe2+) and total Fe concentrations. Both fungal and bacterial necromass C contents revealed large spatial heterogeneity and declined in the estuarine tidal wetlands with the increase in latitude. Statistical analyses showed that the increases in salinity and pH in the estuarine tidal wetlands suppressed the accumulation of soil microbial necromass C.

An accurate prediction of the origin for bone metastatic cancer using deep learning on digital pathological images.

BACKGROUND: Determining the origin of bone metastatic cancer (OBMC) is of great significance to clinical therapeutics. It is challenging for pathologists to determine the OBMC with limited clinical information and bone biopsy. METHODS: We designed a regional multiple-instance learning algorithm to predict the OBMC based on hematoxylin-eosin (H&E) staining slides alone. We collected 1041 cases from eight different hospitals and labeled 26,431 regions of interest to train the model. The performance of the model was assessed by ten-fold cross validation and external validation. Under the guidance of top3 predictions, we conducted an IHC test on 175 cases of unknown origins to compare the consistency of the results predicted by the model and indicated by the IHC markers. We also applied the model to identify whether there was tumor or not in a region, as well as distinguishing squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumor. FINDINGS: In the within-cohort, our model achieved a top1-accuracy of 91.35% and a top3-accuracy of 97.75%. In the external cohort, our model displayed a good generalizability with a top3-accuracy of 97.44%. The top1 consistency between the results of the model and the immunohistochemistry markers was 83.90% and the top3 consistency was 94.33%. The model obtained an accuracy of 98.98% to identify whether there was tumor or not and an accuracy of 93.85% to differentiate three types of cancers. INTERPRETATION: Our model demonstrated good performance to predict the OBMC from routine histology and had great potential for assisting pathologists with determining the OBMC accurately. FUNDING: National Science Foundation of China (61875102 and 61975089), Natural Science Foundation of Guangdong province (2021A15-15012379 and 2022A1515 012550), Science and Technology Research Program of Shenzhen City (JCYJ20200109110606054 and WDZC20200821141349001), and Tsinghua University Spring Breeze Fund (2020Z99CFZ023).

Synergetic PM2.5 and O3 control strategy for the Yangtze River Delta, China.

PM2.5 concentrations have dramatically reduced in key regions of China during the period 2013-2017, while O3 has increased. Hence there is an urgent demand to develop a synergetic regional PM2.5 and O3 control strategy. This study develops an emission-to-concentration response surface model and proposes a synergetic pathway for PM2.5 and O3 control in the Yangtze River Delta (YRD) based on the framework of the Air Benefit and Cost and Attainment Assessment System (ABaCAS). Results suggest that the regional emissions of NOx, SO2, NH3, VOCs (volatile organic compounds) and primary PM2.5 should be reduced by 18%, 23%, 14%, 17% and 33% compared with 2017 to achieve 25% and 5% decreases of PM2.5 and O3 in 2025, and that the emission reduction ratios will need to be 50%, 26%, 28%, 28% and 55% to attain the National Ambient Air Quality Standard. To effectively reduce the O3 pollution in the central and eastern YRD, VOCs controls need to be strengthened to reduce O3 by 5%, and then NOx reduction should be accelerated for air quality attainment. Meanwhile, control of primary PM2.5 emissions shall be prioritized to address the severe PM2.5 pollution in the northern YRD. For most cities in the YRD, the VOCs emission reduction ratio should be higher than that for NOx in Spring and Autumn. NOx control should be increased in summer rather than winter when a strong VOC-limited regime occurs. Besides, regarding the emission control of industrial processes, on-road vehicle and residential sources shall be prioritized and the joint control area should be enlarged to include Shandong, Jiangxi and Hubei Province for effective O3 control.

Progress in quantitative research on the relationship between atmospheric oxidation and air quality.

Atmospheric oxidizing capacity (AOC) is an essential driving force of troposphere chemistry and self-cleaning, but the definition of AOC and its quantitative representation remain uncertain. Driven by national demand for air pollution control in recent years, Chinese scholars have carried out studies on theories of atmospheric chemistry and have made considerable progress in AOC research. This paper will give a brief review of these developments. First, AOC indexes were established that represent apparent atmospheric oxidizing ability (AOIe) and potential atmospheric oxidizing ability (AOIp) based on aspects of macrothermodynamics and microdynamics, respectively. A closed study refined the quantitative contributions of heterogeneous chemistry to AOC in Beijing, and these AOC methods were further applied in Beijing-Tianjin-Hebei and key areas across the country. In addition, the detection of ground or vertical profiles for atmospheric OH·, HO2·, NO3· radicals and reservoir molecules can now be obtained with domestic instruments in diverse environments. Moreover, laboratory smoke chamber simulations revealed heterogeneous processes involving reactions of O3 and NO2, which are typical oxidants in the surface/interface atmosphere, and the evolutionary and budgetary implications of atmospheric oxidants reacting under multispecies, multiphase and multi-interface conditions were obtained. Finally, based on the GRAPES-CUACE adjoint model improved by Chinese scholars, simulations of key substances affecting atmospheric oxidation and secondary organic and inorganic aerosol formation have been optimized. Normalized numerical simulations of AOIe and AOIp were performed, and regional coordination of AOC was adjusted. An optimized plan for controlling O3 and PM2.5 was analyzed by scenario simulation.

Source and sequestration of sediment organic carbon from different elevation zones in estuarine wetland, North China.

Estuarine wetland plays an important role in regulating global carbon cycle due to high terrestrial carbon input and burial. However, it is unclear how the source and sequestration of sediment organic carbon (SOC) in estuarine wetlands changes under the anthropogenic impact in the past century. In this study, combining parameters of TOC/TN ratios, δ13C, δ15N and 210Pb-chronology, temporal trends of SOC source and sequestration flux in Liaohe estuarine wetland were studied. The results showed that the source of organic carbon in Liaohe estuarine wetland was dominated by terrestrial input (contribution >60 %). Due to vegetation, TOC in shallow reed marsh was significantly higher than that of bare beach and subtidal flat. Affected by elevation, the sediment mass accumulation rate (MAR, kg·m-2·yr-1) showed differences in reed marsh (C1), bare beach (C2) and subtidal flat (C3), which were 6.57, 13.56 and 13.25 respectively in the past century. MAR fluctuated over time, it showed an overall increasing trend, especially since the 1980s. Correspondingly, the sequestration flux of SOC (SF-SOC, g·m-2·yr-1) showed an overall increasing trend with average of 82.84 (reed marsh), 151.93 (bare beach) and 123.71 (subtidal flat). Comparing to TOC, the higher MAR had a more distinct effect on carbon sequestration in Liaohe estuarine wetland. The difference in sedimentation rate and carbon sequestration are linked to the changes in sediment flux of riverine input and land utilization in the catchment area due to human activities in recent decades, including the construction of reservoirs, dams and local ditch wharf.

A clinicopathologic study of 13 cases of primary lymphoma in soft tissue and review of literature.

Primary lymphoma in soft tissue is very rare. In order to understand the clinicopathological features of primary lymphoma in soft tissue, we found 13 cases (0.3%) of primary lymphoma in soft tissue by reviewing 4303 lymphomas diagnosed in our institution from 2010 to 2019. Tumors were found in the following sites: 8 in lower extremity (2 in leg, 1 in calf, 1 in knee and 4 in buttock), 1 in upper extremity (left shoulder) and 4 in the trunk (3 in waist and 1 in thoracolumbar). The most common histologic type was DLBCL (7/13, 54.8%). 6 cases of which had follow-up information. 25 patients were also selected by screening the English literature search (from Jan 2010 to December 2019) including 1102 studies. Compared to the results of literature review, our results are similar with them. The tumor sites were as follows: 10 in lower extremity, 4 in upper extremity, 9 in the trunk and 2 in masticatory muscle. The most common histological type was also DLBCL (n=11/25, 44%). Overall survival analysis of all 31 patients including our 6 cases with primary lymphoma in soft tissue showed no significant difference between different histological type (Log Rank P=0.120, Breslow P=0.157). The differential diagnosis includes malignant melanoma, rhabdomyosarcoma and metastatic carcinoma in soft tissue.

Self-Assembly of a Multifunction DNA Tetrahedron for Effective Delivery of Aptamer PL1 and Pcsk9 siRNA Potentiate Immune Checkpoint Therapy for Colorectal Cancer.

Compared with the traditional single therapy, nanomedicine has promoted a multimodal combination treatment for various carcinomas, especially the development of corresponding intelligent multifunctional biomaterials based on advanced DNA nanotechnology has great potential in cancer combination therapy. Herein, we describe a strategy to "backpack" aptamer PL1, which specifically binds to PD-L1 and Pcsk9 siRNA on well-defined DNA tetrahedral nanoparticles (TDNs) via DNA hybridization, which collectively contributes to the effective therapy for colorectal cancer (CRC). In addition, we designed a targeted TDN upon folic acid (FA) recognition, limiting its release to the sites of tumors where folic acid receptor (FAR) is encountered. Our results demonstrated that the TDN-FA/PL1/Pcsk9-siRNA could free immune cells to target CRC cells and attenuate 83.48% tumor growth in mouse models of CT26 CRC. Mechanically, the cancer-targeting FA guided TDN-FA/PL1/Pcsk9-siRNA into tumor cells, thereby ensuring that the aptamer PL1 could choke the mutual effects between PD-1 and PD-L1, followed by a 1.69-fold increase in T cell number and a 1.9-fold suppression of T cell activity by the PD-1/PD-L1 pathway, while Pcsk9 siRNA decreased Pcsk9 expression averagely to the extent of 65.13% and then facilitated intratumoral infiltration of cytotoxic T cells robustly with IFN-γ and Granzyme B expression. Our results reveal that the multifunctional TND-FA/PL1/Pcsk9-siRNA is effective and safe for CRC therapy, thereby expanding the application of DNA nanotechnology for innovative therapies of various cancers.

Pathological and Prognostic Characterization of Craniopharyngioma Based on the Expression of TrkA, ß-Catenin, Cell Cycle Markers, and BRAF V600E Mutation.

We collected 61 craniopharyngioma (CP) specimens to investigate the expression of TrkA, ß-catenin, BRAF gene mutation, and NTRK1 fusion in CP. There were 37 male and 24 female individuals with a median age of 34 years (range, 4-75 years). Histologically, there were 46 cases of adamantinomatous craniopharyngioma (ACP), 14 cases of papillary craniopharyngioma (PCP), and 1 case with a mixed adamantinomatous and papillary pattern. By immunohistochemistry, we found that moderate/high TrkA expression was detected in 47% (28/60) CP and was significantly higher in adult patients (p = 0.018). Interestingly, TrkA is more expressed in "whorled epithelium" cells in ACP, similar to the localization of abnormal ß-catenin. The abnormal expression rate of ß-catenin was 70% (43/61), and the medium/high cyclin D1 expression rate was 73% (44/60), both of which were significantly higher in ACP than in PCP. Of the CP, 41% (21/51) had a moderate/strong P16-positive signal; 58% (34/59) showed a high Ki-67 expression, and there was a significant correlation between high Ki-67 L.I. and high tumor recurrence (p = 0.021). NTRK1 fusion was not found in CP by fluorescence in situ hybridization (FISH). By PCR, 26% (15/58) CP showed BRAF V600E gene mutation, which mainly occurred in PCP (100%, 14/14) except one case of mixed CP. Moreover, TrkA expression was negatively correlated with Ki-67 index and positively correlated with P16 expression. There was a significantly negative correlation between BRAF V600E mutation and abnormal ß-catenin expression. Our results demonstrate for the first time that TrkA expression might occur in CP, especially in adult CP patients, and suggest that cyclin D1 could be used for ACP histological classification in addition to ß-catenin and BRAF V600E mutation, while Ki-67 could be used as a marker to predict CP recurrence.

AMPK Activation Enhances Neutrophil's Fungicidal Activity in Vitro and Improves the Clinical Outcome of Fusarium solani Keratitis in Vivo.

PURPOSE: To determine whether Activated 5'AMP-activated protein kinase (AMPK) activation enhances Fusarium solani (F. solani) fungicidal capacity of neutrophils. METHODS: The expression of AMPK and phosphorylated-AMPK (p-AMPK) proteins was tested using Western Blot. Plate counting studied the effects of the fungicidal capacity of neutrophils enhanced by AMPK activation. Phagocytized spores by neutrophils were assessed by immunostaining and inhibited hyphal growth images were captured by JULI Stage real-time cell history recorder. Flow cytometry assay tested Reactive Oxygen Species (ROS) production and the percentage of apoptosis neutrophils. ROS Assay Kit also tested ROS production at different time points. The F. solani keratitis murine model was established, and slit-lamp microscopy captured corneal photographs. RESULTS: Our experiments were divided into the following groups. Neutrophils (N), neutrophils + spores (N + S), neutrophils + spores+ 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) (N + S + A), neutrophils + spores + Compound C (N + S + C). AMPK activator AICAR significantly increased the expression of p-AMPK in neutrophils. The plate counting experiment showed that the number of colonies in the N + S + A was significantly less than in the N + S group. Immunostaining results showed phagocytized spores were significantly increased in the N + S + A group compared with the N + S group. Captured photographs by a real-time cell history recorder camera showed F. solani hyphal growth in the N + S + A group was significantly inhibited than in the N + S group. ROS release in the N + S + A group was significantly higher in the N + S + A group than in other groups. The percentage of apoptosis neutrophils in the N + S + A group was decreased than in the N + S group. Captured photographs by slit-lamp showed that AICAR eye drop treatment alleviated the severity and decreased clinical score at 12 and 24 hours post-infection (h.p.i). CONCLUSION: AMPK activation enhances the efficacy of neutrophils in killing F. solani in vitro and in vivo.

TYMS-TM4SF4 axis promotes the progression of colorectal cancer by EMT and upregulating stem cell marker.

BACKGROUND: The expression of thymidylate synthase (TYMS) is significantly up-regulated in various cancers and associated with the poor prognosis of patients. However, the role of TYMS in the progression of colorectal cancer (CRC) is unclear. METHODS: Cell function assay, biology information analysis, and RNA sequencing were used to investigate the role of TYMS in the progression of CRC and underlining molecular mechanism. SPSS22.0 statistical software and GraphPad Prism 5 (Graphpad software) were used for statistical analysis. RESULTS: Our results showed that TYMS expression was higher in CRC tissues than that in non-tumor colorectal mucosa tissues. TYMS knockdown inhibited the proliferation, migration and invasion of HCT116 and HT29 cells, and the spheroid formation of HCT116 cells. The underling mechanism demonstrated that TYMS promoted the progression of CRC by regulating EMT-related proteins including E-cadherin, Vimentin, MMP-9 and stem cell biomarkers including CD133 and CD44. Furthermore, DEG sequencing showed that TYMS knockdown enriched the pathways of metastasis and metabolism by GO and KEGG analysis. We identified TM4SF4 was the downstream target of TYMS in CRC cells. TM4SF4 overexpression increased migration and invasion of CRC cells by regulating EMT and CD133 expression. CONCLUSIONS: Our findings suggest that TYMS-TM4SF4 axis may promote the progression of CRC by EMT and upregulating stem cell markers.

Role of black carbon in modulating aerosol direct effects driven by air pollution controls during 2013-2017 in China.

Aerosol direct effects (ADEs) can modulate shortwave radiation as well as atmospheric dynamics and air quality. As the key absorbing component of aerosol, the black carbon (BC) largely determines the aerosol optical properties. Therefore, it is expected that BC emission controls might gain co-benefits from the simultaneous reduction of ADEs. To demonstrate such synergy, here we quantified the ADEs changes and the role of BC controls in China during 2013-2017 using a regional two-way coupled meteorology chemistry transport model. Simulated results suggest that the control action effectively reduced the wintertime PM2.5 concentration (-26.0 µg m-3) and associated ADEs. In January, the influence of ADEs on surface shortwave radiation, 2-meter temperature, and planetary boundary layer height was weakened from -16.7 W m-2, -0.20 °C, and -15.4 m in 2013 to -11.3 W m-2, -0.06 °C, and -10.7 m in 2017, respectively. The enhancement of SO2, NO2, and PM2.5 concentrations due to ADEs was reduced from +3.1%, +5.2%, and +5.4% in 2013 to +2.6%, +4.5%, and +3.3% in 2017, respectively, demonstrating the extra benefit of air pollution controls for improving air quality by reducing ADEs. Meanwhile, the BC emission reduced by 12.5% simultaneously along with the effective controls on SO2 and NO2 emissions during 2013-2017, mainly from domestic combustion (-11.7%), resulting in 30.3% (-0.9 µg m-3) reduction of BC concentration. Such BC controls contributed 15.6-60.2% of such changes in the ADEs influence on meteorological variables, and 32.6-41.1% on air pollutants. More specially, the effectiveness of collaborative reduction of BC further reduced surface shortwave radiation in China by 3.6 W m-2 in January and 1.0 W m-2 in July, leading to a more weakened ADEs that bring extra benefits in reducing PM2.5 concentrations by 1.8 µg m-3 in January and 0.3 µg m-3 in July. Apparently, BC played an important role in modulating the ADEs and associated influences on meteorology and air quality, suggesting a wise control strategy by targeting absorbing component of PM2.5 reduction to address both air pollution and climate change in the future.