Holistic immunomodulation for small cell lung cancer.

Small cell lung cancer (SCLC) is characterized by a high mortality rate, rapid growth, and early metastasis, which lead to a poor prognosis. Moreover, limited clinical treatment options further lower the survival rate of patients. Therefore, novel technology and agents are urgently required to enhance clinical efficacy. In this review, from a holistic perspective, we summarized the therapeutic targets, agents and strategies with the most potential for treating SCLC, including chimeric antigen receptor (CAR) T therapy, immunomodulating antibodies, traditional Chinese medicines (TCMs), and the microbiota, which have been found recently to improve the clinical outcomes and prognosis of SCLC. Multiomics technologies can be integrated to develop effective diagnostic methods and identify new targets for new drug discovery in SCLC. We discussed in depth the feasibility, potential, and challenges of these new strategies, as well as their combinational treatments, which may provide promising alternatives for enhancing the clinical efficacy of SCLC in the future.

Mitotic gene conversion can be as important as meiotic conversion in driving genetic variability in plants and other species without early germline segregation.

In contrast to common meiotic gene conversion, mitotic gene conversion, because it is so rare, is often ignored as a process influencing allelic diversity. We show that if there is a large enough number of premeiotic cell divisions, as seen in many organisms without early germline sequestration, such as plants, this is an unsafe position. From examination of 1.1 million rice plants, we determined that the rate of mitotic gene conversion events, per mitosis, is 2 orders of magnitude lower than the meiotic rate. However, owing to the large number of mitoses between zygote and gamete and because of long mitotic tract lengths, meiotic and mitotic gene conversion can be of approximately equivalent importance in terms of numbers of markers converted from zygote to gamete. This holds even if we assume a low number of premeiotic cell divisions (approximately 40) as witnessed in Arabidopsis. A low mitotic rate associated with long tracts is also seen in yeast, suggesting generality of results. For species with many mitoses between each meiotic event, mitotic gene conversion should not be overlooked.

Artificial intelligence in predicting recurrence after first-line treatment of liver cancer: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to conduct a systematic review and meta-analysis to comprehensively evaluate the performance and methodological quality of artificial intelligence (AI) in predicting recurrence after single first-line treatment for liver cancer. METHODS: A rigorous and systematic evaluation was conducted on the AI studies related to recurrence after single first-line treatment for liver cancer, retrieved from the PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The area under the curve (AUC), sensitivity (SENC), and specificity (SPEC) of each study were extracted for meta-analysis. RESULTS: Six percutaneous ablation (PA) studies, 16 surgical resection (SR) studies, and 5 transarterial chemoembolization (TACE) studies were included in the meta-analysis for predicting recurrence after hepatocellular carcinoma (HCC) treatment, respectively. Four SR studies and 2 PA studies were included in the meta-analysis for recurrence after intrahepatic cholangiocarcinoma (ICC) and colorectal cancer liver metastasis (CRLM) treatment. The pooled SENC, SEPC, and AUC of AI in predicting recurrence after primary HCC treatment via PA, SR, and TACE were 0.78, 0.90, and 0.92; 0.81, 0.77, and 0.86; and 0.73, 0.79, and 0.79, respectively. The values for ICC treated with SR and CRLM treated with PA were 0.85, 0.71, 0.86 and 0.69, 0.63,0.74, respectively. CONCLUSION: This systematic review and meta-analysis demonstrates the comprehensive application value of AI in predicting recurrence after a single first-line treatment of liver cancer, with satisfactory results, indicating the clinical translation potential of AI in predicting recurrence after liver cancer treatment.

The structure of cognitive strategies for wayfinding decisions.

Literature proposes five distinct cognitive strategies for wayfinding decisions at intersections. Our study investigates whether those strategies rely on a generalized decision-making process, on two frame-specific processes-one in an egocentric and the other in an allocentric spatial reference frame, and/or on five strategy-specific processes. Participants took six trips along a prescribed route through five virtual mazes, each designed for decision-making by a particular strategy. We found that wayfinding accuracy on trips through a given maze correlated significantly with the accuracy on trips through another maze that was designed for a different reference frame (rbetween-frames = 0.20). Correlations were not significantly higher if the other maze was designed for the same reference frame (rwithin-frames = 0.19). However, correlations between trips through the same maze were significantly higher than those between trips through different mazes that were designed for the same reference frame (rwithin-maze = 0.52). We conclude that wayfinding decisions were based on a generalized cognitive process, as well as on strategy-specific processes, while the role of frame-specific processes-if any-was relatively smaller. Thus, the well-established dichotomy of egocentric versus allocentric spatial representations did not translate into a similar, observable dichotomy of decision-making.

Hypermethylation of BMPR2 and TGF-ß Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude.

Although the expression of many genes is associated with adaptation to high-altitude hypoxic environments, the role of epigenetics in the response to this harsh environmental stress is currently unclear. We explored whether abnormal DNA promoter methylation levels of six genes, namely, ABCA1, SOD2, AKT1, VEGFR2, TGF-ß, and BMPR2, affect the occurrence and development of high-altitude polycythemia (HAPC) in Tibetans. The methylation levels of HAPC and the control group of 130 Tibetans from very high altitudes (> 4500 m) were examined using quantitative methylation-specific real-time PCR (QMSP). Depending on the type of data, the Pearson chi-square test, Wilcoxon rank-sum test, and Fisher exact test were used to assess the differences between the two groups. The correlation between the methylation levels of each gene and the hemoglobin content was explored using a linear mixed model. Our experiment revealed that the methylation levels of the TGF-ß and BMPR2 genes differed significantly in the two groups (p < 0.05) and linear mixed model analysis showed that the correlation between the hemoglobin and methylation of ABCA1, TGF-ß, and BMPR2 was statistically significant (p < 0.05). Our study suggests that levels of TGF-ß and BMPR2 methylation are associated with the occurrence of HAPC in extreme-altitude Tibetan populations among 6 selected genes. Epigenetics may be involved in the pathogenesis of HAPC, and future experiments could combine gene and protein levels to verify the diagnostic value of TGF-ß and BMPR2 methylation levels in HAPC.

Pharmacokinetics and pharmacodynamic evaluation of hyaluronic acid-modified imatinib-loaded PEGylated liposomes in CD44-positive Gist882 tumor-bearing mice.

To develop a PEGylated and CD44-targeted liposomes, enabled by surface coating with hyaluronic acid (HA) via amide bond to improve the efficacy of imatinib mesylate (IM), for tumor-targeted cytoplasmic drug delivery. HA was covalently grafted on DSPE-PEG2000-NH2 polymer. HA-modified or unmodified PEGylated liposomes were prepared with ethanol injection method, and the stability, drug release, and cytotoxicity of these liposomes were studied. Meanwhile, intracellular drug delivery efficiency, antitumor efficacy, and pharmacokinetics were also investigated. Ex vivo fluorescence biodistribution was also detected by small animal imaging. In addition, endocytosis mechanism was also explored HA-coated PEGylated liposomes (137.5 nm ± 10.24) had a negative zeta potential (-29.3 mV ± 5.44) and high drug loading (27.8%, w/w). The liposomes were stable with cumulative drug leakage (<60%) under physiological conditions. Blank liposomes were nontoxic to Gist882 cells, and IM-loaded liposomes had higher cytotoxicity to Gist882 cells. HA-modified PEGylated liposomes were internalized more effectively than non-HA coating via CD44-mediated endocytosis. Besides, the cellular uptake of HA-modified liposomes also partly depends on caveolin-medicated endocytosis and micropinocytosis. In rats, both liposomes produced a prolonged half-life of IM (HA/Lp/IM: 14.97h; Lp/IM: 11.15h) by 3- to 4.5-folds compared with the IM solution (3.61h). HA-decorated PEGylated liposomes encapsulated IM exhibited strong inhibitory effect on tumor growth in Gist882 cell-bearing nude mice and formation of 2D/3D tumor spheroids. The Ki67 immunohistochemistry result was consistent with the above results. IM-loaded PEGylated liposomes modified with HA exerted the excellent anti-tumor effect on tumor-bearing mice and more drugs accumulated into the tumor site.

A decade of the anaphase-promoting complex in the nervous system.

Control of protein abundance by the ubiquitin-proteasome system is essential for normal brain development and function. Just over a decade ago, the first post-mitotic function of the anaphase-promoting complex, a major cell cycle-regulated E3 ubiquitin ligase, was discovered in the control of axon growth and patterning in the mammalian brain. Since then, a large number of studies have identified additional novel roles for the anaphase-promoting complex in diverse aspects of neuronal connectivity and plasticity in the developing and mature nervous system. In this review, we discuss the functions and mechanisms of the anaphase-promoting complex in neurogenesis, glial differentiation and migration, neuronal survival and metabolism, neuronal morphogenesis, synapse formation and plasticity, and learning and memory. We also provide a perspective on future investigations of the anaphase-promoting complex in neurobiology.

Compact and water flushing resistant mesh biofilms forming at short SRT disappeared naturally under extended SRT in dynamic membrane bioreactor.

Extending the solids retention time (SRT) has been demonstrated to mitigate membrane biofouling. Nevertheless, it remains an intriguing question whether the compact and water flushing resistant mesh biofilms developed at short SRT can undergo biodegradation and be removed with extended SRT. In present study, the bio-fouled mesh filter in the 10d-SRT dynamic membrane bioreactor (DMBR), with mesh surfaces and pores covered by compact and water flushing resistant biofilms exhibiting low water permeability, was reused in the 40d-SRT DMBR without any cleanings. After being reused at 40d-SRT, its flux driven by gravity occurred from the 10th day and recovered to a regular level of 36.7 L m-2·h-1 on the 27th day. Both scanning electron microscope (SEM) and confocal laser scanning microscopy (CLSM) analyses indicated that the compact mesh biofilms formed at10d-SRT biodegraded and were removed at 40d-SRT, with the residual biofilms becoming removable by water flushing. As a result, the hydraulic resistance of the bio-fouled mesh filter decreased from 4.36 × 108 to 6.97 × 107 m-1, and its flux fully recovered. The protein and polysaccharides densities in mesh-biofilms decreased from 24.4 to 9.7 mg/cm2 and from 10.7 to 0.10 mg/cm2, respectively, which probably have contributed to the disappearance of compact biofilms and the decrease in adhesion. Furthermore, the sludge and mesh-biofilms in the 40d-SRT reactor contained a higher relative abundance of dominant quorum quenching bacteria, such as Rhizobium (3.52% and 1.35%), compared to those in the 10d-SRT sludge (0.096%) and mesh biofilms (0.79%), which might have been linked to a decline in extracellular polymeric substances and, consequently, the biodegradation and disappearance of compact biofilms.

Chalcone-Synthase-Encoding RdCHS1 Is Involved in Flavonoid Biosynthesis in Rhododendron delavayi.

Flower color is an important ornamental feature that is often modulated by the contents of flavonoids. Chalcone synthase is the first key enzyme in the biosynthesis of flavonoids, but little is known about the role of R. delavayi CHS in flavonoid biosynthesis. In this paper, three CHS genes (RdCHS1-3) were successfully cloned from R. delavayi flowers. According to multiple sequence alignment and a phylogenetic analysis, only RdCHS1 contained all the highly conserved and important residues, which was classified into the cluster of bona fide CHSs. RdCHS1 was then subjected to further functional analysis. Real-time PCR analysis revealed that the transcripts of RdCHS1 were the highest in the leaves and lowest in the roots; this did not match the anthocyanin accumulation patterns during flower development. Biochemical characterization displayed that RdCHS1 could catalyze p-coumaroyl-CoA and malonyl-CoA molecules to produce naringenin chalcone. The physiological function of RdCHS1 was checked in Arabidopsis mutants and tobacco, and the results showed that RdCHS1 transgenes could recover the color phenotypes of the tt4 mutant and caused the tobacco flower color to change from pink to dark pink through modulating the expressions of endogenous structural and regulatory genes in the tobacco. All these results demonstrate that RdCHS1 fulfills the function of a bona fide CHS and contributes to flavonoid biosynthesis in R. delavayi.

Optimizing Photoelectrochemical UV Imaging Photodetection: Construction of Anatase/Rutile Heterophase Homojunctions and Oxygen Vacancies Engineering in MOF-Derived TiO2.

Self-powered photoelectrochemical (PEC) ultraviolet photodetectors (UVPDs) are promising for next-generation energy-saving and highly integrated optoelectronic systems. Constructing a heterojunction is an effective strategy to increase the photodetection performance of PEC UVPDs because it can promote the separation and transfer of photogenerated carriers. However, both crystal defects and lattice mismatch lead to deteriorated device performance. Here, we introduce a structural regulation strategy to prepare TiO2 anatase-rutile heterophase homojunctions (A-R HHs) with oxygen vacancies (OVs) photoanodes through an in situ topological transformation of titanium metal-organic framework (Ti-MOF) by pyrolysis treatment. The cooperative interaction between A-R HHs and OVs suppresses carrier recombination and accelerates carrier transport, thereby significantly enhancing the photodetection performance of PEC UVPDs. The obtained device realizes a high on/off ratio of 10,752, a remarkable responsivity of 24.15 mA W-1, an impressive detectivity of 3.28 × 1011 Jones, and excellent cycling stability. More importantly, under 365 nm light illumination, a high-resolution image of "HUST" (the abbreviation of Harbin University of Science and Technology) was obtained perfectly, confirming the excellent optical imaging capability of the device. This research not only presents an advanced methodology for constructing TiO2-based PEC UVPDs, but also provides strategic guidance for enhancing their performance and practical applications.

Effects of functional defects in the NMD pathway on rice phenotype and transcriptome.

Nonsense-mediated mRNA decay (NMD) is an important RNA quality control pathway. It aids in degrading harmful erroneous mRNA, thereby preserving a stable and healthy internal environment. In this study, we employed CRISPR/Cas9 and amiRNA technology to generate knock out or knock down mutants of realted genes in the rice NMD pathway. Through transcriptome sequencing and observing phenotype changes, the study explored the impact of NMD pathway defects on rice gene expression and alternative splicing. The results suggest that even partial defects will induce phenotypic changes such as plant height and pollen vitality to different degrees, showing necessity of NMD factors. Gene expression analysis reveals that most differentially expressed genes are upregulated in the mutants, with ko-upf1-like and kd-upf1 defects having a more significant impact than kd-upf2 and kd-upf3. Specifically, NMD pathway defects result in increased expression levels of rice defense response-related genes and decreased expression levels of secondary metabolism-related genes, with a wider range of affected genes observed in 60-day-old senescence mutants. Transcript analysis indicates that different NMD related genes defects alter hundreds of alternative splicing events, mostly enriched in genes involving alternative splicing regulatory pathways. Approximately half of these events are shared among different mutants, and a substantial number of affected transcripts show NMD target features. NMD could affect both the transcript abundance and their splicing subtypes to regulate the defense response and early-senescence associated pathways, which plays a vital role in rice growth and reproduction.

[Using Multiple Strategies to Improve the Accuracy of Hemodynamic Monitoring].

BACKGROUND & PROBLEMS: Hemodynamic monitoring is an important part of nursing care in the intensive care unit. Recent advances in medical technology and the diversification of intensive care equipment have increased the variety of instruments used in clinical hemodynamic monitoring. Many nurses who use new hemodynamic monitors are not familiar with instrument care, resulting in patient safety incidents caused by nurses not identifying warnings of hemodynamic data change and notifying doctors to provide treatment. The accuracy of hemodynamic monitoring care in our ward of 74.0% motivated this improvement project. PURPOSE: To improve the accuracy of hemodynamic monitoring care to 98.3%. RESOLUTION: Conduct educational training and plan professional education; establish an audit system to regularly monitor the accuracy of nursing care; provide tips to make the operation manual easier to read and understand; establish mobile learning to make learning immediate and more accessible; hold instrument operation practice sessions to improve nursing staff proficiency; monitor and upload data to the hospital information system. RESULTS: After the improvement project, the accuracy of hemodynamic monitoring care increased to 98.7%. CONCLUSIONS: The impact achieved met expectations, and the improvement project will be extended to other intensive care units in the hospital. Our nurses are now more familiar with the operation methods and the significance of monitoring values and interpretation of data. Also, when a value changes or becomes abnormal, they immediately notify the doctor for further evaluation and interventions to improve patient safety.

[Mechanism of Biejiajian Pills against non-alcoholic steatohepatitis based on lipidomics].

This study aims to explore the potential mechanism of Biejiajian Pills in the treatment of non-alcoholic steatohepatitis(NASH) based on lipidomics. A mouse model of NASH was induced by high-fat/high cholesterol diet, and the mice of the normal group were fed with a normal diet. The therapeutic efficacy of Biejiajian Pills against NASH was evaluated through biochemical indexes in both of serum and liver, as well as the hepatic histopathology. Lipid metabolites in the liver were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS)-based lipidomics. Then the partial least-squares discriminant analysis, t-test and receiver operating characteristic curve analysis were performed to screen the differential lipid metabolites and the main biomarkers. The proteins and genes involved in the lipid metabolism and inflammatory response were detected by Western blot and qPCR. The results demonstrated that Biejiajian Pills notably lowered the levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) in the serum and the levels of triglyceride(TG) and total cholesterol(TC) in the liver tissue. In addition, Biejiajian Pills alleviated the lipid accumulation, hepatocyte ballooning, and liver fibrosis. Lipidomics revealed that Biejiajian Pills regulated the content of 11 biomarkers including phosphatidyl choline(PC), phosphatidyl ethanolamine(PE), sphingomyelin(SM), and ceramide(Cer). The results of Western blot and qPCR demonstrated that Biejiajian Pills regulated the expression of sterol regulatory element-binding protein 1(SREBP1), peroxisome proliferator-activated receptor gamma(PPARγ) and phospho-AMP-activated protein kinase(p-AMPK), and the mRNA level of fatty acid translocase 36 gene(Cd36), Pparγ, cardiolipin synthase 1 gene(Crls1), and phospholipase Cß2 gene(Plcß2). Furthermore, Biejiajian Pills displayed inhibitory effects on phospho-p38 MAPK(p-p38 MAPK) and phospho-ERK1/2(p-ERK1/2) and the mRNA levels of interleukin-6 gene(Il-6), interleukin-1ß gene(Il-1ß) and tumor necrosis factor-α gene(Tnf-α). In conclusion, Biejiajian Pills could alleviate the lipid metabolism disorders and regulate the expression of SREBP1, PPARγ, and p-AMPK and the mRNA levels of pro-inflammatory cytokines.

High level of somatic mutations detected in a diploid banana wild relative Musa basjoo.

Plants are thought to lack an early segregating germline and often retain both asexual and sexual reproduction, both of which may allow somatic mutations to enter the gametes or clonal progeny, and thereby impact plant evolution. It is yet unclear how often these somatic mutations occur during plant development and what proportion is transmitted to their sexual or cloned offspring. Asexual "seedless" propagation has contributed greatly to the breeding in many fruit crops, such as citrus, grapes and bananas. Whether plants in these lineages experience substantial somatic mutation accumulation is unknown. To estimate the somatic mutation accumulation and inheritance among a clonal population of plant, here we assess somatic mutation accumulation in Musa basjoo, a diploid banana wild relative, using 30 whole-genome resequenced samples collected from five structures, including leaves, sheaths, panicle, roots and underground rhizome connecting three clonal individuals. We observed 18.5 high proportion de novo somatic mutations on average between each two adjacent clonal suckers, equivalent to ~ 2.48 × 10-8 per site per asexual generation, higher than the per site per sexual generation rates (< 1 × 10-8) reported in Arabidopsis and peach. Interestingly, most of these inter-ramet somatic mutations were shared simultaneously in different tissues of the same individual with a high level of variant allele fractions, suggesting that these somatic mutations arise early in ramet development and that each individual may develop only from a few apical stem cells. These results thus suggest substantial mutation accumulation in a wild relative of banana. Our work reveals the significance of somatic mutation in Musa basjoo genetics variations and contribute to the trait improvement breeding of bananas and other asexual clonal crops.

MEIOK21 regulates oocyte quantity and quality via modulating meiotic recombination.

The reproductive life span of females is largely determined by the number and quality of oocytes. Previously, we identified MEIOK21 as a meiotic recombination regulator required for male fertility. Here, we characterize the important roles of MEIOK21 in regulating female meiosis and oocyte number and quality. MEIOK21 localizes at recombination sites as a component of recombination bridges in oogenesis like in spermatogenesis. Meiok21-/- female mice show subfertility. Consistently, the size of the primordial follicle pool in Meiok21-/- females is only ~40% of wild-type females because a great number of oocytes with defects in meiotic recombination and/or synapsis are eliminated. Furthermore, the numbers of primordial and growing follicles show a more marked decrease in an age-dependent manner compared with wild-type females. Further analysis shows Meiok21-/- oocytes also have reduced rates of germinal vesicle breakdown and the first polar body extrusion when cultured in vitro, indicating poor oocyte quality. Additionally, Meiok21-/- oocytes have more chromosomes bearing a single distally localized crossover (chiasmata), suggesting a possible defect in crossover maturation. Taken together, our findings indicate critical roles for MEIOK21 in ensuring the number and quality of oocytes in the follicles.

CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the main malignant tumors with high mortality and short survival time. Immunotherapy has become the standard treatment for advanced NSCLC, but it has the problems of drug resistance and low response rate. Therefore, obtaining effective biomarkers to predict and enhance immune checkpoint inhibitors (ICIs) efficacy in NSCLC is important. Sphingolipid metabolism is recently found to be closely involved in tumor immunotherapy. CERS4, an important sphingolipid metabolizing enzyme, is positively correlated with the efficacy of anti-PD-1 therapy for NSCLC. Upregulation of CERS4 expression could improve the efficacy of anti-PD-1 therapy for NSCLC. High expression of CERS4 could downregulate the expression of Rhob in tumor. Significantly, the ratio of CD4+/CD8+ T cell increased and the ratio of Tim-3+/CD8+ T cell decreased in spleen and peripheral blood cells. When Rhob was knocked out, the efficacy of PD-1 mAb treatment increased, and the frequency of Tim-3+ CD8+ T cell decreased. This finding further confirmed the role of sphingolipid metabolites in regulating the immunotherapeutic function of NSCLC. These metabolites may improve the efficacy of PD-1 mAb in NSCLC by regulating the CERS4/Rhob/Tim-3 axis. Overall, this study provided a potential and effective target for predicting and improving the efficacy of ICIs for NSCLC. It also provided a new perspective for the study on the mechanisms of ICIs resistance for NSCLC.

ß-Elemene enhances erlotinib sensitivity through induction of ferroptosis by upregulating lncRNA H19 in EGFR-mutant non-small cell lung cancer.

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. ß-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that ß-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that ß-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

Changes of equality of medical service utilization in China between 1993 and 2018: findings from six waves of nationwide household interview survey.

BACKGROUND: Changes in China's health care system in the last three decades was remarkable. The current study aims on examine the change of equality of health care utilization in mainland China based on a nationwide household interview survey. METHODS: We used household interview data extracted from six waves of National Health Service Survey between 1993 and 2018. Changes of health care utilization were descripted. Equality of the utilization were examined with univariate meta-regression across urban and rural areas, socioeconomic development regions and income groups. RESULTS: The proportion of outpatient visits within last two weeks experienced a decrease from 17.0% in 1993 to 13.0% in 2013 and bounced back to 24.0% in 2018. The age-standardized trend remained unchanged. Hospitalization in the last 12 month increased from 2.6% in 1998 to 13.8% in 2018. The perceived unmet need of hospital admission fell from 35.9% in 1998 to 21.5% in 2018. The gaps in health care utilization between urban and rural areas, across regions and by income groups have been narrowed, implying improved equality of using medical services in the last two and a half decades. CONCLUSION: China has experienced significant increases in health care utilization over the past 25 years. Meanwhile, the unmet needs for health care decreased remarkably and the equality of health care utilization improved significantly. These results imply significant achievements in health service accessibility in China.

Choice between decision-making strategies in human route-following.

To follow a prescribed route, we must decide which way to turn at intersections. To do so, we can memorize either the serial order of directions or the associations between spatial cues and directions ("at the drug store, turn left"). Here, we investigate which of these two strategies is used if both are available. In Task S, all intersections looked exactly alike, and participants therefore had to use the serial order strategy to decide which way their route continued. In Task SA, each intersection displayed a unique spatial cue, and participants therefore could use either strategy. In Task A, each intersection displayed a unique cue, but the serial order of cues varied between trips, and participants therefore had to use the associative cue strategy. We found that route-following accuracy increased from trip to trip, was higher on routes with 12 rather than 18 intersections, and was higher on Task SA than on the other two tasks, both with 12 and with 18 intersections. Furthermore, participants on Task SA acquired substantial knowledge about the serial order of directions as well as about cue-direction associations, both with 12 and with 18 intersections. From this we conclude that, when both strategies were available, participants did not pick the better one but rather used both. This represents dual encoding, a phenomenon previously described for more elementary memory tasks. We further conclude that dual encoding may be implemented even if the memory load is not very high (i.e., even with only 12 intersections).

In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer.

Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.