Search

Abstract Background The strong invasiveness and rapid expansion of dengue virus (DENV) pose a great challenge to global public health. However, dengue epidemic patterns and mechanisms at a genetic scale, particularly in term of cross-border transmissions, remain poorly understood. Importation is considered as the primary driver of dengue outbreaks in China, and since 1990 a frequent occurrence of large outbreaks has been triggered by the imported cases and subsequently spread to the western and northern parts of China. Therefore, this study aims to systematically reveal the invasion and diffusion patterns of DENV-1 in Guangdong, China from 1990 to 2019. Methods These analyses were performed on 179 newly assembled genomes from indigenous dengue cases in Guangdong, China and 5152 E gene complete sequences recorded in Chinese mainland. The genetic population structure and epidemic patterns of DENV-1 circulating in Chinese mainland were characterized by phylogenetics, phylogeography, phylodynamics based on DENV-1 E-gene-based globally unified genotyping framework. Results Multiple serotypes of DENV were co-circulating in Chinese mainland, particularly in Guangdong and Yunnan provinces. A total of 189 transmission clusters in 38 clades belonging to 22 subgenotypes of genotype I, IV and V of DENV-1 were identified, with 7 Clades of Concern (COCs) responsible for the large outbreaks since 1990. The epidemic periodicity was inferred from the data to be approximately 3 years. Dengue transmission events mainly occurred from Great Mekong Subregion-China (GMS-China), Southeast Asia (SEA), South Asia Subcontinent (SASC), and Oceania (OCE) to coastal and land border cities respectively in southeastern and southwestern China. Specially, Guangzhou was found to be the most dominant receipting hub, where DENV-1 diffused to other cities within the province and even other parts of the country. Genome phylogeny combined with epidemiological investigation demonstrated a clear local consecutive transmission process of a 5C1 transmission cluster (5C1-CN4) of DENV-1 in Guangzhou from 2013 to 2015, while the two provinces of Guangdong and Yunnan played key roles in ongoing transition of dengue epidemic patterns. In contextualizing within Invasion Biology theories, we have proposed a derived three-stage model encompassing the stages of invasion, colonization, and dissemination, which is supposed to enhance our understanding of dengue spreading patterns. Conclusions This study demonstrates the invasion and diffusion process of DENV-1 in Chinese mainland within a global genotyping framework, characterizing the genetic diversities of viral populations, multiple sources of importation, and periodic dynamics of the epidemic. These findings highlight the potential ongoing transition trends from epidemic to endemic status offering a valuable insight into early warning, prevention and control of rapid spreading of dengue both in China and worldwide. Graphical Abstract

The mucus layer and intestine epithelium pose challenges to the bioavailability of orally administered paclitaxel (PTX). A novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI), was synthesized in this study. Its structure was characterized using 1H NMR, 13C NMR, ESI-MS and IR spectroscopies. The efficacy and in vivo toxicity of PgpI were comprehensively evaluated by R8-PEG@PLs&PgpI, i.e., the oral combination of PgpI and octaarginine R8-PEG-DSPE modified PTX liposomes (R8-PEG@PLs), for lung cancer treatment. The joint forms between PgpI and R8-PEG@PLs were investigated and the affinity of PgpI for intestinal P-glycoprotein remained unaffected when combined externally with R8-PEG@PLs (R8-PEG@PLs&PgpI), compared to the diminished affinity for internal combination. The primary endocytic pathway for R8-PEG@PLs&PgpI in Caco-2 cells was the lipid raft, with increased percentage of macropinocytosis compared to unmodified PTX liposomes (PLs). The established physiology-based cellular kinetic models revealed that the net internalization rate of PTX was 2.3 times higher in R8-PEG@PLs&PgpI than in PLs, correlating with in vivo 2.2 times of antitumor rate. R8-PEG@PLs&PgpI may address the deficits of PLs in human lung A549 tumor-bearing mice due to the lower drug concentration than in normal mice. The external combination of R8-PEG@PLs&PgpI, offering maximal efficacy and security of PgpI, is promising for oral PTX delivery.

Triple-negative breast cancer (TNBC) still one of the most challenging sub-type in breast cancer clinical. Caffeic acid (CA) derived from effective components of traditional Chinese herbal medicine has been show potential against TNBCs. Our research has found that CA can inhibit the proliferation of TNBC cells while also suppressing the size of cancer stem cell spheres. Additionally, it reduces reactive oxygen species (ROS) levels and disruption of mitochondrial membrane potential. Simultaneously, CA influences the stemness of TNBC cells by reducing the expression of the stem cell marker protein CD44. Furthermore, we have observed that CA can modulate the FOXO1/FIS signaling pathway, disrupting mitochondrial function, inducing mitochondrial autophagy, and exerting anti-tumor activity. Additionally, changes in the immune microenvironment were detected using a mass cytometer, we found that CA can induce M1 polarization of macrophages, enhancing anti-tumor immune responses to exert anti-tumor activity. In summary, CA can be considered as a lead compound for further research in targeting TNBC.

Abstract Background The patterns of blood pressure (BP) change throughout the pregnancy were related to adverse birth outcomes. However, little is known about the long-term effect of BP change patterns on child neurodevelopment. This study aimed to explore the relationship between the BP trajectory and BP variability during pregnancy and early childhood neurodevelopment. Method A total of 2797 mother-newborn pairs were derived from the Wuhan Healthy Baby Cohort Study. BP was measured during each antenatal visit, and Mental and Psychomotor Development Indexes (MDI and PDI) were assessed using the Bayley Scales of Infant Development (BSID) when the children were 2 years old. Delayed neurodevelopment was defined as scores of PDI or MDI less than − 1SD relative to the mean score of the study population. A group-based multi-trajectory model was adopted to identify multi-trajectories of systolic blood pressure (SBP) and diastolic blood pressure (DBP). Visit-to-visit BP variability was assessed by the coefficient of variation (CV), standard deviation (SD), and average real variability (ARV). Generalized linear models and multivariate logistic regressions were used to assess the associations of BP trajectories and variability with BSID scores and delayed neurodevelopment, respectively. Results Five distinct trajectories for SBP and DBP were identified, namely, “Low-increasing,” “Low-stable,” “Moderate-decreasing,” “Moderate-increasing,” and “High-stable” groups. Compared with the “Low-stable” group, the children whose mothers’ BP fell into the other four groups had lower PDI scores, and mothers in the “Low-increasing,” “Moderate-increasing,” and “Moderate-decreasing” groups had 43% (OR: 1.43, 95% CI: 1.01, 2.03), 48% (OR: 1.48, 95% CI: 1.05, 2.08) and 45% (OR:1.45, 95% CI: 1.03, 2.04) higher risk of having offspring with delayed psychomotor neurodevelopment, respectively. High DBP variability was associated with lower BSID scores, and delayed psychomotor neurodevelopment (OR = 1.46, 95% CI: 1.10, 1.92 for DBP-SD; OR = 1.53, 95% CI: 1.16, 2.02 for DBP-CV). Conclusion Our findings suggest that BP change patterns assessed by multi-trajectory and visit-to-visit variability were associated with lower BSID scores and delayed neurodevelopment. Health professionals should be aware of the influence of BP level and its oscillations during pregnancy on the risk of delayed neurodevelopment.

Abstract Background Assessment ability lies at the core of midwives’ capacity to judge and treat clinical problems effectively. Influenced by the traditional teaching method of “teacher-led and content-based”, that teachers involve imparting a large amount of knowledge to students and students lack active thinking and active practice, the clinical assessment ability of midwifery students in China is mostly at a medium or low level. Improving clinical assessment ability of midwifery students, especially critical thinking, is highly important in practical midwifery education. Therefore, we implemented a new teaching program, “typical case discussion and scenario simulation”, in the Midwifery Health Assessment course. Guided by typical cases, students were organized to actively participate in typical case discussions and to promote active thinking and were encouraged to practice actively through scenario simulation. In this study, we aimed to evaluate the effect of this strategy on the critical thinking ability of midwifery students. Method A total of 104 midwifery students in grades 16–19 at the West China School of Nursing, Sichuan University, were included as participants through convenience sampling. All the students completed the Midwifery Health Assessment course in the third year of university. Students in grades 16 and 17 were assigned to the control group, which received routine teaching in the Midwifery Health Assessment, while students in grades 18 and 19 were assigned to the experimental group, for which the “typical case discussion and scenario simulation” teaching mode was employed. The Critical Thinking Disposition Inventory-Chinese Version (CTDI-CV) and Midwifery Health Assessment Course Satisfaction Questionnaire were administered after the intervention. Results After the intervention, the critical thinking ability of the experimental group was greater than that of the control group (284.81 ± 27.98 and 300.94 ± 31.67, p = 0.008). Furthermore, the experimental group exhibited higher scores on the four dimensions of Open-Mindedness (40.56 ± 5.60 and 43.59 ± 4.90, p = 0.005), Analyticity (42.83 ± 5.17 and 45.42 ± 5.72, p = 0.020), Systematicity (38.79 ± 4.70 and 41.88 ± 6.11, p = 0.006), and Critical Thinking Self-Confidence (41.35 ± 5.92 and 43.83 ± 5.89, p = 0.039) than did the control group. The course satisfaction exhibited by the experimental group was greater than that exhibited by the control group (84.81 ± 8.49 and 90.19 ± 8.41, p = 0.002). Conclusion The “typical case discussion and scenario simulation” class mode can improve the critical thinking ability of midwifery students and enhance their curriculum satisfaction. This approach carries a certain degree of promotional significance in medical education.

Abstract The rapid proliferation of tumors is highly dependent on the nutrition supply of blood vessels. Cutting off the nutrient supply to tumors is an effective strategy for cancer treatment, known as starvation therapy. Although various hydrogel-based biomaterials have been developed for starvation therapy through glucose consumption or intravascular embolization, the limitations of single-mode starvation therapy hinder their therapeutic effects. Herein, we propose a dual-function nutrition deprivation strategy that can block the nutrients delivery through extravascular gelation shrinkage and inhibit neovascularization through angiogenesis inhibitors based on a novel NIR-responsive nanocomposite hydrogel. CuS nanodots-modified MgAl-LDH nanosheets loaded with angiogenesis inhibitor (sorafenib, SOR) are incorporated into the poly(n-isopropylacrylamide) (PNIPAAm) hydrogel by radical polymerization to obtain the composite hydrogel (SOR@LDH-CuS/P). The SOR@LDH-CuS/P hydrogel can deliver hydrophobic SOR with a NIR-responsive release behavior, which could decrease the tumor vascular density and accelerate cancer cells apoptosis. Moreover, the SOR@LDH-CuS/P hydrogel exhibits higher (3.5 times) compressive strength than that of the PNIPAAm, which could squeeze blood vessels through extravascular gelation shrinkage. In vitro and in vivo assays demonstrate that the interruption of nutrient supply by gelation shrinkage and the prevention of angiogenesis by SOR is a promising strategy to inhibit tumor growth for multimode starvation therapy.

Background: Hip dislocation represents a significant complication encountered following hip arthroplasty procedures. In this investigation, we conducted a comparative analysis of the biomechanical characteristics exhibited by the piriformis and the conjoined tendon after total hip arthroplasty (THA) via the direct anterior approach (DAA), utilizing cadaveric specimens. The objective is to ascertain the relative significance of the piriformis muscle and the conjoined tendon in mitigating hip dislocation. Methods: A total of 16 hip joints from 8 freshly frozen cadavers were selected and stratified into 2 groups: the piriformis tendon (PT) group and the conjoined tendon (CT) group. Following THA via the DAA, measurements were taken to record the torque required to induce hip dislocation under various conditions. Torque readings were obtained with the tendon in its intact state (intact group) and after preservation or reconstruction of either the PT or the CT. Results: The torques of anterior and posterior dislocation in PT group were 22.24 ± 4.53 N.m and 30.7 ± 15.5 N.m following tendon severed, and 20.04 ± 2.67 N.m and 17.5 ± 6.7 N.m following reconstruction. There were no differences compared to the intact group. The torque decreased in the CT group after CT was severed with the torques dropping from 31.2 ± 7.6 N.m to 8.18 ± 2.6 N.m (P < .0001) for anterior dislocation, and from 34.9 ± 8.3 N.m to 9.8 ± 2.8 N.m (P < .0001) for posterior dislocation. Following reconstruction, the torque required for dislocation significantly increased (P < .0001). Conclusions: This study underscores the preeminent role of the CT in ensuring hip stability following THA via DAA, highlighting the cruciality of its preservation and reconstruction during surgical interventions.

Abstract Sonodynamic therapy (SDT) is demonstrated to trigger the systemic immune response of the organism and facilitate the treatment of metastatic tumors. However, SDT‐mediated neutrophil extracellular traps (NETs) formation can promote tumor cell spread, thus weakening the therapeutic effectiveness of metastatic tumors. Herein, the amorphous CoW‐layered double hydroxide (a‐CoW‐LDH) nanosheets are functionalized with a peptidyl arginine deiminase 4 (PAD4) inhibitor, i.e., YW3‐56, to construct a multifunctional nanoagent (a‐LDH@356) for synergistic SDT/immunotherapy. Specifically, a‐CoW‐LDH nanosheets can act as a sonosensitizer to generate abundant reactive oxygen species (ROS) under US irradiation. After loading with YW3‐56, a‐LDH@356 plus US irradiation not only effectively induces ROS generation and immunogenic cell death, but also inhibits the elevation of citrullinated histone H3 (H3cit) and the release of NETs, enabling a synergistic enhancement of anti‐tumor metastasis effect. Using 4T1 tumor model, it is demonstrated that combining a‐CoW‐LDH with YW3‐56 stimulates an anti‐tumor response by upregulating the proportion of immune‐activated cells and inducing polarization of M1 macrophages, and inhibits immune escape by downregulating the expression of PD‐1 on immune cells under US irradiation, which not only arrests primary tumor progression with a tumor inhibition rate of 69.5% but also prevents tumor metastasis with the least number of lung metastatic nodules.

Abstract Background More than half of the global population lives in areas at risk of dengue (DENV) transmission. Developing an efficient risk prediction system can help curb dengue outbreaks, but multiple variables, including mosquito-based surveillance indicators, still constrain our understanding. Mosquito or oviposition positive index (MOI) has been utilized in field surveillance to monitor the wild population density of Aedes albopictus in Guangzhou since 2005. Methods Based on the mosquito surveillance data using Mosq-ovitrap collection and human landing collection (HLC) launched at 12 sites in Guangzhou from 2015 to 2017, we established a MOI-based model of the basic dengue reproduction number (R 0) using the classical Ross-Macdonald framework combined with a linear mixed-effects model. Results During the survey period, the mean MOI and adult mosquito density index (ADI) using HLC for Ae. albopictus were 12.96 ± 17.78 and 16.79 ± 55.92, respectively. The R 0 estimated from the daily ADI (ADID) showed a significant seasonal variation. A 10-unit increase in MOI was associated with 1.08-fold (95% CI 1.05, 1.11) ADID and an increase of 0.14 (95% CI 0.05, 0.23) in the logarithmic transformation of R 0. MOI-based R 0 of dengue varied by month and average monthly temperature. During the active period of Ae. albopictus from April to November in Guangzhou region, a high risk of dengue outbreak was predicted by the MOI-based R 0 model, especially from August to October, with the predicted R 0 > 1. Meanwhile, from December to March, the estimates of MOI-based R 0 were < 1. Conclusions The present study enriched our knowledge about mosquito-based surveillance indicators and indicated that the MOI of Ae. albopictus could be valuable for application in estimating the R 0 of dengue using a statistical model. The MOI-based R 0 model prediction of the risk of dengue transmission varied by month and temperature in Guangzhou. Our findings lay a foundation for further development of a complex efficient dengue risk prediction system. Graphical Abstract

Abstract Introduction To explore if digital protractor could guide the anteversion of acetabular cup during primary THA and make it consistent with preoperative. Methods We retrospectively reviewed 172 cases of primary THA with direct anterior approach (DAA) over 2 years. The anteversion of acetabular cup were measured from computed tomography (CT) scan preoperative and de-identified plain radiographs postoperative by two blinded investigators who were not involved in the surgery. The effect of the digital protractor on the anteversion was determined using regression analysis. Results The mean anteversion for the THAs in digital protractor group was 15.5°and 21.4°in control group (P 25°. The correlation coefficient for the interobserver reliability of the measurement of the two investigators was 0.94. Conclusion The digital protractor is a practical tool in the DAA for THA to determine the anteversion of the acetabular prosthesis.

PAD4 expression and activity were significantly up-regulated in lung cancer tissues suggesting that PAD4 could be a possible target for lung cancer treatment. In this study we had demonstrated that PAD4 expression was higher in lung cancer patients whom with lymphnode metastasis and pleural invasion. Inhibiting PAD4 with a small molecular inhibitor could induce apoptosis and suppress growth in lung cancer cells. We used RNA-sequencing to further investigate transcriptional changes that induced by PAD4 inhibition, and results suggested its affected mostly on the cell cycle, mitotic cell cycle process, p53 signaling pathway. By using image flow cytometry analysis, we found that PAD4 inhibited by YW3-56 could accumulate cells in the G1/G0 phases and reducing the fraction of G2/M and S phase cells. Quantification of different phase of mitosis in cells treated with YW3-56 revealed an increasing trend of telophase and prophase cells. Taken together, our data indicated that PAD4 inhibitor could affect cell cycle and mitosis of lung cancer cells, and targeting PAD4 could be a promising strategy for discovery novel anti-NSCLC treatments.

Abstract Background Aedes albopictus is an invasive vector of serious Aedes-borne diseases of global concern. Habitat management remains a critical factor for establishing a cost-effective systematic strategy for sustainable vector control. However, the community-based characteristics of Ae. albopictus habitats in complex urbanization ecosystems are still not well understood. Methods A large-scale investigation of aquatic habitats, involving 12 sites selected as representative of four land use categories at three urbanization levels, was performed in Guangzhou, China during 2015–2017. The characteristics and dynamics of these Ae. albopictus habitats were assessed using habitat-type composition, habitat preference, diversity indexes and the Route index (RI), and the temporal patterns of these indexes were evaluated by locally weighted scatterplot smoothing models. The associations of RI with urbanization levels, land use categories and climatic variables were inferred using generalized additive mixed models. Results A total of 1994 potential habitats and 474 Ae. albopictus-positive habitats were inspected. The majority of these habitats were container-type habitats, with Ae. albopictus showing a particularly higher habitat preference for plastic containers, metal containers and ceramic vessels. Unexpectedly, some non-container-type habitats, especially ornamental ponds and surface water, were found to have fairly high Ae. albopictus positivity rates. Regarding habitats, the land use category residential and rural in Jiangpu (Conghua District, Guangzhou) had the highest number of Ae. albopictus habitats with the highest positive rates. The type diversity of total habitats (H-total) showed a quick increase from February to April and peaked in April, while the H-total of positive habitats (H-positive) and RIs peaked in May. RIs mainly increased with the monthly average daily mean temperature and monthly cumulative rainfall. We also observed the accumulation of diapause eggs in the winter and diapause termination in the following March. Conclusions Ecological heterogeneity of habitat preferences of Ae. albopictus was demonstrated in four land use categories at three urbanization levels. The results reveal diversified habitat-type compositions and significant seasonal variations, indicating an ongoing adaptation of Ae. albopictus to the urbanization ecosystem. H-positivity and RIs were inferred as affected by climatic variables and diapause behavior of Ae. albopictus, suggesting that an effective control of overwintering diapause eggs is crucial. Our findings lay a foundation for establishing a stratified systematic management strategy of Ae. albopictus habitats in cities that is expected to complement and improve community-based interventions and sustainable vector management. Graphical Abstract

Stimulus-responsive nanodrugs have been extensively studied and their structural changes in the cells are important for controlled intracellular drug release. Histone citrullination of peptidylarginine deiminase 4 (PAD4) regulates the expression of tumor suppressor genes. In our previous study, compounds such as YW3–56 (356) were developed as potent PAD4 inhibitors with excellent anti-tumor activity in vitro and in vivo. To enhance the antitumor activity and improve the bioavailability, we further optimized the structure by modifying the phenylboronic acid moiety to the PAD4 inhibitor (4B). Taking advantage of the oxidative stress responsiveness of the phenylboronic acid moiety, in this study, we covalently attached 4B to RGD sequence peptide modified chitosan (K-CRGDV) to construct this new oxidative stress responsive nanodrug (K-CRGDV-4B). The modification of RGD sequence peptide conferred the nanodrug the ability to actively target tumors. The release mechanism was verified by UV-Vis spectroscopy, NMR. The anti-tumor and anti-metastatic properties of K-CRGDV-4B were demonstrated by in vitro cytotoxicity assay and in vivo mouse Lewis lung cancer metastasis model. In addition, K-CRGDV-4B modulates the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins such as PD1 were inhibited, while IFN-γ and IFN-β, which are stimulators of tumor immune responses, were upregulated. Overall, K-CRGDV-4B is a stimulus-responsive nanodrug that responds to the tumor microenvironment by inhibiting PAD4 activity, blocking the formation of neutrophil extracellular traps (NETs), and improving the tumor immune microenvironment.

Vorinostat (SAHA) is a histone deacetylase inhibitor that exerts its effects through epigenetic regulation. Specifically, SAHA can inhibit the proliferation of triple-negative breast cancer (TNBC) cells alone or in combination with other chemotherapeutic agents. Doxorubicin (DOX), a traditional chemotherapeutic drug, exhibits a potent cytotoxic effect on cancer cells while also inducing strong toxic effects. In this study, we investigated the synergistic potential of these two drugs in combination against TNBC. Our results suggested that the combination of these two drugs could enhance the inhibitory effect on cancer cell proliferation, resulting in alterations in cell mitotic phase, and suppression of cancer cell stemness. Moreover, our in vivo study unveiled that when SAHA was combined with DOX, it not only exhibited an inhibitory effect on tumor metastasis but also played a role in regulating the immune microenvironment within tumors. Overall, the combination of DOX and SAHA presents a promising avenue for innovative combination chemotherapy in the context of TNBC.

Context Genistein is a multifunctional natural compound.Objective In this study, we demonstrate the activity of genistein on non-small lung cancer A549 and 95D cells.Materials and methods A CCK8 assay was used to detect the cytotoxicity of genistein (0, 25, 50, 100, 150, 200 and 250 μM) on A549 and 95D cells for 48 h. AnnexinV-FITC/PI and TUNEL assay were performed to examine the apoptotic cell death induced by genistein (0, 50, 100 and 150 μM, 48 h). Intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential were measured by flow cytometry. Mitochondrial activity in A549 and 95D cells, treated with 0, 50, 100 and 150 μM genistein for 48 h was detected by MitoTracker Orange staining. Western blot analysis was performed to evaluate the expression of the mitochondrial apoptosis-related proteins. Meanwhile, the expression level of FOXO3a/PUMA signalling was measured by flow cytometry and Western blot assay.Results IC50 value of genistein against 95D cells and A549 cells was 32.96 ± 2.91 and 110.6 ± 2.41 μM, respectively. The percentage of apoptotic death cells was 20.03%, 29.26% and 27.14% in 95D cells, and 41.62%, 55.24% and 43.45% in A549 cells when treated with 50, 100 and 150 μM genistein, respectively. Our observations also revealed that genistein could elevate intracellular ROS generation, decrease mitochondrial membrane potential, decrease mitochondrial activity (MitoTracker Orange staining), and up-regulate the expression of mitochondrial apoptosis-related proteins. Further examinations revealed that the expression level of FOXO3a and PUMA in NSCLC was significantly increased by genistein.Discussion and conclusions Our data may provide basic information for further development of genistein as a promising lead compound targeting NSCLC by inducing mitochondrial apoptosis.

Abstract Background Dengue is the fastest spreading arboviral disease, posing great challenges on global public health. A reproduceable and comparable global genotyping framework for contextualizing spatiotemporal epidemiological data of dengue virus (DENV) is essential for research studies and collaborative surveillance. Methods Targeting DENV-1 spreading prominently in recent decades, by reconciling all qualified complete E gene sequences of 5003 DENV-1 strains with epidemiological information from 78 epidemic countries/areas ranging from 1944 to 2018, we established and characterized a unified global high-resolution genotyping framework using phylogenetics, population genetics, phylogeography, and phylodynamics. Results The defined framework was discriminated with three hierarchical layers of genotype, subgenotype and clade with respective mean pairwise distances 2–6%, 0.8–2%, and ≤ 0.8%. The global epidemic patterns of DENV-1 showed strong geographic constraints representing stratified spatial-genetic epidemic pairs of Continent-Genotype, Region-Subgenotype and Nation-Clade, thereby identifying 12 epidemic regions which prospectively facilitates the region-based coordination. The increasing cross-transmission trends were also demonstrated. The traditional endemic countries such as Thailand, Vietnam and Indonesia displayed as persisting dominant source centers, while the emerging epidemic countries such as China, Australia, and the USA, where dengue outbreaks were frequently triggered by importation, showed a growing trend of DENV-1 diffusion. The probably hidden epidemics were found especially in Africa and India. Then, our framework can be utilized in an accurate stratified coordinated surveillance based on the defined viral population compositions. Thereby it is prospectively valuable for further hampering the ongoing transition process of epidemic to endemic, addressing the issue of inadequate monitoring, and warning us to be concerned about the cross-national, cross-regional, and cross-continental diffusions of dengue, which can potentially trigger large epidemics. Conclusions The framework and its utilization in quantitatively assessing DENV-1 epidemics has laid a foundation and re-unveiled the urgency for establishing a stratified coordinated surveillance platform for blocking global spreading of dengue. This framework is also expected to bridge classical DENV-1 genotyping with genomic epidemiology and risk modeling. We will promote it to the public and update it periodically. Graphical Abstract

ObjectiveThis study aimed to determine the clinical characteristics of obese pediatric non-alcoholic fatty liver disease (NAFLD) in central China and verify the applicability of some known risk factors for pediatric NAFLD before late puberty.MethodsThis was a retrospective case–control study. A total of 1,029 inpatients at Wuhan Children’s Hospital before the late puberty stage were enrolled in the study, including 815 children with obesity (non-NAFLD group) and 214 children with obesity and NAFLD (NAFLD group) diagnosed by liver ultrasound. Subgroup analyses were performed according to sex and puberty. The anthropometric indices and laboratory test data of these 1,029 children were sorted. After intergroup comparison, a logistic regression model was used to determine the risk factors for pediatric NAFLD. Significant risk factors for NAFLD were further tested using receiver operating characteristic (ROC) curves to evaluate their ability to predict an early diagnosis of NAFLD.ResultsThe NAFLD group had a mean age of 11.03 ± 1.66, with 11.18 ± 1.66 and 10.27 ± 1.45 years for male and female children, respectively (p < 0.05 and p < 0.01, respectively). Even subdivided by both sex and puberty, raised body mass index (BMI), homeostatic model-insulin resistance, triglycerides, alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (γ-GT) were still found in the non-NAFLD and NAFLD groups (p < 0.05 and p < 0.01, respectively). The results of logistic regression analysis showed that BMI (odds ratio [OR], 1.468;95% confidence interval [CI], 1.356-1.590; p

Protein arginine deiminase 4 (PAD4) plays an important role in cancer progression by participating in gene regulation, protein modification, and neutrophil extracellular trap (NET) formation. Many reversible and irreversible PAD4 inhibitors have been reported recently. In this review, we summarize the structure–activity relationships of newly investigated PAD4 inhibitors to bring researchers up to speed by guiding and describing new scaffolds as optimization and development leads for new effective, safe, and selective cancer treatments. In addition, some recent reports have shown evidence that PAD4 inhibitors are expected to trigger antitumor immune responses, regulate immune cells and related immune factors, enhance the effects of immune checkpoint inhibitors, and enhance their antitumor efficacy. Therefore, PAD4 inhibitors may potentially change tumor immunotherapy and provide an excellent direction for the development and clinical application of immunotherapy strategies for related diseases.

Increased glycolysis is a key characteristic of malignant cells that contributes to their high proliferation rates and ability to develop drug resistance. The glycolysis rate-limiting enzyme hexokinase II (HK II) is overexpressed in most tumor cells and significantly affects tumor development. This paper examines the structure of HK II and the specific biological factors that influence its role in tumor development, as well as the potential of HK II inhibitors in antitumor therapy. Furthermore, we identify and discuss the inhibitors of HK II that have been reported in the literature.

Wumei Bolus is a traditional Chinese medicine prescription, first appeared in Shennong Bencao Jing. Modern pharmacology believes that Wumei Bolus has antibacterial, antitussive, sedative, antiviral and anti-tumor effects, and plays a therapeutic role by acting on multi-target/multi-pathway. Moreover, it has great advantages in digestive system diseases, such as repairing the damaged gastrointestinal mucosa and improving the inflammatory environment. Aim of the study: This review aimed to evaluate the efficacy and safety of prescriptions based on the Wumei Bolus treating ulcerative colitis (UC). Materials and methods: In this meta-analysis, we searched CNKI, Wanfang Database, VIP, Pubmed, Web of Science (WOS) with language restrictions of Chinese and English for articles published from the establishment of the database to Dec 2022. This meta-analysis controlled randomized controlled trials (RCTs) assessing the efficacy and safety of Wumei Bolus against ulcerative colitis and using RevMan 5.4 and Stata 15.0to analyze information from the compliant studies. Results: The search incorporated 3145 results (1617 cases assigned into Wumei Bolus group and 1528 cases assigned into control group), from which 37 studies fulfilled our inclusion criteria and were included. The outcomes of this meta-analysis showed that compared to the control group, the Experiment group was significantly more effective (RR = 1.24，95%CI [1.20，1.28])and lower adverse reactions (RR = 0.32, 95%CI [0.20, 0.53]). According to the subgroup analysis, The results showed that the RR = 1.23 and 95%CI [1.16, 1.30] in the group treated with Wumei Bolus alone and the group treated with Western medicine with RR = 1.25 and 95%CI [1.20, 1.30], indicating that the efficacy of Wumei Bolus in the treatment of UC was better and the difference was statistically significant (P

Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention (EPR) effect without introduction of inactive substances, and some nanodrugs can alter the immune environment. We synthesized a peptidyl arginine deiminase 4 (PAD4) molecular inhibitor, ZD-E-1M. It could self-assembled into nanodrug ZD-E-1. Using confocal laser scanning microscopy, we observed its cellular colocalization, PAD4 activity and neutrophil extracellular traps (NETs) formation. The populations of immune cells and expression of immune-related proteins were determined by single-cell mass cytometry. ZD-E-1 formed nanoflowers in an acidic environment, whereas it formed nanospheres at pH 7.4. Accumulation of ZD-E-1 at tumor was pH-responsive because of its pH-dependent differences in the size and shape. It could enter the nucleus and bind to PAD4 to prolong the intracellular retention time. In mice, ZD-E-1 inhibited tumor growth and metastasis by inhibiting PAD4 activity and NETs formation. Besides, ZD-E-1 could regulate the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins like LAG3 were suppressed, while IFN-γ and TNF-α as stimulators of tumor immune response were upregulated. Overall, ZD-E-1 is a self-assembling carrier-free nanodrug that responds to pH, inhibits PAD4 activity, blocks neutrophil extracellular traps formation, and improves the tumor immune microenvironment.

Hydrogels are particularly suitable materials for loading drug delivery agents; their high water content provides a biocompatible environment for most biomolecules, and their cross-linked nature protects the loaded agents from damage. During delivery, the delivered substance usually needs to be released gradually over time, which can be achieved by degradable cross-linked chains. In recent years, biodegradable hydrogels have become a promising technology in new methods of disease treatment and drug delivery methods due to their many advantageous properties. This review briefly discusses the degradation mechanisms of different types of biodegradable hydrogel systems and introduces the specific applications of degradable hydrogels in several new methods of disease treatment and drug delivery methods.

Abstract Background Grain size is one of the major determinants of cereal crop yield. As a class of plant polyhydroxysteroids, brassinosteroids (BRs) play essential roles in the regulation of grain size and plant architecture in rice. In a previous research, we cloned qGL3/OsPPKL1 encoding a protein phosphatase with Kelch-like repeat domains, which negatively regulates BR signaling and grain length in rice. Results Here, we screened qGL3-interacting proteins (GIPs) via yeast two-hybrid assay and analyzed the phenotypes of the T-DNA insertion mutants of GIPs. Among these mutants, mutant osak3 presents shorter grain length and dwarfing phenotype. OsAK3 encodes an adenylate kinase, which regulates grain size by controlling cell expansion of rice spikelet glume. Overexpression of OsAK3 resulted in longer grain length. OsAK3 interacts with qGL3 in vivo and in vitro. Lamina inclination, coleoptile elongation and root inhibition experiments showed that the osak3 mutant was less sensitive to exogenous brassinolide (BL) treatment. The transcriptional level of OsAK3 was up-regulated under BL induction. In addition, RNA-Seq data indicate that OsAK3 is involved in a variety of biological processes that regulate BR signaling and grain development in rice. Conclusions Our study reveals a novel BR signaling component OsAK3 in the regulation of grain length, and provides novel clues for uncovering the potential functions of OsAK3 in rice growth and development.

BackgroundHere, a bibliometric and knowledge map analysis are used to analyze the research hot spots and development trends regarding the antibacterial effect of lactoferrin (LF). By looking for research hot spots and new topics, we provide new clues and research directions for future research.MethodsArticles and reviews regarding the antibacterial effect of LF were retrieved and from the Web of Science Core Collection (WoSCC) on 25 June 2022. CiteSpace and VOSviewer were used to conduct the bibliometric and knowledge map analysis.ResultsIn total, 8,292 authors at 2,151 institutions from 86 countries published 1,923 articles in 770 academic journals. The United States was the leader regarding research on the antibacterial effects of LF, while the Netherlands was a pioneer in conducting research in this field. The University of California system contributed the most publications. Bolscher JGM published most articles, while Wayne Bellamy had most cocitations. However, there was insufficient cooperation among the various institutions and authors. BioMetals published most LF-antibacterial activity-related articles, whereas Infection and Immunity was most commonly cocited journal. The most influential research hot spots about the antibacterial effect of LF focused on antimicrobial peptides, casein, human milk, expression, and Escherichia coli-related research. The latest hot spots and research frontier included COVID-19, antibiofilm activity, and immune defense.ConclusionsLF is a multifunctional protein with a broad spectrum of antimicrobial activities. The related field of antibacterial properties of LF will remain a research hot spot in future.

Abstract Background Many studies have found that ruthenium complexes possess unique biochemical characteristics and inhibit tumor growth or metastasis. Results Here, we report the novel dual-targeting ruthenium candidate 2b, which has both antitumor and antimetastatic properties and targets tumor sites through the enhanced permeability and retention (EPR) effect and transferrin/transferrin receptor (TF/TFR) interaction. The candidate 2b is composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b triggered DNA cleavage and thus blocked cell cycle progression and induced apoptosis via the PARP/ATM pathway. In vivo, 2b inhibited not only Lewis lung cancer (LLC) tumor growth but also lung metastasis. We detected apoptosis and decreased CD31 expression in tumor tissues, and ruthenium accumulated in the primary tumor tissue of C57BL/6 mice implanted with LLC cells. Conclusions Thus, we conclude that 2b targets tumors, inhibits tumor growth and prevents lung metastasis.

Octadecylazanediyl dipropionic acid (C18ADPA) is a zwitterionic amphiphile with a dendritic headgroup. C18ADPA self-assembles to lamellar networks, which encompasses water and forms a low-molecular-weight hydrogel (LMWG). In this study, we use the C18ADPA hydrogel as a drug carrier for the in vivo delivery of a copper salt for wound healing in a mouse model. A structural transition was observed based on cryo-scanning electron microscope (cryo-SEM) images after drug loading. The C18ADPA hydrogel, which had a layered structure, transformed into a self-assembled fibrillar network (SAFiN). The mechanical strength of the LMWG has always been an important issue in its applications. However, due to the structural transition, both the storage and loss moduli increased. In vivo tests showed that wound closure was faster after applying the hydrogel formulation compared with the Vaseline formulation. For the first time, we have also provided histological evidence of these effects on skin tissue. The hydrogel formulation exhibited clear advantages in regenerating tissue structure over traditional delivery formulations.

The most concerning adverse effects of thrombolytic agents are major bleeding and intracranial hemorrhage due to their short half-life, low fibrin specificity, and high dosage. To alleviate bleeding side effects during thrombolytic therapy which would bring about the risk of aggravation, we try to find a novel biodegradable delivery nanosystem to carry drugs to target the thrombus, reduce the dosage of the drug, and system side effects. A novel urokinase/poly-α, β-d, l-aspartyl-Arg-Gly-Asp-Ser complex (UK/PD-RGDS) was synthesized and simply prepared. Its thrombolytic potency was assayed by the bubble-rising method and in vitro thrombolytic activity by the thrombus clot lysis assay separately. The in vivo thrombolytic activity and bleeding complication were evaluated by a rat model of carotid arteriovenous bypass thrombolysis. The thrombolytic potency (1288.19 ± 155.20 U/mg) of the UK/PD-RGDS complex nano-globule (18–130 nm) was 1.3 times that of commercial UK (966.77 ± 148.08 U/mg). In vivo, the UK/PD-RGDS complex (2000 IU/kg) could reduce the dose of UK by 90% while achieving the equivalent thrombolysis effect as the free UK (20,000 IU/kg). Additionally, the UK/PD-RGDS complex decreased the tail bleeding time compared with UK. The organ distribution of the FITC-UK/PD-RGDS complex was explored in the rat model. The UK/PD-RGDS complex could provide a promising platform to enhance thrombolytic efficacy significantly and reduce the major bleeding degree.

Abstract Objective Chondrocyte apoptosis plays a vital role in osteoarthritis (OA) progression. Angelica sinensis polysaccharide (ASP), a traditional Chinese medicine, possesses anti-inflammatory and anti-apoptotic properties in chondrocytes. This study aimed to determine the protective role of ASP on sodium nitroprusside (SNP)-induced chondrocyte apoptosis, and explore the underlying mechanism. Method Human primary chondrocytes isolated from the articular cartilage of OA patients were treated with SNP alone or in combination with different doses of ASP. Cell viability and apoptosis were assessed, and apoptosis-related proteins including Bcl-2 and Bax were detected. Autophagy levels were evaluated by light chain 3 (LC3) II immunofluorescence staining, mRFP-GFP-LC3 fluorescence localization, and western blot (LC3II, p62, Beclin-1, Atg5). Meanwhile, activation of the ERK 1/2 pathway was determined by western blot. The autophagy inhibitors, 3-methyladenine (3-MA), chloroquine (CQ), and a specific inhibitor of ERK1/2, SCH772984, were used to confirm the autophagic effect of ASP. Results The results showed that SNP-induced chondrocyte apoptosis was significantly rescued by ASP, whereas ASP alone promoted chondrocyte proliferation. The anti-apoptotic effect of ASP was related to the enhanced autophagy and depended on the activation of the ERK1/2 pathway. Conclusion ASP markedly rescued SNP-induced apoptosis by activating ERK1/2-dependent autophagy in chondrocytes, and it made ASP as a potential therapeutic supplementation for OA treatment.

Abstract Background The direct anterior approach for total hip arthroplasty (THA) has specific advantages, but injury to the tensor fasciae lata muscle (TFLM) remains a concern. This injury in part negates some of the advantages of the intermuscular approach, because injury of the muscle fibers of the TFLM can lead to less satisfactory clinical results. Thus, in this study, we propose an intraoperative method to protect the TFLM and demonstrate its feasibility. Methods Fifty-six patients undergoing THA by the direct anterior approach were divided randomly into two groups. In group A, the TFLM was protected by an autogenous tissue “pad” created from the anterior capsule of the joint which protect the TFLM from direct contact with the retractors. In group B, the operation was carried out with no protection of the TFLM except the attempt by the surgeons to consciously avoid injury of the TFLM. We evaluated magnitude of changes in the muscle cross-sectional area (MSCA) and fatty atrophy (FA) by magnetic resonance imaging. The differences in blood hemoglobin and serum levels of myoglobin, lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were compared at different time, postoperatively. The Harris hip score, postoperative drainage volume and visual analogue scores (VAS) were compared between the two groups. Results LDH, CPK and myoglobin in group B were significantly higher than group A at 8, 24, and 48 h after the surgery. (p

Delineation of agricultural fields is desirable for operational monitoring of agricultural production and is essential to support food security. Due to large within-class variance of pixel values and small inter-class difference, automated field delineation remains to be a challenging task. In this study, a strategy is proposed to effectively address this issue. Firstly, a framework was developed using the Canny operator connected with the Watershed segmentation algorithm (CW) to quickly label the training dataset, which minimizes the workload of dataset generation in comparison with the commonly used manual vectorization. Secondly, a CW-trained deep semantic segmentation network, recurrent residual U-Net, was selected to mine the low level and deep semantic features. Finally, a boundary connecting method (to integrate fragmented boundaries) was used to generate the agricultural field boundary. The proposed methods are tested over smallholder agricultural landscape in Heilongjiang province, China, using Sentinel-2 imagery. Compared with the U-Net (overall accuracy (OA) 82.18%), the residual U-Net (ResU-Net, with OA 85.78%), traditional object-based image analysis (OBIA, with OA about 82%), and the existing 10-m resolution global land cover map (FROM-GLC10), the proposed method shows an improved performance (OA 89.28%, and Kappa 0.85). The successful application of the proposed method suggests that the recurrent residual U-Net model has great universality in agricultural field boundary extraction, and the automated technique has the potential of being applied to other regions.

Timely and accurate mapping crops is essential for agricultural management, policy making and food security. The smallholder agricultural systems lead to large number of fragmented and heterogeneous landscape, making fine crop mapping a huge challenge. Feature and classifier selection are two important influencing factors in crop classification. However, there are few systematic tests to determine the specific features and classifiers needed for heterogeneous agricultural landscapes. In this study, 24 candidate spectral features, 8 spatial texture features from the red-edge (RE) and near-infrared (NIR) bands, and 4 supervised classifiers (i.e. random forest (RF), support vector machine (SVM), artificial neural network (ANN), and maximum likelihood classifier (MLC)) were used for crop mapping. 60 spatially heterogeneous landscapes in Heilongjiang Province, northeastern China were selected as the study areas, evaluated by compositional heterogeneity (homogeneity index, HOI) and configurational heterogeneity (splitting index, SPLIT). The results summarized a look-up table for searching the optimum classification features and classifiers in different landscape, providing a reference for future crop classifications and preventing the consumption of computing time. The results revealed that (1) an optimal feature-subset (with reduced data volume by 65%) can achieve high-accuracy crop mapping in heterogeneous regions. (2) The optimum type and number of features and classifiers are landscape sensitive. When a specific accuracy was required, homogenous regions need a smaller number of features and a simple MLC could meet the requirement. (3) The impact of configurational heterogeneity on textural features is more significant, while compositional heterogeneity performs better on spectral Vegetation Indices (VIs). Findings from this study provide a general guideline for crop mapping in plains or fragmented landscape and areas with single or complex planting structure.

The systemic spread of malignancies and the risk of cancer-associated thrombosis are major clinical challenges in cancer therapy worldwide. As an important post-translational modification enzyme, peptidyl arginine deiminase 4 (PAD4) could mediate the citrullination of protein in different components (including nucleus and cytoplasm, etc.) of a variety of cells (tumor cells, neutrophils, macrophages, etc.), thus participating in gene regulation, neutrophil extracellular trap (NET) and macrophage extracellular trap (MET). Thereby, PAD4 plays an important role in enhancing the growth of primary tumors and facilitating the distant metastasis of cancer cells. In addition, it is related to the formation of cancer-associated thrombosis. Therefore, the development of PAD4-specific inhibitors may be a promising strategy for treating cancer, and it may improve patient prognosis. In this review, we describe PAD4 involvement in gene regulation, protein citrullination, and NET formation. We also discuss its potential role in cancer and cancer-associated thrombosis, and we summarize the development and application of PAD4 inhibitors.

Phytantriol-based lyotropic liquid crystals (LLCs) have emerged as a new nanodrug delivery system. However, the understanding of phytantriol-based LLCs is lacking. In this study, we use NMR technology to characterize LLC formation over two months. Three samples in different phases were prepared with different hydration states. NMR data, including 1D-1H, 13C-{1H}, 2D-HSQC, HMBC, COSY, NOESY, etc., were collected. A comprehensive analysis of these NMR data was performed on the three phases of phytantriol-based LLCs. The following results were achieved from the study. First, the 1H and 13C-{1H} spectra of phytantriol were assigned. Second, the change of NMR spectra during the formation of the phases was observed, and the change of hydration was calculated for the time-dependent phase formation. Third, the correlation peaks of 2D-NOESY were used to describe the spatial relationship of lipids–water interaction and lipid–lipid interaction.

Objective: Neutrophil infiltration plays an important role in the initiation and development of abdominal aortic aneurysm (AAA). Recent studies suggested that neutrophils could release neutrophil extracellular traps (NETs), leading to tissue injury in cardiovascular diseases. However, the role of NETs in AAA is elusive. This study aimed to investigate the role and underlying mechanism of NETs in AAA development.Methods and Results: An angiotensin II (Ang II) infusion-induced AAA model was established to investigate the role of NETs during AAA development. Immunofluorescence staining showed that citrullinated histone 3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) (NET marker) expressions were significantly increased in Ang II-infused ApoE−/− mice. The circulating double-stranded DNA (dsDNA) level was also elevated, indicating the increased NET formation during AAA. PAD4 inhibitor YW3-56 inhibited Ang II-induced NET formation. Disruption of NET formation by YW3-56 markedly reduced Ang II-induced AAA rupture, as revealed by decreased aortic diameter, vascular smooth muscle cell (VSMC) apoptosis, and elastin degradation. Apoptosis of VSMC was evaluated by TUNEL staining and Annexin V-FITC/PI staining through flow cytometry. Western blot and inhibition experiments revealed that NETs induced VSMC apoptosis via p38/JNK pathway, indicating that PAD4-dependent NET formation played an important role in AAA.Conclusions: This study suggests that PAD4-dependent NET formation is critical for AAA rupture, which provides a novel potential therapeutic strategy for AAA disease.

Abstract Background The global spread of mosquito-borne diseases (MBD) has presented increasing challenges to public health. The transmission of MBD is mainly attributable to the biting behaviors of female mosquitoes. However, the ecological pattern of hourly host-seeking behavior in Aedes albopictus and its association with climatic variables are still not well understood, especially for a precise requirement for establishing an effective risk prediction system of MBD transmission. Methods Mosquito samples and data on mosquito hourly density and site-specific climatic variables, including temperature, relative humidity, illuminance and wind speed, were collected simultaneously in urban outdoor environments in Guangzhou during 2016–2018. Kernel regression models were used to assess the temporal patterns of hourly host-seeking behavior in mosquito populations, and negative binomial regression models in the Bayesian framework were used to investigate the associations of host-seeking behavior with climatic variables. Results Aedes albopictus was abundant, constituting 82% (5569/6790) of the total collected mosquitoes. Host-seeking behavior in Ae. albopictus varied across time and was significantly influenced by climatic variables. The predicted hourly mosquito densities showed non-linear relationships with temperature and illuminance, whereas density increased with relative humidity but generally decreased with wind speed. The range of temperature estimates for female biting was 16.4–37.1 °C, peaking at 26.5 °C (95% credible interval: 25.3–28.1). During the favorable periods, biting behavior of female Ae. albopictus was estimated to occur frequently all day long, presenting a bimodal distribution with peaks within 2–3 h around both dawn and dusk (05:00–08:00 h and 16:00–19:00 h). Moreover, a short-term association in hourly density between the females and males was found. Conclusions Our field-based modeling study reveals that hourly host-seeking behavior of Ae. albopictus exhibits a complex pattern, with hourly variation constrained significantly by climatic variables. These findings lay a foundation for improving MBD risk assessments as well as practical strategies for vector control. For instances of all-day-long frequent female biting during the favorable periods in Guangzhou, effective integrated mosquito control measures must be taken throughout the day and night.

(1) Background: Children under 5 years of age are the most vulnerable to malaria infection, and they suffer serious complications. Sierra Leone is one of the countries with the highest malaria burden in the world. This study aimed to assess the knowledge, attitudes, and practices (KAPs) toward malaria control and prevention among caregivers of children under 5 in the Western Area of Sierra Leone. (2) Methods: A cross-sectional survey was conducted among caregivers of children under-5 visiting the out-patient department of six selected hospitals/community health centers. Data were collected via questionnaire interviews with 350 caregivers. (3) Results: A total of 97.1% of the respondents were women and the majority of them were young mothers; 46.3% of respondents were unemployed; and 27.1% received no education. Only 1.4% accessed malaria related information from the internet/social media. This KAPs survey indicated that a misconception of the cause, transmission, and clinical symptoms of malaria; unawareness of its lethality and its severity; and inappropriate prevention and treatment behaviors, such as self-medicating, were still in existence among some caregivers. However, a positive correlation in knowledge–attitudes (rs = 0.13, p < 0.05) and in attitudes–practices (rs = 0.45, p < 0.001) was revealed. The caregivers, being mothers and having at least a secondary education, demonstrated positive attitudes and practices. Meanwhile, more urban caregivers (79.8%) followed a complete malaria treatment course of artemisinin-based combination therapies than the rural (63.3%), but in view of insecticide treated net use, more rural caregivers presented positive attitudes (85.3%) and practices (70.1%) than the urban (69.9%, 52.0%). (4) Conclusions: For better protection of children under-5 against lethal malaria, it is essential to provide better guidance at the community level for their caregivers, especially young mothers, in order to reduce some misconceptions and inappropriate behaviors. An increase in education and employment opportunities for women, establishment of an accessible community-based malaria counselling service, and construction of an effective communication channel are also needed.

Abstract Background With the patient in a constant supine position, elevation of the femur in THA (DAA) provides a more intuitive and conducive location of the acetabulum for the correct placement of the acetabular prosthesis, but elevation of the femur for broaching becomes more challenging. The purpose of this study is to analyze the restriction of the ischiofemoral ligament and short external rotation muscles, and its effect on the elevation of the proximal femur in the DAA. Methods The study subjects comprised 5 freshly frozen cadavers with 10 normal hips. All of the anatomic dissections of all of the hips were performed through the DAA. The ischiofemoral ligament, piriformis, conjoint tendon, and external obturator were successively resected. All of the proximal femurs of the specimens were levered by a point tip curved retractor that was connected with a dynamometer. Through preliminary measurements, an applied force of 80 N was adopted and maintained on the curved retractor. The experiment was repeated to measure the displacement of the proximal femur being raised after the posterior structures of the hip joint had been resected in a stepwise fashion. The displacement of the retractor was recorded, and the data were then analyzed. Results The distance significantly increased after the ischiofemoral ligament was severed (P 0.05). After the obturator externus was cut off, the distance increased by an insignificant amount (P > 0.05). Conclusion In DAA, the ischiofemoral ligament contributed stability when the femur was being raised. The main contribution of restriction was provided by the conjoint tendon. The tendons of the obturator externus muscle and piriformis muscle did not provide any significant restriction when the femur was being raised.

Peri-prosthetic osteolysis (PPO) and following aseptic loosening are regarded as the prime reasons for implant failure after joint replacement. Increasing evidence indicated that wear-debris-irritated inflammatory response and macrophage polarization state play essential roles in this osteolytic process. Harmine, a β-carboline alkaloid primitively extracted from the Peganum harmala seeds, has been reported to have various pharmacological effects on monoamine oxidase action, insulin intake, vasodilatation and central nervous systems. However, the impact of harmine on debris-induced osteolysis has not been demonstrated, and whether harmine participates in regulating macrophage polarization and subsequent osteogenic differentiation in particle-irritated osteolysis remains unknown. In the present study, we investigated the effect of harmine on titanium (Ti) particle-induced osteolysis in vivo and in vitro. The results suggested harmine notably alleviated Ti particle-induced bone resorption in a murine PPO model. Harmine was also found to suppress the particle-induced inflammatory response and shift the polarization of macrophages from M1 phenotypes to M2 phenotypes in vivo and in vitro, which improved anti-inflammatory and bone-related cytokines levels. In the conditioned medium from Ti particle-stimulated murine macrophage RAW264.7 cells treated with harmine, the osteoblast differentiation ability of mouse pre-osteoblastic MC3T3-E1 cells was greatly increased. And we also provided evidences that the immunomodulatory capacity of harmine might be attributed to the inhibition of the c-Jun N-terminal kinase (JNK) in wear particle-treated macrophages. All the results strongly show that harmine might be a promising therapeutic agent to treat PPO.

Dengue virus, one of the most important mosquito-borne viruses, has shown a sharp upward trend, spreading around the world in recent years. Control of vectors Aedes aegypti and Ae. albopictus remains crucial for blocking dengue transmission. The lethal ovitrap (LO) is one of the cost-effective traps based on the classic “lure and kill” strategy, and finding a proper long-lasting effective toxin is key to achieving the desired effect. The concentration of inorganic salts of habitat environment plays a strong role in affecting oviposition, hatching, and development of mosquitoes, but the potential insecticide activity of Sodium Chloride (NaCl) in habitat water as well as LO still lacks research. In this study, we carried out laboratory experiments to systematically explore the effects of different concentrations of NaCl solutions on oviposition, egg hatching, and larval development of Ae. albopictus. Consequently, Ae. albopictus was found to prefer freshwater to lay eggs; whereas 48.8 ± 2.6% eggs were laid in freshwater and 20% in ≥1.0% brackish water, few eggs were laid in 3.0% NaCl solution. Compared with egg hatching, larval development of Ae. albopictus presented a higher sensibility to NaCl concentration. The mortality of the 3rd–4th larvae in 1.0% NaCl solution was 83.8 ± 8.7%, while in 3.0% it reached 100%. Considering the cumulative effect of NaCl, when NaCl concentration was ≥1.0%, no eggs could successfully develop into adults. These data suggested that NaCl solutions with a concentration ≥1.0% can be used as an effective cheap insecticide for Ae. albopictus in subtropical inland aquatic habitats, and also as the “kill” toxin in LOs. Meanwhile, the concentration range from 0 to 2.0% of NaCl solution has the potential to be used as the “lure” in LOs. The technological processes of how to use NaCl as insecticide or in LOs still needs further in-depth exploration.

Aim: The study aims to describe a less invasive technique for displaced tibial intercondylar eminence fractures, using only one bone tunnel with suture anchor and EndoButton system. Methods: Seventeen patients were followed up after arthroscopic fixation for tibial eminence fractures using suture anchor and EndoButton. The patients were followed with clinical examinations such as Lysholm, Tegner, and International Knee Documentation Committee (IKDC) rating scales. Radiographic assessments were also performed during the follow-up for evaluating the healing of the fracture. Results: There were 14 male patients and 3 female patients with 10 right knees, and 7 left knees included. All the fractures healed anatomically at final follow-up. Also, no clinical signs of anterior cruciate ligament deficiency were detected. The mean Lysholm score improved significantly from 74.72 ± 3.24 (range from 70 to 79) to 96.2 ± 2.54 (range from 89 to 98) ( p < 0.001). The IKDC category was abnormal or severely abnormal preoperatively and all the patients improved to normal or nearly normal at final follow-up. The Tegner score also improved significantly postoperatively from 3.45 ± 1.02 to 6.34 ± 1.22 ( p < 0.001). Conclusion: The study demonstrated that the procedure is safe and effective, which can be another option for tibial intercondylar eminence fractures.

The antitumor activity of roscovitine was tested in four cervical carcinoma cells: C33A, HCE-1, HeLa, and SiHa. The effects of roscovitine on ATP Lite assay, cell cycle, and apoptosis were assessed. The Sub-G1 DNA content occurred great increasing, and this indicates that apoptosis was induced quickly in HeLa cells, but slowly in the other cells. The morphological observation results showed that roscovitine induced apoptosis and cell death in the cervical carcinoma cells. Results revealed that roscovitine exhibited selective cytotoxicity towards 4 cervical carcinoma cells, and the cells showed different morphologic and apoptotic changes at the same concentration. It was estimated that cervical carcinoma cells responded differently to roscovitine because of differences in apoptotic and genetic background in different cervical carcinoma cells. This study suggested that roscovitine had the potential to be a chemotherapeutic agent against cervical carcinoma.

Alsterpaullone, a small molecule cyclin-dependent kinase (CDK) inhibitor, regulates the cell cycle progression. Beyond death-inducing properties, we identified the effect of alsterpaullone on cycle procedure and apoptosis of HeLa cell. It was found that alsterpaullone inhibited HeLa cells in a time-dependent (0–72 h) and dose-dependent (0–30 μM) manner. In the presence of alsterpaullone, HeLa cells were arrested in G2/M prior to undergoing apoptosis via a mechanism that is involved in the regulation of various antiapoptotic genes, DNA-repair, transcription, and cell cycle progression. Compared to controls, alsterpaullone effectively prevented HeLa cells from entering S-phase. These potential therapeutic efficacies could be correlated with the activation of caspase-3.