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Abstract Background Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored. Methods tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM. Results We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation. Conclusions Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM. Graphical Abstract

Abstract Polyploidization plays an important role in plant evolution and biodiversity. However, intraspecific polyploidy compared to interspecific polyploidy received less attention. Clintonia udensis (Liliaceae) possess diploid (2n = 2x = 14) and autotetraploid (2n = 4x = 28) cytotypes. In the Hualongshan Mountains, the autotetraploids grew on the northern slope, while the diploids grew on the southern slopes. The clonal growth characteristics and clonal architecture were measured and analyzed by field observations and morphological methods. The diversity level and differentiation patterns for two different cytotypes were investigated using SSR markers. The results showed that the clonal growth parameters, such as the bud numbers of each rhizome node and the ratio of rhizome branches in the autotetraploids were higher than those in the diploids. Both the diploids and autotetraploids appeared phalanx clonal architectures with short internodes between ramets. However, the ramets or genets of the diploids had a relatively scattered distribution, while those of the autotetraploids were relatively clumping. The diploids and autotetraploids all allocated more biomass to their vegetative growth. The diploids had a higher allocation to reproductive organs than that of autotetraploids, which indicated that the tetraploids invested more resources in clonal reproduction than diploids. The clone diversity and genetic diversity of the autotetraploids were higher than that of the diploids. Significant genetic differentiation between two different cytotypes was observed (P

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, characterized by high morbidity, high mortality, and poor prognosis. Collagen triple helix repeat containing 1 (CTHRC1) has been shown to be highly expressed in various cancers. However, its biological functions, potential role as a biomarker, and its relationship with immune infiltrates in HNSCC remain unclear. Our principal objective was to analyze CTHRC1 expression, its prognostic implications, biological functions, and its effects on the immune system in HNSCC patients using bioinformatics analysis. Methods The expression matrix was obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). CTHRC1 expression in HNSCC was analyzed between tumor and adjacent normal tissues, different stages were compared, and its impact on clinical prognosis was assessed using Kaplan-Meier analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA) were employed for enrichment analysis. The Search Tool for the Retrieval of Interacting Genes database (STRING) was used to analyze protein-protein interactions. Pearson correlation tests were used to investigate the association between CTHRC1 expression and immune checkpoints. The correlation between CTHRC1 and immune infiltration was investigated using CIBERSORT, TIMER, and ESTIMATE. Results Compared to adjacent normal tissues, CTHRC1 was found to be highly overexpressed in tumors. Increased expression of CTHRC1 was more evident in the advanced stage of HNSCC and predicted a poor prognosis. Most genes related to CTHRC1 in HNSCC were enriched in physiological functions of Extracellular matrix(ECM) and tumor. Furthermore, several immune checkpoints, such as TNFSF4 and CD276 have been shown to be associated with CTHRC1 expression. Notably, the level of CTHRC1 expression correlated significantly with immune infiltration levels, particularly activated macrophages in HNSCC. Conclusions High expression of CTHRC1 predicts poor prognosis and is associated with immune infiltration in HNSCC, confirming its utility as a tumor marker for HNSCC. Trial registration Not applicable. All data are from public databases and do not contain any clinical trials.

Water resource carrying capacity is a critical measure of the ability of water resources within a region to support social, ecological, and economic scales. This study establishes an evaluation index system for the water resource carrying capacity of Golmud City and calculates the weights of the indices using the Analytic Hierarchy Process (AHP). Based on an analysis of the current status of Golmud’s socio-economic development, agriculture, and water resource utilization, a simulation model based on system dynamics is constructed. By setting 162 different scenario plans and normalizing the simulation results, the development trend of Golmud City’s water resource carrying capacity is studied, and an evaluation is made for the sustainable development of water resources in Golmud City. Using data from 2001 to 2018 as the basic data, a carrying capacity analysis of water resources for the future from 2019 to 2030 is conducted. The study reveals that continuing the current development pattern will lead to unsustainable water resource carrying capacity. Among the scenarios aimed at coordinated development in all aspects, the best water resource carrying index is achieved, reaching 0.698 by 2030. By analyzing the development trend of the water resource carrying capacity index, existing problems in the utilization of water resources in Golmud City are identified, and feasible strategies for the sustainable use of water resources in Golmud City are proposed.

Abstract Background The C2H2 zinc finger protein family plays important roles in plants. However, precisely how C2H2s function in Opisthopappus (Opisthopappus taihangensis and Opisthopappus longilobus) remains unclear. Results In this study, a total of 69 OpC2H2 zinc finger protein genes were identified and clustered into five Groups. Seven tandem and ten fragment repeats were found in OpC2H2s, which underwent robust purifying selection. Of the identified motifs, motif 1 was present in all OpC2H2s and conserved at important binding sites. Most OpC2H2s possessed few introns and exons that could rapidly activate and react when faced with stress. The OpC2H2 promoter sequences mainly contained diverse regulatory elements, such as ARE, ABRE, and LTR. Under salt stress, two up-regulated OpC2H2s (OpC2H2-1 and OpC2H2-14) genes and one down-regulated OpC2H2 gene (OpC2H2-7) might serve as key transcription factors through the ABA and JA signaling pathways to regulate the growth and development of Opisthopappus species. Conclusion The above results not only help to understand the function of C2H2 gene family but also drive progress in genetic improvement for the salt tolerance of Opisthopappus species.

Lung cancer is a highly prevalent malignancy with poor prognosis and rapid progression. It most frequently metastasizes to the bone, where it can pose a severe threat to the patient's survival. Once metastasized, the disease is often incurable and can result in severe complications such as hypercalcemia, bone pain, fractures, spinal cord compression, and subsequent paralysis. Exosomes are bilayer vesicle nanoparticles secreted by most of the extracellular vesicles, which can be found in almost all organisms and play an essential role in intercellular communication. Through their ability to regulate related bone cells, exosomes carry bioactive molecules, including proteins, lipids, and non-coding RNAs (ncRNAs), that can be extremely important in bone remodeling. Studies have been conducted on the role play by proteins, lncRNA, and microRNA—all ncRNAs—carried by exosomes in the bone metastases of lung cancer. In this review, the latest progress of the regulatory mechanism of ncRNAs carried by exosomes in lung cancer bone metastasis has been reviewed. The clinical use of exosomes as a promising biomarker, drug transporter, and therapeutic target was highlighted to offer a novel diagnostic and treatment approach for patients with lung cancer bone metastases.

Abstract Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta‐hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood‐brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO‐ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO‐1 by enhancing local β‐hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO‐ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

Background The dysfunction of the immune system is one of the pathogeneses of endometriosis. Immune cells can not only affect the microenvironment of the endometrium by secreting cytokines and defensins but also promote angiogenesis, growth and invasion of endometrial stromal cells.Result ATP is a key mediator in the immune mechanism of endometriosis and plays a crucial role in endometriosis. While ATP acts as a purinergic signalling molecule, it has a close relationship with the pain of endometriosis via activating ATP receptors, including P2X3, P2X4, P2X7 and P2Y receptors, after being activated by the immune system. Besides, ATP levels reflect the impairment of mitochondrial function in granulosa cells, which could lead to infertility. The modulation of ATP expression levels is controlled by ectonucleotidases. The content of ectonucleotidases is altered in endometriosis which may be emerging non-invasive biomarkers.Conclusion In the present review, we briefly introduce the relationship between the change of ATP level controlled by ectonucleotidases and endometriosis-associated infertility and pain, and illustrate our prospects for future research.

Abstract As integral components of the immune microenvironment, tissue resident macrophages (TRMs) represent a self-renewing and long-lived cell population that plays crucial roles in maintaining homeostasis, promoting tissue remodeling after damage, defending against inflammation and even orchestrating cancer progression. However, the exact functions and roles of TRMs in cancer are not yet well understood. TRMs exhibit either pro-tumorigenic or anti-tumorigenic effects by engaging in phagocytosis and secreting diverse cytokines, chemokines, and growth factors to modulate the adaptive immune system. The life-span, turnover kinetics and monocyte replenishment of TRMs vary among different organs, adding to the complexity and controversial findings in TRMs studies. Considering the complexity of tissue associated macrophage origin, macrophages targeting strategy of each ontogeny should be carefully evaluated. Consequently, acquiring a comprehensive understanding of TRMs' origin, function, homeostasis, characteristics, and their roles in cancer for each specific organ holds significant research value. In this review, we aim to provide an outline of homeostasis and characteristics of resident macrophages in the lung, liver, brain, skin and intestinal, as well as their roles in modulating primary and metastatic cancer, which may inform and serve the future design of targeted therapies.

Abstract Objectives Deep learning-based auto-segmentation of head and neck cancer (HNC) tumors is expected to have better reproducibility than manual delineation. Positron emission tomography (PET) and computed tomography (CT) are commonly used in tumor segmentation. However, current methods still face challenges in handling whole-body scans where a manual selection of a bounding box may be required. Moreover, different institutions might still apply different guidelines for tumor delineation. This study aimed at exploring the auto-localization and segmentation of HNC tumors from entire PET/CT scans and investigating the transferability of trained baseline models to external real world cohorts. Methods We employed 2D Retina Unet to find HNC tumors from whole-body PET/CT and utilized a regular Unet to segment the union of the tumor and involved lymph nodes. In comparison, 2D/3D Retina Unets were also implemented to localize and segment the same target in an end-to-end manner. The segmentation performance was evaluated via Dice similarity coefficient (DSC) and Hausdorff distance 95th percentile (HD95). Delineated PET/CT scans from the HECKTOR challenge were used to train the baseline models by 5-fold cross-validation. Another 271 delineated PET/CTs from three different institutions (MAASTRO, CRO, BERLIN) were used for external testing. Finally, facility-specific transfer learning was applied to investigate the improvement of segmentation performance against baseline models. Results Encouraging localization results were observed, achieving a maximum omnidirectional tumor center difference lower than 6.8 cm for external testing. The three baseline models yielded similar averaged cross-validation (CV) results with a DSC in a range of 0.71–0.75, while the averaged CV HD95 was 8.6, 10.7 and 9.8 mm for the regular Unet, 2D and 3D Retina Unets, respectively. More than a 10% drop in DSC and a 40% increase in HD95 were observed if the baseline models were tested on the three external cohorts directly. After the facility-specific training, an improvement in external testing was observed for all models. The regular Unet had the best DSC (0.70) for the MAASTRO cohort, and the best HD95 (7.8 and 7.9 mm) in the MAASTRO and CRO cohorts. The 2D Retina Unet had the best DSC (0.76 and 0.67) for the CRO and BERLIN cohorts, and the best HD95 (12.4 mm) for the BERLIN cohort. Conclusion The regular Unet outperformed the other two baseline models in CV and most external testing cohorts. Facility-specific transfer learning can potentially improve HNC segmentation performance for individual institutions, where the 2D Retina Unets could achieve comparable or even better results than the regular Unet.

The serine/threonine kinase PAK4 plays a crucial role in regulating cell proliferation, survival, migration, and invasion. Overexpression of PAK4 correlates with poor prognosis in some cancers. KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells. Interestingly, although it was first identified as a PAK4 inhibitor, KPT-9274 was also found to inhibit the enzyme NAMPT (nicotinamide phosphoribosyltransferase), which is crucial for NAD (nicotinamide adenine dinucleotide) synthesis and vital for cellular energy and growth. These results made us question whether growth inhibition in response to KPT-9274 was due to PAK4 inhibition, NAMPT inhibition, or both. To address this, we tested several other PAK4 inhibitors that also inhibit cell growth, to determine whether they also inhibit NAMPT activity. Our findings confirm that multiple PAK4 inhibitors also inhibit NAMPT activity. This was assessed both in cell-free assays and in a breast cancer cell line. Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4. Our results suggest that PAK4 inhibitors may have a more complex mechanism of action than previously understood, necessitating further exploration of how they influence cancer cell growth.

Cell size is a key morphological trait which is associated with microbial activity and nutrient acquisition. However, it is still unclear whether bacteria of different sizes have similar structural and functional properties. In this study, we sorted bacterial cells into five size classes (small, slightly small, medium, slightly large, large) using FACS and compared their structural and functional profiles in soils from deciduous and evergreen forests. The results showed that most (about 60%) of the bacterial cells fell under small or slightly small size classes. The five size classes harbored distinct bacterial communities in both types of forest soil. In spite of the lower relative abundance, slightly large and large bacterial cells had higher diversity compared to other size classes. Core communities of the five size classes in evergreen forest soil harbored more ubiquitous OTUs when compared with deciduous forest soil. Bacterial functional structures of the five size classes were significantly different in deciduous forest soil, while similar across size classes in evergreen forest soil. We conclude that cell size is an important factor that determines bacterial structure and function, and this relationship is depended on ecosystem or soil type. This study emphasizes cell size as a useful tool when assessing bacterial diversity and uncovers a direct relationship between microbial morphology and ecological traits.

Abstract Soil harbors a vast expanse of unidentified microbes, termed as microbial dark matter, presenting an untapped reservoir of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conduct a large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalogue) from 3304 soil metagenomes. We identify 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which expand archaeal and bacterial diversity across the tree of life. We also illustrate the pivotal role of uSGBs in augmenting soil microbiome’s functional landscape and intra-species genome diversity, providing large proportions of the 43,169 biosynthetic gene clusters and 8545 CRISPR-Cas genes. Additionally, we determine that uSGBs contributed 84.6% of previously unexplored viral-host associations from the SMAG catalogue. The SMAG catalogue provides an useful genomic resource for further studies investigating soil microbial biodiversity and genetic resources.

Abstract Background Bulimia nervosa (BN) is an eating disorder characterized by recurrent binge eating and compensatory behaviors. The thalamus plays a crucial role in the neural circuitry related to eating behavior and needs to be further explored in BN. Methods In this study, 49 BN patients and 44 healthy controls (HCs) were recruited. We applied the fractional amplitude of low-frequency fluctuation to investigate regional brain activity in the thalamus and functional connectivity (FC) to examine the synchronization of activity between thalamic subregions and other brain regions in both groups. All results underwent false discovery rate (p

Using dodecyl acrylate as a raw material and 2-Cyanoprop-2-yl-dithiobenzoate as a chain transfer agent, poly(dodecyl acrylate) is synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. Using poly(dodecyl acrylate) as stabilizers, narrowly dispersed poly(ε-caprolactone) microspheres with particle sizes ranging from 0.5 to 1.5 μm are successfully synthesized by ring-opening dispersion polymerization. The effects of the molecular weight of poly(dodecyl acrylate), the volume proportion of mixed solvent (i.e., 1,4-dioxane/heptane), and the reaction temperature on the particle size and its distribution are investigated. With careful control of the synthesis condition, microspheres can be obtained with a particle size distribution of 1.09 (Dw/Dn). The average particle size of poly(ε-caprolactone) microspheres decreased with the increase in the molecular weight of poly(dodecyl acrylate) and increased with the increase in the relative content of 1,4-dioxane. The uniformity of microspheres decreased with the increase in the polymerization temperature.

Fly ash was used as raw material to prepare zeolites through silicate gels, assisted by the hydrothermal method. The silicate gels could be effectively formed in a few minutes in a molten alkali environment. The zeolites could be prepared by using these silicate gels through the hydrothermal method, which realizes the transformation from useless materials to highly valuable materials. The obtained zeolites were applied to the removal of ammonium in water, achieving the highvalue utilization of fly ash. The synthesized zeolites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectrum (EDS), thermogravimetric (TG), and Fourier transform infrared (FTIR) spectroscopy. The study on the adsorption and removal of ammonium in water shows that the adsorption of ammonium is more in line with pseudo first-order kinetics, and the adsorption mainly occurs in the first 20 min. The adsorption can reach equilibrium in 30 min, and the maximum adsorption capacity can reach 49.1 mg/g. The adsorption capacity of ammonium has the best performance at pH = 5. Furthermore, within a certain range, an increase in temperature is beneficial for the removal of ammonium.

The effective treatment and recovery of fracturing wastewater has always been one of the difficult problems to be solved in oilfield wastewater treatment. Accordingly, in this paper, photocatalytic-coupled low-temperature plasma technology was used to degrade the simulated wastewater containing hydroxypropyl guar, the main component of fracturing fluid. Results indicated that hydroxypropyl-guar wastewater could be degraded to a certain extent by either photocatalytic technology or plasma technology; the chemical oxygen demand and viscosity of the treated wastewater under two single-technique optimal conditions were 781 mg·L−1, 0.79 mPa·s−1 and 1296 mg·L−1, 1.01 mPa·s−1, respectively. Furthermore, the effective coupling of AgIn5S8/gC3N4 photocatalysis and dielectric-barrier discharge–low-temperature plasma not only enhanced the degradation degree of hydroxypropyl guar but also improved its degradation efficiency. Under the optimal conditions of coupling treatment, the hydroxypropyl-guar wastewater achieved the effect of a single treatment within 6 min, and the chemical oxygen demand and viscosity of the treated wastewater reduced to below 490 mg·L−1 and 0.65 mPa·s−1, respectively. In the process of coupled treatment, the AgIn5S8/gC3N4 could directly absorb the light and strong electric field generated by the system discharge and play an important role in the photocatalytic degradation, thus effectively improving the energy utilization rate of the discharge system and enhancing the degradation efficiency of hydroxypropyl guar.

Green credit is an important way to achieve global green development. Using the adoption of the Green Credit Guidance (GCG) policy implemented by the Chinese government in 2012 as a quasi-natural experiment, this article examines the impact of the GCG on the digital transformation of highly polluting firms. This research uses text analysis to assess the extent of digital transformation. The empirical findings show that the GCG has a considerable detrimental effect on the digital transformation of significantly polluting businesses. According to the underlying mechanics, the GCG prevents extremely polluting firms from digitalization by tightening financial restrictions and lowering innovation inputs. The GCG’s disincentive effect on heavy polluters is especially more pronounced in state-owned listed corporations and the Central and Western areas of China, as demonstrated by heterogeneity research. Our research offers novel ideas for creating a digital economy and promoting sustainable development in emerging developing nations like China.

Disentangling how climate oscillations and geographical events significantly influence plants’ genetic architecture and demographic history is a central topic in phytogeography. The deciduous ancient tree species Ulmus macrocarpa is primarily distributed throughout Northern China and has timber and horticultural value. In the current study, we studied the phylogenic architecture and demographical history of U. macrocarpa using chloroplast DNA with ecological niche modeling. The results indicated that the populations’ genetic differentiation coefficient (NST) value was significantly greater than the haplotype frequency (GST) (p < 0.05), suggesting that U. macrocarpa had a clear phylogeographical structure. Phylogenetic inference showed that the putative chloroplast haplotypes could be divided into three groups, in which the group Ⅰ was considered to be ancestral. Despite significant genetic differentiation among these groups, gene flow was detected. The common ancestor of all haplotypes was inferred to originate in the middle–late Miocene, followed by the haplotype overwhelming diversification that occurred in the Quaternary. Combined with demography pattern and ecological niche modeling, we speculated that the surrounding areas of Shanxi and Inner Mongolia were potential refugia for U. macrocarpa during the glacial period in Northern China. Our results illuminated the demography pattern of U. macrocarpa and provided clues and references for further population genetics investigations of precious tree species distributed in Northern China.

Plant NAPDH oxidase (NOX) gene family members are critical producers of ROS and play crucial roles in plant signaling, development, and stress responses. Opisthopappus taihangensis is a pivotal wild genetic resource in Asteraceae. To date, little knowledge exists about the functions of NOXs in O. taihangensis. In this study, seven typical NOXs and seven ferric reduction oxidases (FROs) were identified in O. taihangensis. Dispersed duplication might play a critical role in the expansion of the NOX/FRO gene family in O. taihangensis, and most of the NOX/FRO homologous pairs have undergone purifying selection. Although the results of the collinearity analysis show that these genes were relatively conserved, the gain and loss of members in this gene family occurred frequently during the evolution of Asteraceae. Phylogenetic analysis indicated that the FROs are relatively ancient, and the earliest diverged branch was revealed by the maximum likelihood (ML) tree. The Asteraceae NOXs were divided into six subgroups according to their relationship with Arabidopsis and rice members. The transcriptome profile unveiled tissue-specific expression patterns and complex response modes under drought and salt stresses. OtNOX6 and OtNOX7 could be recognized as important candidates to respond to drought and salt stress. Our results provide clues and references for further in-depth exploration of NOX/FRO function in O. taihangensis and other horticulture plants.

Abstract Antibiotic overuse and the subsequent environmental contamination of residual antibiotics poses a public health crisis via an acceleration in the spread of antibiotic resistance genes (ARGs) through horizontal gene transfer. Although the occurrence, distribution, and driving factors of ARGs in soils have been widely investigated, little is known about the antibiotic resistance of soilborne pathogens at a global scale. To explore this gap, contigs from 1643 globally sourced metagnomes are assembled, yielding 407 ARG‐carrying pathogens (APs) with at least one ARG; APs are detected in 1443 samples (sample detection rate of 87.8%). The richness of APs is greater in agricultural soils (with a median of 20) than in non‐agricultural ecosystems. Agricultural soils possess a high prevalence of clinical APs affiliated with Escherichia, Enterobacter, Streptococcus, and Enterococcus. The APs detected in agricultural soils tend to coexist with multidrug resistance genes and bacA. A global map of soil AP richness is generated, where anthropogenic and climatic factors explained AP hot spots in East Asia, South Asia, and the eastern United States. The results herein advance this understanding of the global distribution of soil APs and determine regions prioritized to control soilborne APs worldwide.

With the implementation of low-carbon energy, the construction of a large number of hydropower stations has caused a large number of reservoir bank landslides. Reservoir bank landslides are significantly different from ordinary landslides, but in the process of actual engineering stability calculations, engineers still confuse the two and use the same ideas and methods for research. In order to better control the reservoir bank slope instability, according to the characteristics of the reservoir bank slope, and long-term field geological survey and indoor literature research, this paper puts forward the principle of reservoir bank slope zoning according to the structural surface characteristics, slope position and landslide material composition. According to the characteristics of reservoir bank landslide, the stability calculation formulas of traction landslide is derived in three cases: the traction section has thrust + the trailing edge tensile fracture surface has shear force, the traction section does not have thrust + the trailing edge tensile fracture surface has shear force, and the traction section does not have thrust + the trailing edge tensile fracture surface has no shear force. Combined with engineering examples, the improved transfer coefficient method for landslide stability evaluation based on reservoir bank slope characteristics is verified.

Malignant tumors have a unique tumor microenvironment (TME), which includes mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), and high glutathione (GSH) levels, among others. Recently, TME regulation approaches have attracted widespread attention in cancer immunotherapy. Nanoparticles as drug delivery systems have ability to modulate the hydrophilicity of drugs to affect drug uptake and efflux in tumor. Especially, the metal nanoparticles have been extensive applied for tumor immunotherapy due to their unique physical properties and elaborate design. However, the potential deficiencies of metal nanoparticles due to their low biodegradability, toxicity and treatment side effects restrict their clinical application. In this review, we briefly introduce the feature characteristics of the TME and the recent advances in tumor microenvironment responsive metal nanoparticles for tumor immunotherapy. In addition, nanoparticles could be combined with other treatments, such as chemotherapy, radiotherapy and photodynamic therapy also is presented. Finally, the challenges and outlook for improving the antitumor immunotherapy efficiency, side effect and potential risks of metal nanoparticles has been discussed.

As the largest global carbon pool system, terrestrial ecosystems have an important role to maintain the stability of ecosystems. Human activities affect the structural changes in the ground surface and interfere with terrestrial ecosystem evolution, and consequently, carbon stock is changed in the region. Therefore, forecasting future carbon stock changes under different land use scenarios has important research implications for promoting stable evolution and cycling of terrestrial ecosystems. This study is conducted with the land use data from 2000 to 2020, and incorporates the Patch-generating Land Use Simulation model with the Integrated Valuation of Ecosystem Services and Trade-Offs model to analyze the changes in land use in Hefei, and its influence on the carbon stock in Hefei in various scenarios. During the study period, the mutual conversion between different land types in Hefei City made the land structure change within the study area more significant. The rapidly evolving surface structure is the reason for the decrease of carbon storage in terrestrial ecosystems, with a cumulative decrease of 1.2 × 108 t. The spatial distribution in carbon storage in the study area shows a distribution pattern of low in the north and high in the south. The high carbon storage area is obviously banded in the study area. The area with obvious changes in surface structure has more obvious changes in carbon storage. Compared with the natural development scenario, the downward trend of carbon storage in the ecological protection scenario and the comprehensive development scenario has slowed down due to the restrictions on the structural transformation of land types and the implementation of relevant ecological protection policies. Therefore, this study will support the future management and policy making of Hefei City with the background of China's “double carbon” target and the significant position of Hefei City.

When plants are exposed to salt stress, endogenous hormones are essential for their responses through biosynthesis and signal transduction pathways. However, the roles of endogenous hormones in two cliff species (Opisthopappus taihangensis and Opisthopappus longilobus (Opisthopappus genus)) in the Taihang Mountains under salt stress have not been investigated to date. Following different time treatments under 500 mM salt concentrations, 239 differentially expressed gene (DEG)-related endogenous hormones were identified that exhibited four change trends, which in Profile 47 were upregulated in both species. The C-DEG genes of AUX, GA, JA, BR, ETH, and ABA endogenous hormones were significantly enriched in Opisthopappus taihangensis (O. taihangensis) and Opisthopappus longilobus (O. longilobus). During the responsive process, mainly AUX, GA, and JA biosynthesis and signal transduction were triggered in the two species. Subsequently, crosstalk further influenced BR, EHT, ABA, and MAPK signal transduction pathways to improve the salt resistance of the two species. Within the protein–protein interactions (PPI), seven proteins exhibited the highest interactions, which primarily involved two downregulated genes (SAUR and GA3ox) and eight upregulated genes (ACX, MFP2, JAZ, BRI1, BAK1, ETR, EIN2, and SNRK2) of the above pathways. The more upregulated expression of ZEP (in the ABA biosynthesis pathway), DELLA (in the GA signaling pathway), ABF (in the ABA signaling pathway), and ERF1 (in the ETH signaling pathway) in O. taihangensis revealed that it had a relatively higher salt resistance than O. longilobus. This revealed that the responsive patterns to salt stress between the two species had both similarities and differences. The results of this investigation shed light on the potential adaptive mechanisms of O. taihangensis and O. longilobus under cliff environments, while laying a foundation for the study of other cliff species in the Taihang Mountains.

Salt stress profoundly affects plant growth, prompting intricate molecular responses, such as alternative splicing (AS), for environmental adaptation. However, the response of AS events to salt stress in Opisthopappus (Opisthopappus taihangensis and Opisthopappus longilobus) remains unclear, which is a Taihang Mountain cliff-dwelling species. Using RNA-seq data, differentially expressed genes (DEGs) were identified under time and concentration gradients of salt stress. Two types of AS, skipped exon (SE) and mutually exclusive exons (MXE), were found. Differentially alternative splicing (DAS) genes in both species were significantly enriched in “protein phosphorylation”, “starch and sucrose metabolism”, and “plant hormone signal transduction” pathways. Meanwhile, distinct GO terms and KEGG pathways of DAS occurred between two species. Only a small subset of DAS genes overlapped with DEGs under salt stress. Although both species likely adopted protein phosphorylation to enhance salt stress tolerance, they exhibited distinct responses. The results indicated that the salt stress mechanisms of both Opisthopappus species exhibited similarities and differences in response to salt stress, which suggested that adaptive divergence might have occurred between them. This study initially provides a comprehensive description of salt responsive AS events in Opisthopappus and conveys some insights into the molecular mechanisms behind species tolerance on the Taihang Mountains.

Catalytic oxidation is used to control carbon monoxide (CO) emissions from industrial exhaust. In this study, a mesoporous silica material, KCC-1, was synthesized and used as a carrier with a high specific surface area to confine active component FeOx nanoparticles (NPs), and the CO catalytic oxidation performance of x%Fe@KCC-1 catalysts (x represents the mass loading of Fe) was studied. The experimental results showed that due to its large specific surface area and abundant mesopores, the FeOx NPs were highly dispersed on the surface of the KCC-1 carrier. The particle size of FeOx was very small, resulting in strong interactions between FeOx NPs and KCC-1, which enhanced the catalytic oxidation reaction on the catalyst. The FeOx loading improved the CO adsorption capability of the catalyst, which facilitated the catalytic oxidation of CO, with the 7%Fe@KCC-1 catalyst achieving 100% CO conversion at 160 °C. The CO catalytic removal mechanism was investigated by a combination of in-situ DRIFTS and DFT calculations. This study advances scientific understanding of the application potential of nano-catalysts in important oxidation reactions and provides valuable insights into the development of efficient CO oxidation catalysts.

Abstract Background Airborne fine particulate matter (PM2.5) has been associated with lung cancer development and progression in never smokers. However, the molecular mechanisms underlying PM2.5-induced lung cancer remain largely unknown. The aim of this study was to explore the mechanisms by which PM2.5 regulated the carcinogenesis of non-small cell lung cancer (NSCLC). Methods Paralleled ribosome sequencing (Ribo-seq) and RNA sequencing (RNA-seq) were performed to identify PM2.5-associated genes for further study. Quantitative real time-PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC) were used to determine mRNA and protein expression levels in tissues and cells. The biological roles of PM2.5 and PM2.5-dysregulated gene were assessed by gain- and loss-of-function experiments, biochemical analyses, and Seahorse XF glycolysis stress assays. Human tissue microarray analysis and 18F-FDG PET/CT scans in patients with NSCLC were used to verify the experimental findings. Polysome fractionation experiments, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were implemented to explore the molecular mechanisms. Results We found that PM2.5 induced a translation shift towards glycolysis pathway genes and increased glycolysis metabolism, as evidenced by increased L-lactate and pyruvate concentrations or higher extracellular acidification rate (ECAR) in vitro and in vivo. Particularly, PM2.5 enhanced the expression of glycolytic gene DLAT, which promoted glycolysis but suppressed acetyl-CoA production and enhanced the malignancy of NSCLC cells. Clinically, high expression of DLAT was positively associated with tumor size, poorer prognosis, and SUVmax values of 18F-FDG-PET/CT scans in patients with NSCLC. Mechanistically, PM2.5 activated eIF4E, consequently up-regulating the expression level of DLAT in polysomes. PM2.5 also stimulated transcription factor Sp1, which further augmented transcription activity of DLAT promoter. Conclusions This study demonstrated that PM2.5-activated overexpression of DLAT and enhancement in glycolysis metabolism contributed to the tumorigenesis of NSCLC, suggesting that DLAT-associated pathway may be a therapeutic target for NSCLC.

This article is concerned with the robust model predictive control (RMPC) problem for polytopic uncertain systems under the round-robin (RR) scheduling in the high-rate communication channel. From a set of sensors to the controller, several sensors transmit the data to the remote controller via a shared high-rate communication network, data collision might happen if these sensors start transmissions at the same time. For the sake of preventing data collision in the high-rate communication channel, a communication scheduling known as RR is used to arrange the data transmission order, where only one node with token is allowed to send data at each transmission instant. In accordance with the token-dependent Lyapunov-like approach, the aim of the problem addressed is to design a set of controllers in the framework of RMPC such that the asymptotical stability of the closed-loop system is guaranteed. By taking the effect of the underlying RR scheduling in the high-rate communication channel into consideration, sufficient conditions are obtained by solving a terminal constraint set of an auxiliary optimization problem. In addition, an algorithm including both off-line and online parts is provided to find a sub-optimal solution. Finally, two simulation examples are used to demonstrate the usefulness and effectiveness of the proposed RMPC strategy.

Leukemia is a malignancy initiated by uncontrolled proliferation of hematopoietic stem cell from the B and T lineages, resulting in destruction of hematopoietic system. The conventional leukemia treatments induce severe toxic and a long series of unwanted side-effects which are caused by lack of specificity of anti-leukemic drugs. Recently, nanotechnology have shown tremendous application and clinical impact with respect to diagnosis and treatment of leukemia. According to considerable researches in the context of finding new nanotechnological platform, iron oxide nanoparticles have been gained increasing attention for the leukemia patients use. In this review, a short introduction of leukemia is described followed by the evaluation of the current approaches of iron oxide nanoparticles applied in the leukemia detection and treatment. The enormous advantages of iron oxide nanoparticles for leukemia have been discussed, which consist of the detection of magnetic resonance imaging (MRI) as efficient contrast agents, magnetic biosensors and targeted delivery of anti-leukemia drugs by coating different targeting moieties. In addition, this paper will briefly describe the application of iron oxide nanoparticles in the combined treatment of leukemia. Finally, the shortcomings of the current applications of iron-based nanoparticles in leukemia diagnosis and treatment will be discussed in particular.

BackgroundIt is well known that the occurrence and development of ovarian cancer are closely related to the patient’s weight and various endocrine factors in the body.AimMendelian randomization (MR) was used to analyze the bidirectional relationship between insulin related characteristics and ovarian cancer.MethodsThe data on insulin related characteristics are from up to 5567 diabetes free patients from 10 studies, mainly including fasting insulin level, insulin secretion rate, peak insulin response, etc. For ovarian cancer, UK Biobank data just updated in 2021 was selected, of which the relevant gene data was from 199741 Europeans. Mendelian randomization method was selected, with inverse variance weighting (IVW) as the main estimation, while MR Pleiotropy, MR Egger, weighted median and other methods were used to detect the heterogeneity of data and whether there was multi validity affecting conclusions.ResultsAmong all insulin related indicators (fasting insulin level, insulin secretion rate, peak insulin response), the insulin secretion rate was selected to have a causal relationship with the occurrence of ovarian cancer (IVW, P < 0.05), that is, the risk of ovarian cancer increased with the decrease of insulin secretion rate. At the same time, we tested the heterogeneity and polymorphism of this indicator, and the results were non-existent, which ensured the accuracy of the analysis results. Reverse causal analysis showed that there was no causal effect between the two (P>0.05).ConclusionThe impairment of the insulin secretion rate has a causal effect on the risk of ovarian cancer, which was confirmed by Mendel randomization. This suggests that the human glucose metabolism cycle represented by insulin secretion plays an important role in the pathogenesis of ovarian cancer, which provides a new idea for preventing the release of ovarian cancer.

Abstract Background Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs. Recent studies suggest that tRFs participate in some pathological processes. However, the biological functions and mechanisms of tRFs in non-small cell lung cancer (NSCLC) are largely unknown. Methods Differentially expressed tRFs were identified by tRF and tiRNA sequencing using 9 pairs of pre- and post-operation plasma from patients with NSCLC. Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to determine the levels of tRF in tissues, plasma, and cells. Gain- and loss-of-function experiments were implemented to investigate the oncogenic effects of tRF on NSCLC cells in vitro and in vivo. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation (RIP), Western blot, co-immunoprecipitation (Co-IP) assays, and rescue experiments were performed to explore the regulatory mechanisms of tRF in NSCLC. Results AS-tDR-007333 was an uncharacterized tRF and significantly up-regulated in NSCLC tissues, plasma, and cells. Clinically, AS-tDR-007333 overexpression could distinguish NSCLC patients from healthy controls and associated with poorer prognosis of NSCLC patients. Functionally, overexpression of AS-tDR-007333 enhanced proliferation and migration of NSCLC cells, whereas knockdown of AS-tDR-007333 resulted in opposite effects. Mechanistically, AS-tDR-007333 promoted the malignancy of NSCLC cells by activating MED29 through two distinct mechanisms. First, AS-tDR-007333 bound to and interacted with HSPB1, which activated MED29 expression by enhancing H3K4me1 and H3K27ac in MED29 promoter. Second, AS-tDR-007333 stimulated the expression of transcription factor ELK4, which bound to MED29 promoter and increased its transcription. Therapeutically, inhibition of AS-tDR-007333 suppressed NSCLC cell growth in vivo. Conclusions Our study identifies a new oncogenic tRF and uncovers a novel mechanism that AS-tDR-007333 promotes NSCLC malignancy through the HSPB1-MED29 and ELK4-MED29 axes. AS-tDR-007333 is a potential diagnostic or prognostic marker and therapeutic target for NSCLC.

Background and purpose: Neoadjuvant Chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) is promising in improving the survival rate for advanced nasopharyngeal carcinoma (NPC) patients relative to CCRT alone. However, not all patients respond well to NAC. Therefore, we aimed to develop and evaluate a modified radiomics model for the NAC response prognosis in NPC patients. Methods: A total of 165 patients with biopsy-proven locally advanced NPC were retrospectively selected from the database of our hospital. 85 out of them were for training and cross-validation, while the other 80 patients were for independent testing. All patients were treated with NAC and underwent MRI inspection, including T1-weighted (T1), T2-weighted (T2), and contrast-enhanced T1-weighted (T1-cs) sequences before and after two cycles of NAC. We classified the patients into the response or non-response groups by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Radiomics features were extracted from the primary and lymph node gross tumor volume in each sequence. To further improve the predictive performance, the permutation of multiple combinations of extraction parameters has first ever been investigated in the NAC prognosis for NPC patients. The model was constructed by logistic regression and cross-validated by bootstrapping with a resampling number of 1000. Independent testing was also implemented. In addition, we also applied an imbalance-adjusted bootstrap strategy to decrease the bias of small samples. Results: For the cross-validation cohort, the resultant AUC, sensitivity, and specificity in terms of 95% confidence interval were 0.948 ± 0.004, 0.849 ± 0.005, and 0.840 ± 0.010. For the independent testing cohort, the model reached an AUC of 0.925, a sensitivity of 0.821, and a specificity of 0.792. There was a significant difference in the estimated radiomics score between the response and non-response groups (P

This paper considers the observer-based output feedback robust model predictive control (RMPC) problem for systems with model uncertainties and possible measurement outliers. For the sake of alleviating the effects of possible abnormal measurements, we design a set of observer-based output feedback RMPC controllers with the saturation constraint where the saturation level is adaptive according to the estimation errors. The purpose of the addressed problem is to design a set of desired RMPC controllers so as to guarantee the robustness and the asymptotical stability of the closed-loop system. Sufficient stability conditions are obtained by solving a time-varying terminal constraint set of an auxiliary optimization problem, and the corresponding control law and the upper bound of the quadratic cost function are derived. In addition, an algorithm including both off-line and on-line parts is provided to find a sub-optimal solution. Finally, two simulation examples are employed to illustrate the effectiveness of the proposed RMPC approach.

Opisthopappus is a perennial, endemic herb of the Taihang Mountains in China. Two species of this genus (O. longilobus and O. taihangensis) are important wild genetic resources for Asteraceae; however, their reproductive biology has been lacking until now. This study is the first detailed report on the reproductive biology and breeding systems of two Opisthopappus species. Through field observations, the floral syndromes of O. longilobus and O. taihangensis were found to possess a similar pattern, although O. taihangensis has a relatively larger capitulum, more ray ligules, and disc florets. The flowers of both O. longilobus and O. taihangensis are protandrous, a character that can prevent autogamy at the single-flower level, and insects are required for pollination. Further, brightly ligules, brightly bisexual florets, unique fragrance, and amount of nectar suggest that these species propagate via an entomophilous pollination system. Hymenopteran and Diptera species were observed as the effective pollinators for these two species. The outcrossing index, pollen/ovule ratio and the results of hand pollination indicated that these Opisthopappus species might have a mixed mating system that combines cross-fertilization and partial self-fertilization for O. longilobus and O. taihangensis, outcrossing predominated in the breeding system, while self-pollination played an important role in seed production when insect pollination was unavailable, particularly in a harsh environment, such as the Taihang Mountains cliffs. Meanwhile, O. taihangensis might better adapt to severe surroundings with relatively complex floral syndromes, specifically through the attraction of visiting insects and a high seed set rate. The above results not only provide reference information toward a better understanding of the survival strategies of O. longilobus and O. taihangensis in the Taihang Mountains but also lay a solid foundation for further exploring the molecular mechanisms that underly their adaptation under cliff environments.

Opisthopappus longilobus (Opisthopappus) and its descendant species, Opisthopappus taihangensis, commonly thrive on the Taihang Mountains of China. Being typical cliff plants, both O. longilobus and O. taihangensis release unique aromatics. To determine the potential differentiation and environmental response patterns, comparative metabolic analysis was performed on O. longilobus wild flower (CLW), O. longilobus transplant flower (CLT), and O. taihangensis wild flower (TH) groups. Significant differences in the metabolic profiles were found, not within O. longilobus, but between O. longilobus and O. taihangensis flowers. Within these metabolites, twenty-eight substances related to the scents were obtained (one alkene, two aldehydes, three esters, eight phenols, three acids, three ketones, three alcohols, and five flavonoids), of which eugenol and chlorogenic were the primary aromatic molecules and enriched in the phenylpropane pathway. Network analysis showed that close relationships occurred among identified aromatic substances. The variation coefficient (CV) of aromatic metabolites in O. longilobus was lower than O. taihangensis. The aromatic related compounds were significantly correlated with the lowest temperatures in October and in December of the sampled sites. The results indicated that phenylpropane, particularly eugenol and chlorogenic, played important roles in the responses of O. longilobus species to environmental changes.

The new lower tungsten divertor of EAST uses a right-angle shape consisted by horizontal and vertical targets, which has the capacity of increasing the divertor closure. The strike point (SP) sweeping experiment is carried out to (1) avoid long-term deposition of particle and heat flux at the same location, thus protecting the target, (2) study the dependence of power control capability on the SP location. The particle and energy flux densities to the target depends strongly on their decay width. Therefore, it is important to know how the SP location influences the outer target (OT) particle parallel λ _js _,OT and OT parallel heat flux decay widths λ _q _,OT . In this work, SOLPS-ITER simulations combined with SP sweeping experiment are applied to study this issue. Four cases, which are taken from different time during SP sweeping (including both horizontal and vertical divertor) in L-mode experiment with high heating power, are selected for investigation. The simulation result is in satisfactory agreement with experiment data, suggesting the simulation is valid. The results indicate that the SP location can affect neutral particles accumulation and ionization positions, thus affecting λ _js _,OT and λ _q _,OT . (1) When SP is located in horizontal target, the higher neutral particle ionization in common flux region leads to wider λ _js _,OT than those of vertical target. (2) When SP is located on horizontal target, the divertor power radiation is higher than that of vertical target, resulting in wider λ _q _,OT . (3) Increasing upstream plasma density can effectively broaden λ _q _,OT , while λ _js _,OT remains almost unchanged. This study improves the understanding of the influence of divertor shape on λ _js _,OT and λ _q _,OT , and can be applied to heat flux control during long-pulse high-power discharges on EAST.

Injectability of the polymer solution is a very important factor that determines the effectiveness of polymer flooding for enhanced oil recovery. Here, the medium and low permeability oil reservoir was taken as a research object, and effects of relative molecular weight, concentration and core permeability on the flow and injection performance of a partially hydrolyzed polyacrylamide (HPAM) solution with and without anionic-nonionic surfactant (ANS) were studied by indoor outcrop core physical model experiments. It was found that the influence of HPAM concentration on the flow performance was related to the core permeability. When the core permeability was lower than 59 mD, the resistance factor and residual resistance factor of HPAM increased with increasing the concentration. High molecular weight and low core permeability were not conducive to the injectability of HPAM solutions. The addition of ANS was beneficial in enhancing the injectability of HPAM solution by reducing the critical value of injectability of HPAM solution, which was elucidated by the Hall curve derivative method. In the presence of ANS, the flow pressure gradient and the residual resistance factor of the HPAM solution decreased. It is believed that the injectability of HPAM solution improved by ANS in the medium and low permeability reservoirs can be attributed to decrease in fluid viscosity and competitive adsorption on the surface of porous media. The study provides a new idea and theoretical basis for improving the injectability of an HPAM solution and the application of polymer flooding and a polymer/surfactant binary flooding system in medium and low permeability reservoirs.

Breast cancer is the second leading cause of death for women worldwide. While monotherapy (single agent) treatments have been used for many years, they are not always effective, and many patients relapse after initial treatment. Moreover, in some patients the response to therapy becomes weaker, or resistance to monotherapy develops over time. This is especially problematic for metastatic breast cancer or triple-negative breast cancer. Recently, combination therapies (in which two or more drugs are used to target two or more pathways) have emerged as promising new treatment options. Combination therapies are often more effective than monotherapies and demonstrate lower levels of toxicity during long-term treatment. In this review, we provide a comprehensive overview of current combination therapies, including molecular-targeted therapy, hormone therapy, immunotherapy, and chemotherapy. We also describe the molecular basis of breast cancer and the various treatment options for different breast cancer subtypes. While combination therapies are promising, we also discuss some of the challenges. Despite these challenges, the use of innovative combination therapy holds great promise compared with traditional monotherapies. In addition, the use of multidisciplinary technologies (such as nanotechnology and computer technology) has the potential to optimize combination therapies even further.

P21-activated kinases (PAKs) are serine/threonine kinases involved in the regulation of cell survival, proliferation, inhibition of apoptosis, and the regulation of cell morphology. Some members of the PAK family are highly expressed in several types of cancer, and they have also been implicated in several other medical disorders. They are thus considered to be good targets for treatment of cancer and other diseases. Although there are several inhibitors of the PAKs, the utility of some of these inhibitors is reduced for several reasons, including limited metabolic stability. One way to overcome this problem is the use of nanoparticles, which have the potential to increase drug delivery. The overall goals of this review are to describe the roles for PAK kinases in cell signaling and disease, and to describe how the use of nanomedicine is a promising new method for administering PAK inhibitors for the purpose of disease treatment and research. We discuss some of the basic mechanisms behind nanomedicine technology, and we then describe how these techniques are being used to package and deliver PAK inhibitors.