The mammalian actin elongation factor ENAH/MENA contributes to autophagosome formation via its actin regulatory function.

Macroautophagy/autophagy is a catabolic process crucial for degrading cytosolic components and damaged organelles to maintain cellular homeostasis, enabling cells to survive in extreme extracellular environments. ENAH/MENA, a member of the Ena/VASP protein family, functions as a highly efficient actin elongation factor. In this study, our objective was to explore the role of ENAH in the autophagy process. Initially, we demonstrated that depleting ENAH in cancer cells inhibits autophagosome formation. Subsequently, we observed ENAH's colocalization with MAP1LC3/LC3 during tumor cell starvation, dependent on actin cytoskeleton polymerization and the interaction between ENAH and BECN1 (beclin 1). Additionally, mammalian ATG9A formed a ring-like structure around ENAH-LC3 puncta during starvation, relying on actin cytoskeleton polymerization. Furthermore, ENAH's EVH1 and EVH2 domains were found to be indispensable for its colocalization with LC3 and BECN1, while the PRD domain played a crucial role in the formation of the ATG9A ring. Finally, our study revealed ENAH-led actin comet tails in autophagosome trafficking. In conclusion, our findings provide initial insights into the regulatory role of the mammalian actin elongation factor ENAH in autophagy.

Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.

Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-ß) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-ß+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-ß+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.

Neural Network Excitation/Inhibition: A Key to Empathy and Empathy Impairment.

Empathy is an ability to fully understand and feel the mental states of others. We emphasize that empathy is elicited by the transmission of pain, fear, and sensory information. In clinical studies, impaired empathy has been observed in most psychiatric conditions. However, the precise impairment mechanism of the network systems on the pathogenesis of empathy impairment in psychiatric disorders is still unclear. Multiple lines of evidence suggest that disturbances in the excitatory/inhibitory balance in neurologic disorders are key to empathetic impairment in psychiatric disorders. Therefore, we here describe the roles played by the anterior cingulate cortex- and medial prefrontal cortex-dependent neural circuits and their impairments in psychiatric disorders, including anxiety, depression, and autism. In addition, we review recent studies on the role of microglia in neural network excitation/inhibition imbalance, which contributes to a better understanding of the neural network excitation/inhibition imbalance and may open up innovative psychiatric therapies.

Construction of Successive Proton Conduction Channels to Accelerate the Proton Conduction Process in Flexible Proton Exchange Membranes.

Successive proton conduction channels are constructed with the spin coating method in flexible proton exchange membranes (PEMs). In this research, phosphoric acid (PA) molecules are immobilized in the multilayered microstructure of Kevlar nanofibers and polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS) polymer molecular chains. As a result, successive proton conduction channels can accelerate the proton conduction process in the prepared membrane with the multilayered microstructure. Additionally, the microstructure fractures of the composite membranes from the external force of folding and stretching operations are modified by the inner PA molecules. Notably, numerous PA molecules are further combined through formed intermolecular hydrogen bonding. The stretched membrane absorbs more PA molecules owing to the arrangement of PA molecules, Kevlar nanofibers, and SEBS molecular chains. The stretched membrane thus exhibits the enhanced proton conduction ability, such as the through-plane proton conductivity of 1.81 × 10-1 S cm-1 at 160 °C and that of 4.53 × 10-2 S cm-1 at 120 °C lasting for 600 h. Furthermore, the tensile stress of PA-doped stretched membranes reaches (3.91 ± 0.40)-(6.15 ± 0.43) MPa. A single proton exchange membrane fuel cell exhibits a peak power density of 483.3 mW cm-2 at 120 °C.

Application of the partial least square regression method in determining the natural background of soil heavy metals: A case study in the Songhua River basin, China.

The "background" is an essential index for identifying anthropogenic inputs and potential ecological risks of soil heavy metals. However, the lithology of bedrock can cause significant spatial variation in the natural background of soil elements, posing considerable difficulties in estimating background values. In this study, an attempt was made to calculate the natural background through regression analysis of soil chemical composition, and reasonably evaluate the impact of lithology. A total of 1771 surface soil samples were collected from the Songhua River Basin, China, for chemical composition analysis, and the partial least square regression (PLSR) method was employed to establish the relationship between heavy metals (As, Hg, Cr, Cd, Pb, Cu, Zn, and Ni) and soil chemical composition/environmental parameters (SiO2, Al2O3, TFe2O3, MgO, CaO, K2O, Na2O, La, Y, Zr, V, Sc, Sr, Li and pH). The result shows that As, Cr, Pb, Cu, Zn, and Ni have significant linear relationships with soil chemical composition. Each of these six heavy metals obtained 1771 regression background values; some were higher than the uniform background value obtained from the boxplot, while others were lower. The regression background values recognized not only subtle anthropogenic inputs and potential ecological risks in low-background regions but also spurious contamination in high-background areas. All these indicate that the PLSR method can effectively improve the determination accuracy of the natural background of soil heavy metals. More attention should be paid to the serious anthropogenic inputs appearing in some places of the study area.

Erianin promotes endogenous neurogenesis in traumatic brain injury rats.

The objective of this study was to explore the positive influence and potential mechanism of Erianin on the recovery of brain cells following a traumatic brain injury (TBI). TBI rat models were prepared and treated with Erianin injection via tail vein. The assessment included evaluating the rats' levels of oxidative stress, inflammation, neuronal damage, mitochondrial damage, neuronal regeneration, transformation of pro-inflammatory microglial cells, activation status of the ERK signal pathway, and the functionality of their learning and memory. After administering Erianin, there was a suppression of oxidative stress, inflammation, nerve cell damage, and mitochondrial damage in the TBI rats. Additionally, there was an increase in neuronal regeneration in the cortex and hippocampus, inhibition of pro-inflammatory microglial cell transformation in the cortex, improvement in learning and memory function in TBI rats, and simultaneous inhibition of the activation of the ERK1/c-Jun signal pathway. The findings suggest that Erianin has the potential to reduce oxidative stress and inflammatory reaction in rats with TBI, safeguard nerve cells against apoptosis, stimulate the growth of new neural cells, ultimately enhancing the cognitive abilities and memory function of the rats. The inhibition of the ERK signaling pathway could be closely associated with these effects.

Pangenome analysis reveals genomic variations associated with domestication traits in broomcorn millet.

Broomcorn millet (Panicum miliaceum L.) is an orphan crop with the potential to improve cereal production and quality, and ensure food security. Here we present the genetic variations, population structure and diversity of a diverse worldwide collection of 516 broomcorn millet genomes. Population analysis indicated that the domesticated broomcorn millet originated from its wild progenitor in China. We then constructed a graph-based pangenome of broomcorn millet based on long-read de novo genome assemblies of 32 representative accessions. Our analysis revealed that the structural variations were highly associated with transposable elements, which influenced gene expression when located in the coding or regulatory regions. We also identified 139 loci associated with 31 key domestication and agronomic traits, including candidate genes and superior haplotypes, such as LG1, for panicle architecture. Thus, the study's findings provide foundational resources for developing genomics-assisted breeding programs in broomcorn millet.

Human Expansion-Induced Biodiversity Crisis over Asia from 2000 to 2020.

Asia stands out as a priority for urgent biodiversity conservation due to its large protected areas (PAs) and threatened species. Since the 21st century, both the highlands and lowlands of Asia have been experiencing the dramatic human expansion. However, the threat degree of human expansion to biodiversity is poorly understood. Here, the threat degree of human expansion to biodiversity over 2000 to 2020 in Asia at the continental (Asia), national (48 Asian countries), and hotspot (6,502 Asian terrestrial PAs established before 2000) scales is investigated by integrating multiple large-scale data. The results show that human expansion poses widespread threat to biodiversity in Asia, especially in Southeast Asia, with Malaysia, Cambodia, and Vietnam having the largest threat degrees (∼1.5 to 1.7 times of the Asian average level). Human expansion in highlands induces higher threats to biodiversity than that in lowlands in one-third Asian countries (most Southeast Asian countries). The regions with threats to biodiversity are present in ∼75% terrestrial PAs (including 4,866 PAs in 26 countries), and human expansion in PAs triggers higher threat degrees to biodiversity than that in non-PAs. Our findings provide novel insight for the Sustainable Development Goal 15 (SDG-15 Life on Land) and suggest that human expansion in Southeast Asian countries and PAs might hinder the realization of SDG-15. To reduce the threat degree, Asian developing countries should accelerate economic transformation, and the developed countries in the world should reduce the demands for commodity trade in Southeast Asian countries (i.e., trade leading to the loss of wildlife habitats) to alleviate human expansion, especially in PAs and highlands.

YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis.

Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC's high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer.

Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

GPR43 protects human A16 cardiomyocytes against hypoxia/reoxygenation injury by regulating nesfatin1.

BACKGROUND: The purpose of this study is to investigate the regulatory role of G coupled-protein receptor 43 (GPR43) during myocardial ischemia/reperfusion (I/R) injury and to explore the relevant molecular mechanism. MATERIALS AND METHODS: AC16 hypoxia/reoxygenation (H/R) model was established to simulate I/R injury in vitro. Gain- and loss-of-function experiments were conducted to regulate GPR43 or nesfatin1 expression. Cell viability and apoptosis was examined adopting CCK-8 and TUNEL assays. Commercial kits were applied for detecting ROS and inflammatory cytokines. Quantitative real-time PCR (qRT-PCR) and western blotting were conducted to measure the expression level of critical genes and proteins. RESULTS: GPR43 was downregulated in H/R-mediated AC16 cells. GPR43 overexpression or the GPR43 agonist greatly inhibited H/R-induced cell viability loss, cell apoptosis, and excessive production of ROS and pro-inflammatory cytokines in AC16 cardiomyocytes. Co-immunoprecipitation (Co-IP) assay identified an interaction between GPR43 and nesfatin1, and GPR43 could positively regulate nesfatin1. In addition, the protective role of GPR43 against H/R injury was partly abolished upon nesfatin1 knockdown. Eventually, GPR43 could inhibit H/R-stimulated JNK/P38 MAPK signaling in AC16 cells, which was also hindered by nesfatin1 knockdown. CONCLUSIONS: Our findings demonstrated the protective role of GPR43 against H/R-mediated cardiomyocytes injury through up-regulating nesfatin1, providing a novel target for the prevention and treatment of myocardial I/R injury.

A graph-based genome and pan-genome variation of the model plant Setaria.

Setaria italica (foxtail millet), a founder crop of East Asian agriculture, is a model plant for C4 photosynthesis and developing approaches to adaptive breeding across multiple climates. Here we established the Setaria pan-genome by assembling 110 representative genomes from a worldwide collection. The pan-genome is composed of 73,528 gene families, of which 23.8%, 42.9%, 29.4% and 3.9% are core, soft core, dispensable and private genes, respectively; 202,884 nonredundant structural variants were also detected. The characterization of pan-genomic variants suggests their importance during foxtail millet domestication and improvement, as exemplified by the identification of the yield gene SiGW3, where a 366-bp presence/absence promoter variant accompanies gene expression variation. We developed a graph-based genome and performed large-scale genetic studies for 68 traits across 13 environments, identifying potential genes for millet improvement at different geographic sites. These can be used in marker-assisted breeding, genomic selection and genome editing to accelerate crop improvement under different climatic conditions.

Hydroxyphenylpyruvate Dioxygenase Is a Metabolic Immune Checkpoint for UTX-deficient Colorectal Cancer.

BACKGROUND & AIMS: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contribute to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood. METHODS: UTX conditional knockout mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed time of flight mass cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs. RESULTS: We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid by hydroxyphenylpyruvate dioxygenase. Homogentisic acid modified protein inhibitor of activated STAT3 via carbonylation of Cys 176, and relieved the inhibitory effect of protein inhibitor of activated STAT3 on signal transducer and activator of transcription 5 transcriptional activity. This in turn, promoted MDSC survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits. CONCLUSIONS: Collectively, these findings highlight hydroxyphenylpyruvate dioxygenase as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.

Impact of Human Mobility on COVID-19 Transmission According to Mobility Distance, Location, and Demographic Factors in the Greater Bay Area of China: Population-Based Study.

BACKGROUND: Mobility restriction was one of the primary measures used to restrain the spread of COVID-19 globally. Governments implemented and relaxed various mobility restriction measures in the absence of evidence for almost 3 years, which caused severe adverse outcomes in terms of health, society, and economy. OBJECTIVE: This study aimed to quantify the impact of mobility reduction on COVID-19 transmission according to mobility distance, location, and demographic factors in order to identify hotspots of transmission and guide public health policies. METHODS: Large volumes of anonymized aggregated mobile phone position data between January 1 and February 24, 2020, were collected for 9 megacities in the Greater Bay Area, China. A generalized linear model (GLM) was established to test the association between mobility volume (number of trips) and COVID-19 transmission. Subgroup analysis was also performed for sex, age, travel location, and travel distance. Statistical interaction terms were included in a variety of models that express different relations between involved variables. RESULTS: The GLM analysis demonstrated a significant association between the COVID-19 growth rate ratio (GR) and mobility volume. A stratification analysis revealed a higher effect of mobility volume on the COVID-19 GR among people aged 50-59 years (GR decrease of 13.17% per 10% reduction in mobility volume; P<.001) than among other age groups (GR decreases of 7.80%, 10.43%, 7.48%, 8.01%, and 10.43% for those aged ≤18, 19-29, 30-39, 40-49, and ≥60 years, respectively; P=.02 for the interaction). The impact of mobility reduction on COVID-19 transmission was higher for transit stations and shopping areas (instantaneous reproduction number [Rt] decreases of 0.67 and 0.53 per 10% reduction in mobility volume, respectively) than for workplaces, schools, recreation areas, and other locations (Rt decreases of 0.30, 0.37, 0.44, and 0.32, respectively; P=.02 for the interaction). The association between mobility volume reduction and COVID-19 transmission was lower with decreasing mobility distance as there was a significant interaction between mobility volume and mobility distance with regard to Rt (P<.001 for the interaction). Specifically, the percentage decreases in Rt per 10% reduction in mobility volume were 11.97% when mobility distance increased by 10% (Spring Festival), 6.74% when mobility distance remained unchanged, and 1.52% when mobility distance declined by 10%. CONCLUSIONS: The association between mobility reduction and COVID-19 transmission significantly varied according to mobility distance, location, and age. The substantially higher impact of mobility volume on COVID-19 transmission for longer travel distance, certain age groups, and specific travel locations highlights the potential to optimize the effectiveness of mobility restriction strategies. The results from our study demonstrate the power of having a mobility network using mobile phone data for surveillance that can monitor movement at a detailed level to measure the potential impacts of future pandemics.

Ectopic invasive ACTH-secreting pituitary adenoma mimicking chordoma: a case report and literature review.

BACKGROUND: Ectopic pituitary adenoma (EPA) is defined as a special type of pituitary adenoma that originates outside of the sellar region, is extra- or intra-cranially located, and without connection to normal pituitary tissue. EPA is extremely rare, with most cases presented as case reports or small case series. Due to nonspecific symptoms and laboratory indicators, the preoperative diagnosis, treatment and management for EPA remain challenging. CASE PRESENTATION: Here, we report the imaging phenotype and pathological findings of a case of invasive EPA in a 47-year-old woman. A preoperative non-contrast CT scan revealed a 5.8 × 3.6 × 3.7 cm soft tissue mass located in the sphenoid sinus and clivus. MRI showed an ill-defined solid mass with heterogeneous signals on T1-weighted and T2-weighted images. The mass displayed infiltrative growth pattern, destroying bone of the skull base, invading adjacent muscles and encasing vessels. The patient underwent partial tumor resection via transsphenoidal endoscopic surgery. Pathological examination led to diagnosis of ectopic ACTH-secreting pituitary adenoma. Post-surgery, the patient received external beam radiotherapy. CONCLUSION: EPA with invasive growth pattern has rarely been reported. The imaging phenotype displays its relationship to the pituitary tissue and surrounding structures. Immunohistochemical examination acts as a crucial role in differentiating EPA from other skull base tumors. This case report adds to the literature on EPA by summarizing its characteristics alongside a review of the literature.

The Impact of Community Shuttle Services on Traffic and Traffic-Related Air Pollution.

Community shuttle services have the potential to alleviate traffic congestion and reduce traffic pollution caused by massive short-distance taxi-hailing trips. However, few studies have evaluated and quantified the impact of community shuttle services on urban traffic and traffic-related air pollution. In this paper, we propose a complete framework to quantitatively assess the positive impacts of community shuttle services, including route design, traffic congestion alleviation, and air pollution reduction. During the design of community shuttle services, we developed a novel method to adaptively generate shuttle stops with maximum service capacity based on residents' origin-destination (OD) data, and designed shuttle routes with minimum mileage by genetic algorithm. For traffic congestion alleviation, we identified trips that can be shifted to shuttle services and their potential changes in traffic flow. The decrease in traffic flow can alleviate traffic congestion and indirectly reduce unnecessary pollutant emissions. In terms of environmental protection, we utilized the COPERT III model and the spatial kernel density estimation method to finely analyze the reduction in traffic emissions by eco-friendly transportation modes to support detailed policymaking regarding transportation environmental issues. Taking Chengdu, China as the study area, the results indicate that: (1) the adaptively generated shuttle stops are more responsive to the travel demands of crowds compared with the existing bus stops; (2) shuttle services can replace 30.36% of private trips and provide convenience for 50.2% of commuters; (3) such eco-friendly transportation can reduce traffic emissions by 28.01% overall, and approximately 42% within residential areas.

Ginsenosides Rg1 and CK Control Temozolomide Resistance in Glioblastoma Cells by Modulating Cholesterol Efflux and Lipid Raft Distribution.

Background: Cholesterol efflux and lipid raft redistribution contribute to attenuating temozolomide resistance of glioblastoma. Ginsenosides are demonstrated to modify cholesterol metabolism and lipid raft distribution, and the brain distribution and central nervous effects of whose isoforms Rb1, Rg1, Rg3, and CK have been identified. This study aimed to reveal the role of Rb1, Rg1, Rg3, and CK in the drug resistance of glioblastoma. Methods: The effects of ginsenosides on cholesterol metabolism in temozolomide-resistant U251 glioblastoma cells were evaluated by cholesterol content and efflux assay, confocal laser, qRT-PCR, and Western blot. The roles of cholesterol and ginsenosides in temozolomide resistance were studied by CCK-8, flow cytometry, and Western blot, and the mechanism of ginsenosides attenuating resistance was confirmed by inhibitors. Results: Cholesterol protected the survival of resistant U251 cells from temozolomide stress and upregulated multidrug resistance protein (MDR)1, which localizes in lipid rafts. Resistant cells tended to store cholesterol intracellularly, with limited cholesterol efflux and LXRα expression to maintain the distribution of lipid rafts. Ginsenosides Rb1, Rg1, Rg3, and CK reduced intracellular cholesterol and promoted cholesterol efflux in resistant cells, causing lipid rafts to accumulate in specific regions of the membrane. Rg1 and CK also upregulated LXRα expression and increased the cytotoxicity of temozolomide in the presence of cholesterol. We further found that cholesterol efflux induction, lipid raft redistribution, and temozolomide sensitization by Rg1 and CK were induced by stimulating LXRα. Conclusions: Ginsenosides Rg1 and CK controlled temozolomide resistance in glioblastoma cells by regulating cholesterol metabolism, which are potential synergists for temozolomide therapy.

Towards a new paradigm for segregation measurement in an age of big data.

Recent theoretical and methodological advances in activity space and big data provide new opportunities to study socio-spatial segregation. This review first provides an overview of the literature in terms of measurements, spatial patterns, underlying causes, and social consequences of spatial segregation. These studies are mainly place-centred and static, ignoring the segregation experience across various activity spaces due to the dynamism of movements. In response to this challenge, we highlight the work in progress toward a new paradigm for segregation studies. Specifically, this review presents how and the extent to which activity space methods can advance segregation research from a people-based perspective. It explains the requirements of mobility-based methods for quantifying the dynamics of segregation due to high movement within the urban context. It then discusses and illustrates a dynamic and multi-dimensional framework to show how big data can enhance understanding segregation by capturing individuals' spatio-temporal behaviours. The review closes with new directions and challenges for segregation research using big data.

Combined HASPIN and mTOR inhibition is synergistic against KRAS-driven carcinomas.

BACKGROUND: Oncogenic mutations in the KRAS gene are very common in human cancers, resulting in cells with well-characterized selective advantages. For more than three decades, the development of effective therapeutics to inhibit KRAS-driven tumorigenesis has proved a formidable challenge and KRAS was considered 'undruggable'. Therefore, multi-targeted therapy may provide a reasonable strategy for the effective treatment of KRAS-driven cancers. Here, we assess the efficacy and mechanistic rationale for combining HASPIN and mTOR inhibition as a potential therapy for cancers carrying KRAS mutations. METHODS: We investigated the synergistic effect of a combination of mTOR and HASPIN inhibitors on cell viability, cell cycle, cell apoptosis, DNA damage, and mitotic catastrophe using a panel of human KRAS-mutant and wild-type tumor cell lines. Subsequently, the human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of the dual therapy. RESULTS: We demonstrated that the combination of mTOR and HASPIN inhibitors induced potent synergistic cytotoxic effects in KRAS-mutant cell lines and delayed the growth of human tumor xenograft. Mechanistically, we showed that inhibiting of mTOR potentiates HASPIN inhibition by preventing the phosphorylation of H3 histones, exacerbating mitotic catastrophe and DNA damage in tumor cell lines with KRAS mutations, and this effect is due in part to a reduction in VRK1. CONCLUSIONS: These findings indicate that increased DNA damage and mitotic catastrophe are the basis for the effective synergistic effect observed with mTOR and HASPIN inhibition, and support the clinical evaluation of this dual therapy in patients with KRAS-mutant tumors.