Neurovascular coupling alteration in drug-naïve Parkinson's disease: The underlying molecular mechanisms and levodopa's restoration effects.

BACKGROUND: Parkinson's disease (PD) patients exhibit an imbalance between neuronal activity and perfusion, referred to as abnormal neurovascular coupling (NVC). Nevertheless, the underlying molecular mechanism and how levodopa, the standard treatment in PD, regulates NVC is largely unknown. MATERIAL AND METHODS: A total of 52 drug-naïve PD patients and 49 normal controls (NCs) were enrolled. NVC was characterized in vivo by relating cerebral blood flow (CBF) and amplitude of low-frequency fluctuations (ALFF). Motor assessments and MRI scanning were conducted on drug-naïve patients before and after levodopa therapy (OFF/ON state). Regional NVC differences between patients and NCs were identified, followed by an assessment of the associated receptors/transporters. The influence of levodopa on NVC, CBF, and ALFF within these abnormal regions was analyzed. RESULTS: Compared to NCs, OFF-state patients showed NVC dysfunction in significantly lower NVC in left precentral, postcentral, superior parietal cortex, and precuneus, along with higher NVC in left anterior cingulate cortex, right olfactory cortex, thalamus, caudate, and putamen (P-value <0.0006). The distribution of NVC differences correlated with the density of dopaminergic, serotonin, MU-opioid, and cholinergic receptors/transporters. Additionally, levodopa ameliorated abnormal NVC in most of these regions, where there were primarily ALFF changes with limited CBF modifications. CONCLUSION: Patients exhibited NVC dysfunction primarily in the striato-thalamo-cortical circuit and motor control regions, which could be driven by dopaminergic and nondopaminergic systems, and levodopa therapy mainly restored abnormal NVC by modulating neuronal activity.

Microstructural alterations of the hypothalamus in Parkinson's disease and probable REM sleep behavior disorder.

BACKGROUND: Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial. OBJECTIVES: We aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels. METHODS: This study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4. RESULTS: PD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I. CONCLUSIONS: Our study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.

Cholinergic basal forebrain system degeneration underlies postural instability/gait difficulty and attention impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: The specific pathophysiological mechanisms underlying postural instability/gait difficulty (PIGD) and cognitive function in Parkinson's disease (PD) remain unclear. Both postural and gait control, as well as cognitive function, are associated with the cholinergic basal forebrain (cBF) system. METHODS: A total of 84 PD patients and 82 normal controls were enrolled. Each participant underwent motor and cognitive assessments. Diffusion tensor imaging was used to detect structural abnormalities in the cBF system. The cBF was segmented using FreeSurfer, and its fiber tract was traced using probabilistic tractography. To provide information on extracellular water accumulation, free-water fraction (FWf) was quantified. FWf in the cBF and its fiber tract, as well as cortical projection density, were extracted for statistical analyses. RESULTS: Patients had significantly higher FWf in the cBF (p < 0.001) and fiber tract (p = 0.021) than normal controls, as well as significantly lower cBF projection in the occipital (p < 0.001), parietal (p < 0.001) and prefrontal cortex (p = 0.005). In patients, a higher FWf in the cBF correlated with worse PIGD score (r = 0.306, p = 0.006) and longer Trail Making Test A time (r = 0.303, p = 0.007). Attentional function (Trail Making Test A) partially mediated the association between FWf in the cBF and PIGD score (indirect effect, a*b = 0.071; total effect, c = 0.256; p = 0.006). CONCLUSIONS: Our findings suggest that degeneration of the cBF system in PD, from the cBF to its fiber tract and cortical projection, plays an important role in cognitive-motor interaction.

Increased OIT3 in macrophages promotes PD-L1 expression and hepatocellular carcinogenesis via NF-κB signaling.

Oncoprotein-induced transcript 3 (OIT3) facilitates macrophage M2 polarization and hepatocellular carcinoma (HCC) progression, however, whether OIT3 regulates tumor immunity remains largely unknown. Here we found that OIT3 was upregulated in HCC-associated macrophages, which inhibited CD4+ and CD8+ T-cell infiltration in the tumor microenvironment (TME). Mechanistically, OIT3 increased the expression of PD-L1 on tumor-associated macrophages (TAMs) by activating NF-κB signaling, blockade of NF-κB reversed the immunosuppressive activity of TAMs and dampens HCC tumorigenesis. Our findings provide the molecular basis for OIT3 enhancing tumor immunosuppression and highlighted a potential therapeutic strategy for targeting the TAMs of HCC.

Comparative transcriptome analysis reveals the molecular mechanism of sterility induced by irradiation of Plutella xylostella (Linnaeus).

Plutella xylostella (Linnaeus) is an important pest of cruciferous plants, which is harmful all over the world, causing serious economic losses, and its drug resistance is increasing rapidly. The sterile insect technique (SIT) is a green control method and does not cause resistance. In this study, transcriptomics and bioinformatics were used to explore the effects of irradiation on the reproductive function of Plutella xylostella, and the response mechanism of sterility under irradiation was initially revealed. We identified 3342 (1682 up-regulated, 1660 down-regulated), 1963 (1042 up-regulated, 921 down-regulated) and 1531 (721 up-regulated, 810 down-regulated) differentially expressed genes (DEGs) in the 200 Gy vs CK (Control Check), 400 Gy vs CK and 400 Gy vs 200 Gy groups, respectively. GO and KEGG analyses were performed for DEGs in each group. The results showed that 200 Gy activated the downstream phosphorylation pathway and inhibited the cytochrome p450 immune response mechanism. 400 Gy promoted protein decomposition and absorption pathways, autophagy pathways, etc. Down-regulated genes were concentrated in the transformation process of energy metabolizing substances such as ATP, phosphorylation signaling pathway, and insulin, while up-regulated genes were concentrated in biological regulation and metabolic processes. Eight genes in the phosphorylation pathway were selected for qRT-PCR verification, and the results showed that the phosphorylation of different dose groups was regulated in different ways. 400 Gy used positive feedback regulation, while the phosphorylation of F1 used negative feedback regulation.

Bacillus velezensis strain NA16 shows high poultry feather-degrading efficiency, protease and amino acid production.

Isolated Bacillus velezensis strain NA16, which produces proteases, amino acids and the transcription levels of different keratinolytic enzymes and disulfide reductase genes in whole gene sequencing, was evaluated during feather degradation. The result shows under optimum fermentation conditions, chicken feather fermentation showed total amino acid concentration of 7599 mg/L, degradation efficiency of 99.3% at 72 h, and protease activity of 1058 U/mL and keratinase activity of 288 U/mL at 48 h. Goose feather fermentation showed total amino acid concentration of 4918 mg/L (96 h), and degradation efficiency was 98.9% at 120 h. Chicken feather fermentation broth at 72 h showed high levels of 17 amino acids, particularly phenylalanine (1050 ± 1.90 mg/L), valine (960 ± 1.04 mg/L), and glutamic (950 ± 3.00 mg/L). Scanning electron microscopy and Fourier transform infrared analysis revealed the essential role of peptide bond cleavage in structural changes and degradation of feathers. Protein purification and zymographic analyses revealed a key role in feather degradation of the 39-kDa protein encoded by gene1031, identified as an S8 family serine peptidase. Whole genome sequencing of NA16 revealed 26 metalloproteinase genes and 22 serine protease genes. Among the proteins, S8 family serine peptidase (gene1031, gene1428) and S9 family peptidase (gene3132) were shown by transcription analysis to play major roles in chicken feather degradation. These findings revealed the transcription levels of different families of keratinolytic enzymes in the degradation of feather keratin by microorganisms, and suggested potential applications of NA16 in feather waste management and amino acid production.

Verification of AKT and CDK5 Gene and RNA Interference Combined with Irradiation to Mediate Fertility Changes in Plutella xylostella (Linnaeus).

Plutella xylostella (Linnaeus) mainly damages cruciferous crops and causes huge economic losses. Presently, chemical pesticides dominate its control, but prolonged use has led to the development of high resistance. In contrast, the sterile insect technique provides a preventive and control method to avoid the development of resistance. We discovered two genes related to the reproduction of Plutella xylostella and investigated the efficacy of combining irradiation with RNA interference for pest management. The results demonstrate that after injecting PxAKT and PxCDK5, there was a significant decrease of 28.06% and 25.64% in egg production, and a decrease of 19.09% and 15.35% in the hatching rate compared to the control. The ratio of eupyrene sperm bundles to apyrene sperm bundles also decreased. PxAKT and PxCDK5 were identified as pivotal genes influencing male reproductive processes. We established a dose-response relationship for irradiation (0-200 Gy and 200-400 Gy) and derived the irradiation dose equivalent to RNA interference targeting PxAKT and PxCDK5. Combining RNA interference with low-dose irradiation achieved a sub-sterile effect on Plutella xylostella, surpassing either irradiation or RNA interference alone. This study enhances our understanding of the genes associated with the reproduction of Plutella xylostella and proposes a novel approach for pest management by combining irradiation and RNA interference.

Functional connectome predicting individual gait function and its relationship with molecular architecture in Parkinson's disease.

Gait impairment is a common symptom of Parkinson's disease (PD), but its neural signature remains unclear due to the interindividual variability of gait performance. Identifying a robust gait-brain correlation at the individual level would provide insight into a generalizable neural basis of gait impairment. In this context, this study aimed to detect connectome that can predict individual gait function of PD, and follow-up analyses assess the molecular architecture underlying the connectome by relating it to the neurotransmitter-receptor/transporter density maps. Resting-state functional magnetic resonance imaging was used to detect the functional connectome, and gait function was assessed via a 10 m-walking test. The functional connectome was first detected within drug-naive patients (N = 48) by using connectome-based predictive modeling following cross-validation and then successfully validated within drug-managed patients (N = 30). The results showed that the motor, subcortical, and visual networks played an important role in predicting gait function. The connectome generated from patients failed to predict the gait function of 33 normal controls (NCs) and had distinct connection patterns compared to NCs. The negative connections (connection negatively correlated with 10 m-walking-time) pattern of the PD connectome was associated with the density of the D2 receptor and VAChT transporter. These findings suggested that gait-associated functional alteration induced by PD pathology differed from that induced by aging degeneration. The brain dysfunction related to gait impairment was more commonly found in regions expressing more dopaminergic and cholinergic neurotransmitters, which may aid in developing targeted treatments.

Presence but not the timing of onset of REM sleep behavior disorder distinguishes evolution patterns in Parkinson's disease.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) could develop preceding or come after motor symptoms during Parkinson's disease (PD). It remains unknown that whether PD with different timing of RBD onset relative to motor symptoms suggests different spatiotemporal sequence of neurodegeneration. This study aimed to explore the sequence of disease progression in crucially involved brain regions in PD with different timing of RBD onset. METHOD: We recruited 157 PD, 16 isolated RBD (iRBD), and 78 healthy controls. PD patients were identified as (1) PD with RBD preceding motor symptoms (PD-preRBD, n = 50), (2) PD with RBD posterior to motor symptoms (PD-postRBD, n = 31), (3) PD without RBD (PD-nonRBD, n = 75). The volumes of crucial brain regions, including the basal ganglia and limbic structures in T1-weighted imaging, and the contrast-noise-ratios of locus coeruleus (LC) and substantia nigra (SN) in neuromelanin-sensitive magnetic resonance imaging, were extracted. To simulate the sequence of disease progression for cross-sectional data, an event-based model was introduced to estimate the maximum likelihood sequence of regions' involvement for each group. Then, a statistical parameter, the Bhattacharya coefficient (BC), was used to evaluate the similarity of the sequence. RESULTS: The model predicted that SN occupied the highest likelihood in the maximum likelihood sequence of disease progression in the all PD subgroups, while LC was specifically positioned earlier to SN in iRBD, a prodromal phase of PD. Subsequent early involvement of LC was observed in the both PD-preRBD and PD-postRBD. In contrast, atrophy in the para-hippocampal gyrus but relatively intact LC in the early stage was demonstrated in PD-nonRBD. Then, the similarity comparisons indicated higher BC between PD-postRBD and PD-preRBD (BC = 0.76) but lower BC between PD-postRBD and PD-nonRBD group (BC = 0.41). iRBD had higher BC against PD-preRBD (BC = 0.66) and PD-postRBD (BC = 0.63) but lower BC against PD- nonRBD (BC = 0.48). CONCLUSION: The spatiotemporal sequence of neurodegeneration between PD-pre and PD-post were similar but distinct from PD-nonRBD. The presence of RBD may be the essential factor for differentiating the degeneration patterns of PD, but the timing of RBD onset has currently proved to be not.

Normalization effect of dopamine replacement therapy on brain functional connectome in Parkinson's disease.

Dopamine replacement therapy (DRT) represents the standard treatment for Parkinson's disease (PD), however, instant and long-term medication influence on patients' brain function have not been delineated. Here, a total of 97 drug-naïve patients, 43 patients under long-term DRT, and 94 normal control (NC) were, retrospectively, enrolled. Resting-state functional magnetic resonance imaging data and motor symptom assessments were conducted before and after levodopa challenge test. Whole-brain functional connectivity (FC) matrices were constructed. Network-based statistics were performed to assess FC difference between drug-naïve patients and NC, and these significant FCs were defined as disease-related connectomes, which were used for further statistical analyses. Patients showed better motor performances after both long-term DRT and levodopa challenge test. Two disease-related connectomes were observed with distinct patterns. The FC of the increased connectome, which mainly consisted of the motor, visual, subcortical, and cerebellum networks, was higher in drug-naïve patients than that in NC and was normalized after long-term DRT (p-value <.050). The decreased connectome was mainly composed of the motor, medial frontal, and salience networks and showed significantly lower FC in all patients than NC (p-value <.050). The global FC of both increased and decreased connectome was significantly enhanced after levodopa challenge test (q-value <0.050, false discovery rate-corrected). The global FC of increased connectome in ON-state was negatively associated with levodopa equivalency dose (r = -.496, q-value = 0.007). Higher global FC of the decreased connectome was related to better motor performances (r = -.310, q-value = 0.022). Our findings provided insights into brain functional alterations under dopaminergic medication and its benefit on motor symptoms.

Improving the cytotoxicity of immunotoxins by reducing the affinity of the antibody in acidic pH.

BACKGROUND: Immunotoxins are antibody-toxin conjugates that bind to surface antigens and exert effective cytotoxic activity after internalization into tumor cells. Immunotoxins exhibit effective cytotoxicity and have been approved by the FDA to treat multiple hematological malignancies, such as hairy cell leukemia and cutaneous T-cell lymphoma. However, most of the internalized immunotoxin is degraded in lysosomes, and only approximately 5% of free toxin escapes into the cytosol to exert cytotoxicity. Many studies have improved immunotoxins by engineering the toxin fragment to reduce immunogenicity or increase stability, but how the antibody fragment contributes to the activity of immunotoxins has not been well demonstrated. METHODS: In the current study, we used 32A9 and 42A1, two anti-GPC3 antibodies with similar antigen-binding capabilities and internalization rates, to construct scFv-mPE24 immunotoxins and evaluated their in vitro and in vivo antitumor activities. Next, the antigen-binding capacity, trafficking, intracellular protein stability and release of free toxin of 32A9 scFv-mPE24 and 42A1 scFv-mPE24 were compared to elucidate their different antitumor activities. Furthermore, we used a lysosome inhibitor to evaluate the degradation behavior of 32A9 scFv-mPE24 and 42A1 scFv-mPE24. Finally, the antigen-binding patterns of 32A9 and 42A1 were compared under neutral and acidic pH conditions. RESULTS: Although 32A9 and 42A1 had similar antigen binding capacities and internalization rates, 32A9 scFv-mPE24 had superior antitumor activity compared to 42A1 scFv-mPE24. We found that 32A9 scFv-mPE24 exhibited faster degradation and drove efficient free toxin release compared to 42A1 scFv-mPE24. These phenomena were determined by the different degradation behaviors of 32A9 scFv-mPE24 and 42A1 scFv-mPE24 in lysosomes. Moreover, 32A9 was sensitive to the low-pH environment, which made the 32A9 conjugate easily lose antigen binding and undergo degradation in lysosomes, and the free toxin was then efficiently produced to exert cytotoxicity, whereas 42A1 was resistant to the acidic environment, which kept the 42A1 conjugate relatively stable in lysosomes and delayed the release of free toxin. CONCLUSIONS: These results showed that a low pH-sensitive antibody-based immunotoxin degraded faster in lysosomes, caused effective free toxin release, and led to improved cytotoxicity compared to an immunotoxin based on a normal antibody. Our findings suggested that a low pH-sensitive antibody might have an advantage in the design of immunotoxins and other lysosomal degradation-dependent antibody conjugate drugs.

Molecular Mechanism of Male Sterility Induced by 60Co γ-Rays on Plutella xylostella (Linnaeus).

Plutella xylostella (Linnaeus) is one of the notorious pests causing substantial loses to numerous cruciferous vegetables across many nations. The sterile insect technique (SIT) is a safe and effective pest control method, which does not pollute the environment and does not produce drug resistance. We used proteomics technology and bioinformatics analysis to investigate the molecular mechanisms responsible for the effects of different doses of radiation treatment on the reproductive ability of male P. xylostella. A total of 606 differentially expressed proteins (DEPs) were identified in the 200 Gy/CK group, 1843 DEPs were identified in the 400 Gy/CK group, and 2057 DEPs were identified in the 400 Gy/200 Gy group. The results showed that after 200 Gy irradiation, the testes resisted radiation damage by increasing energy supply, amino acid metabolism and transport, and protein synthesis, while transcription-related pathways were inhibited. After 400 Gy irradiation, the mitochondria and DNA in the testis tissue of P. xylostella were damaged, which caused cell autophagy and apoptosis, affected the normal life activities of sperm cells, and greatly weakened sperm motility and insemination ability. Meanwhile, Western blotting showed that irradiation affects tyrosine phosphorylation levels, which gradually decrease with increasing irradiation dose.

Altered brain iron depositions from aging to Parkinson's disease and Alzheimer's disease: A quantitative susceptibility mapping study.

Brain iron deposition is a promising marker for human brain health, providing insightful information for understanding aging as well as neurodegenerations, e.g., Parkinson's disease (PD) and Alzheimer's disease (AD). To comprehensively evaluate brain iron deposition along with aging, PD-related neurodegeneration, from prodromal PD (pPD) to clinical PD (cPD), and AD-related neurodegeneration, from mild cognitive impairment (MCI) to AD, a total of 726 participants from July 2013 to December 2020, including 100 young adults, 189 old adults, 184 pPD, 171 cPD, 31 MCI and 51 AD patients, were included. Quantitative susceptibility mapping data were acquired and used to quantify regional magnetic susceptibility, and the resulting spatial standard deviations were recorded. A general linear model was applied to perform the inter-group comparison. As a result, relative to young adults, old adults showed significantly higher iron deposition with higher spatial variation in all of the subcortical nuclei (p < 0.01). pPD showed a high spatial variation of iron distribution in the subcortical nuclei except for substantia nigra (SN); and iron deposition in SN and red nucleus (RN) were progressively increased from pPD to cPD (p < 0.01). AD showed significantly higher iron deposition in caudate and putamen with higher spatial variation compared with old adults, pPD and cPD (p < 0.01), and significant iron deposition in SN compared with old adults (p < 0.01). Also, linear regression models had significances in predicting motor score in pPD and cPD (Rmean = 0.443, Ppermutation = 0.001) and cognition score in MCI and AD (Rmean = 0.243, Ppermutation = 0.037). In conclusion, progressive iron deposition in the SN and RN may characterize PD-related neurodegeneration, namely aging to cPD through pPD. On the other hand, extreme iron deposition in the caudate and putamen may characterize AD-related neurodegeneration.

Identifying a whole-brain connectome-based model in drug-naïve Parkinson's disease for predicting motor impairment.

Identifying a whole-brain connectome-based predictive model in drug-naïve patients with Parkinson's disease and verifying its predictions on drug-managed patients would be useful in determining the intrinsic functional underpinnings of motor impairment and establishing general brain-behavior associations. In this study, we constructed a predictive model from the resting-state functional data of 47 drug-naïve patients by using a connectome-based approach. This model was subsequently validated in 115 drug-managed patients. The severity of motor impairment was assessed by calculating Unified Parkinson's Disease Rating Scale Part III scores. The predictive performance of model was evaluated using the correlation coefficient (rtrue ) between predicted and observed scores. As a result, a connectome-based model for predicting individual motor impairment in drug-naïve patients was identified with significant performance (rtrue  = .845, p < .001, ppermu  = .002). Two patterns of connection were identified according to correlations between connection strength and the severity of motor impairment. The negative motor-impairment-related network contained more within-network connections in the motor, visual-related, and default mode networks, whereas the positive motor-impairment-related network was constructed mostly with between-network connections coupling the motor-visual, motor-limbic, and motor-basal ganglia networks. Finally, this predictive model constructed around drug-naïve patients was confirmed with significant predictive efficacy on drug-managed patients (r = .209, p = .025), suggesting a generalizability in Parkinson's disease patients under long-term drug influence. In conclusion, this study identified a whole-brain connectome-based model that could predict the severity of motor impairment in Parkinson's patients and furthers our understanding of the functional underpinnings of the disease.

Substantia nigra iron affects functional connectivity networks modifying working memory performance in younger adults.

Brain iron affects working memory (WM) but the impact of iron content in deep grey matter nuclei on WM networks is unknown. We aimed to test whether deep grey matter nuclei iron concentration can affect resting-state functional connectivity (rsFC) within brain networks modifying WM performance. An N-back WM paradigm was applied in a hundred healthy younger adults. The participants then underwent a resting-state functional magnetic resonance imaging (fMRI) for brain network analysis and quantitative susceptibility mapping (QSM) imaging for assessment of deep grey matter nuclei iron concentration. Higher substantia nigra (SN) iron concentration was associated with lower rsFC between SN and brain regions of the temporal/frontal lobe but with better WM performance after controlling for age, gender and education. A follow-up mediation analysis also indicated that functional connectivity may mediate the link between SN iron and WM performance. Our results suggest that high SN iron concentration may affect communication between the SN and temporal/frontal lobe and is associated with strengthened WM performance in younger adults.

Selective elimination of CML stem/progenitor cells by picropodophyllin in vitro and in vivo is associated with p53 activation.

Chronic myeloid leukemia (CML) is a hematologic malignancy originating from BCR-ABL oncogene-transformed hematopoietic stem cells (HSCs) known as leukemia stem cells (LSCs). Therefore, targeting LSCs is of primary importance to eradicate CML. The present study demonstrates that picropodophyllin (PPP) effectively induces apoptosis and inhibits colony formation in CML stem/progenitor cells as well as quiescent CML progenitors resistant to imatinib therapy, while sparing normal hematopoietic cells in vitro. Administration of PPP in vivo markedly diminishes CML stem/progenitor cells in a transgenic mouse model of CML by inhibition of cell proliferation and enhancement of apoptosis in LSK cells, and significantly improves survival of CML mice. Furthermore, PPP treatment preferentially leads to transcriptional activation of p53 in CML but not normal CD34+ cells, upregulation of p53 protein in LSCs-enriched Sca-1+ cells from CML mice, and increased phosphorylation of p53 and upregulation of Bax protein in Ku812 cells. These results suggest that the inhibitory effects of PPP on CML stem/progenitor cells are associated with selective activation of p53 pathway and propose that PPP is a potent agent that selectively targets CML LSCs, and may be of value in the CML therapy.

Comparison of Four Amendments for Arsenic and Cadmium Combined Contaminated Soil.

Arsenic (As) and cadmium (Cd) are common soil pollutants whose opposing geochemical behaviors must be taken into account in the development of cost-effective, environmentally friendly remediation strategies. In this study, a pot experiment with lettuce and a field experiment with wheat were performed to examine the impacts of zeolite, biochar, MnO2, zero-valent iron (ZVI) individually and in binary combinations thereof on As-Cd pollution. The results of the pot experiment showed that biochar, MnO2 and ZVI had good passivation effects on As and Cd when provided individually, but the effects of a combination of 0.2% ZVI/0.5% biochar or 0.2% MnO2/0.5% ZVI were even better. These amendments were further investigated in a field experiment, which confirmed the positive effect of 0.2% MnO2/0.5% ZVI. Therefore, ZVI/biochar and MnO2/ZVI mixtures may offer effective solutions to the remediation of farmland soil contaminated with both As and Cd.

Evolutionary Digital Twin-Oriented Complex Networked Systems driven by node features and the mutation of feature preferences.

Accurate modelling of complex social systems, where people interact with each other and those interactions change over time, has been a research challenge for many years. This study proposes an evolutionary Digital Twin-Oriented Complex Networked System (DT-CNS) framework that considers heterogeneous node features and changeable connection preferences. We create heterogeneous preference mutation mechanisms to characterise nodes' adaptive decisions on preference mutation in response to interaction patterns and epidemic risks. In this space, we use nodes' interaction utilities to characterise the positive feedback from interactions and negative impact of epidemic risks. We also introduce social capital constraint to harness the density of social connections better. The nodes' heterogeneous preference mutation styles include the (i)inactive style that keeps initial social preferences, (ii) ignorant style that randomly mutates preferences, (iii) egocentric style that optimises individual interaction utility, (iv) cooperative style that optimises the total interaction utilities by group decisions and (v) collaborative style that further allows the cooperative nodes to transfer social capital. Our simulation experiments on evolutionary DT-CNSs reveal that heterogeneous preference mutation styles lead to various interaction and infection patterns. The results also show that (i) increasing social capital enables higher interactions but higher infection risks and uncertainty in decision-making; (ii) group decisions outperform individual decisions by eliminating the unawareness of the decisions of other nodes; (iii) the collaborative nodes under a strict social capital limit can promote interactions, reduce infection risks and achieve higher overall interaction utilities.

Towards Digital Twin-Oriented Complex Networked Systems: Introducing heterogeneous node features and interaction rules.

This study proposes an extendable modelling framework for Digital Twin-Oriented Complex Networked Systems (DT-CNSs) with a goal of generating networks that faithfully represent real-world social networked systems. Modelling process focuses on (i) features of nodes and (ii) interaction rules for creating connections that are built based on individual node's preferences. We conduct experiments on simulation-based DT-CNSs that incorporate various features and rules about network growth and different transmissibilities related to an epidemic spread on these networks. We present a case study on disaster resilience of social networks given an epidemic outbreak by investigating the infection occurrence within specific time and social distance. The experimental results show how different levels of the structural and dynamics complexities, concerned with feature diversity and flexibility of interaction rules respectively, influence network growth and epidemic spread. The analysis revealed that, to achieve maximum disaster resilience, mitigation policies should be targeted at nodes with preferred features as they have higher infection risks and should be the focus of the epidemic control.

A survey of deep learning applications in cryptocurrency.

This study aims to comprehensively review a recently emerging multidisciplinary area related to the application of deep learning methods in cryptocurrency research. We first review popular deep learning models employed in multiple financial application scenarios, including convolutional neural networks, recurrent neural networks, deep belief networks, and deep reinforcement learning. We also give an overview of cryptocurrencies by outlining the cryptocurrency history and discussing primary representative currencies. Based on the reviewed deep learning methods and cryptocurrencies, we conduct a literature review on deep learning methods in cryptocurrency research across various modeling tasks, including price prediction, portfolio construction, bubble analysis, abnormal trading, trading regulations and initial coin offering in cryptocurrency. Moreover, we discuss and evaluate the reviewed studies from perspectives of modeling approaches, empirical data, experiment results and specific innovations. Finally, we conclude this literature review by informing future research directions and foci for deep learning in cryptocurrency.