Prospective association of comorbid hypertension and depressive symptoms with C-reactive protein in older adults.

BACKGROUND: Hypertension and depressive symptoms often occur together in the older population, and each has been separately linked to elevated C-reactive protein (CRP). This study investigated the prospective association between comorbid hypertension and depressive symptoms and high-sensitivity CRP (hs-CRP) in a Chinese older population. METHODS: This study used data from 4978 participants aged 50 and above, who took part in two waves (2011 and 2015) of the China Health and Retirement Longitudinal Study (CHARLS). Hypertension, depressive symptoms and hs-CRP were measured. Logistic regressions adjusted for confounding variables were used to examine the association between the baseline comorbidity of hypertension and depressive symptoms and the change in hs-CRP levels. RESULTS: Hypertension and depressive symptoms did not show independent associations with an elevated level of hs-CRP. Participants with comorbid hypertension and depressive symptoms were more likely to develop a higher level of hs-CRP at follow-up (OR = 1.39, 95 % CI: 1.12-1.74) even after adjusting for covariates. Sex- and age-stratified analyses indicated that the association between the comorbidity and higher levels of hs-CRP were prone to be observed in women (OR = 1.55, 95 % CI: 1.16-2.08) and older adults (OR = 1.74, 95 % CI: 1.20-2.52). CONCLUSIONS: Comorbid hypertension and depressive symptoms is related to a higher risk of elevated hs-CRP levels. This association appears to be more pronounced among women and older adults compared to their counterparts. LIMITATION: Depression was self-reported by participants, which might be considered less unreliable than clinical diagnoses.

A framework to evaluate the impact of a hazard chain and geographical covariates on spatial extreme water levels: A case study in the Pearl River Delta.

The interactions and collective impacts of different types of hazards within a compound hazard system, along with the influence of geographical covariates on flooding are presently unclear. Understanding these relationships is crucial for comprehending the formation and dynamic processes of the hazard chain and improving the ability to identify flood warning signals in complex hazard scenarios. In this study, we presented a multivariate spatial extreme value hierarchical (MSEVH) framework to assess the spatial extreme water levels (EWL) at different return levels under the influence of a hazard chain and geographical covariates. The Pearl River Delta (PRD) was selected as a research example to assess the effectiveness of the MSEVH framework. Firstly, we identified a hazard chain (extreme streamflow from the Xijiang River (XR) - extreme streamflow from the Beijiang River (BR) - extreme sea level) and three geographical covariates influencing EWL in the PRD. Then, we compared four hazard scenarios in the MSEVH framework to evaluate the spatial EWL at different return levels under the influence of the hazard chain in the PRD. The final step involves assessing spatial EWL with the effect of the hazard chain and geographical covariates. The results indicate that when extreme streamflow from XR and BR occurs concurrently, the extreme streamflow from BR weakens the influence of extreme streamflow from XR on EWL in the PRD. However, it cannot fully offset the overall impact of extreme streamflow from XR on EWL. In addition, when extreme streamflow from XR, extreme streamflow from BR, and extreme sea level occur simultaneously, the extreme sea level enhances the influence of concurrent extreme streamflow from XR and BR on EWL in the PRD. The proposed MSEVH is not only applicable to the PRD but also shows promising potential for evaluating extreme hydrometeorological variables under the influence of other hazard chains.

Effects of different roasting temperatures on rabbit meat protein oxidation and fluorescent carbon nanoparticle formation.

This study explores the oxidation of rabbit meat proteins and the physicochemical properties of the resulting fluorescent carbon nanoparticles (CNPs) under various roasting temperatures (180, 210, 240, 270, and 300 °C). The determination of sulfhydryl content, along with the results from UV and fluorescence spectroscopy, indicates that the protein structure undergoes changes during the roasting process, and the degree of oxidation shows an increasing trend with rising roasting temperatures. The CNP solution obtained exhibits a typical blue fluorescence. Moreover, as the roasting temperature increases from 180 °C to 300 °C, the relative content of the three elements in CNPs, namely C, N, and O, increases by 12 %, -3%, and -9 %, respectively. The surface of the obtained rabbit meat CNPs contains hydrophilic and polycyclic groups, such as carbonyl, hydroxyl, and amide bonds. Correlation analysis reveals a significant positive correlation between the degree of protein oxidation and the fluorescence intensities of CNPs.

Reaching the limit in autonomous racing: Optimal control versus reinforcement learning.

A central question in robotics is how to design a control system for an agile mobile robot. This paper studies this question systematically, focusing on a challenging setting: autonomous drone racing. We show that a neural network controller trained with reinforcement learning (RL) outperformed optimal control (OC) methods in this setting. We then investigated which fundamental factors have contributed to the success of RL or have limited OC. Our study indicates that the fundamental advantage of RL over OC is not that it optimizes its objective better but that it optimizes a better objective. OC decomposes the problem into planning and control with an explicit intermediate representation, such as a trajectory, that serves as an interface. This decomposition limits the range of behaviors that can be expressed by the controller, leading to inferior control performance when facing unmodeled effects. In contrast, RL can directly optimize a task-level objective and can leverage domain randomization to cope with model uncertainty, allowing the discovery of more robust control responses. Our findings allowed us to push an agile drone to its maximum performance, achieving a peak acceleration greater than 12 times the gravitational acceleration and a peak velocity of 108 kilometers per hour. Our policy achieved superhuman control within minutes of training on a standard workstation. This work presents a milestone in agile robotics and sheds light on the role of RL and OC in robot control.

Agilicious: Open-source and open-hardware agile quadrotor for vision-based flight.

Autonomous, agile quadrotor flight raises fundamental challenges for robotics research in terms of perception, planning, learning, and control. A versatile and standardized platform is needed to accelerate research and let practitioners focus on the core problems. To this end, we present Agilicious, a codesigned hardware and software framework tailored to autonomous, agile quadrotor flight. It is completely open source and open hardware and supports both model-based and neural network-based controllers. Also, it provides high thrust-to-weight and torque-to-inertia ratios for agility, onboard vision sensors, graphics processing unit (GPU)-accelerated compute hardware for real-time perception and neural network inference, a real-time flight controller, and a versatile software stack. In contrast to existing frameworks, Agilicious offers a unique combination of flexible software stack and high-performance hardware. We compare Agilicious with prior works and demonstrate it on different agile tasks, using both model-based and neural network-based controllers. Our demonstrators include trajectory tracking at up to 5g and 70 kilometers per hour in a motion capture system, and vision-based acrobatic flight and obstacle avoidance in both structured and unstructured environments using solely onboard perception. Last, we demonstrate its use for hardware-in-the-loop simulation in virtual reality environments. Because of its versatility, we believe that Agilicious supports the next generation of scientific and industrial quadrotor research.

The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

A molecular beam-surface apparatus for quantum state-resolved adsorption studies.

Understanding the microscopic mechanism of molecule-surface interaction is of great importance in the study of chemical dynamics. Yet, it remains challenging to experimentally acquire quantum state resolved results, particularly the results related to different degrees of freedom of the reactants. Here, we report the design and performance of a new apparatus for molecule-surface dynamics studies, which enable the measurement of quantum state-resolved adsorption. A continuous narrow-linewidth infrared laser source and molecular beam unit were developed and employed in this new apparatus to achieve independent control on different degrees of freedom (translation, vibration, and rotation) of the molecule. Preliminary results on hydrogen and hydrogen chloride adsorption on the Cu (111) surface were also presented.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Epidemiology and evolution of Norovirus in China.

Norovirus (NoV) has been recognized as a leading cause of gastroenteritis worldwide. This review estimates the prevalence and genotype distribution of NoV in China to provide a sound reference for vaccine development. Studies were searched up to October 2020 from CNKI database and inclusion criteria were study duration of at least one calendar year and population size of >100. The mean overall NoV prevalence in individuals with sporadic diarrhea/gastroenteritis was 16.68% (20796/124649, 95% CI 16.63-16.72), and the detection rate of NoV was the highest among children. Non-GII.4 strains have replaced GII.4 as the predominant caused multiple outbreaks since 2014. Especially the recombinant GII.P16-GII.2 increased sharply, and virologic data show that the polymerase GII.P16 rather than VP1 triggers pandemic. Due to genetic diversity and rapid evolution, predominant genotypes might change unexpectedly, which has become major obstacle for the development of effective NoV vaccines.

SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA.

HBV infection initiates hepatitis B and promotes liver cirrhosis and hepatocellular carcinoma. IFN-α is commonly used in hepatitis B therapy, but how it inhibits HBV is not fully understood. We screened 285 human interferon-stimulated genes (ISGs) for anti-HBV activity using a cell-based assay, which revealed several anti-HBV ISGs. Among these ISGs, SAMD4A was the strongest suppressor of HBV replication. We found the binding site of SAMD4A in HBV RNA, which was a previously unidentified Smaug recognition region (SRE) sequence conserved in HBV variants. SAMD4A binds to the SRE site in viral RNA to trigger its degradation. The SAM domain in SAMD4A is critical for RNA binding and the C-terminal domain of SAMD4A is required for SAMD4A anti-HBV function. Human SAMD4B is a homolog of human SAMD4A but is not an ISG, and the murine genome encodes SAMD4. All these SAMD4 proteins suppressed HBV replication when overexpressed in vitro and in vivo. We also showed that knocking out the Samd4 gene in hepatocytes led to a higher level of HBV replication in mice and AAV-delivered SAMD4A expression reduced the virus titer in HBV-producing transgenic mice. In addition, a database analysis revealed a negative correlation between the levels of SAMD4A/B and HBV in patients. Our data suggest that SAMD4A is an important anti-HBV ISG for use in IFN therapy of hepatitis B and that the levels of SAMD4A/B expression are related to HBV sensitivity in humans.

The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice.

BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear. RESULTS: Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice. CONCLUSIONS: Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD. Video abstract.

A discrete serotonergic circuit regulates vulnerability to social stress.

Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDR→VTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDR→VTA neurons. Importantly, the bidirectional manipulation of 5-HTDR→VTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDR→VTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.

Simultaneous H2S mitigation and methanization enhancement of chicken manure through the introduction of the micro-aeration approach.

The impact on H2S alleviation and methane yield enhancement after submitting the anaerobic digestion of chicken manure to a finite amount of air was investigated. The largest reduction in the H2S biogas content (58% lower) occurred when air intensity of 30 ml/g VSin was injected into the reactors. Consequently, a maximum methane yield (335 mL-g VSin-1), which was 77% higher than the control, was concurrently achieved. Slight sulfate accumulation (<330 mg L-1) was observed inside the micro-aerated digesters with higher air intensities, suggesting a suppression of sulfide inhibition. Bacterial diversity/richness was enhanced in these digesters while the relative abundance of Methanocelleus increased by 36%. The most important contributing factor to enhancement was the synergistic effect resulting from increments in the hydrolysis rate and the suppression of sulfide inhibition. The results highlighted the potential of in situ H2S mitigation with the added benefit of methane yield enhancement.

Exosomal MicroRNAs as Liquid Biopsy Biomarkers in Hepatocellular Carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) has a high incidence in China and exploring effective ways for early diagnosis is an important method to improve the prognosis of patients with HCC. Additional studies reported that. Some kinds of microRNA (miRNA) in plasma will change accordingly during HCC progress, and this change can be used to diagnose HCC, especially with miRNA-122, miRNA-21 and miRNA-96. We were aiming at investigating the values of the exosomal miRNAs in diagnosis and prognosis for HCC patients. PATIENTS AND METHODS: Blood samples from 50 patients with HCC and 50 patients with hepatic cirrhosis and 50 healthy volunteers were obtained. The diagnostic accuracy of the plasma and exosomal miRNAs and the comparisons among different groups were measured by the area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis. RESULTS: Expression levels of miRNA-21 and miRNA-96 were significantly higher in patients with HCC and of miRNA-122 were significantly lower in HCC compared with cirrhotic patients in both exosomes and plasma. Among different groups, exosomal miRNA-122, miRNA-21 and miRNA-96 were significantly more accurate in diagnosing HCC than those miRNAs in plasma and the alpha-fetoprotein (AFP) level. The miRNA panel had high accuracy in discriminating HCC from the cirrhosis group (AUC 0.924; 95% CI; sensitivity 82%, specificity 92%) and healthy volunteers' group. Exosomal miRNA-21 and miRNA-96 with low expression and miRNA-122 with high expression could be associated with a patient's survival time. However, the miRNA panel could better predict the HCC patient's survival time compared with each miRNA individually. CONCLUSION: This study showed that the expression levels of miRNA-122, miRNA-21 and miRNA-96 in exosomes were more significantly changed than those miRNAs in plasma in patients with HCC compared with cirrhotic patients, and the exosomal miRNA panel containing miRNA-122, miRNA-21 and miRNA-96 could be defined as a diagnostic biomarker for patients with HCC. We also conclude that different expression of exosomal miRNAs, especially the miRNA panel, could predict the HCC patient's prognosis.

Metabolic performance of anaerobic digestion of chicken manure under wet, high solid, and dry conditions.

The anaerobic digestion (AD) of chicken manure as a solo substrate has been challenging due to the ammonium inhibition effects when adopting a high organic loading rate (OLR). In this study, through increasing both the total solid in the feeding materials from 5% to 20%, and the OLR from 1.7 to 7.1 g-volatile solids (VS)/(L·d), the AD of chicken manure under wet, high solid, and dry conditions, with a fixed hydraulic retention time of 20 days, was investigated. The results obtained indicated that the wet AD system could achieve a methane yield of 0.28 L/g-VS and a low volatile fatty acid level. However, the process deteriorated under dry conditions, and methane formed mainly through acetate oxidation and methanogenesis. Methanosarcina and Methanoplasma were found to be more tolerant But, whether the dry AD of chicken manure can survive an ammonia-stressed environment when the OLR is lowered, still needs investigation.

Response of the microbial community to the methanogenic performance of biologically hydrolyzed sewage sludge with variable hydraulic retention times.

Hyperthermophilic biological hydrolysis of sewage sludge was applied before long-term anaerobic digestion to investigate how shortening hydraulic retention times (HRT, 20-5d) affected methanogenic performances and microbial dynamics. Results indicated that although the three different HRTs provided a stable process with a steady-state of methane production, both methane yield (161 L kg-VSin-1, 25% higher) and volatile solids removal (VS, 50%, 2-fold higher) increased during longer HRTs. Redundancy analysis results indicated that Sporosarcina and Methnosarcina positively correlated to VS removal and methane yield, and negatively correlated to volatile fatty acids (VFAs) accumulation. The relative abundance of Coprothermobacter (>60%), syntrophic acetate oxidation bacteria (SAOB), and Methanospirillum (8-15%), increased during shorter HRTs. A slight shift to two-stage acetate conversion was observed during shorter HRTs. The results demonstrated that HRTs played a key role in shaping microbial structure, leading to a new steady-state of microbial community profiles and process performances at variable HRTs.

Intravoxel Incoherent Motion Combined With Dynamic Contrast-Enhanced Perfusion MRI of Early Cervical Carcinoma: Correlations Between Multimodal Parameters and HIF-1α Expression.

BACKGROUND: The identification of hypoxia inducible factor (HIF-1α) expression is helpful for the quantitative assessment of tumor hypoxia. The application of multimodal imaging techniques may play a part in the assessment of HIF-1α expression of cervical carcinoma. PURPOSE: To investigate the correlations between multiple imaging parameters and HIF-1α expression of early cervical carcinoma and to determine whether tumor hypoxia can be predicted using multisequence imaging parameters. STUDY TYPE: Prospective observational. POPULATION: One hundred patients with early cervical carcinoma. FIELD STRENGTH/SEQUENCES: 3.0 T MRI including intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) perfusion MRI sequences. ASSESSMENT: DCE-MRI and IVIM DWI were performed for all patients. The imaging parameters included volume transfer constant (Ktrans ), rate constant (Kep ), extravascular extracellular volume fraction (Ve ), D, D*, and f. STATISTICAL TESTS: The comparisons of imaging parameters between two independent groups were performed using the Mann-Whitney U-test. Multiple linear regression analysis was performed to determine the correlation between multiple imaging parameters and HIF-1α expression. The diagnostic ability of DCE-MRI, IVIM DWI, and the combination of two techniques for discriminating high-expression and low-expression groups were analyzed. RESULTS: The high-expression group had a lower Ktrans or Kep value than the low-expression group (P = 0.03; 0.02), while the high-expression group had a higher Ve value than the low-expression group (P = 0.03). The high-expression group had a higher D or f value than the low-expression group (P = 0.02; 0.02). Ktrans , Kep , D, Ve , and f values were independently correlated with HIF-1α expression. The sensitivity or accuracy of a combined method was higher than that of DCE-MRI or IVIM DWI individually (P = 0.03, 0.02; 0.04, 0.03). DATA CONCLUSION: The combination of DCE-MRI and IVIM DWI can improve the diagnostic ability of discriminating different HIF-1α expression levels for early cervical tumors. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:918-929.

Retraction of: A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis.

Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.

Intravoxel incoherent motion MR imaging of early cervical carcinoma: correlation between imaging parameters and tumor-stroma ratio.

OBJECTIVES: To investigate if intravoxel incoherent motion (IVIM) MR imaging can predict the tumour-stroma ratio (TSR) in patients with early cervical carcinoma. METHODS: Fifty-four patients with early cervical carcinoma were prospectively enrolled into this study. All patients underwent IVIM imaging and parameters including D, D* and f value were measured. The tumours were classified into stroma-rich and stroma-poor group according to TSR, and comparisons of IVIM parameters between two groups were performed. The relationships between IVIM parameters and TSR were analysed by using a multivariate multi-regression analysis. RESULTS: D and f values were significantly lower in stroma-poor tumours than in stroma-rich tumours (p=0.02, 0.04), while the difference in D* value between two groups didn't achieve statistical significance (p=0.09). The areas under ROC curves of D and f values in discriminating stroma-rich and stroma-poor tumours were 0.835 (95%CI=0.616~0.905) and 0.686 (95%CI=0.575~0.798). In multiple linear regression analysis, D value, pathologic type, histologic grade, tumour size and f value were independently correlated with TSR of cervical carcinoma. CONCLUSIONS: D and f values are independently correlated with TSR of cervical carcinoma and have the potential for quantitative measurement of TSR. KEY POINTS: • TSR is a recognized independent prognostic factor in many solid tumours. • D and f values measured by IVIM MRI are independently correlated with TSR while D* is not. • IVIM offers the potential to predict TSR.

A Novel High Throughput Virtual Screening Protocol to Discover New Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) plays an important role in the immune escape of tumors and has emerged as a promising target for cancer immunotherapy. Despite its potential in immuno-oncology, very few chemotypes have been reported to date. Here, we disigned a novel high throughput virtual screening (HTVS) cascade protocol, combining both pharmacophore modeling and molecular docking and it was employed to query commercially available compounds to identify novel inhibitors. Among the 23 compounds selected for the in vitro IDO1 inhibitory activity assay, five compounds exhibit greater than 20% inhibition at a test concentration of 10 µM, with two compounds having an IC50 value of 23.8 and 8.8 µM, respectively. The novel scaffold together with a ligand efficiency of 0.28 kcal/mol per heavy atom makes both compounds as suitable starting points for future chemistry elaboration. Our HTVS protocol was validated and could be employed in discovery of IDO1 inhibitors.