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Cytochrome P450 3A4 (CYP3A4) is one of the major drug metabolizing enzymes in the human body and metabolizes ∼30-50% of clinically used drugs. Inhibition of CYP3A4 must always be considered in the development of new drugs. Time-dependent inhibition (TDI) is an important P450 inhibition type that could cause undesired drug-drug interactions. Therefore, identification of CYP3A4 TDI by a rapid convenient way is of great importance to any new drug discovery effort. Here, we report the development of in silico classification models for prediction of potential CYP3A4 time-dependent inhibitors. On the basis of the CYP3A4 TDI data set that we manually collected from literature and databases, both conventional machine learning and deep learning models were constructed. The comparisons of different sampling strategies, molecular representations, and machine-learning algorithms showed the benefits of a balanced data set and the deep-learning model featured by GraphConv. The generalization ability of the best model was tested by screening an external data set, and the prediction results were validated by biological experiments. In addition, several structural alerts that are relevant to CYP3A4 time-dependent inhibitors were identified via information gain and frequency analysis. We anticipate that our effort would be useful for identification of potential CYP3A4 time-dependent inhibitors in drug discovery and design.

In Part I, the Chebyshev polynomial fitting (CPF) method has been proved to be effective to construct reliable cotidal charts for the eight major tidal constituents (M2, S2, K1, O1, N2, K2, P1, and Q1) near Hawaii and yields accurate results which are consistent with the Finite Element Solutions 2014 (FES2014), National Astronomical Observatory 99b (NAO.99b), and TPXO9 models. In this paper, the method is extended to estimate the harmonic constants of some minor tidal constituents. The mesoscale variation correction is applied to tidal elevations from satellite altimeters to eliminate the potential influence of background mesoscale ocean noise when estimating minor tidal constituents. This correction is necessary and makes the amplitude ratio between P1 and K1 constituents more consistent with the equilibrium tidal theory. Compared with the harmonic constants directly extracted from satellite altimeter data, FES2014 and NAO.99b yield mean root-mean-square (RMS) errors of 0.238 and 0.226 cm, respectively, while CPF method yields a mean RMS error of 0.210 cm, causing a 7%–12% decrease in the RMS error. At the crossover points between ascending and descending tracks, the decrease of RMS errors becomes 15%–18%. The accuracy of this method is also validated by comparing the estimated harmonic constants with those derived from tidal gauges and bottom-pressure recorders. These results indicate that the CPF method is also effective for estimating harmonic constants of minor tidal constituents. More importantly, the CPF method can obtain the harmonic constants of minor tidal constituents directly from satellite altimeter data, instead of being inferred via admittance theory. Significance Statement Ocean tides originate from the gravitational attraction of the sun and moon. Among the large number of tidal constituents, the major tidal constituents have been extensively studied. We extend the method proposed in Part I to estimate the harmonic constants of some minor tidal constituents with low amplitudes. The method relies on actual observations of water level variations from satellite altimeters without considering the hydrodynamic equations. We compared the results of this method with those of other models, using the data from satellite altimeters, tidal gauges, and bottom-pressure recorders. We find that the method performs well in estimating harmonic constants for some minor tidal constituents and causes a decrease of 7%–18% in RMS errors compared to other models.

Present evidence suggests that the administration of antibiotics, particularly aminopenicillins, may increase the risk of rash in children with infectious mononucleosis (IM). This retrospective, multicenter cohort study of children with IM was conducted to explore the association between antibiotic exposure in IM children and the risk of rash.

Despite mounting attention paid to vegetation growth and their driving forces for water-limited ecosystems, the relative contributions of atmospheric and soil moisture dryness stress on vegetation growth are an ongoing debate. Here we comprehensively compare the impacts of high vapor pressure deficit (VPD) and low soil water content (SWC) on vegetation growth in Eurasian drylands during 1982–2014. The analysis indicates a gradual decoupling between atmospheric dryness and soil dryness over this period, as the former has expanded faster than the latter. Moreover, the VPD-SWC relation and VPD-greenness relation are both non-linear, while the SWC-greenness relation is near-linear. The loosened coupling between VPD and SWC, the non-linear correlations among VPD-SWC-greenness, and the expanded area extent where SWC acts as the dominant stress factor all provide compelling evidence that SWC is a more influential stressor than VPD on vegetation growth in Eurasian drylands. In addition, a set of 11 Earth system models projected a continuously growing constraint of SWC stress on vegetation growth towards 2100. Our results are vital to dryland ecosystems management and drought mitigation in Eurasia.

Fish is one of the model animals used to evaluate the adverse effects of a chemical exposed to the ecosystem. However, its low throughput and relevantly high expense make it impossible to test all new chemicals in manufacture. Hence, using in silico models to prioritize compounds to be tested has been widely applied in environmental risk assessment and drug discovery. In this study, we constructed the local predictive models for four fish species, including bluegill sunfish, rainbow trout, fathead minnow, and sheepshead minnow, and the global models with all four fish data. A total of 1874 unique compounds with their labels, that is, toxic (LC

Aim: We aimed to identify how the COVID-19 lockdown affected changes, including the potential for longer term sustained changes, in physical activity, as compared to immediately prior to the pandemic. Background: Physical activity’s significant role in overall health is known to be influenced by the surrounding environment, such as one’s neighborhood, prompting this study of physical activity and its relationship with individual-level and neighborhood-level factors within the pandemic timeline. Methods: A statewide online survey assessed adults’ self-reported weekly minutes of moderate-to-vigorous physical activity (MVPA) comparing a typical week immediately prior to the pandemic and during the pandemic (prewidespread vaccination) using negative binomial models. Results: Overall, MVPA decreased during the pandemic, though the decrease was driven largely by the reduction in MVPA outside one’s neighborhood. In contrast, MVPA done within one’s neighborhood increased over time. This change in MVPA done within one’s neighborhood was not uniform across several characteristics including income level favoring those with the highest income ( p < .05) and race/ethnicity favoring those self-reporting as non-Hispanic White ( p < .05). While several factors, including higher Walk Scores, were associated with higher levels of MVPA without evidence of change over time, evidence of a differential effect over time was seen for other key indicators of social and structural determinants of health including income and race/ethnicity. Conclusions: This study can add to the existing literature surrounding not only COVID-19 but also neighborhood built environmental research seeking to identify factors associated with changes in MVPA, a known indicator of overall health and health-related outcomes.

Background Complications such as cognitive impairment are common in stroke victims. The goal of this study was to see if there was a link between blood iron levels and post-stroke cognitive impairment (PSCI) within 2 weeks after stroke. Methods A total of 313 patients with ischemic stroke were recruited and separated into two groups: PSCI (n = 202) and non-PSCI (n = 111). The Mini-mental state examination scale was used to evaluate the cognitive status within 2 weeks after stroke (acute phase). The serum iron levels were divided into 4 layers: Q1 ≤ 11.7 μmol/L, Q2 11.8-15.1 μmol/, Q3 15.2-19.3 μmol/L, Q4 ≥ 19.4 μmol/L, respectively. The connection between serum iron and PSCI was then investigated further using binary logistic regression, which was adjusted for confounders. Results The difference in serum iron levels between the PSCI and non-PSCI group was initially conducted by the Mann-Whitney test, and a significant difference was found (14.5 (11.0-17.8) vs. 16.9 (13.7-21.8), p < .001), with no confounders being adjusted. After adjusting for confounding factors, the binary regression analysis showed that the Q4 layer showed the lowest risk of PSCI, with the Q1 layer being the reference. (odds ratio (OR) = 0.297, 95% confidence interval (CI) = 0.136-0.649, p = 0.002). Conclusion A decreased risk of early-onset PSCI was linked to high serum iron levels. Low serum iron levels were found to be a risk factor for acute cognitive impairment following stroke, which could help physicians identify and take intervention measures early to reduce the risk of cognitive impairment after stroke.

Post-stroke anxiety (PSA) is a common neuropsychiatric affective disorder occurring after a stroke. Animal experiments have indicated that serum S-100β levels are closely related to anxiety disorder. No clinical study has been done to explore the relationship between serum S-100β levels and anxiety symptoms in patients with acute stroke. The aim of our study was to investigate the association between serum S-100β levels and PSA.One hundred twenty-six acute stroke patients were recruited and followed up for 1 month. Blood samples were collected within 24 h after admission. The levels of serum S-100β were measured by enzyme-linked immunosorbent assays. Patients with significant clinical symptoms of anxiety and a Hamilton Anxiety Rating Scale score7 at 1 month after stroke were diagnosed as PSA.Serum S-100β levels in the non-PSA group were lower than the PSA group (838.97 (678.20-993.59) ng/L vs. 961.87 (796.09-1479.59) ng/L, Z = -2.661, P = 0.008). In multivariate analyses, we found that decreased risk of PSA was associated with low tertile serum S-100β levels (≤753.8 ng/L, OR 0.062, 95% CI 0.008-0.475, P = 0.007).Low serum S-100β levels at admission may be associated with the decreased risk of PSA.

The structural and electronic modifications of χ-Fe5C2 by MgO contribute to the high selectivity towards lower olefins and the high catalyst stability.

Citrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Although anuclear in nature, platelets have an intricate post-translational modification machinery. Till now, citrullination in platelets and its contribution to trigger autoantibodies ACPA production in RA is an unexplored research direction. Herein, we investigated the expression of peptidylarginine deiminase (PAD) enzymes and citrullinated proteins/peptides in the human platelets and platelet derived microparticles (PDP). Both PAD4 mRNA and protein, but not the other PAD isoforms, are detectable in the human platelets. With a strict filtering criterion,108 citrullination sites present on 76 proteins were identified in the human platelets, and 55 citrullinated modifications present on 37 different proteins were detected in the PDPs. Among them, some are well-known citrullinated autoantigens associated with RA. Citrullinated forms of thrombospondin-1, β-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and bound by autoantibodies ACPA. Furthermore, ACPA from RA sera and synovial fluids recognized citrullinated proteins from platelets and significantly activated them as evidenced by P-selectin upregulation and sCD40 L secretion. These results clearly demonstrate the presence of citrullinated autoantigens in platelets and PDPs, thus could serve as potential targets of ACPA in RA.

IntroductionPost-stroke aphasia (PSA) is a language disorder caused by left hemisphere stroke. Electroacupuncture (EA) is a minimally invasive therapeutic option for PSA treatment. Tongli (HT5) and Xuanzhong (GB39), two important language-associated acupoints, are frequently used in the rehabilitation of patients with PSA. Preliminary evidence indicated functional activation in distributed cortical areas upon HT5 and GB39 stimulation. However, research on the modulation of dynamic and static functional connectivity (FC) in the brain by EA in PSA is lacking.MethodThis study aimed to investigate the PSA-related effects of EA stimulation at HT5 and GB39 on neural processing. Thirty-five participants were recruited, including 19 patients with PSA and 16 healthy controls (HCs). The BOLD signal was analyzed by static independent component analysis, generalized psychophysiological interactions, and dynamic independent component analysis, considering variables such as age, sex, and years of education.ResultsThe results revealed that PSA showed activated clusters in the left putamen, left postcentral gyrus (PostCG), and left angular gyrus in the salience network (SN) compared to the HC group. The interaction effect on temporal properties of networks showed higher variability of SN (F = 2.23, positive false discovery rate [pFDR] = 0.017). The interaction effect on static FC showed increased functional coupling between the right calcarine and right lingual gyrus (F = 3.16, pFDR = 0.043). For the dynamic FC, at the region level, the interaction effect showed lower variability and higher frequencies of circuit 3, with the strongest connections between the supramarginal gyrus and posterior cingulum (F = 5.42, pFDR = 0.03), middle cingulum and PostCG (F = 5.27, pFDR = 0.036), and triangle inferior frontal and lingual gyrus (F = 5.57, pFDR = 0.026). At the network level, the interaction effect showed higher variability in occipital network–language network (LN) and cerebellar network (CN) coupling, with stronger connections between the LN and CN (F = 4.29, pFDR = 0.042). Dynamic FC values between the triangle inferior frontal and lingual gyri were anticorrelated with transcribing, describing, and dictating scores in the Chinese Rehabilitation Research Center for Chinese Standard Aphasia Examination.DiscussionThese findings suggest that EA stimulation may improve language function, as it significantly modulated the nodes of regions/networks involved in the LN, SN, CN, occipital cortex, somatosensory regions, and cerebral limbic system.

The ecosystem parameters are critical for precisely determining the marine ecological process and improving the simulations of the marine ecological model. In this study, based on the NPZD (nutrient, phytoplankton, zooplankton and detritus) model, the surface chlorophyll-a observations obtained from Sea-viewing Wide Field-of-view Sensor (SeaWiFS) data were assimilated to estimate spatially ecosystem parameters in the Bohai, Yellow, and East China Seas using an adjoint assimilation method with characteristic finite difference scheme. The experiments of the moving Gaussian hump indicated that the characteristic finite difference method (CFDM) can get rid of the limit of stability and permit using large time steps, which reduces long computation durations and large memory requirements. The model performance was significantly improved after data assimilation with CFDM using a large time step of 6 hours. Moreover, the distributions of parameters of the NPZD model in winter in the Bohai Sea, the Yellow Sea, and the East China Sea were simulated by our method. Overall, the developed method can efficiently optimize the ecosystem parameters and the results can be beneficial for determining reasonable parameters of the marine ecological model.

For pancreatic ductal adenocarcinoma (PDAC) treatment, the deactivation of pancreatic stellate cells (PSCs) by blocking the transforming growth factor β (TGF-β) pathway is a promising strategy to inhibit stroma, enhance drug penetration, and greatly amplify chemotherapeutic efficacy. It is known that photothermal therapy (PTT) locally depletes stroma and enhances permeability but whether and how PTT reacts in the molecular pathway to induce PSC deactivation in PDAC has rarely been investigated so far. Herein, C-G NPs are synthesized by loading both acid-responsive photothermal molecules and gemcitabine for investigating both the combinatory chemophotothermal therapy and the interaction between the PTT and TGF-β pathway in PDAC. Notably, C-G NPs exhibit tumoral acidic pH-activated PTT and succeeded in deactivating PSCs and suppressing the expression level for both TGF-β and collagen fiber. Furthermore, hyperthermia remodels the tumoral extracellular matrix, significantly improves NP penetration, and boosts the ultimate synergistic chemophotothermal therapeutic efficacy. Importantly, the molecular biology study reveals that hyperthermia leads to the decrease in the mRNA expression of

High-precision tidal harmonic constants are necessary for studies involving tides. This study proposes a new method combined with the adjoint assimilation model and the Chebyshev polynomial fitting (CPF) method to obtain the tidal harmonic constants in the shallow-water region of the Bohai and Yellow Sea (BYS). Based on the CPF method, the full-field harmonic constants and reliable cotidal charts of the eight major constituents (M2, S2, K1, O1, N2, K2, P1 and Q1) were fitted from the X-TRACK products briefly and this method was effectively for coastal conditions. Compared with the observations of the X-TRACK products and tidal gauges, for the M2 constituent, the TPXO9, Finite Element Solutions 2014 (FES2014), National Astronomical Observatory 99b (NAO.99b) and Empirical Ocean Tide 20 (EOT20) models yield the root-mean-square errors (RMSEs) of 18.50, 7.31, 18.73 and 13.32 cm, respectively, while the CPF method yields an RMSE of 10.74 cm. These results indicate that the CPF method could maintain high resolution and obtain accurate cotidal charts consistent with the simulations of the four models in shallow-water regions.

Post-stroke cognitive impairment (PSCI) is the most prevalent complication of acute ischemic stroke(AIS) in individuals. The lactate dehydrogenase-to albumin ratio (LAR) is a novel indicator that measures systemic inflammation and nutritional status. The purpose of this research was to investigate the connection between the LAR and PSCI.Following inclusion criteria, this study recruited 701 AIS patients who were segmented into the PSCI (n = 441) and non-PSCI (n = 260) groups according to the Mini-Mental State Examination (MMSE) within 2 weeks after stroke. The lactate dehydrogenase and albumin levels were measured within 24 h after hospitalization. A binary logistic regression was constructed to examine the association between LAR and PSCI with the LAR divided into tertiles.The PSCI group showed a higher level of LAR in comparison to the non-PSCI group (p 0.001). Compared with T1 (≦4.93), patients in the highest quartile of LAR (≧5.93) had a greater risk of PSCI after controlling for confounding factors, as demonstrated by logistic regression (odds ratio (OR) = 2.003, 95 % confidence interval (CI) = 1.305-3.074, P = 0.001).Higher LAR is independently related to the development of cognitive impairment in the early phase after stroke, which may help physicians in the early identification of patients with PSCI.

BackgroundIt has been proven that the ratio of albumin to globulin (A/G) is a typical biomarker for monitoring inflammation and nutritional status. But the potential role of A/G in stroke-associated pneumonia (SAP) after acute ischemic stroke (AIS) remained unknown.Patients and methodsFollowing inclusion criteria, 5,173 AIS patients were included and segmented into SAP (n = 897) and non-SAP (n = 4,276) groups. The differences in variables between groups were compared. The logistic regression model was used to determine the association between A/G and SAP, and a forest plot was drawn.ResultsCompared with the non-SAP group, the SAP group had a lower A/G level (P < 0.001). Then, A/G was divided into quartiles. In comparison to Q3 (A/G = 1.25–1.39), logistic regression revealed that patients with a lower A/G (A/G ≤ 1.09) had a higher risk of SAP (OR = 1.96, 95% CI, 1.56–2.46, P < 0.001). On the contrary, those with a higher A/G (A/G ≥ 1.4) had a lower SAP risk (OR = 0.73, 95% CI, 0.54–0.97, P = 0.029).ConclusionThe study revealed that a low A/G level was associated with an increased SAP risk. Appropriate preventative measures for SAP should be taken in AIS patients with a low A/G level.

Introduction: Hemorrhagic transformation (HT) is a severe but frequent complication of acute ischemic stroke (AIS). This study aimed to evaluate the relationship between serum LDH levels and HT. Methods: We retrospectively included 542 AIS patients with HT and 1091 age and gender-matched patients without HT. Demographic and clinical data were obtained from medical records, and blood samples were obtained within 24 hours after admission. The characteristics of groups were compared. With the receiver operating characteristic curve (ROC) analysis, we assessed the discriminating capacity of LDH levels in predicting HT in patients with AIS. The logistic regression model was used to determine the connection between LDH and HT. Results: The HT group had considerably higher LDH levels than the non-HT group [263.0 (216.0-323.3) U/L vs. 178.0 (162.0-195.0) U/L, P < 0.001]. We also observed that the levels of LDH in the parenchymal hemorrhage (PH) subgroup were significantly higher than those in the hemorrhagic infarction (HI) subgroup [281.0 (230.0-340.0) U/L vs. 258.0 (209.0-311.0) U/L, P < 0.001]. The area under the ROC curve (AUC) of LDH was 0.890 (95% CI 0.874-0.905, P < 0.001). Besides, logistic regression revealed that high LDH levels (LDH > 215 U/L) showed a higher risk of HT [odds ratio (OR) = 10.958, 95% confidence level (CI) 7.964-15.078, P < 0.001]. Conclusion: High LDH levels were linked with an increased risk of HT in AIS patients. Practical measures should be considered in patients with increased LDH levels (LDH > 215 U/L).

The HALP score (hemoglobin, albumin, lymphocyte, and platelet) is a novel indicator that measures systemic inflammation and nutritional status. The goal of this study was to look into the relationship between the HALP score and post-stroke cognitive impairment (PSCI) in people who had an acute ischemic stroke (AIS).A total of 592 individuals with ischemic stroke were included in the research, and the PSCI (n = 382) and non-PSCI (n = 210) groups were determined using the Mini-Mental State Examination scale 2 weeks following the stroke. HALP score was computed by the formula: hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L) / platelets (/L), and was split into three layers according to the tertiles. The connection between the HALP and cognitive results was investigated by binary logistic regression.The PSCI group's HALP score was much lower than the non-PSCI group's (p 0.001). The HALP score was divided into three layers: T1 ≤ 34.0, T2 34.1-49.4, and T3 ≥ 49.5, respectively. In the binary regression analysis, taking the T3 layer as the reference, the T1 layer showed the highest risk of PSCI after adjusting for confounding factors (odds ratio (OR) = 1.965, 95% confidence interval (CI) = 1.237-3.122, p = 0.004), while there was no increased risk of PSCI in the T2 layer (OR = 1.538, 95%CI = 0.983-2.404, p = 0.059).Low HALP score at admission was found to be correlated with early-onset PSCI and may help clinicians in the early identification of high-risk patients.

Stroke-associated pneumonia (SAP) occurs frequently after a stroke. Geriatric Nutritional Risk Index (GNRI) is a valuable indicator of elderly individuals' nutritional status. This research was designed to obtain insight into the link between GNRI and SAP.Patients with acute ischemic stroke (AIS) were categorized into the SAP and non-SAP groups. GNRI scores were divided into four layers: Q1, GNRI 82; Q2, 82≤ GNRI 92; Q3, 92≤ GNRI ≤98; Q4, GNRI 98. To identify the independent risk and protective factors of developing SAP, logistic regression analyses were conducted. Additionally, we utilized the restricted cubic spline (RCS) analysis to test the effect of GNRI on the SAP risk.The SAP group showed lower GNRI scores than the non-SAP group (96.88 ± 9.36 vs. 100.88 ± 8.25, p 0.001). According to the logistic regression model, the Q1 and Q2 layers showed a higher risk of SAP than the Q3 layer, while the Q4 layer showed a lower SAP risk (all p 0.05). Besides, the RCS model found that the risk of SAP dropped dramatically as GNRI scores increased, which got stable when the GNRI score was more significant than 100.Lower GNRI scores were linked to a higher prevalence of SAP. In clinical practice, GNRI showed predictive value for SAP, which could be helpful in early SAP intervention and therapy.

Sufficient and accurate tide data are essential for analyzing physical processes in the ocean. A method is developed to spatially fit the tidal amplitude and phase lag data along satellite altimeter tracks near Hawaii and construct reliable cotidal charts by using the Chebyshev polynomials. The method is completely dependent on satellite altimeter data. By using the cross-validation method, the optimal orders of Chebyshev polynomials are determined and the polynomial coefficients are calculated by the least squares method. The tidal amplitudes and phase lags obtained by the method are compared with those from the Finite Element Solutions 2014 (FES2014), National Astronomical Observatory 99b (NAO.99b), and TPXO9 models. Results indicate that the method yields accurate results as its fitting results are consistent with the harmonic constants of the three models. The feasibility of this method is also validated by the harmonic constants from tidal gauges near Hawaii.

The promotional effects of sodium on Fe5C2 catalysts for CO2 hydrogenation were systematically investigated by a synergistic combination of density functional theory (DFT) calculations and experime...

Structure-based prediction of a compound's potential sites of metabolism (SOMs) mediated by cytochromes P450 (CYPs) is highly advantageous in the early stage of drug discovery. However, the SOMs prediction accuracy could be influenced by several factors. CYP2C9 is one of the major drug metabolizing enzymes in humans and is responsible for the metabolism of ~13% of clinically used drugs. In this study, we systematically evaluated the effects of protein crystal structural models, scoring functions, heme forms, conserved active site water molecule, and protein flexibility on SOMs prediction of CYP2C9 substrates. Our results demonstrated that ChemScore and GlideScore outperformed four other scoring functions including Vina, GoldScore, ChemPLP, and ASP on average. The performance of the crystal structural models with the pentacoordinated heme was generally superior to that of the hexacoordinated iron-oxo heme (referred to as Compound I) models. The inclusion of the conserved active site water molecule improved the prediction accuracy by GlideScore but reduced the accuracy by ChemScore. In addition, the effect of the conserved water on SOMs prediction was found to be dependent on the receptor model and the substrate. We further found that one of snapshots from molecular dynamics simulations on the apo form can improve the prediction accuracy when compared to the crystal structural model.

By reviewing the development history of stimulation techniques for deep/ultra-deep oil and gas reservoirs, the new progress in this field in China and abroad has been summed up, including deeper understanding on formation mechanisms of fracture network in deep/ultra-deep oil and gas reservoir, performance improvement of fracturing fluid materials, fine stratification of ultra-deep vertical wells, and mature staged multi-cluster fracturing technique for ultra-deep and highly deviated wells/horizontal wells. In light of the exploration and development trend of ultra-deep oil and gas reservoirs in China, the requirements and technical difficulties in ultra-deep oil and gas reservoir stimulation are discussed: (1) The research and application of integrated geological engineering technology is difficult. (2) The requirements on fracturing materials for stimulation are high. (3) It is difficult to further improve the production in vertical profile of the ultra-deep and hugely thick reservoirs. (4) The requirements on tools and supporting high-pressure equipment on the ground for stimulation are high. (5) It is difficult to achieve efficient stimulation of ultra-deep, high-temperature and high-pressure wells. (6) It is difficult to monitor directly the reservoir stimulation and evaluate the stimulation effect accurately after stimulation. In line with the complex geological characteristics of ultra-deep oil and gas reservoirs in China, seven technical development directions are proposed: (1) To establish systematic new techniques for basic research and evaluation experiments; (2) to strengthen geological research and improve the operational mechanism of integrating geological research and engineering operation; (3) to develop high-efficiency fracturing materials for ultra-deep reservoirs; (4) to research separated layer fracturing technology for ultra-deep and hugely thick reservoirs; (5) to explore fracture-control stimulation technology for ultra-deep horizontal well; (6) to develop direct monitoring technology for hydraulic fractures in ultra-deep oil and gas reservoirs; (7) to develop downhole fracturing tools with high temperature and high pressure tolerance and supporting wellhead equipment able to withstand high pressure.

Photothermal therapy (PTT) based on semiconducting polymer nanoparticles (SPNs) is a promising strategy to treat solid tumors, but its ability to combine with chemotherapy for immune remodeling to efficiently suppress metastatic cancers has rarely been studied. Here, we demonstrate that PTT combined with chemotherapy can efficiently elicit immunity to suppress metastatic tumor growth. Specifically, we rationally designed a new SPN (PDPSe NPs) as a photothermal agent for PTT with a large mass extinction coefficient in the near-infrared region (e.g., 44.9 L g-1 cm-1 at 808 nm), high photothermal conversion efficiency (62.5%) and excellent biocompatibility. A hypoxia-activated anti-tumor drug, tirapazamine (TPZ), was selected for chemotherapy. Strikingly, the combination therapy not only induced tumor cell death in the primary tumor, but also effectively suppressed the growth of distant tumors (mimicking metastatic tumors) without PTT. Importantly, the combined therapies exhibit synergistic effects on immune remodeling. Immunofluorescence data suggest that the inhibition of metastatic tumor growth is attributed to the immune remodeling triggered by PTT and chemotherapy. This work demonstrates a new paradigm of utilizing PTT together with hypoxia-activated drugs to effectively retard metastatic tumor growth.

Stroke-associated pneumonia (SAP) is the most common early consequence in patients suffering from an acute ischaemic stroke (AIS). The purpose of this study was to explore the possible relationship between low triiodothyronine (T3) syndrome and SAP in stroke patients.This study recruited 2460 consecutive AIS patients. SAP was defined according to the modified Centers for Disease Control and Prevention criteria for hospital-acquired pneumonia. The thyroid hormones levels were measured within 24 h after admission. Low T3 syndrome was characterized as T3 below the lower limit of the reference interval accompanied by normal TSH levels.Among the total patients, 336 (13.7%) patients were diagnosed with SAP. SAP in individuals with low T3 syndrome was substantially greater (p .001) as compared to those without low T3 syndrome. After adjusting for possible confounders, low T3 syndrome (adjusted odds ratio [aOR] = 1.59; 95% confidence interval [CI], 1.20-2.09; p = .001) remained significant in our logistic model. Patients with low T3 syndrome had a higher risk of severe SAP (aOR = 2.17, 95% confidence interval [CI] 1.38-3.44; p = .001).Low T3 syndrome, independent of recognized risk factors, is a possible risk factor for in-hospital SAP, which can help clinicians in the early detection and treatment of high-risk patients.

PAP (3'-phosphoadenosine 5'-phosphate) is a ubiquitous phosphoric acid and a natural inhibitor of the XRN (5'-3'exoribonuclease) family. It was proved to enter the nucleus through the retrograde signaling pathway and inhibit XRN2 to prevent the degradation of miRNA precursors, thus promoting the anti-oxidation miRNA level in Arabidopsis thaliana. Vitamin E (tocopherol) was proved to promote the accumulation of PAP in the plant, which facilitates PAP into the nucleus to accomplish its antioxidant function. However, the relationship between VE and PAP in animals is unclear. To identify the relationship between VE and PAP and to uncover the function of PAP in fish, we investigated the performance of VE and PAP in Nile tilapia by comparing the antioxidant indicators (SOD, GSH-Px, and CAT), the Keap1-Nrf2 signaling pathway, and the miRNA expression profiles. Results showed that the antioxidant effect of VE and PAP showed similar character either in tilapia liver or in serum: the activities of GSH-Px and CAT of both groups were significantly increased (P 0.05); the SOD activity of the VE group was significantly increased (P 0.05), and although the result of the PAP group was not so significant (P 0.05), PAP improved the SOD level, too. The two groups also showed similar character in the tilapia liver; both did not significantly increase the liver δ-VE content (P 0.05). However, VE significantly increased the content of α-VE and γ-VE (P 0.05), while the PAP group was insignificant (P 0.05). Feed with VE and intraperitoneal injection of PAPs reagent both increased the PAP content in the liver of tilapia, and the effect of the VE group was more significant (P 0.05) than that of the PAP group (P 0.05). Both groups reduced the expression of Keap1 and Cullin3 genes and improved the level of HO-1 gene expression, with the improved miRNA level of Nrf2. As a logical result, they decreased the expression of XRN1 and XRN2. By profile sequencing, we further identified some antioxidant closely related miRNAs shared in the VE and PAP groups, including miR-30, miR-24, miR-19b, and miR-100. By comparing the regulating mechanism of VE and PAP of feed supply and intraperitoneal injection, we proved that VE and PAP were closely related in fish; VE promoted the gathering of PAP. The latter retrograded into the nucleus of the fish liver to inhibit the expression of XRN genes and to up-regulate antioxidant miRNA levels as it does in plants. Only the PAP can accomplish the antioxidant activities, while VE promotes the process. Our study laid the foundation for the application of PAP as a new antioxidant agent in fish farming and benefit a further understanding of the VE antioxidant function in fish.

BackgroundStakeholders from multiple sectors are increasingly aware of the critical need for identifying sustainable interventions that promote healthy lifestyle behaviors. Activity-friendly communities (AFCs) have been known to provide opportunities for engaging in physical activity (PA) across the life course, which is a key to healthy living and healthy aging.PurposeOur purpose is to describe the study protocol developed for a research project that examines: (a) the short- and long-term changes in total levels and spatial and temporal patterns of PA after individuals move from non-AFCs to an AFC; and (b) what built and natural environmental factors lead to changes in PA resulting from such a move, either directly or indirectly (e.g., by affecting psychosocial factors related to PA).MethodsThis protocol is for a longitudinal, case-comparison study utilizing a unique natural experiment opportunity in Austin, Texas, USA. Case participants were those adults who moved from non-AFCs to an AFC. Matching comparison participants were residents from similar non-AFCs who did not move during the study period. Recruitment venues included local businesses, social and print media, community events, and individual referrals. Objectively measured moderate-to-vigorous PA and associated spatial and temporal patterns served as the key outcomes of interest. Independent (e.g., physical environments), confounding (e.g., demographic factors), and mediating variables (e.g., psychosocial factors) were captured using a combination of objective (e.g., GIS, GPS, Tanita scale) and subjective measures (e.g., survey, travel diary). Statistical analyses will be conducted using multiple methods, including difference-in-differences models, repeated-measures linear mixed models, hierarchical marked space-time Poisson point pattern analysis, and hierarchical linear mixed models.ConclusionNatural experiment studies help investigate causal relationships between health and place. However, multiple challenges associated with participant recruitment, extensive and extended data collection activities, and unpredictable intervention schedules have discouraged many researchers from implementing such studies in community-based populations. This detailed study protocol will inform the execution of future studies to explore how AFCs impact population health across the life course.

GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

PURPOSE: Changes in DNA methylation modifications have been associated with male infertility. With the development of assisted reproductive technologies (ARTs), abnormal DNA methylation in sperm, especially in imprinted genes, may impact the health of offspring and requires an in-depth study. METHODS: In this study, we collected abnormal human semen samples, including asthenospermic, oligospermic, oligoasthenospermic and deformed sperm, and investigated the methylation of imprinted genes by reduced representation bisulfite sequencing (RRBS) and bisulfite amplicon sequencing on the Illumina platform. RESULTS: The differentially methylated regions (DMRs) of imprinted genes, including H19, GNAS, MEG8 and SNRPN, were different in the abnormal semen groups. MEG8 DMR methylation in the asthenospermic group was significantly increased. Furthermore, higher methylation levels of MEG8, GNAS and SNRPN DMR in the oligospermic and oligoasthenospermic groups and a decrease in the H19 DMR methylation level in the oligospermic group were observed. However, the methylation levels of these regions varied greatly among the different semen samples and among individual sperm within the same semen sample. The SNP rs2525883 genotype in the H19 DMR affected DNA methylation. Moreover, DNA methylation levels differed in the abnormal semen groups in the non-imprinted genomic regions, including repetitive sequence DNA transposons and long/short interspersed nuclear elements (LINEs and SINEs). CONCLUSION: Our study established that imprinted gene DMRs, such as H19, GNAS, SNRPN and MEG8, were differentially methylated in the abnormal semen groups with obvious inter- and intra-sample heterogeneities. These results suggest that special attention needs to be paid to possible epigenetic risks during reproduction.

Purpose Hereditary skeletal muscle channelopathies are characterized by muscle stiffness and/or periodic muscle weakness because of different gene mutations. The objective of this study was to investigate the clinical and electromyographic phenotypes in Chinese patients with different skeletal ion channel mutations. Methods The electromyographic results of 61 Chinese patients with skeletal muscle channelopathies were retrospectively reviewed and the differential features were characterized. Results Myotonic discharges were in patients with chloride voltage-gated channel 1 and sodium voltage-gated channel alpha subunit 4 mutations. Subclinical myotonia was identified in four patients with hypokalemic periodic paralysis because of sodium voltage-gated channel alpha subunit 4 mutations. Patients with potassium voltage-gated channel subfamily J member 2 mutations had an early decline after exercise (5.7 ± 4.9 minutes) and patients with calcium voltage-gated channel subunit alpha 1S mutations have a relatively lower baseline amplitude (4.6 ± 2 mV). Specific patterns were characterized in patients with Becker disease and paramyotonia congenital after short exercise. Conclusions Myotonic discharges help to discriminate chloride and sodium from other channelopathies. Early decline and low baseline compound motor action potential amplitude in long exercise test are significant in patients with potassium voltage-gated channel subfamily J member 2 and calcium voltage-gated channel subunit alpha 1S mutations, respectively. Electromyographic patterns in the electromyography study and exercise test may help in better providing the comprehensive picture for patients with primary skeletal muscle channelopathies.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic is having a dramatic impact on acute stroke care. Its effects may accompany stroke care for a long time. We compared the treatment, short-term and long-term functional outcomes of patients with AIS from 2019 to 2020. Our objective was to evaluate the effect of COVID-19 epidemic on mechanical thrombectomy (MT) in patients in our hospital.MethodsWe collected information on subjects treated with MT in 2019–2020, including age, sex, time from the onset to arterial sheath insertion, time from the onset to recanalization, the rate of lung infection and hemorrhagic transformation, modified Rankin scale (mRS), NHISS, and ASPECTS.ResultsThe number of patients with MT decreased significantly by 26.6% in 2020 (p = 0.025). The pretreatment ASPECTS score for 2020 was significantly higher than 2019 (p = 0.004). Besides, the patients were more likely to develop lung infection (65 vs. 54.1%, p = 0.042) and had a higher risk of hemorrhagic transformation (47.4% vs. 30.4%, p = 0.005) in 2019. The discharged mRS reflected the worse short-term functional prognosis of patients with MT in 2019 (66 vs. 44.9%, p = 0.046). In the subgroup analysis of bridging thrombolysis (BT), more patients with BT are expected to have a poor short-term functional prognosis in 2020, according to the discharged mRS (62.5 vs. 37.5%, p = 0.024). However, there was no difference in mRS at 180 days between the two groups (p = 0.094).ConclusionFor patients with MT, both short- and long-term functional outcomes were not significantly affected due to the mild condition of patients admitted to hospital in 2020. For patients with BT, the COVID-19 pandemic has prolonged the green channel time of stroke, leading to a poor short-term functional prognosis of patients with stroke in the pandemic period. There was no difference in the effectiveness of direct MT and BT during the COVID-19 pandemic.

Background:Stroke-associated pneumonia (SAP) is associated with poor prognosis after acute ischemic stroke (AIS).Purpose:This study aimed to describe the parameters of coagulation function and evaluate the association between the fibrinogen-to-albumin ratio (FAR) and SAP in patients with AIS.Patients and methods:A total of 932 consecutive patients with AIS were included. Coagulation parameters were measured at admission. All patients were classified into two groups according to the optimal cutoff FAR point at which the sum of the specificity and sensitivity was highest. Propensity score matching (PSM) was performed to balance potential confounding factors. Univariate and multivariate logistic regression analyses were applied to identify predictors of SAP.Results:A total of 100 (10.7%) patients were diagnosed with SAP. The data showed that fibrinogen, FAR, and D-dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT) were higher in patients with SAP, while albumin was much lower. Patients with SAP showed a significantly increased FAR when compared with non-SAP (P< 0.001). Patients were assigned to groups of high FAR (≥0.0977) and low FAR (P< 0.001). In addition, the FAR was higher in the severe pneumonia group when it was assessed by pneumonia severity index (P= 0.008).Conclusions:High FAR is an independent potential risk factor of SAP, which can help clinicians identify high-risk patients with SAP after AIS.

BackgroundPost-stroke fatigue (PSF) is a frequent complication of stroke. Serum uric acid (SUA) is frequently thought to be a risk factor for stroke. This study aimed to investigate whether SUA also played a role in PSF.MethodsSubjects with ischemic stroke were screened from The First Affiliated Hospital of Wenzhou Medical University between January 2020 and October 2020. Patients' fatigue symptoms were assessed by the Fatigue severity scale (FSS). To investigate the relationship between SUA and PSF, binary logistic regression analysis was conducted, with the confounders being controlled. SUA levels were divided into four layers (Q1 ≤ 245 μmol/L; Q2 246–308 μmol/L; Q3 309–365 μmol/L; Q4 ≥366 μmol/L) based on the quartiles.ResultsSUA levels were significantly higher in the PSF group (345.96 ± 73.78 μmol/L) than the non-PSF group (295.97 ± 87.8 μmol/L, P < 0.001). There were no differences in any other variables between these two groups. After adjusting the confounders, the risk of PSF in the Q4 layer (≥366 μmol/L) was 6.05 times (95% CI 1.79–20.43, P = 0.004) higher than that in Q1 (≤245 μmol/L).ConclusionHigh SUA at admission was an independent risk factor for fatigue 1 year after stroke onset. High SUA (≥366 μmol/L) during stroke deserves more attention, and active control of high SUA levels may be beneficial to reduce the incidence of PSF in the chronic stage following stroke.

There is an urgent need of developing grape picking robot with intelligent recognition function due to the decrease of grape picking workers’ population. Acquiring the 3D information of picking coordinate is the key process of constructing intelligent picking equipment. In this paper, based on SSD MobileNet neural network model, transfer learning and central deviation angle method were used to realize the positioning of picking coordinate points of facility cultivation grape by machine vision. After testing 720 fruit labels, 633 stem labels and 603 leaf labels labelled by pretreatment, the general precision was 79.5%, which was close to the inherent accuracy of the original model before transfer learning.

330 Background: Gastrointestinal (GI) cancers totally account for more than one third of the cancerous deaths, yet there is no cost-effective blood-based assay for the early detection of GI cancers. We sought to develop GutSeer, a noninvasive test based on cell-free DNA (cfDNA) methylation and fragmentation signatures derived from one single targeted DNA methylation sequencing panel, for early detection and localization of five major GI cancers, including colorectal (CC), gastric (GC), liver (LC), esophageal (EC), and pancreatic cancer (PC). Methods: A DNA methylation targeted sequencing panel with 1656 target regions was designed. It was then verified in a large cohort of retrospective cancer and control plasma samples for feature selection and modeling. The participants were randomly divided into a training cohort and a validation cohort in a 1:1 ratio. DNA methylation and fragmentomic features were calculated based on GutSeer sequencing data. An ensemble stacked machine learning approach was built to classify cancer and healthy samples in training cohort and tested in validation cohort. We also constructed a TOO model to predict the tissue of origin of detected cancer samples. Results: To develop GutSeer assay, we have enrolled and tested a total of 1844 retrospective plasma samples (787 healthy, 342 LC, 239 GC, 209 EC, 180 CC, and 87 PC), over half of the cancer samples were diagnosed with early-stage disease (TNM stage I 35.6%; stage II 23.3%; stage III 21.7%; stage IV 12.5%). Cancer- vs-healthy model was built on training cohort and tested in validation cohort, achieving an AUC of 0.94 (sensitivity=77.7%, specificity=96.4%) with methylation features, and 0.95 (sensitivity=77.1%, specificity=95.9%) with fragmentomic features. Combining these features could achieve AUC of 0.963 (sensitivity = 86.2%, specificity = 96.7%). For individual cancer types, the sensitivity was 93.3% (CC), 81.1% (EC), 70.3% (GC), 96.5% (LC) and 86.4% (PC), respectively. For predicted cancer samples, we achieved an 82% top-one (66.7% CC, 87.0% GC/EC, 89.0% LC, 63.2% PC) and 95.2% top-two (86,9% CC, 98.2% GC/EC, 97.6% LC, 89.5% PC) TOO accuracy (ACC, accuracy of predicting the most likely, and the top 2 most likely tissue or organ types where the identified cancer was located, respectively) in validation cohort with TOO model combined all features. Conclusions: Based on a single targeted DNA methylation sequencing assay, GutSeer, which combined cfDNA methylation and fragmentomic signatures, could detect and localize the major five GI cancers with high accuracy but low cost. Although this is a pilot study with limited sample size, GutSeer demonstrated the potential to be further optimized into non-invasive diagnostics for blood-based early screening and diagnosis for GI cancers.

Purpose Multiple anthropogenic disturbances, such as climate warming and nitrogen deposition are affecting terrestrial ecosystems. Different disturbances may have some consistent effects on the soil microbial community, which remains largely unexplored. Methods We mimicked 16 anthropogenic disturbances in a steppe ecosystem, and measured the absolute abundance and taxonomic composition of soil bacterial communities with qPCR and amplicon sequencing, respectively. Results We found that while the absolute abundance of each of the four dominant bacterial phyla did not show a consistent response to these disturbances, that of the five subdominant phyla showed a consistent increase. Meanwhile, these disturbances consistently stimulated the relative abundances of metabolic functions for high-growth-yield, including the transport/metabolism of amino acids and carbohydrates. Stochastic processes (e.g., random birth) played more critical roles in structuring the subdominant than dominant phyla, and the disturbances promoted the stochastic processes. Conclusions Overall, the high-yield traits and stochasticity of subdominant phyla led to their positive responses to disturbances. Furthermore, our findings indicate that the intensifying human activities are likely to cause a high-yield-strategies-toward shift in soil microbial composition in the Eurasian steppe ecosystem.