Enhanced Calvarial Bone Repair Using ASCs Engineered with RNA-Guided Split dCas12a System that Co-Activates Sox 5, Sox6, and Long Non-Coding RNA H19.

Healing of large calvarial bone defects remains challenging. An RNA-guided Split dCas12a system is previously harnessed to activate long non-coding RNA H19 (lncRNA H19, referred to as H19 thereafter) in bone marrow-derived mesenchymal stem cells (BMSCs). H19 activation in BMSCs induces chondrogenic differentiation, switches bone healing pathways, and improves calvarial bone repair. Since adipose-derived stem cells (ASCs) can be harvested more easily in large quantity, here it is aimed to use ASCs as an alternative cell source. However, H19 activation alone using the Split dCas12a system in ASCs failed to elicit evident chondrogenesis. Therefore, split dCas12a activators are designed more to co-activate other chondroinductive transcription factors (Sox5, Sox6, and Sox9) to synergistically potentiate differentiation. It is found that co-activation of H19/Sox5/Sox6 in ASCs elicited more potent chondrogenic differentiation than activation of Sox5/Sox6/Sox9 or H19 alone. Co-activating H19/Sox5/Sox6 in ASCs significantly augmented in vitro cartilage formation and in vivo calvarial bone healing. These data altogether implicated the potentials of the Split dCas12a system to trigger multiplexed gene activation in ASCs for differentiation pathway reprogramming and tissue regeneration.

Auto-inducible synthetic pathway in E. coli enhanced sustainable indigo production from glucose.

Indigo is widely used in textile industries for denim garments dyeing and is mainly produced by chemical synthesis which, however, raises environmental sustainability issues. Bio-indigo may be produced by fermentation of metabolically engineering bacteria, but current methods are economically incompetent due to low titer and the need for an inducer. To address these problems, we first characterized several synthetic promoters in E. coli and demonstrated the feasibility of inducer-free indigo production from tryptophan using the inducer-free promoter. We next coupled the tryptophan-to-indigo and glucose-to-tryptophan pathways to generate a de novo glucose-to-indigo pathway. By rational design and combinatorial screening, we identified the optimal promoter-gene combinations, which underscored the importance of promoter choice and expression levels of pathway genes. We thus created a new E. coli strain that exploited an indole pathway to enhance the indigo titer to 123 mg/L. We further assessed a panel of heterologous tryptophan synthase homologs and identified a plant indole lyase (TaIGL), which along with modified pathway design, improved the indigo titer to 235 mg/L while reducing the tryptophan byproduct accumulation. The optimal E. coli strain expressed 8 genes essential for rewiring carbon flux from glucose to indole and then to indigo: mFMO, ppsA, tktA, trpD, trpC, TaIGL and feedback-resistant aroG and trpE. Fed-batch fermentation in a 3-L bioreactor with glucose feeding further increased the indigo titer (≈965 mg/L) and total quantity (≈2183 mg) at 72 h. This new synthetic glucose-to-indigo pathway enables high-titer indigo production without the need of inducer and holds promise for bio-indigo production.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Database-aided ultrahigh-performance liquid chromatography Q-Exactive-Orbitrap tandem mass spectrometry putatively identifies 16 unexpected compounds and three anticounterfeiting pharmacopoeia quality markers for Perillae Fructus.

RATIONALE: Perillae Fructus (PF) is a common traditional Chinese medicine (TCM) for the treatment of asthma. It has not been effectively characterized by rosmarinic acid (RosA), which is currently designed as the sole quality indicator in the Chinese Pharmacopoeia. METHODS: This study introduced a database-aided ultrahigh-performance liquid chromatography equipped with quadrupole-Exactive-Orbitrap mass spectrometry (UHPLC/Q-Exactive-Orbitrap MS/MS) technology to putatively identify the compounds in PF, followed by literature research, quantum chemical calculation, and molecular docking to screen potential quality markers (Q-markers) of PF. RESULTS: A total of 27 compounds were putatively identified, 16 of which had not been previously found from PF. In particular, matrine, scopolamine, and RosA showed relatively high levels of content, stability, and drug-likeness. They exhibited interactions with the asthma-related target and demonstrated the TCM properties of PF. CONCLUSIONS: The database-aided UHPLC/Q-Exactive-Orbitrap MS/MS can identify at least 27 compounds in PF. Of these, 16 compounds are unexpected, and three compounds (matrine, scopolamine, and RosA) should be considered anticounterfeiting pharmacopoeia Q-markers of PF.

Collaborative effect of the energy conservation and emission reduction fiscal policy in China.

Government-led national comprehensive demonstration cities for Energy Conservation and Emission Reduction Fiscal Policy (ECERFP) are pivotal for China in addressing environmental governance. Using a panel dataset covering 278 Chinese cities from 2003 to 2019, this study adopts the staggered difference-in-differences (DID) approach to investigate the synergistic impacts of ECERFP on pollution and carbon reduction. The findings indicate that ECERFP contributes to a 3% improvement in pollution reduction performance, a 1.5% enhancement in carbon reduction performance, and a 4% overall increase in combined pollution and carbon reduction efforts. Furthermore, the study examines the heterogeneous effects of ECERFP on environmental performance. ECERFP significantly influences the synergistic efforts in pollution and carbon reduction by fostering green innovation, enhancing energy allocation, and optimizing industrial structures. This study both theoretically and empirically outlines the specific pathways and mechanisms through which "incentive-based" green fiscal policy promotes synergistic pollution and carbon reduction, thus providing a pragmatic foundation for enhancing the role of fiscal policy in environmental governance.

Selenium Lessens Osteoarthritis by Protecting Articular Chondrocytes from Oxidative Damage through Nrf2 and NF-κB Pathways.

Osteoarthritis (OA) causes joint pain and disability due to the abnormal production of inflammatory cytokines and reactive oxygen species (ROS) in chondrocytes, leading to cell death and cartilage matrix destruction. Selenium (Se) intake can protect cells against oxidative damage. It is still unknown whether Se supplementation is beneficial for OA. This study investigated the effects of Se on sodium iodoacetate (MIA)-imitated OA progress in human chondrocyte cell line (SW1353 cells) and rats. The results showed that 0.3 µM of Se treatment could protect SW1353 cells from MIA-induced damage by the Nrf2 pathway by promoting the gene expression of glutathione-synthesis-related enzymes such as the glutamate-cysteine ligase catalytic subunit, the glutamate-cysteine ligase modifier subunit, and glutathione synthetase. In addition, glutathione, superoxide dismutase, glutathione peroxidase, and glutathione reductase expressions are also elevated to eliminate excessive ROS production. Moreover, Se could downregulate NF-κB, leading to a decrease in cytokines, matrix proteases, and glycosaminoglycans. In the rats, MIA-induced cartilage loss was lessened after 2 weeks of Se supplementation by oral gavage; meanwhile, glutathione synthesis was increased, and the expressions of pro-inflammatory cytokines were decreased. These results suggest that Se intake is beneficial for OA due to its effects of decreasing cartilage loss by enhancing antioxidant capacity and reducing inflammation.

Visualizing the global trends of peptides in wound healing through an in-depth bibliometric analysis.

Wound healing is a complicated and multistage biological process for the repair of damaged/injured tissues, which requires intelligent designs to provide comprehensive and convenient treatment. Peptide-based wound dressings have received extensive attention for further development and application due to their excellent biocompatibility and multifunctionality. However, the current lack of intuitive analysis of the development trend and research hotspots of peptides applied in wound healing, as well as detailed elaboration of possible research hotspots, restricted obtaining a comprehensive understanding and development in this field. The present study analysed publications from the Web of Science (WOS) Core Collection database and visualized the hotspots and current trends of peptide research in wound healing. Data between January 1st, 2003, and December 31st, 2022, were collected and subjected to a bibliometric analysis. The countries, institutions, co-authorship, co-citation reference, and co-occurrence of keywords in this subject were examined using VOSviewer and CiteSpace. We provided an intuitive, timely, and logical overview of the development prospects and challenges of peptide application in wound healing and some solutions to the major obstacles, which will help researchers gain insights into the investigation of this promising field.

Stepwise Assembly of Quinary Multivariate Metal-Organic Frameworks via Diversified Linker Exchange and Installation.

Multivariate MOFs (MTV-MOFs) constructed from multiple components with atomistic precision hold the promise for many fascinating developments in both fundamental sciences and applications. Sequential linker installation can be an effective method to introduce different functional linkers into an MOF that contains coordinatively unsaturated metal sites. However, in many cases, these linkers must be installed according to a specific sequence and the complete synthetic flexibility and freedom is yet to be realized. Here, we rationally decreased the size of the primary ligand used in NPF-300, a Zr-MOF with scu topology (NPF = Nebraska Porous Framework), and synthesized its isostructure, NPF-320. NPF-320 exhibits optimized pocket sizes which allow for the post-synthetic installation of three secondary linkers in all six permuted sequences via both linker exchange and installation, forming a final quinary MTV-MOF via single-crystal-to-single-crystal transformation. With the functionalization of the linkers from the quinary MOF system, one will be able to construct MTV-MOFs not only with variable porosity but also with unprecedented complexity and encoded synthetic sequence information. The utility of sequential linker installation was further demonstrated by the construction of a donor-acceptor pair-based energy transfer system.

Rational genome and metabolic engineering of Candida viswanathii by split CRISPR to produce hundred grams of dodecanedioic acid.

Candida viswanathii is a promising cell factory for producing dodecanedioic acid (DDA) and other long chain dicarboxylic acids. However, metabolic engineering of C. viswanathii is difficult partly due to the lack of synthetic biology toolkits. Here we developed CRISPR-based approaches for rational genome and metabolic engineering of C. viswanathii. We first optimized the CRISPR system and protocol to promote the homozygous gene integration efficiency to >60%. We also designed a split CRISPR system for one-step integration of multiple genes into C. viswanathii. We uncovered that co-expression of CYP52A19, CPRb and FAO2 that catalyze different steps in the biotransformation enhances DDA production and abolishes accumulation of intermediates. We also unveiled that co-expression of additional enzyme POS5 further promotes DDA production and augments cell growth. We harnessed the split CRISPR system to co-integrate these 4 genes (13.6 kb) into C. viswanathii and generated a stable strain that doubles the DDA titer (224 g/L), molar conversion (83%) and productivity (1.87 g/L/h) when compared with the parent strain. This study altogether identifies appropriate enzymes/promoters to augment dodecane conversion to DDA and implicates the potential of split CRISPR system for metabolic engineering of C. viswanathii.

Scaling of Energy, Water, and Waste Flows in China's Prefecture-Level and Provincial Cities.

Cities have been envisioned as biological organisms as the integral part of nature's energy and material flows. Recent advances in urban scaling research have uncovered systematic changes in socioeconomic rates and infrastructural networks as urban population increases, providing predictive contents for the comparison between cities and organisms. However, it is still unclear how and why larger and smaller cities may differ in their per capita environmental impacts. Here, we study scaling patterns of urban energy, water, and waste flows as well as other relevant measures in Chinese cities. We divide cities into different groups using an algorithm that automatically assigns cities to clusters with distinct scaling patterns. Despite superlinear scaling of urban GDP, as predicted by urban scaling theories, resource consumption, such as the supply of electricity and water, and waste generation, such as wastewater and domestic waste, do not show significant deviations from linear scaling. The lengths of resource pipelines scale linearly in most cases, as opposed to sub-linearity predicted by theory. Furthermore, we show two competing forces underlying the overall observed effects of scale: a higher population density tends to decrease per capita resource consumption and infrastructure provisions, while intensified socioeconomic activities have the opposite effect.

Bi-directional gene activation and repression promote ASC differentiation and enhance bone healing in osteoporotic rats.

Calvarial bone healing is challenging, especially for individuals with osteoporosis because stem cells from osteoporotic patients are highly prone to adipogenic differentiation. Based on previous findings that chondrogenic induction of adipose-derived stem cells (ASCs) can augment calvarial bone healing, we hypothesized that activating chondroinductive Sox Trio genes (Sox5, Sox6, Sox9) and repressing adipoinductive genes (C/ebp-α, Ppar-γ) in osteoporotic ASCs can reprogram cell differentiation and improve calvarial bone healing after implantation. However, simultaneous gene activation and repression in ASCs is difficult. To tackle this problem, we built a CRISPR-BiD system for bi-directional gene regulation. Specifically, we built a CRISPR-AceTran system that exploited both histone acetylation and transcription activation for synergistic Sox Trio activation. We also developed a CRISPR interference (CRISPRi) system that exploited DNA methylation for repression of adipoinductive genes. We combined CRISPR-AceTran and CRISPRi to form the CRISPR-BiD system, which harnessed three mechanisms (transcription activation, histone acetylation, and DNA methylation). After delivery into osteoporotic rat ASCs, CRISPR-BiD significantly enhanced chondrogenesis and in vitro cartilage formation. Implantation of the engineered osteoporotic ASCs into critical-sized calvarial bone defects significantly improved bone healing in osteoporotic rats. These results implicated the potential of the CRISPR-BiD system for bi-directional regulation of cell fate and regenerative medicine.

Joint Data Transmission and Energy Harvesting for MISO Downlink Transmission Coordination in Wireless IoT Networks.

The advent of simultaneous wireless information and power (SWIPT) has been regarded as a promising technique to provide power supplies for an energy sustainable Internet of Things (IoT), which is of paramount importance due to the proliferation of high data communication demands of low-power network devices. In such networks, a multi-antenna base station (BS) in each cell can be utilized to concurrently transmit messages and energies to its intended IoT user equipment (IoT-UE) with a single antenna under a common broadcast frequency band, resulting in a multi-cell multi-input single-output (MISO) interference channel (IC). In this work, we aim to find the trade-off between the spectrum efficiency (SE) and energy harvesting (EH) in SWIPT-enabled networks with MISO ICs. For this, we derive a multi-objective optimization (MOO) formulation to obtain the optimal beamforming pattern (BP) and power splitting ratio (PR), and we propose a fractional programming (FP) model to find the solution. To tackle the nonconvexity of FP, an evolutionary algorithm (EA)-aided quadratic transform technique is proposed, which recasts the nonconvex problem as a sequence of convex problems to be solved iteratively. To further reduce the communication overhead and computational complexity, a distributed multi-agent learning-based approach is proposed that requires only partial observations of the channel state information (CSI). In this approach, each BS is equipped with a double deep Q network (DDQN) to determine the BP and PR for its UE with lower computational complexity based on the observations through a limited information exchange process. Finally, with the simulation experiments, we verify the trade-off between SE and EH, and we demonstrate that, apart from the FP algorithm introduced to provide superior solutions, the proposed DDQN algorithm also shows its performance gain in terms of utility to be up to 1.23-, 1.87-, and 3.45-times larger than the Advantage Actor Critic (A2C), greedy, and random algorithms, respectively, in comparison in the simulated environment.

Visualizing Large Facet-Dependent Electronic Tuning in Monolayer WSe2 on Au Surfaces.

Two-dimensional transition metal dichalcogenides (TMDs) have shown great importance in the development of novel ultrathin optoelectronic devices owing to their exceptional electronic and photonic properties. Effectively tuning their electronic band structures is not only desired in electronics applications but also can facilitate more novel properties. In this work, we demonstrate that large electronic tuning on a WSe2 monolayer can be realized by different facets of a Au-foil substrate, forming in-plane p-n junctions with remarkable built-in electric fields. This facet-dependent tuning effect is directly visualized by using scanning tunneling microscopy and differential conductance (dI/dV) spectroscopy. First-principles calculations reveal that the atomic arrangement of the Au facet effectively changes the interfacial coupling and charge transfer, leading to different magnitudes of charge doping in WSe2. Our study would be beneficial for future customized fabrication of TMD-junction devices via facet-specific construction on the substrate.

Transplantation of Adipose-Tissue-Engineered Constructs with CRISPR-Mediated UCP1 Activation.

Thermogenic adipocytes have potential utility for the development of approaches to treat type 2 diabetes and obesity-associated diseases. Although several reports have proved the positive effect of beige and brown adipocyte transplantation in obese mice, translation to human cell therapy needs improvement. Here, we describe the application of CRISPR activation (CRISPRa) technology for generating safe and efficient adipose-tissue-engineered constructs with enhanced mitochondrial uncoupling protein 1 (UCP1) expression. We designed the CRISPRa system for the activation of UCP1 gene expression. CRISPRa-UCP1 was delivered into mature adipocytes by a baculovirus vector. Modified adipocytes were transplanted in C57BL/6 mice, followed by analysis of grafts, inflammation and systemic glucose metabolism. Staining of grafts on day 8 after transplantation shows them to contain UCP1-positive adipocytes. Following transplantation, adipocytes remain in grafts and exhibit expression of PGC1α transcription factor and hormone sensitive lipase (HSL). Transplantation of CRISPRa-UCP1-modified adipocytes does not influence glucose metabolism or inflammation in recipient mice. We show the utility and safety of baculovirus vectors for CRISPRa-based thermogenic gene activation. Our findings suggest a means of improving existing cell therapy approaches using baculovirus vectors and CRISPRa for modification and transplantation of non-immunogenic adipocytes.

Rotablation for Octogenarians in a Modern Cathlab: Short- and Intermediate-Term Results.

Background: There are limited reports on the treatment of complex calcified lesions using rotational atherectomy (RA) in octogenarians, particularly in high-risk patients. Objective: To evaluate procedural and clinical outcomes of RA in octogenarians. Methods: Consecutive RA patients from 2010 to 2018 were selected from our catheterization laboratory database, stratified into two groups (≥ or < 80 years old), and analyzed. Results: A total of 411 patients (269 males and 142 females) with a mean age of 73.8 ± 11.3 years were enrolled, of whom 153 were ≥ 80 years old and 258 were < 80 years old. Most of the patients displayed high-risk features. The baseline Syntax scores were high in both groups, and most lesions were heavily calcified (96.1% vs. 97.3%, p = 0.969, respectively). The use of hemodynamic support intra-aortic balloon pump was more frequent in the octogenarians (21.6% vs. 11.6%, p = 0.007), but the RA completion rate was similarly high (95.9% vs. 99.1%, p = 0.842). There was no difference in acute complications. The total/cardiovascular (CV) death rate within one year was higher in the octogenarians, along with higher major adverse cardiovascular event (MACE)/CV MACE rates in the first month. Cox regression analysis showed that age ≥ 80 years, acute coronary syndrome, ischemic cardiomyopathy/shock, multi-vessel disease and serum creatinine were all predictors of MACE, and that these factors plus peripheral artery disease were predictors of all-cause mortality in these patients. Conclusions: RA is feasible with a very high success rate in high-risk octogenarians with complex anatomies, and with equal safety and no increase in complications. The higher rates of all-cause death and MACE were attributed to an older age and other traditional risk factors.

Joint Beamforming, Power Allocation, and Splitting Control for SWIPT-Enabled IoT Networks with Deep Reinforcement Learning and Game Theory.

Future wireless networks promise immense increases on data rate and energy efficiency while overcoming the difficulties of charging the wireless stations or devices in the Internet of Things (IoT) with the capability of simultaneous wireless information and power transfer (SWIPT). For such networks, jointly optimizing beamforming, power control, and energy harvesting to enhance the communication performance from the base stations (BSs) (or access points (APs)) to the mobile nodes (MNs) served would be a real challenge. In this work, we formulate the joint optimization as a mixed integer nonlinear programming (MINLP) problem, which can be also realized as a complex multiple resource allocation (MRA) optimization problem subject to different allocation constraints. By means of deep reinforcement learning to estimate future rewards of actions based on the reported information from the users served by the networks, we introduce single-layer MRA algorithms based on deep Q-learning (DQN) and deep deterministic policy gradient (DDPG), respectively, as the basis for the downlink wireless transmissions. Moreover, by incorporating the capability of data-driven DQN technique and the strength of noncooperative game theory model, we propose a two-layer iterative approach to resolve the NP-hard MRA problem, which can further improve the communication performance in terms of data rate, energy harvesting, and power consumption. For the two-layer approach, we also introduce a pricing strategy for BSs or APs to determine their power costs on the basis of social utility maximization to control the transmit power. Finally, with the simulated environment based on realistic wireless networks, our numerical results show that the two-layer MRA algorithm proposed can achieve up to 2.3 times higher value than the single-layer counterparts which represent the data-driven deep reinforcement learning-based algorithms extended to resolve the problem, in terms of the utilities designed to reflect the trade-off among the performance metrics considered.

χ2-BidLSTM: A Feature Driven Intrusion Detection System Based on χ2 Statistical Model and Bidirectional LSTM.

In a network architecture, an intrusion detection system (IDS) is one of the most commonly used approaches to secure the integrity and availability of critical assets in protected systems. Many existing network intrusion detection systems (NIDS) utilize stand-alone classifier models to classify network traffic as an attack or as normal. Due to the vast data volume, these stand-alone models struggle to reach higher intrusion detection rates with low false alarm rates( FAR). Additionally, irrelevant features in datasets can also increase the running time required to develop a model. However, data can be reduced effectively to an optimal feature set without information loss by employing a dimensionality reduction method, which a classification model then uses for accurate predictions of the various network intrusions. In this study, we propose a novel feature-driven intrusion detection system, namely χ2-BidLSTM, that integrates a χ2 statistical model and bidirectional long short-term memory (BidLSTM). The NSL-KDD dataset is used to train and evaluate the proposed approach. In the first phase, the χ2-BidLSTM system uses a χ2 model to rank all the features, then searches an optimal subset using a forward best search algorithm. In next phase, the optimal set is fed to the BidLSTM model for classification purposes. The experimental results indicate that our proposed χ2-BidLSTM approach achieves a detection accuracy of 95.62% and an F-score of 95.65%, with a low FAR of 2.11% on NSL-KDDTest+. Furthermore, our model obtains an accuracy of 89.55%, an F-score of 89.77%, and an FAR of 2.71% on NSL-KDDTest-21, indicating the superiority of the proposed approach over the standard LSTM method and other existing feature-selection-based NIDS methods.

Computer-Aided Design and Synthesis of (Functionalized quinazoline)-(α-substituted coumarin)-arylsulfonate Conjugates against Chikungunya Virus.

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the ß carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC50 = 6.46 µM, low toxicity with CC50 = 59.7 µM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC50 = 3.84 µM, CC50 = 72.3 µM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.

The Chinese plug-in electric vehicles industry in post-COVID-19 era towards 2035: Where is the path to revival?

The sudden Coronavirus Disease reported at the end of 2019 (COVID-19) has brought huge pressure to Chinese Plug-in Electric Vehicles (PEVs) industry which is bearing heavy burden under the decreasing fiscal subsidy. If the epidemic continues to rage as the worst case, analysis based on System Dynamics Model (SDM) indicates that the whole PEVs industry in China may shrink by half compared with its originally expected level in 2035. To emerge from the recession, feasible industrial policies include (1) accelerating the construction of charging infrastructures, (2) mitigating the downtrend of financial assistance and (3) providing more traffic privilege for drivers. Extending the deadline of fiscal subsidy by only 2 years, which has been adopted by the Chinese central government, is demonstrated to achieve remarkable effect for the revival of PEVs market. By contrast, the time when providing best charging service or most traffic privilege to get the PEVs industry back to normal needs to be advanced by 10 years or earlier. For industrial policy makers, actively implementing the other two promoting measures on the basis of existing monetary support may be a more efficient strategy for Chinese PEVs market to revive from the shadow in post-COVID-19 era.

Intracerebral Hemorrhage in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prevalence, Clinical and Neuroimaging Features and Risk Factors.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small vessel disease. The role of intracerebral hemorrhage (ICH) in CADASIL remains elusive. The present study aims to investigate the prevalence, characteristics, and risk factors for ICH in CADASIL. METHODS: This retrospective cross-sectional study investigated ICH and cerebral microbleeds (CMBs) in brain susceptibility-weighted imaging or T2*-weighted gradient-recalled echo images of 127 Taiwanese patients with genetically confirmed CADASIL. We analyzed CMBs, lacunes, white matter hyperintensity, and perivascular space. The total small vessel disease score (range, 0-4) was calculated to estimate the overall magnetic resonance imaging burden of small vessel disease. Multivariate regression analysis was performed to identify factors related to ICH lesions in CADASIL. RESULTS: Thirty-seven ICH lesions, including 15 symptomatic and 22 asymptomatic lesions, were found in 27 (21.3% [95% CI, 14.0%-30.9%]) of the 127 patients with CADASIL. The thalamus and lobar regions were the most common ICH locations, and 72.7% of the lobar hemorrhages occurred silently. Patients with CADASIL with ICH lesions more often had hypertension and a higher total small vessel disease score than those without ICH (odds ratio [95% CI]: 3.22 [1.25-8.30] and 3.79 [1.51-9.51]). The presence of CMBs in the brain stem and a total CMB count >10 were independently associated with ICH lesions in patients with CADASIL, with odds ratio (95% CI) of 5.82 (1.80-18.80) and 3.83 (1.08-13.67), respectively. CONCLUSIONS: ICH is an underestimated but important manifestation of CADASIL. The location and number of CMBs are associated with the presence of ICH lesions in patients with CADASIL.