Discovery and Mechanistic Understanding of a Lipase from Rhizorhabdus dicambivorans for Efficient Ester Aminolysis in Aromatic Amines.

The formation of amide bonds via aminolysis of esters by lipases generates a diverse range of amide frameworks in biosynthetic chemistry. Few lipases have satisfactory activity towards bulky aromatic amines despite numerous attempts to improve the efficiency of this transformation. Here, we report the discovery of a new intracellular lipase (Ndbn) with a broad substrate scope. Ndbn turns over a range of esters and aromatic amines in the presence of water (2 %; v/v), producing a high yield of multiple valuable amides. Remarkably, a higher conversion rate was observed for the synthesis of amides from substrates with aromatic amine rather than aliphatic amines. Molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) studies showcase the mechanism for the preference for aromatic amines, including a more suitable orientation, shorter catalytic distances in the active site pocket and a lower reaction barrier for aromatic than for aliphatic amines. This unique lipase is thus a promising biocatalyst for the efficient synthesis of aromatic amides.

Natural compounds modulating mitophagy: Implications for cancer therapy.

Cancer is considered as the second leading cause of mortality, and cancer incidence is still growing rapidly worldwide, which poses an increasing global health burden. Although chemotherapy is the most widely used treatment for cancer, its effectiveness is limited by drug resistance and severe side effects. Mitophagy is the principal mechanism that degrades damaged mitochondria via the autophagy/lysosome pathway to maintain mitochondrial homeostasis. Emerging evidence indicates that mitophagy plays crucial roles in tumorigenesis, particularly in cancer therapy. Mitophagy can exhibit dual effects in cancer, with both cancer-inhibiting or cancer-promoting function in a context-dependent manner. A variety of natural compounds have been found to affect cancer cell death and display anticancer properties by modulating mitophagy. In this review, we provide a systematic overview of mitophagy signaling pathways, and examine recent advances in the utilization of natural compounds for cancer therapy through the modulation of mitophagy. Furthermore, we address the inquiries and challenges associated with ongoing investigations concerning the application of natural compounds in cancer therapy based on mitophagy. Overcoming these limitations will provide opportunities to develop novel interventional strategies for cancer treatment.

Effect of acupuncture on regulating IL-17, TNF-ɑ and AQPs in Sjögren's syndrome.

AIM: The aim of the study was to observe the effect of acupuncture on regulating interleukin (IL)-17, tumor necrosis factor (TNF)-ɑ, and aquaporins (AQPs) in Sjögren's syndrome (SS) on patients and on non-obese diabetic (NOD) models. METHODS: Levels of anti-AQP 1, 5, 8, and 9 antibodies, IL-17, and TNF-ɑ in the serum of SS patients were compared prior and following 20 acupuncture treatment visits during 8 weeks. While in murine model, five groups were divided to receive interventions for 4 weeks, including control, model, acupuncture, isoflurane, and hydroxychloroquine. The submaxillofacial gland index, histology, immunohistochemistry of AQP1, 5, salivary flow, together with IL-17, and TNF-ɑ expression in peripheral blood were compared among the groups. RESULTS: Acupuncture reduced IL-17, TNF-ɑ, and immunoglobin A levels, and numeric analog scale of dryness in 14 patients with SS (p < 0.05). The salivary flow was increased, and the water intake decreased in NOD mice receiving acupuncture treatments. IL-17 and TNF-ɑ levels in peripheral serum were down-regulated (p < 0.05) and AQP1, 5 expression in the submandibular glands up-regulated in mice. CONCLUSION: The effect on relieving xerostomia with acupuncture may be achieved by up-regulating the expression of AQP1. AQP5, down-regulating levels of IL-17 and TNF-ɑ, and a decrease in inflammation of glands.

DegronMD: Leveraging Evolutionary and Structural Features for Deciphering Protein-Targeted Degradation, Mutations, and Drug Response to Degrons.

Protein-targeted degradation is an emerging and promising therapeutic approach. The specificity of degradation and the maintenance of cellular homeostasis are determined by the interactions between E3 ubiquitin ligase and degradation signals, known as degrons. The human genome encodes over 600 E3 ligases; however, only a small number of targeted degron instances have been identified so far. In this study, we introduced DegronMD, an open knowledgebase designed for the investigation of degrons, their associated dysfunctional events, and drug responses. We revealed that degrons are evolutionarily conserved and tend to occur near the sites of protein translational modifications, particularly in the regions of disordered structure and higher solvent accessibility. Through pattern recognition and machine learning techniques, we constructed the degrome landscape across the human proteome, yielding over 18,000 new degrons for targeted protein degradation. Furthermore, dysfunction of degrons disrupts the degradation process and leads to the abnormal accumulation of proteins; this process is associated with various types of human cancers. Based on the estimated phenotypic changes induced by somatic mutations, we systematically quantified and assessed the impact of mutations on degron function in pan-cancers; these results helped to build a global mutational map on human degrome, including 89,318 actionable mutations that may induce the dysfunction of degrons and disrupt protein degradation pathways. Multiomics integrative analysis unveiled over 400 drug resistance events associated with the mutations in functional degrons. DegronMD, accessible at https://bioinfo.uth.edu/degronmd, is a useful resource to explore the biological mechanisms, infer protein degradation, and assist with drug discovery and design on degrons.

Endotype evaluation of Hispanic/Latinx-American patients with chronic rhinosinusitis with nasal polyps.

KEY POINTS: Hispanic-American patients with chronic rhinosinusitis with nasal polyps have a comparable level of tissue eosinophilia compared to their Caucasian counterparts in the United States. Mixed inflammation involving both neutrophils and eosinophils is more common in this population compared to Caucasians. Findings from this study may indicate that Hispanic-American patients have a unique endotype or endotypes that deserves further investigation.

Identification of a Potential Antimycobacterial Drug Sensitizer Targeting a Flavin-Independent Methylenetetrahydrofolate Reductase.

The increasing antibiotic resistance of Mycobacterium tuberculosis and pathogenic nontuberculosis mycobacteria highlights the urgent need for new prevention and treatment strategies. Recently, the cocrystal structure of a Mycobacterium smegmatis flavin-independent 5,10-methylenetetrahydrofolate reductase (MsmMTHFR) that binds with a reduced nicotinamide adenine dinucleotide (NADH) has been well-determined, providing a structural basis for the screening of antimycobacterial leads targeting MsmMTHFR, a new enzyme involved in tetrahydrofolic acid (THF) biosynthesis. In this study, we identified compound AB131 as a promising candidate that fits well into the NADH binding pocket of MsmMTHFR through virtual screening. We discovered that AB131 and its derivatives (13 and 14) can sensitize the antimycobacterial activity of the antitubercular drug para-aminosalicyclic acid (PAS) by 2-5-fold against various species of mycobacteria. Although the compounds themselves do not exhibit any antimycobacterial activity, the high binding affinity of AB131 with MsmMTHFR or Rv2172c was evaluated by microscale thermophoresis analysis. Additionally, we predicted and validated the key residues (V115, V117, P118, and R163) of MsmMTHFR that are involved in the interaction with AB131 by using molecular docking and mutagenesis analysis. These findings offer a potential exploitable target for developing potent and specific antimycobacterial drug sensitizers.

Alkali-Amide-Catalyzed One-Pot Aminoallylation of Aldehydes with Allylbenzenes.

The deprotonation of allylbenzene was successfully demonstrated with a catalytic alkali amide base (NaN(SiMe3)2). The deprotonated allyl anion could be trapped by in situ generated N-(trimethylsilyl) aldimines to provide value-added homoallylic amines (39 examples, 68-98% yields) in a one-pot manner with excellent liner selectivity. Compared with the previously reported method for the synthesis of homoallylic amines, this method does not need to use the preinstalled protection groups on the imines, which need to be removed after the reaction to obtain the N-H free homoallylic amine derivatives.

Deep learning for detecting and elucidating human T-cell leukemia virus type 1 integration in the human genome.

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, is the causative agent for adult T cell leukemia/lymphoma and many other human diseases. Accurate and high throughput detection of HTLV-1 virus integration sites (VISs) across the host genomes plays a crucial role in the prevention and treatment of HTLV-1-associated diseases. Here, we developed DeepHTLV, the first deep learning framework for VIS prediction de novo from genome sequence, motif discovery, and cis-regulatory factor identification. We demonstrated the high accuracy of DeepHTLV with more efficient and interpretive feature representations. Decoding the informative features captured by DeepHTLV resulted in eight representative clusters with consensus motifs for potential HTLV-1 integration. Furthermore, DeepHTLV revealed interesting cis-regulatory elements in regulation of VISs that have significant association with the detected motifs. Literature evidence demonstrated nearly half (34) of the predicted transcription factors enriched with VISs were involved in HTLV-1-associated diseases. DeepHTLV is freely available at https://github.com/bsml320/DeepHTLV.

An interpretable ML model to characterize patient-specific HLA-I antigen presentation.

Personalized immunotherapy holds the promise of revolutionizing cancer prevention and treatment. However, selecting HLA-bound peptide targets that are specific to patient tumors has been challenging due to a lack of patient-specific antigen presentation models. Here, we present epiNB, a white-box, positive-example-only, semi-supervised method based on Naïve Bayes formulation, with information content-based feature selection, to achieve accurate modeling using Mass Spectrometry data eluted from mono-allelic cell lines and patient-derived cell lines. In addition to achieving state-of-the-art accuracy, epiNB yields novel insights into the structural properties, such as interactions of peptide positions, that appear important for modeling personalized, tumor-specific antigen presentation. epiNB uses substantially less parameters than neural networks, does not require hyperparameter tweaking and can efficiently train and run on our web portal (https://epinbweb.streamlit.app/) or a regular PC/laptop, making it easily applicable in translational settings.

Properties of flame-retardant leaf fiber cement-based composites at high temperatures.

Flame retardant modification of leaf fibers was carried out to solve the technical problem of poor fire resistance of plant fibers and improve the utilization rate of urban fallen leaves in building materials. The modification scheme adopts three flame retardants, i.e., ammonium polyphosphate (APP), magnesium hydroxide (MH), and aluminum hydroxide (ATH), and two covering layers, i.e., pure acrylic polymer lotion and water glass (Na2O · nSiO2) solution. The modified leaf fiber's combustion behavior and pyrolysis properties were tested and analyzed. The physical and mechanical characteristics, as well as the thermal insulation qualities, of leaf fiber cement-based composites (LFCC) were studied at high temperatures. The findings revealed that the three flame retardants had an effect on the chemical structure of leaf fibers. In comparison to leaf fibers without flame-retardant modification, flame-retardant-modified leaf fibers have a much greater thermal stability. and its LOI is greater than 27.0%, which is a fire-retardant material. Except for the sample with water glass as the modified cover layer, at high temperatures, the composite flame-retardant fiber LFCC's mass-loss rate is lower compared with fibers without flame-retardant modification or fibers modified with only one kind of flame-retardant. In the composite flame-retardant modified fiber LFCC, the samples with better strength at high temperature are those with ATH replacing 30% and 50% MH. The thermal conductivity of LFCC is negatively correlated with the range of temperature change.

NetBCE: An Interpretable Deep Neural Network for Accurate Prediction of Linear B-cell Epitopes.

Identification of B-cell epitopes (BCEs) plays an essential role in the development of peptide vaccines and immuno-diagnostic reagents, as well as antibody design and production. In this work, we generated a large benchmark dataset comprising 124,879 experimentally supported linear epitope-containing regions in 3567 protein clusters from over 1.3 million B cell assays. Analysis of this curated dataset showed large pathogen diversity covering 176 different families. The accuracy in linear BCE prediction was found to strongly vary with different features, while all sequence-derived and structural features were informative. To search more efficient and interpretive feature representations, a ten-layer deep learning framework for linear BCE prediction, namely NetBCE, was developed. NetBCE achieved high accuracy and robust performance with the average area under the curve (AUC) value of 0.8455 in five-fold cross-validation through automatically learning the informative classification features. NetBCE substantially outperformed the conventional machine learning algorithms and other tools, with more than 22.06% improvement of AUC value compared to other tools using an independent dataset. Through investigating the output of important network modules in NetBCE, epitopes and non-epitopes tended to be presented in distinct regions with efficient feature representation along the network layer hierarchy. The NetBCE is freely available at https://github.com/bsml320/NetBCE.

Does ambient air quality standard contribute to green innovation of enterprises in China? Implications for environmental protection and public health.

In the post-COVID-19 era, environmental pollution has been a serious threat to public health. Enterprises are in urgent need of enhancing green technology innovation as the main source of pollutant emissions, and it is necessary for governments to support green innovation of enterprises to reduce pollutant emissions and promote public health. In this context, this paper investigates whether the Ambient Air Quality Standard (AAQS) implemented in 2012 in China contributes to green innovation of enterprises, to provide implications for environmental protection and public health. By using panel data of Chinese A-share listed companies from 2008 to 2020, this study adopts the difference-in-difference model to analyze the policy impact of environmental regulation on green innovation of enterprises and its internal mechanism. The results show that AAQS has significantly improved the green innovation of enterprises. Furthermore, AAQS affects the green innovation of enterprises by virtue of two mechanism paths: compliance cost effect and innovation offset effect. On the one hand, AAQS leads to an increase in production costs of enterprises, thus inhibiting green innovation activities of enterprises. On the other hand, AAQS encourages enterprises to increase R&D investment in green technology, thus enhancing their green innovation. In addition, the impact of AAQS on firms' green innovation has heterogeneous characteristics. Our findings not only enrich the studies of environmental regulation and green innovation of enterprises but also provide policymakers in China and other developing countries with implications for environmental protection and public health improvement.

A high efficiency and high power L-band relativistic magnetron with all-cavity extraction.

Relativistic magnetron (RM) is a promising high-power microwave source, whose advantages include high efficiency, high power, and compact configuration. Enhancing power efficiency and output power are the most important two development directions for RM. Based on the two targets, a high efficiency and high power RM is presented and investigated numerically and experimentally in this paper. When the diode voltage is 485 kV, the beam current is 6.9 kA, and the magnetic field is 0.34 T, and high power microwave is generated with the power of 1.35 GW, frequency of 1.47 GHz, and power efficiency of 40.3% in the experiments.

Micro-opto-electro-mechanical systems accelerometer based on the Talbot effect of double-layer diffraction gratings.

In this paper, we present the design, fabrication, and test of a micro-opto-electro-mechanical systems (MOEMS) accelerometer based on the Talbot effect of double-layer diffraction gratings. The detection of acceleration is realized by using the highly sensitive displacement characteristic of Talbot imaging of near-field diffraction with double-layer gratings. For the purpose of obtaining optimal contrast of the optical interferometric detection, the parameters of the gratings are optimized by the finite-difference time-domain (FDTD) simulation. The experimental results indicate that this MOEMS accelerometer with the proposed design can achieve a resolution of 246 µg, sensitivity of 6.1 V/g, and bias stability of 0.02 mg. The proposed accelerometer can be operated at higher accelerations (∼80g), which shows significant potential for being used in applications that require detection of strong and fast vibrations, especially in vibration sensing of vehicles and geophysical seismic sensing in real time.

Contamination of sea surface water offshore the Tokai region and Tokyo Bay in Japan by small microplastics.

A nested double neuston net was prepared and used to collect samples from the surface of coastal waters around Japan to obtain information about the properties of both small microplastics (SMPs; <350 µm) and large microplastics (LMPs; >350 µm). The SMP concentrations ranged from 1000 to 5900 pieces m-3 in the open ocean and averaged approximately 3000 pieces m-3 in the inner part of Tokyo Bay. The SMP concentrations were around 20-60 times greater than the LMP concentrations. By analyzing the seawater, we obtained a microplastic size distribution that spanned 50-5000 µm. The LMPs mainly comprised packaging-related plastics, such as polyethylene (PE) and polypropylene, while the SMPs were dominated by paint-related plastics. SMPs derived from packaging materials (e.g., PE) may have gradually sank down from the sea surface when they were smaller than 600 µm.

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias.

BACKGROUND: Abnormal myocardial Nav1.5 expression and function cause lethal ventricular arrhythmias during myocardial ischemia-reperfusion (I/R). Protein inhibitor of activated STAT Y (PIASy)-mediated caveolin-3 (Cav-3) SUMO modification affects Cav-3 binding to the voltage-gated sodium channel 1.5 (Nav1.5). PIASy activity is increased after myocardial I/R, but it is unclear whether this is attributable to plasma membrane Nav1.5 downregulation and ventricular arrhythmias. METHODS: Using recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA (shRNA). After two weeks, rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements. RESULTS: PIASy was upregulated by I/R (P < 0.01), with increased SUMO2/3 modification of Cav-3 and reduced membrane Nav1.5 density (P < 0.01). AAV9-PIASy shRNA intraventricular injection into the rat heart downregulated PIASy after I/R, at both mRNA and protein levels (P < 0.05 vs. Scramble-shRNA + I/R group), decreased SUMO-modified Cav-3 levels, enhanced Cav-3 binding to Nav1.5, and prevented I/R-induced decrease of Nav1.5 and Cav-3 co-localization in the intercalated disc and lateral membrane. PIASy silencing in rat hearts reduced I/R-induced fatal arrhythmias, which was reflected by a modest decrease in the duration of ventricular fibrillation (VF; P < 0.05 vs. Scramble-shRNA + I/R group) and a significantly reduced arrhythmia score (P < 0.01 vs. Scramble-shRNA + I/R group). The anti-arrhythmic effects of PIASy silencing were also evidenced by decreased episodes of ventricular tachycardia (VT), sustained VT and VF, especially at the time 5-10 min after ischemia (P < 0.05 vs. Scramble-shRNA + IR group). Using in vitro human embryonic kidney 293 T (HEK293T) cells and isolated adult rat cardiomyocyte models exposed to hypoxia/reoxygenation (H/R), we confirmed that increased PIASy promoted Cav-3 modification by SUMO2/3 and Nav1.5/Cav-3 dissociation after H/R. Mutation of SUMO consensus lysine sites in Cav-3 (K38R or K144R) altered the membrane expression levels of Nav1.5 and Cav-3 before and after H/R in HEK293T cells. CONCLUSIONS: I/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Nav1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Nav1.5 downregulation in the plasma membrane of cardiomyocytes, and subsequent ventricular arrhythmias in rats. PIASy was identified as a potential therapeutic target for life-threatening arrhythmias in patients with ischemic heart diseases.

Whether Green Finance Improves Green Innovation of Listed Companies-Evidence from China.

Facing the intensification of global carbon emissions and the increasingly severe pressure of environmental pollution, listed companies urgently need to promote green innovation, achieve green transformation, and alleviate environmental problems. Green finance policy has played a significant role as a financial strategy for environmental governance in affecting green innovation level over the years. In this context, taking the green finance reform and innovation pilot zone (GFRIPZ) implemented in 2017 in China as a quasi-natural experiment, this paper analyzes the impact of green finance policy on green innovation level of listed companies by the difference-in-difference model. Based on the data of Chinese A-share listed companies from 2008 to 2020, the results of empirical analysis show that green finance significantly promotes green innovation of listed companies. The effect is profound on green utility model patents, but less pronounced on green invention patents. Among all these pilot zones, the policy effects of GFRIPZ ranked in descending order are Zhejiang, Guangdong, Jiangxi, Guizhou, and Xinjiang. In addition, green finance has a more significant impact on heavy-polluting industries, large and state-owned enterprises, and listed companies located in the eastern region. Furthermore, the effects of industry heterogeneity ranked in descending order are energy, manufacturing, processing, and engineering industry, while it is not obvious in the service industry. Mechanism analysis suggests that the effect is driven by a reduction in the cost of debt financing and an increase in the long-term debt ratio. The findings provide implications for policymakers to promote the level of green innovation and environmental governance. Therefore, policymakers should support the long-term creative development of green invention patents by reducing the cost of debt financing and increasing the long-term debt ratio and consider the heterogeneous characteristics of listed companies when formulating green finance policies.

One-Dimensional Strain Solitons Manipulated Superlubricity on Graphene Interface.

The frictional properties of a uniaxial tensile strained graphene interface are studied using molecular dynamics simulations. A misfit interval statistical method (MISM) is applied to characterize the atomistic misfits at the interface and strain soliton pattern. During sliding along both armchair and zigzag directions, the lateral force depends on the ratio of graphene flake length (L) to strain soliton spacing (Ls) and becomes nearly zero when L is an integer multiple of 3Ls. Furthermore, the strain solitons propagate along the armchair sliding direction dynamically, while fission and fusion are repeatedly evidenced along the zigzag sliding direction. The underlying superlubric mechanism is revealed by a single-atom quasi-static model. The cancellation of lateral force for the contacting atoms exhibits a dynamic balance when sliding along the armchair direction but a quasi-static balance along the zigzag direction. A diagram of flake length with respect to tensile strain (L-ε) is proposed to predict the critical condition for the transition from nonsuperlubricity to superlubricity. Our results provide insights on the design of superlubric devices.

Efficacy and Safety of Acupuncture on Symptomatic Improvement in Primary Sjögren's Syndrome: A Randomized Controlled Trial.

Aim: We sought to evaluate the efficacy of acupuncture in treating the main symptoms of primary Sjögren's syndrome, specifically dryness, pain, and fatigue. Methods: A total of 120 patients with primary Sjögren's syndrome were randomized in a parallel-group, controlled trial. Participants received acupuncture or sham acupuncture for the first 8 weeks, then were followed for 16 weeks thereafter. The primary outcome was the proportion of participants with a ≥ 30% reduction in ≥ 2 of 3 numeric analog scale scores for dryness, pain, and fatigue. The secondary outcomes included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-reported Index (ESSPRI); the EULAR Sjögren's Syndrome Disease Activity Index; the Schirmer test score; unstimulated saliva flow; serum immunoglobulin G, A, and M concentrations; the Medical Outcome Study Short Form 36 score; salivary gland ultrasound imaging; and the Hospital Anxiety and Depression Scale score. Results: The proportions of patients meeting the primary endpoint were 28.33% (17/60) in the acupuncture group and 31.66% (19/60) in the sham group, without a statistically significant difference (P = 0.705). The IgG concentration at week 16 and the homogeneity in ultrasonography of the salivary glands at week 8 showed significant differences between the 2 groups (P = 0.0490 and P = 0.0334, respectively). No other differences were observed between the 2 groups. ESSPRI and unstimulated saliva flow were improved in both groups compared to baseline, albeit with a significant difference between them. Conclusion: In patients with primary Sjögren's syndrome, acupuncture did not satisfactorily improve symptoms compared to placebo. However, interesting discoveries and possible underlying reasons were demonstrated and discussed, which may be useful to studies in the future. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT02691377].

The Impact of Ecological Civilization Construction on Environment and Public Health-Evidence from the Implementation of Ecological Civilization Demonstration Area in China.

Faced with an increasingly tight resource supply, serious environmental pollution and degrading ecosystems, human beings are eager to reduce environmental pollution and promote public health. In this context, this paper takes the ecological civilization demonstration area (ECDA) established in China as a quasi-natural experiment to test whether ecological civilization construction (ECC) is an effective solution for the reduction of environmental pollution and improvement of public health. Based on the panel data of 31 provinces in China from 2009 to 2020, the study analyzes the impact of ECC on environmental quality and public health by employing a difference-in-difference model. The results show that ECDA has restrained environmental pollution and reduced the morbidity and mortality, which indicates that ECC effectively promotes environmental quality and public health. The effect of ECC is more pronounced in economically developed regions. In addition, ECC improves environmental quality through scale effects, structural effects, technology effects, and ecological conservation effects, while the positive effects of ECC on public health are driven by scale effects and ecological conservation effects only. Therefore, policymakers should support low-carbon production, promote the upgrade of industrial structures, and encourage enterprises to develop green technologies. Ecological protection projects such as afforestation and greening are necessary. Governments should initiate ecological civilization construction in economically developed regions and then gradually promote the policies in relatively poor areas.