Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression.

N 6-Threonylcarbamoyladenosine at A37 (t6A37) of ANN-decoding transfer RNAs (tRNAs) is a universal modification whose functions have been well documented in bacteria and lower eukaryotes; however, its role in organellar translation is not completely understood. In this study, we deleted the mitochondrial t6A37-modifying enzyme OSGEPL1 in HEK293T cells. OSGEPL1 is dispensable for cell viability. t6A37 hypomodification selectively stimulated N1-methyladenosine at A9 (m1A9) and N2-methylguanosine at G10 (m2G10) modifications and caused a substantial reduction in the aminoacylation of mitochondrial tRNAThr and tRNALys, resulting in impaired translation efficiency. Multiple types of amino acid misincorporation due to the misreading of near-cognate codons by t6A37-unmodified tRNAs were detected, indicating a triggered translational infidelity. Accordingly, the alterations in mitochondrial structure, function, and the activated mitochondrial unfolded protein response were observed. Mitochondrial function was efficiently restored by wild-type, but not by tRNA-binding-defective OSGEPL1. Lastly, in Osgepl1 deletion mice, disruption to mitochondrial translation was evident but resulted in no observable deficiency under physiological conditions in heart, which displays the highest Osgepl1 expression. Taken together, our data delineate the multifaceted roles of mitochondrial t6A37 modification in translation efficiency and quality control in mitochondria.

Machine learning model for anti-cancer drug combinations: Analysis, prediction, and validation.

Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.

[Current Status and New Drugs Progress in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia--Review].

The overall therapeutic outcome of acute myeloid leukemia (AML) is poor, and relapse and refractory are the main reasons for treatment failure. Leukemia cells of relapsed and refractory AML (R/R-AML) patients are usually resistant to conventional chemotherapy, and new treatment regimens are urgently needed to further improve the survival rate and prolong the survival time of these patients.There are no recommended unified treatment regimens other than entering clinical trials.At present,the main options are salvage chemotherapy and hematopoietic stem cell transplantation (HSCT), and HSCT is the only possible cure for R/R-AML, but the prognosis of most of these patients is still poor.In recent years,the treatment status of AML has progressed rapidly, and the new therapies are emerging, many new drugs have become the research focus. Some progress has been made in improving chemosensitivity and overcoming chemoresistance by combining the new drugs with the original chemotherapeutic drugs, which provide a new treatment option and improve the overall prognosis for R/R-AML patients. This article will review the current treatment status and the latest progress in new drug research of R/R-AML.

[Acupuncture mitigates ocular surface inflammatory response via α7nAChR/NF-κB p65 signaling in dry eye guinea pigs].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the ocular surface inflammation and α7 nicotinic acetylcholine receptor (α7nAChR) / nuclear factor kappa-B (NF-κB) p65 signal pathway in guinea pigs with dry eye, so as to explore its underlying mechanism. METHODS: A total of 32 male British tricolor short haired guinea pigs were randomized into blank control, model, EA and sham acupuncture groups, with 8 guinea pigs in each group. The dry eye model was established by subcutaneous injection of scopolamine hydrobromide solution (0.6 mg/0.2 mL each time, 4 times a day for 10 days). Guinea pigs of the EA group was treated with EA at bilateral "Cuanzhu" (BL2) and "Taiyang" (HN5), and manual acupuncture at bilateral "Jingming" (BL1), "Sizhukong" (SJ23), "Tongziliao" (GB1) for 15 min, once daily for 14 days. For animals of the sham acupuncture group, a blunt needle was used to prick the skin surface of the acupoints, the acupoint selection and stimulation time were the same as those in the EA group. Before and after modeling and after the intervention, the breakup time (BUT) of lacrimal film, sodium fluorescein coloring (Fl) state of corneal epithelium and phenol red thread (PRT) moist length were recorded for assessing the severity of dry eye. The density of activated immune cells around the corneal epithelial stromal cells was determined by corneal confocal microscopy. The contents of interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in the cornea and lacri-mal gland tissues were determined by ELISA, and the expression levels of α7nAChR and NF-κB p65 in the cornea and lacrimal gland were detected by immunohistochemistry and Western blot, separately. RESULTS: Compared with the blank control group, the corneal Fl, density of activated immune cells of corneal epithelium, contents of IL-6, IL-10 and TNF-α in both corneal and lacrimal gland tissues, NF-κB p65 cell positive rate and protein expression of lacrimal gland and corneal tissues were significantly increased (P<0.01, P<0.05), while the BUT, PRT and lacrimal gland α7nAChR cell positive rate considerably decreased (P<0.01) in the model group. In comparison with the model group, the level of corneal Fl, density of the activated immune cells of corneal epithelium, contents of corneal and lacrimal IL-6 and TNF-α, and corneal and lacrimal NF-κB p65 cell positive rates and protein expressions were remarkably down-regulated in the EA group (P<0.01, P<0.05), rather than in the sham acupuncture group (P>0.05) except content of corneal IL-10, lacrimal NF-κB p65 cell positive rate and lacrimal α7nAChR protein expression, whereas the levels of BUT, PRT, corneal and lacrimal IL-10 and corneal and lacrimal α7nAChR cell positive rates and protein expressions significantly up-regulated in the EA group (P<0.01, P<0.05), rather than in the sham acupuncture group (P>0.05) except corneal TNF-α and corneal NF-κB p65 protein expression. CONCLUSION: EA can improve corneal and lacrimal function in dry eye guinea pigs, which may be associated with its actions in increasing the expression of α7nAChR, inhibiting the nuclear translocation of NF-κB, and reducing the activated immune cells and inflammatory reaction.

Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8.

METTL8 has recently been identified as the methyltransferase catalyzing 3-methylcytidine biogenesis at position 32 (m3C32) of mitochondrial tRNAs. METTL8 also potentially participates in mRNA methylation and R-loop biogenesis. How METTL8 plays multiple roles in distinct cell compartments and catalyzes mitochondrial tRNA m3C formation remain unclear. Here, we discovered that alternative mRNA splicing generated several isoforms of METTL8. One isoform (METTL8-Iso1) was targeted to mitochondria via an N-terminal pre-sequence, while another one (METTL8-Iso4) mainly localized to the nucleolus. METTL8-Iso1-mediated m3C32 modification of human mitochondrial tRNAThr (hmtRNAThr) was not reliant on t6A modification at A37 (t6A37), while that of hmtRNASer(UCN) critically depended on i6A modification at A37 (i6A37). We clarified the hmtRNAThr substrate recognition mechanism, which was obviously different from that of hmtRNASer(UCN), in terms of requiring a G35 determinant. Moreover, SARS2 (mitochondrial seryl-tRNA synthetase) interacted with METTL8-Iso1 in an RNA-independent manner and modestly accelerated m3C modification activity. We further elucidated how nonsubstrate tRNAs in human mitochondria were efficiently discriminated by METTL8-Iso1. In summary, our results established the expression pattern of METTL8, clarified the molecular basis for m3C32 modification by METTL8-Iso1 and provided the rationale for the involvement of METTL8 in tRNA modification, mRNA methylation or R-loop biogenesis.

Human lysyl-tRNA synthetase evolves a dynamic structure that can be stabilized by forming complex.

The evolutionary necessity of aminoacyl-tRNA synthetases being associated into complex is unknown. Human lysyl-tRNA synthetase (LysRS) is one component of the multi-tRNA synthetase complex (MSC), which is not only critical for protein translation but also involved in multiple cellular pathways such as immune response, cell migration, etc. Here, combined with crystallography, CRISPR/Cas9-based genome editing, biochemistry, and cell biology analyses, we show that the structures of LysRSs from metazoan are more dynamic than those from single-celled organisms. Without the presence of MSC scaffold proteins, such as aminoacyl-tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), human LysRS is free from the MSC. The interaction with AIMP2 stabilizes the closed conformation of LysRS, thereby protects the essential aminoacylation activity under stressed conditions. Deleting AIMP2 from the human embryonic kidney 293 cells leads to retardation in cell growth in nutrient deficient mediums. Together, these results suggest that the evolutionary emergence of the MSC in metazoan might be to protect the aminoacyl-tRNA synthetase components from being modified or recruited for use in other cellular pathways.

Commonality and diversity in tRNA substrate recognition in t6A biogenesis by eukaryotic KEOPSs.

N 6-Threonylcarbamoyladenosine (t6A) is a universal and pivotal tRNA modification. KEOPS in eukaryotes participates in its biogenesis, whose mutations are connected with Galloway-Mowat syndrome. However, the tRNA substrate selection mechanism by KEOPS and t6A modification function in mammalian cells remain unclear. Here, we confirmed that all ANN-decoding human cytoplasmic tRNAs harbor a t6A moiety. Using t6A modification systems from various eukaryotes, we proposed the possible coevolution of position 33 of initiator tRNAMet and modification enzymes. The role of the universal CCA end in t6A biogenesis varied among species. However, all KEOPSs critically depended on C32 and two base pairs in the D-stem. Knockdown of the catalytic subunit OSGEP in HEK293T cells had no effect on the steady-state abundance of cytoplasmic tRNAs but selectively inhibited tRNAIle aminoacylation. Combined with in vitro aminoacylation assays, we revealed that t6A functions as a tRNAIle isoacceptor-specific positive determinant for human cytoplasmic isoleucyl-tRNA synthetase (IARS1). t6A deficiency had divergent effects on decoding efficiency at ANN codons and promoted +1 frameshifting. Altogether, our results shed light on the tRNA recognition mechanism, revealing both commonality and diversity in substrate recognition by eukaryotic KEOPSs, and elucidated the critical role of t6A in tRNAIle aminoacylation and codon decoding in human cells.

Modifications of the human tRNA anticodon loop and their associations with genetic diseases.

Transfer RNAs (tRNAs) harbor the most diverse posttranscriptional modifications. Among such modifications, those in the anticodon loop, either on nucleosides or base groups, compose over half of the identified posttranscriptional modifications. The derivatives of modified nucleotides and the crosstalk of different chemical modifications further add to the structural and functional complexity of tRNAs. These modifications play critical roles in maintaining anticodon loop conformation, wobble base pairing, efficient aminoacylation, and translation speed and fidelity as well as mediating various responses to different stress conditions. Posttranscriptional modifications of tRNA are catalyzed mainly by enzymes and/or cofactors encoded by nuclear genes, whose mutations are firmly connected with diverse human diseases involving genetic nervous system disorders and/or the onset of multisystem failure. In this review, we summarize recent studies about the mechanisms of tRNA modifications occurring at tRNA anticodon loops. In addition, the pathogenesis of related disease-causing mutations at these genes is briefly described.

Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6.

tRNAs harbor the most diverse posttranscriptional modifications. The 3-methylcytidine (m3C) is widely distributed at position C32 (m3C32) of eukaryotic tRNAThr and tRNASer species. m3C32 is decorated by the single methyltransferase Trm140 in budding yeasts; however, two (Trm140 and Trm141 in fission yeasts) or three enzymes (METTL2A, METTL2B and METTL6 in mammals) are involved in its biogenesis. The rationale for the existence of multiple m3C32 methyltransferases and their substrate discrimination mechanism is hitherto unknown. Here, we revealed that both METTL2A and METTL2B are expressed in vivo. We purified human METTL2A, METTL2B, and METTL6 to high homogeneity. We successfully reconstituted m3C32 modification activity for tRNAThr by METT2A and for tRNASer(GCU) by METTL6, assisted by seryl-tRNA synthetase (SerRS) in vitro. Compared with METTL2A, METTL2B exhibited dramatically lower activity in vitro. Both G35 and t6A at position 37 (t6A37) are necessary but insufficient prerequisites for tRNAThr m3C32 formation, while the anticodon loop and the long variable arm, but not t6A37, are key determinants for tRNASer(GCU) m3C32 biogenesis, likely being recognized synergistically by METTL6 and SerRS, respectively. Finally, we proposed a mutually exclusive substrate selection model to ensure correct discrimination among multiple tRNAs by multiple m3C32 methyltransferases.

Computational Studies of the Structural Basis of Human RPS19 Mutations Associated With Diamond-Blackfan Anemia.

Diamond-Blackfan Anemia (DBA) is an inherited rare disease characterized with severe pure red cell aplasia, and it is caused by the defective ribosome biogenesis stemming from the impairment of ribosomal proteins. Among all DBA-associated ribosomal proteins, RPS19 affects most patients and carries most DBA mutations. Revealing how these mutations lead to the impairment of RPS19 is highly demanded for understanding the pathogenesis of DBA, but a systematic study is currently lacking. In this work, based on the complex structure of human ribosome, we comprehensively studied the structural basis of DBA mutations of RPS19 by using computational methods. Main structure elements and five conserved surface patches involved in RPS19-18S rRNA interaction were identified. We further revealed that DBA mutations would destabilize RPS19 through disrupting the hydrophobic core or breaking the helix, or perturb the RPS19-18S rRNA interaction through destroying hydrogen bonds, introducing steric hindrance effect, or altering surface electrostatic property at the interface. Moreover, we trained a machine-learning model to predict the pathogenicity of all possible RPS19 mutations. Our work has laid a foundation for revealing the pathogenesis of DBA from the structural perspective.

Incorporating structural features to improve the prediction and understanding of pathogenic amino acid substitutions.

BACKGROUND: The wide application of gene sequencing has accumulated numerous amino acid substitutions (AAS) with unknown significance, posing significant challenges to predicting and understanding their pathogenicity. While various prediction methods have been proposed, most are sequence-based and lack insights for molecular mechanisms from the perspective of protein structures. Moreover, prediction performance must be improved. METHODS: Herein, we trained a random forest (RF) prediction model, namely AAS3D-RF, underscoring sequence and three-dimensional (3D) structure-based features to explore the relationship between diseases and AASs. RESULTS: AAS3D-RF was trained on more than 14,000 AASs with 21 selected features, and obtained accuracy (ACC) between 0.811 and 0.839 and Matthews correlation coefficient (MCC) between 0.591 and 0.684 on two independent testing datasets, superior to seven existing tools. In addition, AAS3D-RF possesses unique structure-based features, context-dependent substitution score (CDSS) and environment-dependent residue contact energy (ERCE), which could be applied to interpret whether pathogenic AASs would introduce incompatibilities to the protein structural microenvironments. CONCLUSION: AAS3D-RF serves as a valuable tool for both predicting and understanding pathogenic AASs.

IDRMutPred: predicting disease-associated germline nonsynonymous single nucleotide variants (nsSNVs) in intrinsically disordered regions.

MOTIVATION: Despite of the lack of folded structure, intrinsically disordered regions (IDRs) of proteins play versatile roles in various biological processes, and many nonsynonymous single nucleotide variants (nsSNVs) in IDRs are associated with human diseases. The continuous accumulation of nsSNVs resulted from the wide application of NGS has driven the development of disease-association prediction methods for decades. However, their performance on nsSNVs in IDRs remains inferior, possibly due to the domination of nsSNVs from structured regions in training data. Therefore, it is highly demanding to build a disease-association predictor specifically for nsSNVs in IDRs with better performance. RESULTS: We present IDRMutPred, a machine learning-based tool specifically for predicting disease-associated germline nsSNVs in IDRs. Based on 17 selected optimal features that are extracted from sequence alignments, protein annotations, hydrophobicity indices and disorder scores, IDRMutPred was trained using three ensemble learning algorithms on the training dataset containing only IDR nsSNVs. The evaluation on the two testing datasets shows that all the three prediction models outperform 17 other popular general predictors significantly, achieving the ACC between 0.856 and 0.868 and MCC between 0.713 and 0.737. IDRMutPred will prioritize disease-associated IDR germline nsSNVs more reliably than general predictors. AVAILABILITY AND IMPLEMENTATION: The software is freely available at http://www.wdspdb.com/IDRMutPred. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Hearing impairment-associated KARS mutations lead to defects in aminoacylation of both cytoplasmic and mitochondrial tRNALys.

Aminoacyl-tRNA synthetases (aaRSs) are ubiquitously expressed, essential enzymes, synthesizing aminoacyl-tRNAs for protein synthesis. Functional defects of aaRSs frequently cause various human disorders. Human KARS encodes both cytosolic and mitochondrial lysyl-tRNA synthetases (LysRSs). Previously, two mutations (c.1129G>A and c.517T>C) were identified that led to hearing impairment; however, the underlying biochemical mechanism is unclear. In the present study, we found that the two mutations have no impact on the incorporation of LysRS into the multiple-synthetase complex in the cytosol, but affect the cytosolic LysRS level, its tertiary structure, and cytosolic tRNA aminoacylation in vitro. As for mitochondrial translation, the two mutations have little effect on the steady-state level, mitochondrial targeting, and tRNA binding affinity of mitochondrial LysRS. However, they exhibit striking differences in charging mitochondrial tRNALys, with the c.517T>C mutant being completely deficient in vitro and in vivo. We constructed two yeast genetic models, which are powerful tools to test the in vivo aminoacylation activity of KARS mutations at both the cytosolic and mitochondrial levels. Overall, our data provided biochemical insights into the potentially molecular pathological mechanism of KARS c.1129G>A and c.517T>C mutations and provided yeast genetic bases to investigate other KARS mutations in the future.

Molecular basis for t6A modification in human mitochondria.

N 6-Threonylcarbamoyladenosine (t6A) is a universal tRNA modification essential for translational accuracy and fidelity. In human mitochondria, YrdC synthesises an l-threonylcarbamoyl adenylate (TC-AMP) intermediate, and OSGEPL1 transfers the TC-moiety to five tRNAs, including human mitochondrial tRNAThr (hmtRNAThr). Mutation of hmtRNAs, YrdC and OSGEPL1, affecting efficient t6A modification, has been implicated in various human diseases. However, little is known about the tRNA recognition mechanism in t6A formation in human mitochondria. Herein, we showed that OSGEPL1 is a monomer and is unique in utilising C34 as an anti-determinant by studying the contributions of individual bases in the anticodon loop of hmtRNAThr to t6A modification. OSGEPL1 activity was greatly enhanced by introducing G38A in hmtRNAIle or the A28:U42 base pair in a chimeric tRNA containing the anticodon stem of hmtRNASer(AGY), suggesting that sequences of specific hmtRNAs are fine-tuned for different modification levels. Moreover, using purified OSGEPL1, we identified multiple acetylation sites, and OSGEPL1 activity was readily affected by acetylation via multiple mechanisms in vitro and in vivo. Collectively, we systematically elucidated the nucleotide requirement in the anticodon loop of hmtRNAs, and revealed mechanisms involving tRNA sequence optimisation and post-translational protein modification that determine t6A modification levels.

[Analysis of Pollution Characteristics and Sources of PM2.5 During Heavy Pollution in Shijiazhuang City Around New Year's Day 2019].

We report on successive haze weather that occurred in Shijiazhuang City, China, from December 30, 2018 to January 15, 2019. There were 12 days of heavy atmospheric pollution during this period, which primarily involved aerosol fine particulate matter (PM2.5). This study analyzes the causes of the pollution using component analysis and by assessing pollution evolution, spatial and temporal distributions of PM2.5, pollution sources, and meteorological factors. The results showed that PM2.5 was mainly composed of secondary inorganic ions (65.4%) that were mainly sourced from coal combustion (24.4%) and industrial sources (23.7%). The contributions of sulfate and secondary inorganic sources increased significantly with increasing pollution. Pollution was affected by unfavorable meteorological conditions (e.g., a low air mass) and by the particular local terrain, static stability, high humidity, and near-ground reverse temperatures from the south-southeast and west-southwest directions. Contaminants from primary sources including coal combustion, industry, and motor vehicle exhausts accumulated quickly in front of the Taihang Mountains. Secondary transformation of gaseous pollutants and increasing moisture absorption of particulate matter increased PM2.5 concentrations. Sulfate explosion also increased pollution. We recommend that as part of emergency responses to heavy pollution events, emissions reduction measures should be implemented to strengthen the control of SO2, NOx, and NH3 emission sources of secondary inorganic precursors, especially SO2 emission sources (i.e., coal etc.). We further propose a strengthen of the management of atmospheric emission sources in Xinle, Wuji, Shenze, Jinzhou, and Xingtang counties in the northeast of the city to reduce the impact of local transmission.

Mechanism and Selectivity of the Oxidative Ring Contraction of Cyclic α-Formyl Ketones.

The oxidative contraction of α-formal ketone to form continuous all carbon chiral centers promoted by H2 O2 is widely used in natural product total synthesis. Typically, using this transformation, chiral cyclic ketones are obtained as the major products and ring-opening products as the minor products. Herein, DFT calculations have been used to investigate the detailed reaction mechanism and chemoselectivity. In addition, with the widely accepted mechanism of H2 O2 -promoted transformation, our systematic investigation with various explicit-solvent-model calculations for the first time shows that H2 O and H2 O2 are comparable at catalyzing the rate-determining step of this reaction, which emphasis the importance of solvent effect in such transformations. It is found that both the less ring-constrain and a later transition state in an exothermic reaction account for the origin why the reaction favors ring-contraction pathway rather than ring-opening one. By a comprehensive analysis for the substituted groups, it has been disclosed that the steric effects of the substituted groups on R2 and R3 contribute to the selectivity with larger steric hindrance favoring the chiral cyclic products. Moreover, the electronic effects on R1 but not R3 affect the selectivity with electron-donating groups leading to the cyclic products. Based on our calculations, some predictions for higher selectivity have been made.

WDSPdb: an updated resource for WD40 proteins.

SUMMARY: The WD40-repeat proteins are a large family of scaffold molecules that assemble complexes in various cellular processes. Obtaining their structures is the key to understanding their interaction details. We present WDSPdb 2.0, a significantly updated resource providing accurately predicted secondary and tertiary structures and featured sites annotations. Based on an optimized pipeline, WDSPdb 2.0 contains about 600 thousand entries, an increase of 10-fold, and integrates more than 37 000 variants from sources of ClinVar, Cosmic, 1000 Genomes, ExAC, IntOGen, cBioPortal and IntAct. In addition, the web site is largely improved for visualization, exploring and data downloading. AVAILABILITY AND IMPLEMENTATION: http://www.wdspdb.com/wdsp/ or http://wu.scbb.pkusz.edu.cn/wdsp/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase.

Alanyl-tRNA synthetases (AlaRSs) from three domains of life predominantly rely on a single wobble base pair, G3-U70, of tRNAAla as a major determinant. However, this base pair is divergent in human mitochondrial tRNAAla, but instead with a translocated G5-U68. How human mitochondrial AlaRS (hmtAlaRS) recognizes tRNAAla, in particular, in the acceptor stem region, remains unknown. In the present study, we found that hmtAlaRS is a monomer and recognizes mitochondrial tRNAAla in a G3-U70-independent manner, requiring several elements in the acceptor stem. In addition, we found that hmtAlaRS misactivates noncognate Gly and catalyzes strong transfer RNA (tRNA)-independent pre-transfer editing for Gly. A completely conserved residue outside of the editing active site, Arg663, likely functions as a tRNA translocation determinant to facilitate tRNA entry into the editing domain during editing. Finally, we investigated the effects of the severe infantile-onset cardiomyopathy-associated R592W mutation of hmtAlaRS on the canonical enzymatic activities of hmtAlaRS. Overall, our results provide fundamental information about tRNA recognition and deepen our understanding of translational quality control mechanisms by hmtAlaRS.

[Online Source Analysis of Particulate Matter (PM2.5) in a Heavy Pollution Process of Shijiazhuang City During Heating Period in 2015].

In recent years, more and more public attention has been paid to the problem of air pollution during the heating period in North China. This article took a heavy pollution process of Shijiazhuang district from Nov.24th to Dec.4th in 2015 as an example, and analyzed comprehensively the source apportionment in different periods, size distribution of the PM2.5 from each source in different periods, the characteristics of mass spectra of the main emission sources and the meteorological conditions with the method of real-time online source analysis. It turned out:the main sources of pollutants were coal combustions, industrial discharges, vehicle exhausts and secondary inorganic reactions. With the help of meteorological condition of low pressure and low wind speed, the PM2.5 mainly produced by coal combustions and industrial discharges accumulated heavily and went through the second stage conversion, leading to this heavy air pollution. The main particulate matters from coal combustions were the mixed carbons; the main particulate matters from industrial discharges were metals; the main particulate matters from vehicle exhausts were elemental carbon and manganese metal; the main particulate matters from pure secondary inorganic sources were secondary inorganic ions; the main particulate matters from dust pollution were aluminum, calcium, iron and silicate minerals; the main particulate matters from biomass fuel combustions were levoglucosan; the feature signal from restaurant discharges was organic acid. Different from the distribution before and after the heavy pollution period, the particulate matters from the 8 pollution sources presented even distribution during the heavy pollution period.

[Online Sources about Atmospheric Fine Particles During the 70th Anniversary of Victory Parade in Shijiazhuang].

Robust measures were taken to ensure a good air quality for the parade on the 70th Victory Memorial Day for the Chinese People's War of Resistance against Japanese Aggression (VM Day). During the period, the source of fine particulate matter in air was analyzed with the single particle aerosol mass spectrometer (SPAMS) located at Shijiazhuang air automatic monitoring station of 20 meter. The results indicated that, on VM Day the primary sources of air pollution were vehicle exhaust emission (20.9%) and coal-generated emissions (20.6%), which were also at lower degrees than those on pre-and post-VM Day. It turned out that these air quality-improving measures, especially the vehicle restriction and coal consumption reduction, had a good effect. Particles from the vehicle exhaust and coal combustion source were mainly based on short-chain elements, carbon, manganese and organic carbon. The particles from the industry source were mainly organic carbon and metal. Particles from the dust source were mainly composed of silicate and calcium. When air quality-improving measures were stopped, the concentration of particulate matter rapidly rose again, and the contribution of dust and vehicle exhaust emission was remarkable. It was believed that the interaction of low-pressure static stability of adverse weather conditions and southeast direction of low altitude transmission was a major cause in the deterioration of air quality.