Recovery of the procedure of combined handling of elucidation methods for interpretable structure elucidation for decreasing frequencies of organic structure revision

Maybe more than one hundred papers on revision of organic structure appear every year. Most of them derive from unreasonable neglect of correct structures because of picking-up/angling methodology. Antithetically, the present paper recommends scooping-up/netting one as a proper systematic procedure in order to avoid such careless and unreasonable neglect as much as possible by indicating existence of informational homologues, which are answers matching with provided pieces of structure information. This was invented by a Japanese company JEOL for its commercial computer program for automated organic structure elucidation, Combined Handling of Elucidation Methods for Interpretable Chemical Structures (CHEMICS). But the basic policy of CHEMICS has been changed to kinds of picking-up methods by people who carried away the name without understanding importance of the policy. In order to aim to recover scooping-up methodology, the present paper shows four examples of our analysis, exemplifying neglected informational homologues, and demonstrating that scooping-up methodology is better.　　有機化合物の構造決定の誤りを修正する論文の数は年間おそらく100件を越す。これは構造データの解析の誤りによるよりは、つり法（拾い上げ法）手順採用による正しい構造の不当な無視による。つり法手順は見落としをしやすいので初心者が使うべきではない。このような正解の不当な無視をできるだけ減らすために標準的かつ系統的手順として本論文ではあみ法（囲い込みは法）手順を強く推奨する。この方法はもともと日本電子株式会社（JEOL）が自動構造解析システム、商品名Combined Handling of Elucidation Methods forInterpretable Chemical Structures （略称CHEMICS）（解析可能な化学構造のための複数の構造解析法の組み合わせ使用）のために最初に考えだしたものである。四つの事例でこの手順がきわめて有用であることを証明する（実際の文献から拾い出した構造決定の結果は誤まっていて真の正解を見落としている可能性があることを暗示し、真の正解の候補を提示した。）　　注：Appendix は「JEOL のCHEMICS の概念と名前がその基本方針を理解できなかった人たちによって他の機関に持ち出され、その方針が歪曲されてつり法に向いていく過程」を公表された文献で追っている。そこで本論文ではあみ法の復活を試みている

Genomic DNA sequences of non GT-AG introons in human mRNA genes

We searched human genome DNA sequences in the DDBJ/GenBank/EMBL for introns of mRNA genes which do not conform to the GT-AG rule, and collected 5791 fragments which do not form exon parts. Of these 159 are not of GT-AG form. Then we eliminated 19 because of non introns that were yielded by clerical error, frameshift, edition policy, and so on. Major part (94) of the 140 remaining sequences can be considered also to be GT-AG forms with alternative interpretation. There are several mRNAs carrying more than one intron where not GT-AG forms but non-GT-AG ones are chosen. This suggests easy usage of easy selection, even when there is more than one candidate, by easy computer software to infer an intron sequence as the logical difference between a gene and its corresponding cDNA

Effective procedure to develop alternative annotations of bacterial tRNA genes by means of deductive inference on the basis of characteristic tandems of tRNA genes

In a series of analysis of genomic DNA sequences, we have established an induction-deduction method to dig up hidden tRNA and rRNA genes from bacterial genome DNA sequences by means of a concept of a characteristic tRNA-gene tandem we have ldeveloped, and are accumulating information on positions of putative tRNA and rRNA genes to be proposed as alternative annotations to the DDBJ/GenBank/EMBL Database. We have searched the DNA sequences near the existing tRNA genes as golcondas for tRNA genes, and found mord than fifty genes, e.g. tRNA-Ser and tRNA-Met in [AB013377], and 5S rRNAs in [AE014192], [AE017000], and others. A part of miserable states of the Database was partly introduced, and it is discussd how such status will be disso1ved. In addition, we proposed some ideas to maintain and improve the DDBJ/GenBank/EMBL database

Atomic cluster expansion force field based thermal property material design with density functional theory level accuracy in non-equilibrium molecular dynamics calculations over sub-million atoms

Non-equilibrium molecular dynamics (NEMD) techniques are widely used for investigating lattice thermal conductivity. Recently, machine learning force fields (MLFFs) have emerged as a promising approach to enhance the precision in NEMD simulations. This study is aimed at demonstrating the potential of MLFFs in realizing NEMD calculations for large-scale systems containing over 100,000 atoms with density functional theory (DFT)-level accuracy. Specifically, the atomic cluster expansion (ACE) force field is employed, using Si as an example. The ACE potential incorporates 4-body interactions and features a training dataset consisting of 1000 order structures from first-principles molecular dynamics calculations, resulting in a highly accurate vibrational spectrum. Moreover, the ACE potential can reproduce thermal conductivity values comparable with those derived from DFT calculations via the Boltzmann equation. To demonstrate the application of MLFFs to systems containing over 100,000 atoms, NEMD simulations are conducted on thin films ranging from 100 nm to 500 nm, with the 100 nm films exhibiting defect rates of up to 1.5%. The results show that the thermal conductivity deviates by less than 5% from DFT or theoretical results in both scenarios, which highlights the ability of the ACE potential in calculating the thermal conductivity on a large scale with DFT-level accuracy. The proposed approach is expected to promote the application of MLFFs in various fields and serve as a feasible alternative to virtual experiments. Furthermore, this work demonstrates the potential of MLFFs in enhancing the accuracy of NEMD simulations for investigating lattice thermal conductivity for systems with over 100,000 atoms.Comment: 24 pages including with supporting infomatio

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A–geminin–Cdt1 axis therefore represents a critical regulator of proper DNA replication

Characterization of the growth-inhibitory and apoptosis-inducing activities of a triterpene saponin, securioside B against BAC1.2F5 macrophages.

BACKGROUND: Since the growth state of macrophages in local pathological sites is considered a factor that regulates the processes of many disease, such as tumors, inflammation, and atherosclerosis, the substances that regulate macrophage growth or survival may be useful for disease control. We previously reported that securiosides A and B, novel triterpene saponins, exerted macrophage-oriented cytotoxicity in the presence of a L-cell-conditioned medium containing macrophage colony-stimulating factor (M-CSF), while the compounds did not exhibit an effect on macrophages in the absence of the growth-stimulating factors. AIM: This study was undertaken to characterize the growth-inhibitory and the apoptosis-inducing activities of securioside B, focusing on the effects of the macrophage-growth factor(s), and to examine the implication of a mitochondria pathway in apoptosis induction. METHODS: The effect of securioside B on a murine macrophage cell line (BAC1.2F5) was examined by MTT assay and lactose dehydrogenase release assay in the presence of L-cell-conditioned medium, M-CSF, or granulocyte-macrophage CSF (GM-CSF). RESULT: Securioside B inhibited the growth of the cells stimulated by recombinant M-CSF or GM-CSF, but it scarcely induced cytolysis of the cells under the same conditions. Moreover, securioside B did not induce cell death when the compound only was added to the cells. On the other hand, the compound extensively induced apoptotic cell death in the presence of L-cell-conditioned medium, suggesting that apoptosis induction by securioside B requires the additional factor(s) present in L-cell-conditioned medium. Securioside B plus L-cell-conditioned medium induced the activation of caspase-3 and caspase-9, but not caspase-8. In addition, cytochrome c release from the mitochondria into the cytosol, and disrupted mitochondria membrane potential, was also observed in the apoptotic BAC1.2F5 cells. CONCLUSION: These data suggest that securioside B has growth-inhibitory activity against growth factor-stimulated macrophages, and that it induces apoptotic macrophage death through the activation of a mitochondrial pathway in the presence of L-cell-conditioned medium

Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model

An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation