ジェネリックスキルテストを使用した言語学習能力評価の実行可能性：2018 年度多摩大学共同研究プロジェクト報告

This report explains the preliminary findings of a longitudinal study that uses statistical analyses of PROG scores and TOEIC scores to determine if the PROG might be an indicator of language learning ability. PROG scores for Literacy and Competency from 2018 for a group of university freshmen were correlated with English grades, TOEIC scores and changes in TOEIC scores over time. Additional correlations were calculated for sub-groups such as TOEIC range and gender. The preliminary findings indicate weak correlations between PROG scores and TOEIC scores. Similarly, there are weak to moderate correlations between PROG scores and final grades in English classes. More importantly, the correlation coefficients are statistically significant at less than .05 p value and less than .01 p value. Although more data analysis is necessary, the results indicate that generic skills tests can provide language educators with valuable information for both language course design and student placement into language course levels.本稿では、PROG が言語学習能力の指標であるかどうかを判断するために行ったPROG スコアとTOEIC スコアの統計分析を使用した縦断的研究の予備調査結果を報告する。2018 年の大学の新入生のグループが受験したPROG のリテラシーとコンピテンシーのスコアが、英語の成績、TOEIC スコア、及び時間経過に伴うTOEICスコアの変化と相関しているかを分析した。さらに、TOEIC スコアの分布や性別などの下位グループについても相関関係を調べた。予備調査の結果は、PROG スコアとTOEIC スコアの間に弱い相関があることを示している。同様に、PROG スコアと英語クラスの成績との間には弱から中程度の相関がみられた。より重要なことに、相関係数は .05ｐ値未満および .01ｐ値未満で、統計的に有意である。より多くのデータの分析が必要であるが、本研究は、ジェネリックスキルテストが語学コースの設計とコース受講者のプレースメントに役立ち、語学教育の担当者に貴重な情報を提供できる可能性を示している

Bimodal antagonism of PKA signalling by ARHGAP36

Protein kinase A is a key mediator of cAMP signalling downstream of G-protein-coupled receptors, a signalling pathway conserved in all eukaryotes. cAMP binding to the regulatory subunits (PKAR) relieves their inhibition of the catalytic subunits (PKAC). Here we report that ARHGAP36 combines two distinct inhibitory mechanisms to antagonise PKA signalling. First, it blocks PKAC activity via a pseudosubstrate motif, akin to the mechanism employed by the protein kinase inhibitor proteins. Second, it targets PKAC for rapid ubiquitin-mediated lysosomal degradation, a pathway usually reserved for transmembrane receptors. ARHGAP36 thus dampens the sensitivity of cells to cAMP. We show that PKA inhibition by ARHGAP36 promotes derepression of the Hedgehog signalling pathway, thereby providing a simple rationale for the upregulation of ARHGAP36 in medulloblastoma. Our work reveals a new layer of PKA regulation that may play an important role in development and disease

Kinetic analysis of protein stability reveals age-dependent degradation

Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling and quantitative mass spectrometry to obtain degradation profiles for thousands of proteins. We find that gt;10 of proteins are degraded non-exponentially. Specifically, proteins are less stable in the first few hours of their life and stabilize with age. Degradation profiles are conserved and similar in two cell types. Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts. Within complexes, \NED\} proteins have larger interaction interfaces and assemble earlier than \{ED\} subunits. Amplifying genes encoding \{NED\ proteins increases their initial degradation. Consistently, decay profiles can predict protein level attenuation in aneuploid cells. Together, our data show that non-exponential degradation is common, conserved, and has important consequences for complex formation and regulation of protein abundance

Global quantification of cellular protein degradation kinetics

Es wird allgemein angenommen, dass Proteine exponentiell degradiert werden. Das bedeutet, dass neu synthetisierte als auch alte Proteine mit gleicher Wahrscheinlichkeit degradiert werden. Es tauchen jedoch immer mehr Hinweise dafür auf, dass das nicht immer der Fall sein muss. Um diese Fragestellung systematisch anzugehen, haben wir eine Methode zur metabolischen Pulsmarkierung mit der nichtkanonischen Aminosäure Azidohomoalanine (AHA) entwickelt. AHA ermöglicht die Anreicherung von neu synthetisierten Proteinen direkt nach einem Puls oder nach einer „chase“ (Nachverfolgung) Periode in AHA freiem Medium. Wir kombinierten diese Methode mit SILAC und Shotgun Proteomik um zu quantifizieren wieviel Protein nach verschiedenen chase-Perioden übrig bleibt. Damit konnten wir Degradationsprofile für tausende von Proteinen erstellen. Unsere Daten zeigen, dass mehr als 10 % der Proteine nicht exponentiell degradiert werden (NED). Diese Proteine werden mit fortschreitendem Alter ausschließlich stabiler. Proteasomale Degradation von überschüssigen Proteinkomplexuntereinheiten scheint einen Großteil der NEDs zu erklären. Beim Vergleich zwischen murinen und humanen Zellen stellte sich heraus, dass NED teilweise konserviert ist. Das liegt scheinbar daran, dass diese Zellen trotz unterschiedlichem Ursprungs einheitlich bestimmte Untereinheiten überproduzieren. Da überschüssige NED Proteine bereits unter Standardbedingungen degradiert werden, nahmen wir an, dass die zusätzliche Überproduktion eines NED Proteins seine Level im stationären Zustand nicht verändern sollte. Um dies zu zeigen, quantifizierten wir Degradationskinetiken von Proteinen einer aneuploidenZelllinie. Wir fanden, dass NED Proteine, die auf trisomischen Chromosomen codiert sind, nicht in gleichem Maße ihr stationäres Level steigerten wie exponentiell degradierte Proteine. In Übereinstimmung mit unserer Hypothese verzeichneten wir stattdessen eine Zunahme der anfänglichen Degradationsraten dieser NED Proteine.Proteins are thought to be degraded exponentially. That means that newly synthesized proteins have the same probability to be degraded as old proteins. However, evidence has accumulated showing that this is not true in all cases. To analyze this more systematically, we developed a method employing metabolic pulse-labeling by the non-canonical amino acid azidohomoalanine (AHA). AHA enables enrichment of newly synthesized proteins directly after pulse or after chase in AHA-free medium. We used SILAC and shotgun proteomics to quantify how much protein remains after different lengths of chase to create degradation profiles for thousands of proteins. Importantly, these degradation profiles allowed us to detect changes in degradation kinetics as the proteins age. We found that more than 10 % of proteins are non-exponentially degraded (NED). These protein are exclusively stabilized by age. Proteasomal degradation of excess protein complex subunits seems to explain a large fraction of NED. Comparing NED in mouse and human cells, we found that NED is at least partially conserved, seemingly due to cells consistently making too much of certain subunits. These overproduced subunits are on average shorter and more structured than the exponentially degraded proteins within the same complex. Finally, since excess NED proteins are degraded during baseline conditions, we hypothesized that making more of a NED protein would not increase its steady state levels. We employed an aneuploidy cell model and found that indeed NED proteins encoded on trisomic chromosomes did not increase in steady state levels to the same extent as exponentially degraded proteins. Instead, we recorded an increase in initial degradation of these proteins. In summary, we present a method for global pule-chase experiments allowing the detection of age-dependent protein degradation with possible implications for the understanding of aneuploidy and cancer

VLSI technology for efficient and dynamic power management, delivery, and utilization.

VLSI technology for efficient and dynamic power management, delivery, and utilization

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes

Background: Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome. Results: We resolve features of mitochondrial translation initiation and identify a small ORF in the 3' UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways. Conclusions: Based on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability