Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, division and survival. Many haematologic malignancies exhibit elevated or ...aberrant mTOR activation, supporting the launch of numerous clinical trials aimed at evaluating the potential of single agent mTOR‐targeted therapies. While promising early clinical data using allosteric mTOR inhibitors (rapamycin and its derivatives, rapalogs) have suggested activity in a subset of haematologic malignancies, these agents have shown limited efficacy in most contexts. Whether the efficacy of these partial mTOR inhibitors might be enhanced by more complete target inhibition is being actively addressed with second generation ATP‐competitive mTOR kinase inhibitors (TOR‐KIs), which have only recently entered clinical trials. However, emerging preclinical data suggest that despite their biochemical advantage over rapalogs, TOR‐KIs may retain a primarily cytostatic response. Rather, combinations of mTOR inhibition with other targeted therapies have demonstrated promising efficacy in several preclinical models. This review investigates the current status of rapalogs and TOR‐KIs in B cell malignancies, with an emphasis on emerging preclinical evidence of synergistic combinations involving mTOR inhibition.
The contribution of participants, employers, and/or the government is one of the most important things in the National Health Insurance Program-Healthy Indonesia Card (JKN-KIS) implementation. All ...Indonesian residents were required to participate in the JKN-KIS program which is divided into four types of participation, one of which is Non-Wage Recipient Participants (PBPU) whose contributions are paid independently. However, based on December 2021 data, 60% of PBPU participants were late in paying monthly until they were in arrears. Arrears in payment of contributions cause several problems, including payment of claims to deficits. This research utilized big data owned by the Healthcare and Social Security Agency (BPJS Kesehatan) and machine learning based on ensemble trees, namely AdaBoost and random forest to get the predictions of participants in arrears. The results showed that machine learning based on an ensemble tree was able to predict PBPU participants in arrears with high accuracy, as evidenced by the AUC values in both models above 80%. The random forest model has an F1-score and the AUC value is better than the AdaBoost, namely the F1-score of 85,43% and the AUC value of 87,20% in predicting JKN-KIS participants who are in arrears in payment of contributions.
•A novel Cequinquevirus PMBT4 was identified from African fermented milk product by electron microscopy and high-throughput sequencing (HTS).•Complete genome sequence of the virus was obtained by ...HTS.•The Cequinquevirus PMBT4 shares the highest NT identity with Lb. delbrueckii group b phage c5.•No KIS gene element was found in the genome of phage PMBT4 despite the presence of observed collar structures on some phages previously suggested to be encoded by these genes.
A novel Lactobacillus delbrueckii bacteriophage PMBT4 was isolated from the Nigerian fermented milk product nono. The phage possesses a long and thin, non-contractile tail and an isometric head, indicating that it belongs to the Siphoviridae family. A neck passage structure (`collar`), previously hypothesized to be encoded by two genes located in the Lactobacillus delbrueckii phage LL-K insertion sequence (KIS) element, as well as in two additional Lb. delbrueckii phages Ld17 and Ld25A, could also be observed on an estimated 1–5% of phage particles by transmission electron microscopy. However, neither mapping of high throughput sequencing data to KIS element genes from Lb. delbrueckii phages LL-K, Ld17 and Ld25A nor PCR amplification of the KIS element genes could corroborate the presence of these genes in the PMBT4 genome. The PMBT4 genome consists of 31,399 bp with a mol% GC content of 41.6 and exhibits high (95–96%) sequence homologies to Lb. delbrueckii phages c5, Ld3, Ld25A and Ld17, which assigned PMBT4 as a new member of this genus, i.e. the Cequinquevirus genus.
This paper examines the rapid increase of prices in the residential sector of Cluj-Napoca in the context of the housing affordability crisis (Wetzstein, 2017). By using insight from the Growth ...Regimes literature, we look at the internal demand as a main driver of rapid price rise. As Kohl and Spielau (2018) argue, the monetary conditions needed for export-led growth regimes are restricting the outputs of the construction sector, creating under-supplied, demand-driven housing markets. We propose three alternative hypotheses regarding the major agent driving the prices within the city as major source of demand: the employees in knowledge-intensive services, the diffuse regional savings of employees in search for some yields, the specialized real estate investors. We use OLS and spatial regression (lag and error) to model the price per square meter using the social composition of the neighbourhoods, the within and out-of-town origin of investors, and the source of money (bank loans vs. cash payment) to demonstrate that the existing crisis is driven by the middle class’s savings that also benefits from gentrification, while speculative investments in the housing markets are rather limited.
This research note discusses the text of How Is Critical Economic Theory Possible, seeking to locate it in the moment of its own creation; against the object of its critique, in Das Kapital itself; ...and to relate it to the moment of the arrival of the Budapest School in Australia and its effects and influence on the emergent journal Thesis Eleven.
UHMK1 is a novel splicing regulatory kinase Arfelli, Vanessa C.; Chang, Yun-Chien; Bagnoli, Johannes W. ...
The Journal of biological chemistry,
04/2023, Volume:
299, Issue:
4
Journal Article
Peer reviewed
Open access
The U2AF Homology Motif Kinase 1 (UHMK1) is the only kinase that contains the U2AF homology motif, a common protein interaction domain among splicing factors. Through this motif, UHMK1 interacts with ...the splicing factors SF1 and SF3B1, known to participate in the 3′ splice site recognition during the early steps of spliceosome assembly. Although UHMK1 phosphorylates these splicing factors in vitro, the involvement of UHMK1 in RNA processing has not previously been demonstrated. Here, we identify novel putative substrates of this kinase and evaluate UHMK1 contribution to overall gene expression and splicing, by integrating global phosphoproteomics, RNA-seq, and bioinformatics approaches. Upon UHMK1 modulation, 163 unique phosphosites were differentially phosphorylated in 117 proteins, of which 106 are novel potential substrates of this kinase. Gene Ontology analysis showed enrichment of terms previously associated with UHMK1 function, such as mRNA splicing, cell cycle, cell division, and microtubule organization. The majority of the annotated RNA-related proteins are components of the spliceosome but are also involved in several steps of gene expression. Comprehensive analysis of splicing showed that UHMK1 affected over 270 alternative splicing events. Moreover, splicing reporter assay further supported UHMK1 function on splicing. Overall, RNA-seq data demonstrated that UHMK1 knockdown had a minor impact on transcript expression and pointed to UHMK1 function in epithelial-mesenchymal transition. Functional assays demonstrated that UHMK1 modulation affects proliferation, colony formation, and migration. Taken together, our data implicate UHMK1 as a splicing regulatory kinase, connecting protein regulation through phosphorylation and gene expression in key cellular processes.
Restenosis limits the durability of all cardiovascular reconstructions. Vascular smooth muscle cell (VSMC) proliferation drives this process, but an intact, functional endothelium is necessary for ...vessel patency. Current strategies to prevent restenosis employ antiproliferative agents that affect both VSMCs and endothelial cells (ECs). Knockdown of the myristoylated alanine-rich C kinase substrate (MARCKS) arrests VSMC proliferation and paradoxically potentiates EC proliferation. MARCKS knockdown decreases expression of the kinase interacting with stathmin (KIS), increasing p27kip1 expression, arresting VSMC proliferation. Here, we seek to determine how MARCKS influences KIS protein expression in these two cell types.
Primary human coronary artery VSMCs and ECs were used for in vitro experiments. MARCKS was depleted by transfection with small interfering RNA. Messenger RNA was quantitated with the real-time reverse transcription polymerase chain reaction. Protein expression was determined by Western blot analysis. Ubiquitination was determined with immunoprecipitation. MARCKS and KIS binding was assessed with co-immunoprecipitation. Intimal hyperplasia was induced in CL57/B6 mice with a femoral artery wire injury. MARCKS was knocked down in vivo by application of 10 μM of small interfering RNA targeting MARCKS suspended in 30% Pluronic F-127 gel. Intimal hyperplasia formation was assessed by measurement of the intimal thickness on cross sections of the injured artery. Re-endothelialization was determined by quantitating the binding of Evans blue dye to the injured artery.
MARCKS knockdown did not affect KIS messenger RNA expression in either cell type. In the presence of cycloheximide, MARCKS knockdown in VSMCs decreased KIS protein stability but had no effect in ECs. The effect of MARCKS knockdown on KIS stability was abrogated by the 26s proteasome inhibitor MG-132. MARCKS binds to KIS in VSMCs but not in ECs. MARCKS knockdown significantly increased the level of ubiquitinated KIS in VSMCs but not in ECs. MARCKS knockdown in vivo resulted in decreased KIS expression. Furthermore, MARCKS knockdown in vivo resulted in decreased 5-ethynyl-2′-deoxyuridine integration and significantly reduced intimal thickening. MARCKS knockdown enhanced endothelial barrier function recovery 4 days after injury.
MARCKS differentially regulates the KIS protein stability in VSMCs and ECs. The difference in stability is due to differential ubiquitination of KIS in these two cell types. The differential interaction of MARCKS and KIS provides a possible explanation for the observed difference in ubiquitination. The effect of MARCKS knockdown on KIS expression persists in vivo, potentiates recovery of the endothelium, and abrogates intimal hyperplasia formation.
Revascularization procedures open narrowed blood vessels but also induce injury, resulting in intimal hyperplasia, the pathologic migration and subsequent proliferation of vascular smooth muscle cells in the intima. Current therapies to prevent intimal hyperplasia inhibit both smooth muscle and endothelial cell proliferation. Knockdown of the myristoylated alanine-rich C kinase substrate (MARCKS) results in arrest of smooth muscle cell but not endothelial cell proliferation. MARCKS protein expression differentially modulates the regulator of cell cycle progression, kinase interacting with stathmin (KIS). This work seeks to identify how MARCKS differentially regulates KIS expression to identify better or synergistic targets to prevent intimal hyperplasia.
PCK is the teachers’ knowledge about teaching particular content in particular ways to enhance student understanding. This requires adequate knowledge of students’ understanding (KSU) and knowledge ...of instructional strategies (KIS) to shape the practice of PCK. This study aims to explore teachers’ PCK on the content of “Matter,” focusing on KSU and KIS. A PCK survey test grounded in seven classroom scenarios followed by open-ended questions was developed by adapting the model of Park et al. (2018) to challenge 31 experienced chemistry teachers from 25 lower secondary schools in Cambodia. A qualitative content analysis was applied to teachers’ responses to generate a rubric categorization for KSU and KIS. Four categories of responses were created: 1) correct response, 2) partially correct response, 3) insufficient response, and 4) no response. Each response described the extent of teachers’ knowledge of students’ understanding and knowledge of instructional strategies. The frequency of each response category was calculated, and any elaboration of typical instructional strategies was highlighted. The results showed that over half of the teachers could define students’ misconceptions. Still, their knowledge of instructional strategies seemed limited due to their typical strategies, mainly following the traditional approach. Teachers preferred two common ways to address remedial students’ misconceptions: 1) telling the scientific concept directly to the students and 2) acknowledging the constructivist approach, such as inquiry with no explanation of inquiry activities on the content to be taught. Therefore, derived from these findings and discussion, providing PCK-based courses during in-service training and analyzing the pre-service subject matter course should be considered for developing PCK.
Public universities are now expected to play a pivotal role in the knowledge economy/society, by being engaged, entrepreneurial and, more importantly, relevant to the wider society in which they ...operate. However, the challenge of complexity (partly arising from the embedded nature of public universities within the higher education, innovation, and other social systems) makes managing a public university remarkably difficult. This article suggests a way forward for creating resilient public universities capable of making the contributions expected of them. The authors recommend that universities position their business as services, embrace open service innovation, and redesign their business model to maximize shared value for society.
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