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Asymmetric cell division in Saccharomyces cerevisiae involves class V myosin-dependent transport of organelles along the polarised actin cytoskeleton to the emerging bud. Vac17 is the vacuole/lysosome-specific myosin receptor. Its timely breakdown terminates transport and results in the proper positioning of vacuoles in the bud. Vac17 breakdown is controlled by the budconcentrated p21-activated kinase Cla4, and the E3-ubiquitin ligase Dma1. We found that the spindle position checkpoint kinase Kin4 and, to a lesser extent, its paralog Frk1 contribute to successful vacuole transport by preventing the premature breakdown of Vac17 by Cla4 and Dma1. Furthermore, Kin4 and Cla4 contribute to the regulation of peroxisome transport. We conclude that Kin4 antagonises the Cla4/Dma1 pathway to coordinate spatiotemporal regulation of organelle transport. [ABSTRACT FROM AUTHOR]

The health budget over the past five years has experienced a significant increase in 2020, a budget of 119.9 trillion (T) increased to 124.4 trillion (T) in 2021, 134.8 trillion (T) in 2022, and 172.5 trillion (T) in 2023. In 2024, this budget is projected at 186.4 trillion (T), or 5.6% of the state budget. This budget increased by 8.1% or 13.9 trillion compared to 2023. Of the total state budget for the Ministry of Health of 186.4 trillion, it is projected that the distribution will flow to Rp2,537,921,988,000.00 for Vertical Hospitals (RS) and Rp2,021,730,483,000.00 for Regional General Hospitals. The purpose of this research is to see how much potential this business has for the Jakarta and Banten areas. This method uses a working framework for this business plan, which consists of marketing objectives, marketing strategy, mix management, sales volume and company revenue plan. The results of this study are goals and objectives in the pende, long-term and long-term which are the benchmarks for the study in achieving the targets in each division. The conclusion of this study explains how the company achieves the predetermined targets by using methods in marketing planning by using the maximum number of sales and budget. This research explains that the method or way of achieving the company's target needs continuity between each division. [ABSTRACT FROM AUTHOR]

Industry service health in Indonesia is very important important during life in the world still There is so service health still very much needed. This year budget Health in Indonesia has greatly improved. matter This chance big for business company big pharmaceuticals and tools health for supplying the needs of the house hospital Deni Erlangga, Tantri Rahmat Syah, Edi Hamdi, Dihin Septyantos, clinics and non-health institutions. The role of the company big pharmaceuticals and tools health this is very important to use meet the existing needs of each agency health. This research done for know how much big opportunity business This especially in Banten province and DKI Jakarta Province by using human resources in accordance with company characteristics. Research methods This use method qualitative by using technique studies literature and interviews and documentation. results from study This showing that for reach a specified target company must have human resources who have good abilities and analysis, p This For guard connection good with suppliers. role peting from a sales and marketing person is very supportive from sale. Conclusion on research This In order to achieve the company's targets, PT JPA strives increase quality from every employee. with the number such a budget big from government naturally This becomes very big opportunity for company, of course company must prepare talents employees who have capabilities in every field position work. No only PT JPA will to try increase abilities of each employee through training that will be given to every employee and of course level interesting career for employees, p This to provide positive motivation for employee for always increase performance his. [ABSTRACT FROM AUTHOR]

Mitochondria are organelles involved in cellular energetics in all eukaryotes, and changes in their dynamics, fission, fusion, or localization can lead to cell defects and disease in humans. Budding yeast, Saccharomyces cerevisiae, has been shown to be an effective model organism in elucidating mechanisms underpinning these mitochondrial processes. In the work presented here, a genetic screen was performed to identify overexpressing kinases, phosphatases, and ubiquitin ligases, which resulted in mitochondrial defects. A total of 33 overexpressed genes showed mitochondrial phenotypes but without severe growth defects. These included a subset that affected the timing of mitochondrial inheritance and were the focus of further study. Using cell and biochemical approaches, the roles of the PAK-family kinase Cla4 and the E3-ubiquitin ligases Dma1 and Dma2 were investigated. Previous studies have indicated the roles of kinase Cla4 and ligases Dma1 and Dma2 in triggering the degradation of trafficking adaptors in the bud, which leads to disruption of the interaction with the transporting class V myosin, Myo2. Here, we map a key interface between Cla4 and the mitochondrial adaptor Mmr1 necessary for phosphorylation and identify a region of Mmr1 required for its degradation via Dma1 and Dma2. Together, our data provide insights into key regulatory regions of Mmr1 responsible for its function in mitochondrial inheritance. [ABSTRACT FROM AUTHOR]

In the field of theology education, there is a strong desire to understand theology in-depth. Understanding what theology is becomes a primary need, in addition to other knowledge that supports it. Many theologians have produced theological books to answer the need for understanding theology, such as liberal theology. This article aims to discuss the question of liberal theology in relation to Christian Religious Education (CRE) for Christian students. The question is, what motivates the emergence of liberal theology, which emphasizes reason and logic over the Bible as the primary source of Christian theology. Is there any support for liberal theology, and how is it related to Christian Religious Education, especially for teachers and students? This question will be analyzed through the traditional church doctrine, as evidenced in the Bible, connected with contemporary theology. The method used to solve this problem is qualitative research, which collects data from books or journals. Through research and discussion, the author aims to offer a new perspective for the teaching of Christian Religious Education (CRE), providing a strong foundation based on the Bible, which is the primary source of Christian education. The article emphasizes that the Bible is the commandment of God and not based on reason. At the end of the article, there is a conclusion. [ABSTRACT FROM AUTHOR]

Learning outcomes are components that assess the success of the teaching and learning process, so Sociology teachers must apply effective, dynamic and creative learning models. To determine the success of learning outcomes, an evaluation of student learning outcomes is carried out in the form of an assessment. The monotonous learning method on the teacher will reduce students' motivation in following the learning process. The Jigsaw learning model is an effective and dynamic type of learning, so it can improve student learning outcomes, because students are motivated to learn. This study aims to determine whether the application of the Jigsaw learning model can improve sociology learning outcomes about social relationships in class V at SD Negeri 071172 Fabaliwa. This study uses the CAR design (Collaborative Classroom Action Research) with a sample size of 36 respondents. The results of the study found an increase in learning outcomes. This shows that the Jigsaw learning model can improve student learning outcomes which are indicated by a significant value, namely from cycle I to cycle II by 19%. The Jigsaw type cooperative learning model in an effort to understand the social relationship material in class V at SD Negeri 071172 Fabaliwa was successful, so the sociology subject teacher in presenting the social relationship material using the Jigsaw type cooperative learning model very attracted students' interest. [ABSTRACT FROM AUTHOR]

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Christian religious education in schools basically aims to instill Christian values in the social and personal lives of students so that they grow to know the triune God and his work. Christian education implemented in schools has clear objectives. The PAK era is not a current struggle but is taking place in the Christian direction. Where there is a crhistian community, there is a process of struggle, a very important factor in achieving the success of Christian education in schools is the Christian Religious Education teacher. Therefore, a Christian Religious Education teacher in fulfilling his calling must continue to equip himself so that he becomes a useful tool in the hands of God. The phenomenon that occurs at SD inpres 54 Nania is that there are students who commit moral violants “taking other people’s things that do not belong to them”. Therefore, Christian Religious Education Teachers are looking for strategies in teaching PAK to revitalize students morals. Description using a qualitive approach. The data analysis technique used is data triangulation with data collection techniques, namely interviews, field observations and documentation. The results of the research show that strategy developed by PAK teachers is to revitalize the morals of Christian students by strenghthening their faith in the truth in Christ by instilling noble Christian values and the work of God. Teachers are also a factor in playing their role as figures who can be emulated and can have a positive impact on Christian student. Christian Religious Education Teachers take a personal approach when Christian students experience problems, both learning difficulties and moral violations, both in the learning process and outside the learning process. [ABSTRACT FROM AUTHOR]

Abstract Background Actinic keratosis (AK), or solar keratosis, is a precancerous condition of the skin, mainly caused by excessive and chronic exposure to ultraviolet radiation. Pigmented AK (pAK) is a rare variant of AK. Photodynamic therapy (PDT) is widely used to treat the classical variant of AK, but very limited data are available on the use of PDT in patients with pAK. The objective of this study was to assess the usefulness of PDT in the treatment of pAK. Methods The study included 16 patients with 20 pAK lesions treated with PDT. All skin lesions were clinically and dermatoscopically assessed for typical features characteristic of pAK. Reflectance confocal microscopy (RCM) was also used to assess keratinocyte atypia, confirm pAK diagnosis, and rule out other disease entities. Results After three PDT sessions, the complete resolution of all clinical features of pAK was observed in 80% of the studied lesions. Dermatoscopically, 65% of the lesions achieved 100% response and no cellular atypia was seen in the follow-up RCM images of 85% of lesions. Conclusions Photodynamic therapy is an effective treatment modality for pAK in fair-skinned individuals.

Background: Actinic keratosis (AK), or solar keratosis, is a precancerous condition of the skin, mainly caused by excessive and chronic exposure to ultraviolet radiation. Pigmented AK (pAK) is a rare variant of AK. Photodynamic therapy (PDT) is widely used to treat the classical variant of AK, but very limited data are available on the use of PDT in patients with pAK. The objective of this study was to assess the usefulness of PDT in the treatment of pAK. Methods: The study included 16 patients with 20 pAK lesions treated with PDT. All skin lesions were clinically and dermatoscopically assessed for typical features characteristic of pAK. Reflectance confocal microscopy (RCM) was also used to assess keratinocyte atypia, confirm pAK diagnosis, and rule out other disease entities. Results: After three PDT sessions, the complete resolution of all clinical features of pAK was observed in 80% of the studied lesions. Dermatoscopically, 65% of the lesions achieved 100% response and no cellular atypia was seen in the follow-up RCM images of 85% of lesions. Conclusions: Photodynamic therapy is an effective treatment modality for pAK in fair-skinned individuals. [ABSTRACT FROM AUTHOR]

Myoblast differentiation is essential for the formation of skeletal muscle myofibers. Profilin1 (Pfn1) has been identified as an actin-associated protein, and has been shown to be critically important to cellular function. Our previous study found that PFN1 may inhibit the differentiation of bovine skeletal muscle satellite cells, but the underlying mechanism is not known. Here, we confirmed that PFN1 negatively regulated the myogenic differentiation of bovine skeletal muscle satellite cells. Immunoprecipitation assay combined with mass spectrometry showed that Cdc42 was a binding protein of PFN1. Cdc42 could be activated by PFN1 and could inhibit the myogenic differentiation like PFN1. Mechanistically, activated Cdc42 increased the phosphorylation level of p2l-activated kinase (PAK), which further activated the phosphorylation activity of c-Jun N-terminal kinase (JNK), whereas PAK and JNK are inhibitors of myogenic differentiation. Taken together, our results reveal that PFN1 is a repressor of bovine myogenic differentiation, and provide the regulatory mechanism. [ABSTRACT FROM AUTHOR]

The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Using available information and communication technology, Christian Religious Education learning can be implemented using a blended learning model, which means a combination of conventional face-to-face learning and online learning. This study aims to design a blended learning model for learning Christian Religious Education. Qualitative-descriptive approach is used to convey the advantages of the blended learning model which is applied in various schools in the region and abroad. The results of the studies show that the blended learning model shows various advantages when applied in various exact and social subjects, both for basic education, higher education and vocational education. In this paper, a suggestion for the design of a blended learning model for Christian Religious Education is presented. [ABSTRACT FROM AUTHOR]

Juvenile delinquency is an activity or act that violates the norms, provisions, and legal regulations. Usually done by teenagers who are still in school or not in school. Many things behind this juvenile delinquency are coupled with the opportunity and lack of love and attention from the family. The Christian Religious Education Strategy is one of the lessons taught in the world of education. The role of Christian Religious Education teaches about the true basis of faith to know the Lord Jesus and so that humans can understand and believe in Christianity itself. Thus, Christian learning and knowledge can be understood and carried out well within oneself, family, youth, and the wider community. The concepts contained in Christian Religious Education can also relate to cultural concepts that exist in society. Therefore, every teacher of Christian Religious Education must really understand and understand the strategy of the material to be taught so as not to be wrong in delivering the lesson. So Christian Religious Education based on 2 Corinthians 4:1-6 can minimize and overcome juvenile delinquency in this millennial era. [ABSTRACT FROM AUTHOR]

P21-activated kinases (PAK) regulate processes associated with cytoskeleton dynamics. PAK expression in leukemia cells was measured on protein and mRNA levels. In functional assays, we analyzed the effect of PAK inhibitors IPA-3 and FRAX597 on cell adhesivity and viability. PAK2 was dominant in cell lines, whereas primary cells also expressed comparable amount of PAK1 transcription isoforms: PAK1-full and PAK1Δ15. PAK1Δ15 and PAK2 levels correlated with surface density of integrins β1 and αVβ3. PAK1-full, but not PAK2, was present in membrane protrusions. IPA-3, which prevents PAK activation, induced cell contraction in semi-adherent HEL cells only. FRAX597, which inhibits PAK kinase activity, increased cell-surface contact area in all leukemia cells. Both inhibitors reduced the stability of cell attachment and induced cell death.

Finite element method (FEM) has proved to be very successful in solving complex problems in engineering. In medicine, FEM found a special application in simulation of real problems and their solution while eliminating the need of learning from examples. In this paper, FEM was used with viscous fluid dynamics to simulate the function of left heart ventricle. Theoretical fundamentals of FEM and heart function were given. The paper represents illustrative example for educational purposes.

Small GTPases are the key to actin cytoskeleton signaling, which opens the lock of effector proteins to forward the signal downstream in several cellular pathways. Actin cytoskeleton assembly is associated with cell polarity, adhesion, movement and other functions in eukaryotic cells. Rho proteins, specifically Cdc42 and Rac, are the primary regulators of actin cytoskeleton dynamics in higher and lower eukaryotes. Effector proteins, present in an inactive state gets activated after binding to the GTP bound Cdc42/Rac to relay a signal downstream. Cdc42/Rac interactive binding (CRIB) motif is an essential conserved sequence found in effector proteins to interact with Cdc42 or Rac. A diverse range of Cdc42/Rac and their effector proteins have evolved from lower to higher eukaryotes. The present study has identified and further classified CRIB containing effector proteins in lower eukaryotes, focusing on parasitic protozoans causing neglected tropical diseases and taking human proteins as a reference point to the highest evolved organism in the evolutionary trait. Lower eukaryotes' CRIB containing proteins fall into conventional effector molecules, PAKs (p21 activated kinase), Wiskoit-Aldrich Syndrome proteins family, and some have unique domain combinations unlike any known proteins. We also highlight the correlation between the effector protein isoforms and their selective specificity for Cdc42 or Rac proteins during evolution. Here, we report CRIB containing effector proteins; ten in Dictyostelium and Entamoeba , fourteen in Acanthamoeba , one in Trypanosoma and Giardia. CRIB containing effector proteins that have been studied so far in humans are potential candidates for drug targets in cancer, neurological disorders, and others. Conventional CRIB containing proteins from protozoan parasites remain largely elusive and our data provides their identification and classification for further in-depth functional validations. The tropical diseases caused by protozoan parasites lack combinatorial drug targets as effective paradigms. Targeting signaling mechanisms operative in these pathogens can provide greater molecules in combatting their infections. [ABSTRACT FROM AUTHOR]

Small GTPases are the key to actin cytoskeleton signaling, which opens the lock of effector proteins to forward the signal downstream in several cellular pathways. Actin cytoskeleton assembly is associated with cell polarity, adhesion, movement and other functions in eukaryotic cells. Rho proteins, specifically Cdc42 and Rac, are the primary regulators of actin cytoskeleton dynamics in higher and lower eukaryotes. Effector proteins, present in an inactive state gets activated after binding to the GTP bound Cdc42/Rac to relay a signal downstream. Cdc42/Rac interactive binding (CRIB) motif is an essential conserved sequence found in effector proteins to interact with Cdc42 or Rac. A diverse range of Cdc42/Rac and their effector proteins have evolved from lower to higher eukaryotes. The present study has identified and further classified CRIB containing effector proteins in lower eukaryotes, focusing on parasitic protozoans causing neglected tropical diseases and taking human proteins as a reference point to the highest evolved organism in the evolutionary trait. Lower eukaryotes’ CRIB containing proteins fall into conventional effector molecules, PAKs (p21 activated kinase), Wiskoit-Aldrich Syndrome proteins family, and some have unique domain combinations unlike any known proteins. We also highlight the correlation between the effector protein isoforms and their selective specificity for Cdc42 or Rac proteins during evolution. Here, we report CRIB containing effector proteins; ten in Dictyostelium and Entamoeba, fourteen in Acanthamoeba, one in Trypanosoma and Giardia. CRIB containing effector proteins that have been studied so far in humans are potential candidates for drug targets in cancer, neurological disorders, and others. Conventional CRIB containing proteins from protozoan parasites remain largely elusive and our data provides their identification and classification for further in-depth functional validations. The tropical diseases caused by protozoan parasites lack combinatorial drug targets as effective paradigms. Targeting signaling mechanisms operative in these pathogens can provide greater molecules in combatting their infections.

Myoblast differentiation is essential for the formation of skeletal muscle myofibers. Profilin1 (Pfn1) has been identified as an actin-associated protein, and has been shown to be critically important to cellular function. Our previous study found that PFN1 may inhibit the differentiation of bovine skeletal muscle satellite cells, but the underlying mechanism is not known. Here, we confirmed that PFN1 negatively regulated the myogenic differentiation of bovine skeletal muscle satellite cells. Immunoprecipitation assay combined with mass spectrometry showed that Cdc42 was a binding protein of PFN1. Cdc42 could be activated by PFN1 and could inhibit the myogenic differentiation like PFN1. Mechanistically, activated Cdc42 increased the phosphorylation level of p2l-activated kinase (PAK), which further activated the phosphorylation activity of c-Jun N-terminal kinase (JNK), whereas PAK and JNK are inhibitors of myogenic differentiation. Taken together, our results reveal that PFN1 is a repressor of bovine myogenic differentiation, and provide the regulatory mechanism.

Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recent genomic analyses revealed that 4-9% of sun-exposed melanomas bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signalling from RAC1P29S, we here extend this analysis to examine the roles of PI3Ks and SRF/MRTF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036), a pan-PI3K (BKM120), and two PI3Kβ inhibitors (TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not by mutant BRAF, while other PI3K selective inhibitors, including PI3Kα, δ and γ, are less effective. Using these compounds as well as an SRF/MRTF inhibitor (CCG-203,971), we observed similar results in vivo, using embryonic zebrafish development as a readout. These results suggest that targeting Group A PAKs, PI3Kβ, and/or SRF/MRTF represent a promising approach to suppress RAC1 signalling in malignant melanoma. [ABSTRACT FROM AUTHOR]

Endothelial functions are highly regulated by imposed shear stress in vivo. The characteristics of shear stress determine mechanotransduction events that regulate phenotypic outcomes including redox and inflammatory states. Recent data indicate that microRNAs (miRs) in vascular endothelial cells play an essential role in shear stress-regulated endothelial responses. More specifically, atheroprotective pulsatile flow (PS) induces miRs that inhibit mediators of oxidative stress and inflammation while promoting those involved in maintaining vascular homeostasis. Conversely, oscillatory flow (OS) elicits the opposing networks. This is exemplified by the PS-responsive transcription factor Krüppel-like factor 2 (KLF2), which regulates miR expression but is also regulated by OS-sensitive miRs to ultimately regulate the oxidative and inflammatory state of the endothelium. In this review, we outline important findings demonstrating the multifaceted roles of shear stress-regulated miRs in endothelial redox and inflammatory balance. Furthermore, we discuss the use of algorithms in deciphering signaling networks differentially regulated by PS and OS.

The interplay between nutrient scarcity and signal transduction circuits is an important aspect of tumorigenesis that regulates many aspects of cancer progression. Glutamine is a critical nutrient for cancer cells, as it contributes to biosynthetic reactions that sustain cancer proliferation and growth. In tumors, because nutrient utilization can often outpace supply, glutamine levels can become limiting and oncogene-mediated metabolic rewiring triggers signaling cascades that support nutrient stress survival. Recently, we identified that in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine depletion can trigger p21-activated kinase (Pak) activation through EGFR signaling as a means to circumvent metabolic stress. Here, we elucidate that glutamine starvation, as well EGF stimulation, can enhance the presence of many different Pak phosphoforms, and that this activation only occurs in a subset of PDAC cells. Pak is a well-established effector of Rac1, and while Rac1 mutant variants can modulate the metabolic induction of Pak phosphorylation, Rac1 inhibition only partially attenuates Pak activation upon glutamine depletion. We decipher that in order to efficiently suppress metabolic activation of Pak, both EGFR and Rac1 signaling must be inhibited. These results provide a mechanistic understanding of how glutamine-regulated signal transduction can control Pak activation in PDAC cells. • Pak phosphorylation is widely regulated by glutamine depletion and EGFR. • Rac1 mutant variants modulate metabolic activation of Pak. • Glutamine depletion-induced Pak phosphorylation is controlled cooperatively by EGFR and Rac1. [ABSTRACT FROM AUTHOR]

Washington and New Delhi have converged interests in Afghanistan. US aspires a greater Indian role in Afghanistan in the wake of its withdrawal from Afghanistan and India, in order to pose itself an international power, seeks in Afghanistan a deeper involvement. Although both of the states, India and the US, have devised a commonality of interests since 9/11, yet since the current US Administration bilateral ties have been intensified to the extent where Pakistan have severe implications. US President Trump's verdict of regionalization of Afghan issue has implied concerns for Islamabad. Pakistani authorities relate the terrorist activities in the country, particularly insurgency in Baluchistan with the role of various powers' role in Afghanistan. Strategic and security related objectives and concerns would be discussed in this article. [ABSTRACT FROM AUTHOR]

Although selective pruning of subsets of branches is a key step for axonal remodeling, the underlying mechanisms have not fully elucidated. We have reported that the retraction rate of axonal arbor is higher in the terminals, where less kinesin is sorted, and inhibiting actin turnover by treatment with latrunculin A prevented retraction in such terminals. In the present study, we investigated the effects of pharmacological inhibitors for the regulators of actin polymerization/destabilization on the elongation and retraction of arbor terminals in cerebellar granule neurons. Inhibition of an actin nucleator Arp2/3 with CK-666 or CK-869 inhibited the retraction of arbor terminals. However, inhibitors for PAK/LIMK, upstream signaling of ADF/cofilin, reduced the elongation rate but not the retraction rate. A photoconversion analysis revealed that turnover of F-actin at the tip of the axonal terminal is faster in the presence of the Arp2/3 inhibitor compared with the control and neurons treated with the LIMK inhibitor. Our results indicate the important role of Arp2/3 for the retraction of axonal arbor terminals in cerebellar granule neurons. [ABSTRACT FROM AUTHOR]

Background/Aims: Astragaloside (AGS) extracted from radix astragalin (Huangqi) has been considered to be beneficial to liver diseases. In this study, we examined the role played by AGS in alleviating hepatic fibrosis function via protease-activated receptor-2 (PAR2) mechanisms. We hypothesized that AGS affects PAR2 signaling pathway thereby improving hepatic function in rats with hepatic fibrosis induced by carbon tetrachloride (CCl4). We further hypothesized that AGS attenuates impaired hepatic function evoked by CCl4 to a greater degree in diabetic animals. Methods: ELISA and Western Blot analysis were used to examine PAR2 signaling pathway in diabetic CCl4-rats and non-diabetic CCl4-rats. Results: AGS inhibited the protein expression of PAR2 and its downstream pathway PKA and PKCɛ in CCl4-rats. Notably, the effects of AGS were greater in CCl4-rats with diabetes. AGS also significantly attenuated the CCl4-induced upregulations of pro-inflammatory cytokines, namely interleukin-1β, interleukin-6 and tumor necrosis factor-α accompanied with decreases of collagenic parameters such as hexadecenoic acid, laminin and hydroxyproline. Additionally, AGS improved the CCl4-induced exaggerations of liver index and functions including alanine aminotransferase, aspartate aminotransferase. Moreover, TGF-β1, a marker of hepatic fibrosis, was increased in CCl4-rats and AGS inhibited increases in TGF-β1 induced by CCl4. Conclusions: AGS alleviates hepatic fibrosis by inhibiting PAR2 signaling expression and its effects are largely enhanced in diabetic animals. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of hepatic fibrosis; and results of our study are likely to shed light on strategies for application of AGS because it has potentially greater therapeutic effectiveness for hepatic fibrosis in diabetes.

Cancer cells are affected by a wide range of mechanical forces within their extracellular environment. It has been widely shown that these forces can lead to increased metastatic activity of these cells. One such force is a transient tugging-like force that results from contractile forces generated by cells within the tumor microenvironment. When this force is simulated in vitro with a mechano-invasion assay, human fibrosarcoma cells exhibit enhanced cell invasion in a 3D collagen-fibronectin matrix by downregulating the expression of integrin β3. Furthermore, this force stimulates the maturation of invadopodia in an integrin β3-dependent manner that includes an increase in the active form of cofilin and MMP-2 secretion. In the present study we discovered that the decrease in integrin β3 signaling in response to mechanical stimulation is coupled to the activity of p21-activated kinase 1 (PAK1). It was found that PAK1 has decreased activity, as detected by a decrease in Ser144 phosphorylation, with mechanical stimulation. However, this loss in phosphorylation can be reversed if integrin β3 is overexpressed. Furthermore, PAK1 mutants show a correlated response in MMP-2 enzyme expression and activity, in addition to the lengthening of invadopodia, in response to stimulation. These results identify a novel mechano-sensitive response in human fibrosarcoma that utilizes PAK1 as a signaling player positioned downstream of integrin β3.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro-survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT-9274 and KPT-9307) inhibit PDAC cell proliferation through downregulation of Bad phosphorylation and upregulation of tumor suppressive miRNAs (miR-145, let-7c, let-7d, miR-34c, miR320 and miR-100). These results suggest that targeting PAK4 could become a promising approach to restore pro-apoptotic function of Bad and simultaneously activate tumor suppressive miRNAs in therapy resistant PDAC. [ABSTRACT FROM AUTHOR]

PAK1 and PAK4 are members of the p-21 activated kinase family of serine/threonine kinases. PAK1 has previously been implicated in both the formation and disassembly of invasive cell protrusions, termed invadopodia. We recently reported a novel role for PAK4 during invadopodia maturation and confirmed a specific role for PAK1 in invadopodia formation; findings we will review here. Moreover, we found that PAK4 induction of maturation is delivered via interaction with the RhoA regulator PDZ-RhoGEF. We can now reveal that loss of PAK4 expression leads to changes in invadopodia dynamics. Ultimately we propose that PAK4 but not PAK1 is a key mediator of RhoA activity and provide further evidence that modulation of PAK4 expression levels leads to changes in RhoA activity. [ABSTRACT FROM AUTHOR]

Cell polarity is fundamental to the function of most cells. The evolutionarily conserved molecular machinery that controls cell polarity is centered on a family of GTPases related to Cdc42. Cdc42 becomes activated and concentrated at polarity sites, but studies in yeast model systems led to controversy on the mechanisms of polarization. Here we review recent studies that have clarified how Cdc42 becomes polarized in yeast. On one hand, findings that appeared to support a key role for the actin cytoskeleton and vesicle traffic in polarity establishment now appear to reflect the action of stress response pathways induced by cytoskeletal perturbations. On the other hand, new findings strongly support hypotheses on the polarization mechanism whose origins date back to the mathematician Alan Turing. The key features of the polarity establishment mechanism in yeasts include a positive feedback pathway in which active Cdc42 recruits a Cdc42 activator to polarity sites, and differential mobility of polarity "activators" and "substrates." [ABSTRACT FROM AUTHOR]

This paper presents a method for implicit stress integration of the Drucker-Prager material model with kinematic hardening. The stress integration of the material model is conducted using the incremental plasticity method, while the kinematic hardening of material is defined using nonlinear Armstrong-Frederick hardening. This type of granular material hardening occurs as a consequence of the cyclic loading effects, such as the seismic load. For this reason, this material model is used for the earthquake analysis in the soil mechanics. Yield surface of the material model changes its position under the cyclic loads in the stress space, whereas there is no change in the size of the yield surface in deviatoric plane. The developed algorithm of the material model has been implemented in the software package PAK. [Projekat Ministarstva nauke Republike Srbije, br. TR37013 i br. TR32036]

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p27Kip1 (p27) is a cyclin-CDK inhibitor and negative regulator of cell proliferation. p27 also controls other cellular processes including migration and cytoplasmic p27 can act as an oncogene. Furthermore, cytoplasmic p27 promotes invasion and metastasis, in part by promoting epithelial to mesenchymal transition. Herein, we find that p27 promotes cell invasion by binding to and regulating the activity of Cortactin, a critical regulator of invadopodia formation. p27 localizes to invadopodia and limits their number and activity. p27 promotes the interaction of Cortactin with PAK1. In turn, PAK1 promotes invadopodia turnover by phosphorylating Cortactin, and expression of Cortactin mutants for PAK-targeted sites abolishes p27’s effect on invadopodia dynamics. Thus, in absence of p27, cells exhibit increased invadopodia stability due to impaired PAK1-Cortactin interaction, but their invasive capacity is reduced compared to wild-type cells. Overall, we find that p27 directly promotes cell invasion by facilitating invadopodia turnover via the Rac1/PAK1/Cortactin pathway.

Filamin is a scaffolding protein that functions in many cells as an actin-crosslinker. FLN90, an isoform of the Drosophila ortholog Filamin/cheerio that lacks the actin-binding domain, is here shown to govern the growth of postsynaptic membrane folds and the composition of glutamate receptor clusters at the larval neuromuscular junction. Genetic and biochemical analyses revealed that FLN90 is present surrounding synaptic boutons. FLN90 is required in the muscle for localization of the kinase dPak and, downstream of dPak, for localization of the GTPase Ral and the exocyst complex to this region. Consequently, Filamin is needed for growth of the subsynaptic reticulum. In addition, in the absence of filamin, type-A glutamate receptor subunits are lacking at the postsynapse, while type-B subunits cluster correctly. Receptor composition is dependent on dPak, but independent of the Ral pathway. Thus two major aspects of synapse formation, morphological plasticity and subtype-specific receptor clustering, require postsynaptic Filamin.