Extrinsic Regulation Research Articles

RasGRF1 mediates brain-derived neurotrophic factor-induced axonal growth in primary cultured cortical neurons

The appropriate development and regulation of neuronal morphology are important to establish functional neuronal circuits and enable higher brain function of the central nervous system. R-Ras, a member of the Ras family of small GTPases, plays crucial roles in the regulation of axonal morphology, including outgrowth, branching, and guidance. GTP-bound activated R-Ras reorganizes actin filaments and microtubules through interactions with its downstream effectors, leading to the precise control of axonal morphology. However, little is known about the upstream regulatory mechanisms for R-Ras activation in neurons. In this study, we found that brain-derived neurotrophic factor (BDNF) has a positive effect on endogenous R-Ras activation and promotes R-Ras-mediated axonal growth. RNA interference knockdown and overexpression experiments revealed that RasGRF1, a guanine nucleotide exchange factor (GEF) for R-Ras, is involved in BDNF-induced R-Ras activation and the promotion of axonal growth. Phosphorylation of RasGRF1 by protein kinase A at Ser916/898 is needed for the full activation of its GEF activity and to facilitate Ras signaling. We observed that BDNF treatment markedly increased this phosphorylation. Our results suggest that BDNF is one of the critical extrinsic regulators for R-Ras activation, and that RasGRF1 is an intrinsic key mediator for BDNF-induced R-Ras activation and R-Ras-mediated axonal morphological regulation.

Motivation, Cognitive and Resource Management Skills: Association of Self-Regulated Learning Domains with Gender, Clinical Transition and Academic Performance of Undergraduate Medical Students

Studies have associated self-regulated learning with better medical academic performance. However, limited data depicts inter-gender variabilities and differences between pre-clinical students and those undergoing clinical transition. Our study aims to bridge this gap. In this comparative cross-sectional study, Motivated Strategies for Learning Questionnaire was administered to 550 undergraduate students of Army Medical College. Three hundred thirty-nine of 550 students responded. Reliability analysis was performed (Cronbach's α = 0.936). Extrinsic motivation was higher than intrinsic. Use of cognitive, metacognitive, and resource management skills was modest. Academic performance was weakly but significantly correlated with intrinsic goal orientation (p = 0.031), extrinsic goal orientation (p = 0.003), elaboration (p = 0.001), time/study environment (p = 0.009), and effort regulation (p = 0.009). Extrinsic goal orientation mean score was significantly lower (p < 0.001) for third year students when compared with that of pre-clinical students. Females had higher task-value scores (p = 0.009) while males had higher self-efficacy (p = 0.002) and critical thinking (p = 0.012) scores. Study concludes that academic performance and self-regulated learning domains are weakly but significantly correlated. Students undergoing clinical transition have lower extrinsic motivation. Inter-gender variabilities exist in task-value, critical thinking, and self-efficacy domains. This study opens up new vistas for educationists who should revise curricula, academic reward systems, and pedagogy forms. Interventional studies should be designed to bring improvements in self-regulated learning domains.

Panax notoginseng Saponins Protect Cerebral Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Reperfusion-Induced Barrier Dysfunction via Activation of PI3K/Akt/Nrf2 Antioxidant Signaling Pathway.

Oxidative stress plays a critical role in cerebral ischemia/reperfusion (I/R)-induced blood-brain barrier (BBB) disruption. Panax notoginseng saponins (PNS) possess efficient antioxidant activity and have been used in the treatment of cerebral ischemic stroke in China. In this study, we determined the protective effects of PNS on BBB integrity and investigated the underlying mechanism in cerebral microvascular endothelial cells (bEnd.3) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). MTT and LDH release assays revealed that PNS mitigated the OGD/R-induced cell injury in a dose-dependent manner. TEER and paracellular permeability assays demonstrated that PNS alleviated the OGD/R-caused disruption of BBB integrity. Fluorescence probe DCFH-DA showed that PNS suppressed ROS generation in OGD/R-treated cells. Immunofluorescence and western blot analysis indicated that PNS inhibited the degradation of tight junction proteins triggered by OGD/R. Moreover, mechanism investigations suggested that PNS increased the phosphorylation of Akt, the activity of nuclear Nrf2, and the expression of downstream antioxidant enzyme HO-1. All the effects of PNS could be reversed by co-treatment with PI3K inhibitor LY294002. Taken together, these observations suggest that PNS may act as an extrinsic regulator that activates Nrf2 antioxidant signaling depending on PI3K/Akt pathway and protects against OGD/R-induced BBB disruption in vitro.

Sport motivation and doping in adolescent athletes.

BackgroundAlthough performance-enhancing drugs appear to be prevalent in adolescent sports, relatively little attention has been paid to why adolescent athletes decide to use these drugs. In this study, we examine doping among adolescents from a motivational perspective and explore how motivational variables, such as achievement goal orientations and the perceived self-determination of sports activities, may be related to moral attitudes, doping intentions and doping behavior in adolescents who participate in competitive sports.MethodologyThe study included 1035 adolescents participating in competitive sports from all regions of the Czech Republic (mean age = 16.3 years). The respondents completed a battery of questionnaires assessing their achievement goal orientations (task, ego), sports motivation at various levels of self-determination (intrinsic motivation, external regulation, amotivation), moral attitudes toward sport competition (acceptance of cheating, keeping winning in proportion, attitudes toward doping), doping intentions and doping behavior. A structural equation model was used to test the relations among motivational variables, attitudes, intentions and doping behavior.Principal resultsOur analyses indicated a good fit with the proposed model, which explained 59% of the variance in doping intentions and 17.6% of the variance in doping behavior. Within the model, task orientation was positively associated with intrinsic motivation and lower amotivation, whereas ego orientation was positively associated with extrinsic regulation and amotivation. Furthermore, intrinsic motivation was positively associated with keeping winning in proportion and negatively associated with acceptance of cheating and attitudes toward doping; the less self-determined forms of motivation showed opposite relationships. However, only the acceptance of cheating and attitudes toward doping were related to doping intention, which subsequently predicted doping behavior.Conclusions/SignificanceThe results provide further evidence that sports motivation represents a psychological variable that should be considered in anti-doping policies, programs, and interventions aimed at the adolescent population because motivation was linked to the doping-related attitudinal variables and also partially mediated the effect of achievement goal orientations in this regard. On the basis of these results, we may argue that the focus on intrinsic enjoyment, self-referenced criteria of success and self-improvement may be related to more negative attitudes toward doping and cheating, lower doping intentions and less frequent doping behavior, whereas the emphasis on competition, comparison with others and external motivation appear to be related to the opposite outcomes.

Extrinsic Regulation of Hematopoietic Stem Cells and Lymphocytes by Vitamin A

Vitamin A and its receptors, retinoic acid receptors (RARs), are key regulators of hematopoiesis. This review focuses on the extrinsic regulation of hematopoiesis by retinoids, predominantly focusing on studies in mice, but also highlighting some of the studies performed using human hematopoietic stem cells (HSCs). RARγ has key roles in regulating B and T lymphocytes via distinct bone marrow mesenchymal cells and thymic microenvironment cells, respectively. The hematopoietic phenotypes caused by vitamin A deficiency are largely due to microenvironment-induced phenotypes that occur due to RARγ deficiency. Studies using human HSCs have also revealed that the biologically active form of vitamin A increases the HSC-support potential of immature mesenchymal cell lines. Distinct roles have been revealed for different vitamin A receptors in regulating hematopoiesis. Further elucidation of the mechanisms whereby the RARs extrinsically regulate immune cells and HSCs may provide insights leading to the development of improved therapeutics to manipulate the numbers of these cells in normal and diseased states.

Influence of neural mobilization in the sympathetic slump position on the behavior of the autonomic nervous system

Introduction The neural mobilization technique in the sympathetic slump position (NMSS) was based on the slump test, whose purpose was to directly influence the sympathetic trunk and thus provide greater analgesia by sympathetic activation and treat pain syndromes caused by peripheral sympathetic changes. Therefore, as the autonomic nervous system (ANS) is responsible for extrinsic regulation of the cardiovascular system through sympathetic and parasympathetic action, the aim of this study was to investigate the influence of the NMSS technique on the systolic and diastolic blood pressure and heart rate variability in athlete and non-athlete men. Methods Twenty-eight subjects performed the procedure that was divided into three phases: rest; intervention and recovery, lasting 4 minutes and 30 seconds each, totaling a 13-minute and 30 seconds collection time. Results The results showed that the NMSS technique significantly influences the action/activity of the ANS, as there was predominant sympathetic activation during the application of the technique, which was observed by the increase in systolic blood pressure, low frequency (LF), LF/HF ratio and decreased values of high frequency (HF). Conclusion It may be concluded that the neural mobilization technique on the sympathetic slump (NMSS) significantly influences the ANS action/activity. Among the groups there was no statistically significant difference in heart rate variability. It is worth noting that patients with cardiovascular disorders may be at risk if the NMSS technique is applied, since there was an increase in SBP and sympathetic activation during its application in both groups.

1189P - Intrinsic and extrinsic regulation of PD-L2 expression by transcription factor STAT3 or c-FOS in oncogene-driven non-small cell lung cancer

1189P - Intrinsic and extrinsic regulation of PD-L2 expression by transcription factor STAT3 or c-FOS in oncogene-driven non-small cell lung cancer

MTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis

Skeletal osteoblasts are important regulators of B-lymphopoiesis, serving as a rich source of factors such as CXCL12 and IL-7 which are crucial for B-cell development. Recent studies from our laboratory and others have shown that deletion of Rptor, a unique component of the mTORC1 nutrient-sensing complex, early in the osteoblast lineage development results in defective bone development in mice. In this study, we now demonstrate that mTORC1 signalling in pre-osteoblasts is required for normal B-lymphocyte development in mice. Targeted deletion of Rptor in osterix-expressing pre-osteoblasts (Rptorob−/−) leads to a significant reduction in the number of B-cells in the bone marrow, peripheral blood and spleen at 4 and 12 weeks of age. Rptorob−/− mice also exhibit a significant reduction in pre-B and immature B-cells in the BM, indicative of a block in B-cell development from the pro-B to pre-B cell stage. Circulating levels of IL-7 and CXCL12 are also significantly reduced in Rptorob−/− mice. Importantly, whilst Rptor-deficient osteoblasts are unable to support HSC differentiation to B-cells in co-culture, this can be rescued by the addition of exogenous IL-7 and CXCL12. Collectively, these findings demonstrate that mTORC1 plays an important role in extrinsic osteoblastic regulation of B-cell development.

Gastrointestinal Motility and Functional Disorders

Gastrointestinal (GI) motility disorders represent diseases characterized by abnormal, predominantly impaired, sometimes exaggerated, movement of contents through the GI tract due to neuromuscular dysfunctions in the absence of mucosal disease and mechanical causes of impaired passage. By contrast, functional GI disorders represent illnesses, defined only by GI symptoms, which occur in the absence of mucosal or structural abnormality or of known biochemical or metabolic disorders. The first section of this chapter discusses the enteric and extrinsic neural regulation of GI sensorimotor functions and normal GI motility in humans. Disorders such as gastroparesis (including diabetic gastroparesis, idiopathic gastroparesis, and postsurgical gastroparesis), dumping syndrome, intestinal pseudo-obstruction, small intestinal bacterial overgrowth, megacolon (including Hirschsprung disease, toxic megacolon, and colonic pseudo-obstruction), chronic constipation (including defecatory disorders, normal transit constipation, and slow transit constipation), functional dyspepsia, functional diarrhea and irritable bowel syndrome, and fecal incontinence are then discussed in depth. Tables present a comparison of GI motility and functional disorders, the causes of gastroparesis, the etiology of intestinal pseudo-obstruction and fecal incontinence, common medical conditions and medications associated with constipation, and the symptom severity scale in fecal incontinence. Illustrations, graphs, magnetic resonance images, and algorithms are provided. This chapter contains 10 highly rendered figures, 6 tables, 92 references, and 5 MCQs.

Exercise-specific volition and motivation for weight loss maintenance following an intensive lifestyle intervention.

The present study investigated the influence of exercise-specific motivation and volition on weight loss maintenance following an intensive lifestyle intervention (ILI). The study participants were 164 individuals with obesity (body mass index [BMI] > 30 kg/m2) that participated in an ILI. Participants' exercise-specific volition and motivation were assessed before and after the intervention as well as 3 and 12 months after completion. Volition was measured with the Volition in Exercise Questionnaire and motivation was measured with the context translated Sport Motivation Scale. Mixed model analysis revealed that when adjusting for gender, age, and education, the 6 volitional scales and intrinsic motivation predicted BMI across the 4 time points, whereas 6 volitional scales and 2 extrinsic regulation scales showed a time interaction. Backward elimination multiple mixed model analysis revealed that Volitional Inhibition - Postponing Training and Volitional Facilitation - Self-Confidence predicted BMI development, whereas Volitional Inhibition - Unrelated Thoughts, Identified Regulation, and Introjected Regulation showed a time interaction above and beyond the other scales. Exercise-specific volition and motivation influence weight loss maintenance following an ILI. Volitional self-confidence and the tendency to postpone training are of importance above and beyond the previously identified predictor of autonomous exercise motivation. Results of the study also indicate that extrinsic motivation can be either facilitating or counterproductive depending on the level of self-determination. (PsycINFO Database Record

3200 - Identification of Extrinsic Regulators of Hematopoietic Stem Cell Formation in the Embryonic Aorta Microenvironment by Tomo-Sequencing

In all vertebrates, hematopoietic stem cell (HSC) emergence mainly occurs in the dorsal aorta of the embryo. It is now well accepted that HSCs arise from specialized endothelial cells of the aorta, named hemogenic endothelial cells, via an endothelial-to-hematopoietic transition (EHT) process. This process is tightly controlled in time and space by regulatory signals emitted by the surrounding microenvironment in all species (zebrafish, chicken, mouse and human). Nevertheless, a complete picture of the genes expressed in the surrounding tissues of the aorta that are involved during the highly regulated HSC emergence is still missing. o decipher the genes that are (differentially) expressed in specific regions of the aorta during HSC generation, we used a genome-wide RNA tomography (tomo-seq) approach (Junker 2014). Tomo-seq was applied on whole aortas (subdissected with the surrounding mesenchyme) and thick transversal embryo slices from zebrafish, chicken, mouse and human embryos. Using this approach, we provided a complete resource of the gene expression profiles around the dorsal aorta in all species. We then identified a series of genes specifically expressed either in the ventral or dorsal side of the aorta and validated their expression pattern using in situ hybridization and/or immunostainings. We further demonstrated their functional implication in HSC emergence and hematopoietic production by knocking-down these genes in zebrafish embryos. Finally, our comparative data analysis in between species unravelled conserved genes and molecular pathways involved in the regulation of the first HSC generated during embryonic development.

Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation.

In human skin, melanogenesis is a tightly regulated process. Indeed, several extracellular signals are transduced via dedicated signalling pathways and mostly converge to MITF, a transcription factor integrating upstream signalling and regulating downstream genes involved in the various inherent mechanisms modulating melanogenesis. The synthesis of melanin pigments occurs in melanocytes inside melanosomes where melanogenic enzymes (tyrosinase and related proteins) are addressed with the help of specific protein complexes. The melanosomes loaded with melanin are then transferred to keratinocytes. A more elaborate level of melanogenesis regulation comes into play via the action of non-coding RNAs (microRNAs, lncRNAs). Besides this canonical regulation, melanogenesis can also be modulated by other non-specific intrinsic pathways (hormonal environment, inflammation) and by extrinsic factors (solar irradiation such as ultraviolet irradiation, environmental pollution). We developed a bioinformatic interaction network gathering the multiple aspects of melanogenesis and skin pigmentation as a resource to better understand and study skin pigmentation biology.

Hedgehog signaling from the Posterior Signaling Center maintains U-shaped expression and a prohemocyte population in Drosophila

Hematopoietic progenitor choice between multipotency and differentiation is tightly regulated by intrinsic factors and extrinsic signals from the surrounding microenvironment. The Drosophila melanogaster hematopoietic lymph gland has emerged as a powerful tool to investigate mechanisms that regulate hematopoietic progenitor choice in vivo. The lymph gland contains progenitor cells, which share key characteristics with mammalian hematopoietic progenitors such as quiescence, multipotency and niche-dependence. The lymph gland is zonally arranged, with progenitors located in medullary zone, differentiating cells in the cortical zone, and the stem cell niche or Posterior Signaling Center (PSC) residing at the base of the medullary zone (MZ). This arrangement facilitates investigations into how signaling from the microenvironment controls progenitor choice. The Drosophila Friend of GATA transcriptional regulator, U-shaped, is a conserved hematopoietic regulator. To identify additional novel intrinsic and extrinsic regulators that interface with U-shaped to control hematopoiesis, we conducted an in vivo screen for factors that genetically interact with u-shaped. Smoothened, a downstream effector of Hedgehog signaling, was one of the factors identified in the screen. Here we report our studies that characterized the relationship between Smoothened and U-shaped. We showed that the PSC and Hedgehog signaling are required for U-shaped expression and that U-shaped is an important intrinsic progenitor regulator. These observations identify a potential link between the progenitor regulatory machinery and extrinsic signals from the PSC. Furthermore, we showed that both Hedgehog signaling and the PSC are required to maintain a subpopulation of progenitors. This led to a delineation of PSC-dependent versus PSC-independent progenitors and provided further evidence that the MZ progenitor population is heterogeneous. Overall, we have identified a connection between a conserved hematopoietic master regulator and a putative stem cell niche, which adds to our understanding of how signals from the microenvironment regulate progenitor multipotency.

Work motivation and self-rated anxiety: Nurses’ perspectives

Objective: Considering nurses’ psychological status, work decision involvement, emotions, anxiety, and motivation, is an important issue for attaining nurses’ retention and maintaining their preservation in their work positions. Work motivation is the key that enhances employee performance which is influenced by numerous internal and external factors; job anxiety is the apparent one. The current study is directed to achieve two aims: to assess the work motivation level and self-rated anxiety among nurses and to investigate the relationship between them. Therefore, a descriptive, correlative research design was applied with 300 registered nurses in King Abd El Aziz governmental hospital in Jeddah, Saudi Arabia.Methods: A triple-section questionnaire was used for data collection that involved: First, Multidimensional Work Motivation Scale (MWMS) that was developed by Gagne et al. in 2010. Second, Self-Rated Anxiety Sub-scale which was developed by Warr et al. in 1979. Third, sociodemographic questions were included.Results: About three-quarters of Suadi nurses have high work motivation level concerning introjected and identified regulations while more than half of them have a high level of work motivation regarding amotivation and extrinsic regulations. Consequently, most of the participants have high scores in work motivation level. As regards, self-rated anxiety, all study subjects have a certain level of anxiety at work, but the majority of them were with low level. As pertaining the correlation between both study variables, there is a negative correlation between work motivation level and self-rated anxiety and the present study proved that Saudi registered nurses in King Abd El Aziz governmental hospital have high work motivation level scores with low self-rated anxiety scores.Conclusions: The current study confirms that the Saudi nurses in Jeddah have high work motivation level with low anxiety. Furthermore, the study provides evidence of a negative or inverse correlation between work motivation level and self-rated anxiety among Saudi registered nurses in King Abd El Aziz governmental hospital. Nurses should be aware by the importance of motivation in their job and at the same time, be aware of the risks of work-related anxiety. Nurse Managers have to tailor all factors which are surrounding nurses in a hospital environment, organizational structure and culture to be positively motivated and, at the same time, to alleviate any tendency of work-related anxiety. Furthermore, work motivation and anxiety should be involved and integrated into the nursing curriculum in nursing schools.Further researches: A research about the effect of the work motivation educational program on nurse manager’s leadership skills, is needed. A study about the correlation between work motivation and other negative or positive variables in work environment among nurses is necessitated. Also, assessment of nurses’ work motivation and anxiety using different tools such as value test, emotional inventory and adjustment skills measurement.

Strength in diversity: Phenotypic, functional, and molecular heterogeneity within the memory B cell repertoire.

The vast majority of vaccines exploit antibody memory to induce lasting immunity. Memory B cells are generated during the initial response to infection, but persist long after the infection has cleared. Immune memory success relies on its adaptability: in response to different pathogens, variants of a single pathogen, and in balancing persistence with reactivation and plasma cell differentiation. This is likely achieved by producing a B cell memory population that is highly diverse, and recent work has highlighted the importance of memory B cell subsets in mediating the dichotomous roles of the population. This review will detail the characterization, function and both intrinsic and extrinsic regulation of different memory B cell subsets: memory B cell precursors within the germinal center, phenotypic, and functional heterogeneity of the memory B cell population, and memory B cell subsets that reside in tissues. In particular, understanding the genetic and epigenetic regulation of memory B diversity may be critical for gaining insight into B cell memory responses to pathogens that have evaded effective vaccine design. Therefore, there is a vital need to understand the mechanisms underlying the origin, function and translational potential of the heterogeneity within the memory B cell population.

Gastrointestinal Motility and Functional Disorders

Gastrointestinal (GI) motility disorders represent diseases characterized by abnormal, predominantly impaired, sometimes exaggerated, movement of contents through the GI tract due to neuromuscular dysfunctions in the absence of mucosal disease and mechanical causes of impaired passage. By contrast, functional GI disorders represent illnesses, defined only by GI symptoms, which occur in the absence of mucosal or structural abnormality or of known biochemical or metabolic disorders. The first section of this chapter discusses the enteric and extrinsic neural regulation of GI sensorimotor functions and normal GI motility in humans. Disorders such as gastroparesis (including diabetic gastroparesis, idiopathic gastroparesis, and postsurgical gastroparesis), dumping syndrome, intestinal pseudo-obstruction, small intestinal bacterial overgrowth, megacolon (including Hirschsprung disease, toxic megacolon, and colonic pseudo-obstruction), chronic constipation (including defecatory disorders, normal transit constipation, and slow transit constipation), functional dyspepsia, functional diarrhea and irritable bowel syndrome, and fecal incontinence are then discussed in depth. Tables present a comparison of GI motility and functional disorders, the causes of gastroparesis, the etiology of intestinal pseudo-obstruction and fecal incontinence, common medical conditions and medications associated with constipation, and the symptom severity scale in fecal incontinence. Illustrations, graphs, magnetic resonance images, and algorithms are provided. This chapter contains 10 highly rendered figures, 6 tables, 92 references, and 5 MCQs.

Research Project: The Mentoring and Development of Emotional Competence in Nursing Students

&lt;p&gt;&lt;em&gt;Nursing care has a very intense emotional component. Nursing students, in addition to dealing with the frailties inherent in their life processes and personality development, are still subject to an emotionally and socially demanding academic experience. This negatively charged emotionality hinders the teaching-learning process and the academic course. The emotional management depends on perception and individual resources, and it may be necessary for this regulation support and guidance provided by a mentor. The mentoring programs developed in the Institutions of Higher Education contribute to the healthy integration of the student and, consequently, to their socialization and academic success. Mentors provide guidance to students and extrinsic emotional regulation, through support and discussion, and are a resource in managing emotions, contributing to the development of emotional competence in nursing students.&lt;/em&gt;&lt;em&gt; &lt;/em&gt;&lt;em&gt;This quantiquantitative approach research project aims to&lt;/em&gt;&lt;em&gt; &lt;/em&gt;&lt;em&gt;contribute to the construction of a mentoring program that promotes the development of emotional competence, essential to academic success and transformative learning in Nursing Degree.&lt;/em&gt;&lt;/p&gt;

Diagnoza klimatu społecznego młodzieżowych ośrodków wychowawczych w Polsce

Each institution creates and is characterized by a specific atmosphere which may be favorable, beneficial, positive, perhaps even motivating, or, on the other hand, unfavorable, negative or improper. The article presents the issues related to the social climate of youth educational centers (YEC) in Poland. The purpose of the research was to recognize the wards’ and educators’ opinions on the social climate of the institutions, as well as diagnosing it in terms of interpersonal relations, personal development and organization. The Scale of Social Climate by Rudolf H. Moos was used as a research tool. The analysis of the results led to a basic conclusion that an unfavorable climate prevails. The staff are focused mainly on extrinsic discipline and regulations, paying insufficient attention to proper interpersonal relations with their wards. Therapeutic aspects of the social climate are largely neglected.

The Krüppel-Like Factor Gene Target Dusp14 Regulates Axon Growth and Regeneration.

PurposeAdult central nervous system (CNS) neurons are unable to regenerate their axons after injury. Krüppel-like transcription factor (KLF) family members regulate intrinsic axon growth ability in vitro and in vivo, but mechanisms downstream of these transcription factors are not known.MethodsPurified retinal ganglion cells (RGCs) were transduced to express exogenous KLF9, KLF16, KLF7, or KLF11; microarray analysis was used to identify downstream genes, which were screened for effects on axon growth. Dual-specificity phosphatase 14 (Dusp14) was further studied using genetic (siRNA, shRNA) and pharmacologic (PTP inhibitor IV) manipulation to assess effects on neurite length in vitro and survival and regeneration in vivo after optic nerve crush in rats and mice.ResultsBy screening genes regulated by KLFs in RGCs, we identified Dusp14 as a critical gene target limiting axon growth and regeneration downstream of KLF9's ability to suppress axon growth in RGCs. The KLF9-Dusp14 pathway inhibited activation of mitogen-activated protein kinases normally critical to neurotrophic signaling of RGC survival and axon elongation. Decreasing Dusp14 expression or disrupting its function in RGCs increased axon growth in vitro and promoted survival and optic nerve regeneration after optic nerve injury in vivo.ConclusionsThese results link intrinsic and extrinsic regulators of axon growth and suggest modulation of the KLF9-Dusp14 pathway as a potential approach to improve regeneration in the adult CNS after injury.

Multicompartment cell-based modeling of confined migration: regulation by cell intrinsic and extrinsic factors

Though cell and nuclear deformability are expected to influence efficiency of confined migration, their individual and collective influence on migration efficiency remains incompletely understood. In addition to cell intrinsic properties, the relevance of cell extrinsic factors on confined migration, if any, has not been adequately explored. Here we address these questions using a statistical mechanics-based stochastic modeling approach where cell/nuclear dimensions and their deformability are explicitly taken into consideration. In addition to demonstrating the importance of cell softness in sustaining confined migration, our results suggest that dynamic tuning of cell and nuclear properties at different stages of migration is essential for maximizing migration efficiency. Our simulations also implicate confinement shape and confinement history as two important cell extrinsic regulators of cell invasiveness. Together, our findings illustrate the strength of a multicompartment model in dissecting the contributions of multiple factors that collectively influence confined cell migration.