Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle.

Viral oncoproteins that inactivate the retinoblastoma tumor suppressor protein (pRb) family both block skeletal muscle differentiation and promote cell cycle progression. To clarify the dependence of terminal differentiation on the presence of the different pRb-related proteins, we have studied myogenesis using isogenic primary fibroblasts derived from mouse embryos individually deficient for pRb, p107, or p130. When ectopically expressed in fibroblasts lacking pRb, MyoD induces an aberrant skeletal muscle differentiation program characterized by normal expression of early differentiation markers such as myogenin and p21, but attenuated expression of late differentiation markers such as myosin heavy chain (MHC). Similar defects in MHC expression were not observed in cells lacking either p107 or p130, indicating that the defect is specific to the loss of pRb. In contrast to wild-type, p107-deficient, or p130-deficient differentiated myocytes that are permanently withdrawn from the cell cycle, differentiated myocytes lacking pRb accumulate in S and G2 phases and express extremely high levels of cyclins A and B, cyclin-dependent kinase (Cdk2), and Cdc2, but fail to readily proceed to mitosis. Administration of caffeine, an agent that removes inhibitory phosphorylations on inactive Cdc2/cyclin B complexes, specifically induced mitotic catastrophe in pRb-deficient myocytes, consistent with the observation that the majority of pRb-deficient myocytes arrest in S and G2. Together, these findings indicate that pRb is required for the expression of late skeletal muscle differentiation markers and for the inhibition of DNA synthesis, but that a pRb-independent mechanism restricts entry of differentiated myocytes into mitosis

DETERMINANTS OF STRATEGIC RISK MANAGEMENT IN EMERGING MARKETS SUPPLY CHAINS: THE CASE OF MEXICO

Risk mitigation in global supply chains has grown in importance in recent years, in tandem with globalization and both the commercial and security threats faced by firms both large and small. This study hypothesizes that a firm’s ability to manage risk strategy—and therefore support its competitiveness—is determined by a symbiotic triad of factors: the resources it utilizes; network systems; and performance criteria it employs. The study, comprising 24 in-depth interviews with electronics and IT firms, examines resource utilization through the Resource-Based View (RBV), assesses firms’ proclivity to engage in networks for risk mitigation and competitiveness; and highlights the importance of performance evaluation as a critically important component in supply chain management. Findings reveal that both buyers and suppliers believe that the symbiotic triad can provide them with a competitive advantage in addition to improving operational efficiency, effectiveness and quality. Future research should also extend this pilot investigation to other countries and industries, and utilize a larger sample of firms for quantitative as well as qualitative assessment.Risk management; emerging markets; Supply Chain Management; IT

GATA6 Is a Crucial Regulator of Shh in the Limb Bud

In the limb bud, patterning along the anterior-posterior (A-P) axis is controlled by Sonic Hedgehog (Shh), a signaling molecule secreted by the “Zone of Polarizing Activity”, an organizer tissue located in the posterior margin of the limb bud. We have found that the transcription factors GATA4 and GATA6, which are key regulators of cell identity, are expressed in an anterior to posterior gradient in the early limb bud, raising the possibility that GATA transcription factors may play an additional role in patterning this tissue. While both GATA4 and GATA6 are expressed in an A-P gradient in the forelimb buds, the hindlimb buds principally express GATA6 in an A-P gradient. Thus, to specifically examine the role of GATA6 in limb patterning we generated Prx1-Cre; GATA6fl/fl mice, which conditionally delete GATA6 from their developing limb buds. We found that these animals display ectopic expression of both Shh and its transcriptional targets specifically in the anterior mesenchyme of the hindlimb buds. Loss of GATA6 in the developing limbs results in the formation of preaxial polydactyly in the hindlimbs. Conversely, forced expression of GATA6 throughout the limb bud represses expression of Shh and results in hypomorphic limbs. We have found that GATA6 can bind to chromatin (isolated from limb buds) encoding either Shh or Gli1 regulatory elements that drive expression of these genes in this tissue, and demonstrated that GATA6 works synergistically with FOG co-factors to repress expression of luciferase reporters driven by these sequences. Most significantly, we have found that conditional loss of Shh in limb buds lacking GATA6 prevents development of hindlimb polydactyly in these compound mutant embryos, indicating that GATA6 expression in the anterior region of the limb bud blocks hindlimb polydactyly by repressing ectopic expression of Shh

Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways

Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca++-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (Grant AR60331

Hållbarhetsrapportering och drivkraften att arbeta mer hållbart

Hållbarhetsrapportering är en rapport som blir allt vanligare att företag upprättar. Problemet kring hållbarhetsrapportering är att det finns en otydlighet om hur företag kan använda sig av hållbarhetsrapporten utifrån olika aspekter, samt vad den kan gynna företaget vid användning av den som ett verktyg. Utifrån den befintliga forskningen behövs det vidare diskuteras kring hur företag kan använda hållbarhetsrapporten som ett verktyg för att öka drivkrafter att arbeta mer hållbart. Syftet är att utforska hur företag hanterar frivillig hållbarhetsrapportering som både en möjlighet och en utmaning. Studien utforskar hur hållbarhetsrapportering blir ett aktivt verktyg som influerar företagets hållbarhetsarbete. Forskningsfrågan uppsatsen berör är att ta reda på hur hållbarhetsrapportering kan användas som ett aktivt verktyg för att främja drivkraften att arbeta mer hållbart, samt vilka möjligheter och utmaningar hållbarhetsrapportering medför. Avgränsningen av uppsatsen är frivillig hållbarhetsrapportering och hur företag kan använda rapporten som ett verktyg för att öka drivkraften att arbeta mer hållbart. Uppsatsens fokus på att arbeta mer hållbart syftar främst till den miljömässiga dimensionen men tar även hänsyn till de ekonomiska och sociala aspekterna. Detta eftersom de tre dimensioner skapar förutsättningar för varandra. Forskningsmetoden som används i uppsatsen är en kvalitativ metod med en abduktiv ansats. Empirin är baserad på nio intervjuer med företag som antingen hållbarhetsrapporterar åt sin enskilda verksamhet eller hjälper andra företag att hållbarhetsrapportera. Genom en undersökning kring studiens syfte har det resulterat i en slutsats. Företag kan använda sig av deras hållbarhetsrapport som ett aktivt verktyg inom flera områden för att främja drivkraften att arbeta mer hållbart. Denna uppsats vill bidra till vidare forskning genom att ge en förståelse om hur hållbarhetsrapportering kan användas som ett verktyg. Studien ska bidra till en utveckling av empirisk och teoretisk kunskap om ämnet, och för att ge en modern syn på ämnet har studien belyst CSRD som en del av studiens fokusområden. Uppsatsen utgår från företag som frivilligt hållbarhetsrapporterar vilket har gett utrymme för att undersöka drivkrafter än lagkrav som huvudsaklig för de företag som inte frivilligt hållbarhetsrapporterar. Det empiriska bidraget grundar sig främst i att bena ut den oklarhet som finns kring hur företagen i praktiken kan använda sig av sin hållbarhetsrapportering som ett verktyg för att främja drivkraften att arbeta mer hållbart.Sustainability reporting is becoming increasingly common for companies to draw up. The problem is that there is a lack of clarity about how companies can use its sustainability report based on different aspects, as well as what it can benefit the company when using it as a tool. Based on the existing research, there is a further need to discuss how companies can use the sustainability report as a tool to increase impulsion to work more sustainably. The purpose is also to explore how voluntary sustainable reporting can both entail opportunities and challenges. The study explores how sustainability reporting becomes an active tool that influences the company's sustainability work. The research question is to find out how sustainability reporting can be used as an active tool to promote the impulsion to work more sustainably, as well as what opportunities and challenges sustainability reporting entails. The demarcation of this essay is sustainability reporting and how companies can use the report as a tool to increase the impulsion to work sustainably. Working more sustainably refers mainly to the environmental aspects but also considers the economic and social ones, hence the three dimensions have a constant interaction with each other. The research method that is used in the essay is a qualitative method with an abductive approach. The experience is based on nine interviews with enterprises that either produce a report for their own operations or consulting companies that help other companies prepare a sustainability report. Through an investigation about the purpose of the study, it has resulted in a conclusion. Enterprises can use their sustainability report as a tool in several areas to influence the impulsion to work more sustainably. This essay wants to contribute to further research by providing an understanding of how sustainability reporting can be used as a tool to increase the impulsion to work more sustainably. The study should contribute to the development of empirical and theoretical knowledge of the subject. To provide a modern view of the subject, the study has highlighted the framework CSRD as part of the study's main areas. The analysis is based on enterprises that voluntarily sustainability report, which has given space to examine impulsions other than legal requirements. The empirical contribution is primarily based on being able to clarify the uncertainty surrounding how enterprises can in practice use their sustainability reporting as a tool to promote the impulsion to work more sustainably

College Savings Plan Accounts at Birth: Maine\u27s Statewide Program

The Harold Alfond College Challenge offers $500 to every child in the state enrolled in Maine’s NextGen college savings plan within 1 year from birth. As the first U.S. example of a statewide Child Development Account, the Alfond Challenge is a laboratory to study and learn from Maine’s experience. This CSD policy brief provides an overview of the Alfond Challenge, examines administrative and enrollment challenges, and offers recommendations and federal and state policy directions

IPMK and ??-catenin mediate PLC-??1-dependent signaling in myogenic differentiation

In previous studies, we have reported that phospholipase C (PLC)-??1 plays a crucial role in myogenic differentiation and we determined the importance of its catalytic activity for the initiation of this process. Here we define the effectors that take part to its signaling pathway. We show that the Inositol Polyphosphate Multikinase (IPMK) is able to promote myogenic differentiation since its overexpression determines the up-regulation of several myogenic markers. Moreover, we demonstrate that IPMK activates the same cyclin D3 promoter region targeted by PLC-??1 and that IPMKinduced promoter activation relies upon c-jun binding to the promoter, as we have shown previously for PLC-??1. Furthermore, our data shows that IPMK overexpression causes an increase in ??-catenin translocation and accumulation to the nuclei of differentiating myoblasts resulting in higher MyoD activation. Finally, we describe that PLC-??1 overexpression determines too an increase in ??-catenin translocation and that PLC-??1, IPMK and ??-catenin are mediators of the same signaling pathway since their overexpression results in cyclin D3 and myosin heavy chain (MYH) induction.ope

Saving for College: A Policy Primer

To help address the rapidly rising cost of higher education—an obstacle to college access and completion for many low- and moderate-income families—it is increasingly important to save for college. This report highlights key policy considerations and challenges, along with specific strategies, to make 529 college savings plans more accessible to families of all incomes

Toward More Inclusive College Savings Plans: Sample State Legislation

A number of states have created inclusive 529 policy strategies to make college savings plans more accessible and easier to use for families at all income levels. These strategies include facilitating enrollment and contributions, removing saving disincentives, increasing saving incentives, and strengthening tax benefits. In this report, we examine these inclusive state policy strategies, describe their application through legislative and administrative means, and point to specific examples.A related policy brief by the same title is also available

College Savings Match Programs: Design and Policy

We examine here the essential elements and program design of all state 529 savings-match programs as well as the application process and other policy considerations. Like other state programs, 529 savings incentives inevitably reflect the unique demographics, economics, and political makeup of a particular state. This report provides details about inclusive savings-match program features and strategies that could make 529 plans more widely accessible to families of all incomes