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Krüppel-like factor 10 (KLF10) is a phospho-regulated transcriptional factor involved in many biological processes including lipogenesis; however, the transcriptional regulation on lipogenesis by KLF10 remains largely unclear. Lipogenesis is important in the development of nonalcoholic fatty liver disease (NAFLD) which was known regulated mainly by AMP-activated protein kinase (AMPK) and sterol regulatory element-binding protein (SREBP-1C). Interesting, our previous study using phosphorylated site prediction suggested a regulation of AMPK on KLF10. Therefore, we aimed to study the protein–protein interactions of AMPK on the regulation of KLF10, and to delineate the mechanisms of phosphorylated KLF10 in the regulation of NAFLD through SREBP-1C. We performed in vitro and in vivo assays that identified AMPK phosphorylates KLF10 at Thr189 and subsequently modulates the steady state level of KLF10. Meanwhile, a chromatin immunoprecipitation–chip assay revealed the novel target genes and signaling cascades of corresponding to phosphorylated KLF10. SREBP-1C was identified as a target gene suppressed by phosphorylated KLF10 through promoter binding. We further performed high-fat-diet-induced NAFLD models using hepatic-specific KLF10 knockout mice and wild-type mice and revealed that KLF10 knockout markedly led to more severe NAFLD than that in wild-type mice. Taken together, our findings revealed for the first time that AMPK activates and stabilizes the KLF10 protein via phosphorylation at Thr189, thereby repressing the expression of SREBP-1C and subsequent lipogenesis pathways along with metabolic disorders. We suggested that the targeted manipulation of liver metabolism, particularly through increased KLF10 expression, is a potential alternative solution for treating NAFLD.

Amid efforts to limit "divisive concepts" in educational settings, this article investigates the obstruction of a civic-focused early childhood curriculum. Joy Dangora Erickson and Winston Thompson analyze the challenges faced by a resourceful kindergarten teacher striving to uphold curriculum goals despite constraints imposed by the state legislature. Through an empirically informed exploration of political and pedagogical factors, this conceptual analysis elucidates the moral complexities of risks, costs, and outcomes as educators navigate non-ideal political conditions. By doing so, the authors provide valuable insights to scholars and practitioners, suggesting productive avenues for future research on these and related dilemmas of practice.

Justice issues in early childhood education contexts abound; these include substandard developmental opportunities and resource inequalities that disproportionately affect marginalized communities. However, "interpersonal" justice matters are often underexplored in both conceptual and empirical scholarship. It is essential to prioritize how children's voices and views of justice are engaged in their educational environments, alongside questions of which communities' views and values are endorsed. This article focuses on US reading intervention programs, where efforts are made to expand freedoms and develop literacy as a pathway to greater autonomy. To better understand justice requirements for children in these programs, the authors introduce the cases of Adriana, Jason, and Gisela (pseudonyms)--all participants in case studies of young children's motivation to read in mandated reading intervention programs. The children's accounts examined within this article suggest that their intervention programs may undermine their developing capacities for autonomy and violate their rights to an open future, specifically as related to an appreciation for reading.

Despite the development of potent siRNAs that effectively target genes responsible for skin disorders, translation to the clinic has been hampered by inefficient delivery through the stratum corneum barrier and into the live cells of the epidermis. Although hypodermic needles can be used to transport siRNA through the stratum corneum, this approach is limited by pain caused by the injection and the small volume of tissue that can be accessed by each injection. The use of microneedle arrays is a less painful method for siRNA delivery, but restricted payload capacity limits this approach to highly potent molecules. To address these challenges, a commercially available motorized microneedle array skin delivery device was evaluated. This device combines the positive elements of both hypodermic needles and microneedle array technologies with little or no pain to the patient. Application of fluorescently tagged self-delivery (sd)-siRNA to both human and murine skin resulted in distribution throughout the treated skin. In addition, efficient silencing (78% average reduction) of reporter gene expression was achieved in a transgenic fluorescent reporter mouse skin model. These results indicate that this device effectively delivers functional sd-siRNA with an efficiency that predicts successful clinical translation.

Building on the careful racial analyses of Charles W. Mills, this article uses the example case of Black ethnics to illustrate the general plausibility of ethnic identity as a useful political analytic category, suggesting that the absence of ethnic identity in racial analyses mutes important aspects of the lived experiences of racialized persons as individuals and in aggregation. The article establishes the possibility of ethnicity as an identity modifier, providing additional specificity to racial identity narratives. Building on these positions, the article turns to educational contexts to explore the ways in which ethnicity (as introduced in the preceding sections) stands to offer additional specificity to justice-oriented analyses of educational policy and practice.

In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (Δ2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5Δ24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5-independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely restricted CCR5 expression seen in SM and several other natural host species.

The authors describe a collaboration to create a series of social justice-oriented curriculum maps for a predominantly White preschool. The researchers explore their own identities and biases, how racism disadvantages individuals and groups, and the resulting curriculum design.

This article emerges from a stream of scholarship demonstrating the inadequacy of broad arguments favouring 'neutrality' as an alternative to 'directive normative instruction' in the early childhood classroom. We advance a moral educational framing of the tension between neutrality and normativity in education: specifically, we argue that irreplaceably valuable moral aims of public education are jeopardized when a sense of disquiet regarding indoctrination operates unchecked. After detailing several ways in which moral education is entangled with civic and/or political education specific to a conceptualization of educationally desirable 'traits of reasonableness', we locate civic educational goals as a subcategory of moral education. In light of seemingly intensified calls for neutrality and/or the omission of specific topics and perspectives in the U.S. schools, this article draws upon Hand's work on moral education, to recenter and strengthen existing arguments against anti-indoctrination-based defences of 'neutrality' in education. Finally, we detail a meaningful divergence from Hand's moral guidelines; we argue that increased engagement with opaque moral dilemmas may be of substantial benefit, stimulating valuable experiences of critical reflection for young children in their roles as today's and tomorrow's moral, civic, and political actors.

This article provides a definition of monuments and describes their potential for removalist and preservationist controversy. The authors focus on the example of Confederate monuments in the United States as, on the basis of racist impacts, these monuments are candidates for widespread removal. The authors review influential existing philosophical arguments aimed at clarifying this controversy. In this, they draw attention to an especially promising formulation of a moral harm argument. The authors improve upon this argument by offering an educationally sensitive civic harm argument. In this, they advance a view of limited compatibility between removalist and preservationist aims.

Rule violations are expected in schools, and assessments of the severity of those violations and the appropriate disciplinary responses are a significant aspect of educators' responsibilities. While most educators and policy makers reject rule violation as a permissible behavior in schools, is such a categorical rejection always a suitable response, and are there circumstances that might merit an alternative response? In this article, A. C. Nikolaidis and Winston C. Thompson argue that under unjust circumstances, noncompliance with school rules may be permissible and even desirable. Building on a contractual framework placing systemic injustice at the center of inquiry, they show that under unjust conditions schools forfeit their ability to hold students accountable for role-dependent violations.

In recent work, Joseph Fishkin has helpfully enriched understandings of equality of opportunity as a feature of distributive justice schemes. One branch of his argument focuses upon the degree to which 'merit', as a function of talent and effort, is conceptually and practically vexing for these goals. While Thompson is in general agreement with the direction of Fishkin's critiques and new offerings, in this article he extends and strengthens Fishkin's analysis of talent, specifically focusing upon its role as a defensible criterion for access to developmentally useful educational opportunities. Developing an account sympathetic to Fishkin's contributions, Thompson provides a limited defense of talent as a morally relevant criterion for access to some educational opportunities. Of course, Thompson acknowledges that this relevance is not absolute and, therefore, points towards reasons why talent enjoys only this occasionally relevant status in relation to educational opportunities and what systemic issues ought to be avoided as a result.

In this review of the "Educational Goods," the author provides a set of comments that might extend the worthy framework provided by Brighouse, Ladd, Loeb and Swift. In particular, the author calls attention to the ways in which continued work within this project might broaden its conceptualisation of educational goods, increase the scope of potential application of its framework and clarify its forward- or backward-looking character. [For Brighouse et al's "Educational Goods: Values, Evidence, and Decision-Making," see ED592596.]

In the present unjust context of US schools, many educators face uncertainty about the legitimacy of their issuing punishments, especially when their identity meaningfully differs from that of their students. In this article, we address these doubts by acknowledging distinctive elements of schools to provide helpful distinctions and analyses of the legitimacy of punishments within them. Specifically, we interrogate the role that identity categories such as race and gender play in establishing legitimate punishment within schools, with a particular focus on the case of Black girls attending US schools. We offer a taxonomy of legitimate responses to undesired student behavior, arguing that a particular person in their role within a school might lack legitimacy to punish based upon their identity even while other, related yet more nuanced, behavioral responses remain. In this work, we aim to equip educators with tools to better navigate the options available to them and better understand the significance of their actions in response to student behavior.

Amid efforts to limit "divisive concepts" in educational settings, this article investigates the obstruction of a civic‐focused early childhood curriculum. Joy Dangora Erickson and Winston Thompson analyze the challenges faced by a resourceful kindergarten teacher striving to uphold curriculum goals despite constraints imposed by the state legislature. Through an empirically informed exploration of political and pedagogical factors, this conceptual analysis elucidates the moral complexities of risks, costs, and outcomes as educators navigate non‐ideal political conditions. By doing so, the authors provide valuable insights to scholars and practitioners, suggesting productive avenues for future research on these and related dilemmas of practice. [ABSTRACT FROM AUTHOR]

In this article the author considers how social media--a new, evolving, and increasingly pervasive form of communication and community--shapes students' attitudes towards practices of communication and community in their futures as political actors. How ought educators respond to this new world; can they lead their students into a culture of practice that seems, in many significant ways, alien to them? The author employs two potentially laudatory and critical frameworks, building upon the work of both John Stuart Mill and Hannah Arendt, to map the contours of a possible avenue of response to the aforementioned questions via the assertion that the essence of those social media sites and services--paired with their corresponding method(s) of engagement--may be well understood as rooted in a novel culture of sharing. Investigating this push to share allows educators to consider their practice in the face of a new feature of their world, finding themselves and their students in a moment of uncertainty which challenges and reinforces one of the central aims of their common project: the preparation and shaping of future political actors.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis.sup.1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance.sup.6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment--which contributes to virologic failure, resistance generation and viral transmission--as well as of pre-exposure prophylaxis, leading to new infections.sup.1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence.sup.10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log.sub.10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection., Author(s): John O. Link [sup.1] , Martin S. Rhee [sup.1] , Winston C. Tse [sup.1] [sup.8] , Jim Zheng [sup.1] , John R. Somoza [sup.1] , William Rowe [sup.1] , [...]

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

Traits of reasonableness are necessary characteristics of successfully engaged citizens within pluralistic liberal democratic societies. Given the evident unlikelihood of the spontaneous development of these critical characteristics, pedagogical effort ought to be exerted towards ensuring that this goal is realized. In what follows, we argue that preschool presents a unique and compelling opportunity for supporting this worthy pedagogical aim, such that, despite purported prohibitions entailed within arguments for the political neutrality of curricula, it ought to be promoted within this area. In the service of illustrating this point, we provide four examples of promising beginnings for this work.

In this paper, Thompson engages the fact that educators perceive themselves to be faced with an apparent dilemma regarding racial identity education. On one hand, their political obligations may incline them to teach racial identity so as to avoid reifying the reality of a racialized system of power. On the other hand, honoring their epistemic obligations to accurately represent the realities of the world may incline them to teach racial identity in a less consequentialist manner, prioritising the goal that students do not suffer hermeneutical injustices as they grapple with racial identities/consequences. Thompson argues that these seemingly opposed obligations can be united, by attending to their underlying claims. In closing, Thompson provides an example of an educational event that coheres with these conclusions.

In this essay, Winston C. Thompson questions the rigidity of the boundary between ideal and nonideal theory, suggesting a porosity that allows elements of both to be brought to bear upon educational issues in singularly incisive ways. In the service of this goal, Thompson challenges and extends John Rawls's theory of justice as fairness, bringing it to bear upon education in our imperfect world. By showing that this representative work of ideal theory can be meaningfully supplemented and applied to the nonideal fact of race, this essay suggests that recognition of nonideal circumstances and theorizing need not void ideal theory's value to philosophy of education. Instead, the field can engage both ideal and nonideal theory on previously unavailable questions and dimensions of educational justice toward productive ends.

Abstract The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we have performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice have exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 has been deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency has resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion has also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD has been found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells have stimulated Interferon-γ-dependent epithelial regeneration in co-cultured organoids, and Interferon-γ has directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration.