Explore the vast range of titles available.

The myocyte enhancer factor 2 (MEF2) transcription factor requires interactions with co-factors for precise regulation of its target genes. Our lab previously reported that the mammalian MEF2A isoform regulates the cardiomyocyte costamere, a critical muscle-specific focal adhesion complex involved in contractility, through its transcriptional control of genes encoding proteins localized to this cytoskeletal structure. To further dissect the transcriptional mechanisms of costamere gene regulation and identify potential co-regulators of MEF2A, a bioinformatics analysis of transcription factor binding sites was performed using the proximal promoter regions of selected costamere genes. One of these predicted sites belongs to the early growth response (EGR) transcription factor family. The EGR1 isoform has been shown to be involved in a number of pathways in cardiovascular homeostasis and disease, making it an intriguing candidate MEF2 coregulator to further characterize. Here, we demonstrate that EGR1 interacts with MEF2A and is a potent and specific repressor of MEF2 transcriptional activity. Furthermore, we show that costamere gene expression in cardiomyocytes is dependent on EGR1 transcriptional activity. This study identifies a mechanism by which MEF2 activity can be modulated to ensure that costamere gene expression is maintained at levels commensurate with cardiomyocyte contractile activity.

(B) Self-immunoprecipitation of the myc-EGR1 protein shows efficient expression and purification. https://doi.org/10.1371/journal.pone.0131619.g002 thumbnail Download: * PPT PowerPoint slide * PNG larger image * TIFF original image Fig 4. (E) qRT-PCR analysis of 13 MEF2-dependent costamere genes shows 11 of these genes are down-regulated when EGR1 is overexpressed in NRVMs; fold change is in comparison to expression levels in the Adβgal control. (C) EGR1-depletion results in upregulated costamere gene expression in NRVMs. qRT-PCR analysis of 13 MEF2-dependent costamere genes in EGR1 siRNA knockdown NRVMs shows that eight of the genes are significantly upregulated, and the majority of the remaining genes show a nonsignificant trend towards upregulation when EGR1 is knocked down; fold change is in comparison to expression levels in the negative siRNA knockdown controls, results were normalized to 18s.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1–silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition–associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor–resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

We present the case of a 68-year-old man with no known risk factors for HIV infection who developed a new, rapidly growing lesion on the left medial foot. The lesion was biopsied and found to be consistent with Kaposi sarcoma (KS). He subsequently tested positive for HIV and developed cellulitis of the left lower extremity. Treatment involved empiric antibiotics, surgical excision of the lesion, radiation therapy, and antiretroviral therapy. The development of KS with no known history of HIV/AIDS is uncommon, with only a few reported cases. We provide a summary of 18 cases in the current literature of cutaneous KS as an initial presenting sign of HIV/AIDS.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

Abstract Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events1,2. Although the epigenetic landscape has been shown to be altered in therapy-resistant melanomas and other cancers3,4, a specific targetable epigenetic mechanism regulating treatment resistance has not been validated to date. Here we evaluate the CoREST repressor complex and the novel inhibitor, corin5, within the context of melanoma phenotype plasticity and therapeutic resistance in order to define epigenetic mechanisms underlying these processes. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. We further demonstrate that treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin leads to resensitization of tumor cells to BRAFi. Among the transcriptional targets of CoREST in melanoma are the dual-specificity phosphatases (DUSPs). DUSP1 is shown to be consistently downregulated in BRAFi-resistant melanomas which can be reversed by corin treatment, thereby leading to downstream inhibition of p38 MAPK activity and resensitization of resistant cells to targeted BRAFi therapies. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAF-mutant melanomas who have acquired BRAFi-resistance. Competing Interest Statement Jay Kalin and Philip Cole are coinventors on the below application which covers corin. The US patent is pending. U.S. Patent Application No. 15/124,208 Filed: 07-Sep-2016. Based on PCT/US2015/019467 Filed: 09-Mar-2015. Entitled: INHIBITORS OF HISTONE LYSINE SPECIFIC DEMETHYLASE (LSD1) AND HISTONE DEACETYLASES (HDACS)

Agricultural water management is increasingly prioritized throughout the world as producers are tasked with meeting growing crop demand while also managing environmental resources more sustainably. Likewise, agriculture is increasingly modifying the terrestrial water cycle. In response to these dynamics, the informal research discipline of agrohydrology continues to grow, fueled by a new era of rapidly evolving research tools and big data availability. While many researchers are actively invested in agrohydrology as a research topic, there remains a gap in formalizing this valuable discipline. This article aims to: (a) identify key research themes in agrohydrology, (b) conceptualize future research topics within each theme, and (c) estimate a timeframe before topics become pressing (i.e., before a topic becomes a limiting factor in advancing water management in an agricultural context). This commentary is meant to guide the trajectory of an evolving discipline of agrohydrology, the practice of agricultural water management at multiple nested scales, and the conversation of the invested public. Plain Language Summary The study of water in agriculture is an important global research field. Water supports farming and ranching, and agriculture provides food, feed, fiber, and fuel. However, agricultural activities can also stress water resources. As a result, society faces many water challenges in agriculture. The global demand for agricultural products is increasing, but the availability of fresh water is decreasing in many places. Sometimes this is because of a lack of water, contamination, or social changes. We propose the study of such problems and their solutions be recognized as its own subdiscipline, agrohydrology. Here, we imagine the future of the discipline by giving form to research themes and topics that can rally researchers from many existing fields around this revised subdiscipline. Key Points Agrohydrology has yet to materialize as a distinct sub‐discipline in hydrology despite the importance of agriculture in the water cycle We propose agrohydrology as a sub‐discipline that embraces tools from physical and social sciences across diverse agricultural landscapes Agrohydrology as a revised sub‐discipline offers new opportunities for the sustainable management of water for food in a changing world

Innovative carbon dioxide removal strategies using soil amendments like crushed silicate rock may alter soil structure and function by inducing changes in soil mineralogy. We hypothesized that crushed silicate rock would improve soil physical properties. This study investigated how stand‐alone and combined application of crushed metabasalt and olivine rock (40.3 and 26.9 Mg ha−1), compost (9 Mg ha−1), and biochar (10 Mg ha−1) influenced soil physical health over a 2‐year drought period in a Northern California corn (Zea mays L.) cropping system. Rock‐amended soils exhibited greater aggregate stability, up to 400% greater hydraulic conductivity, and up to 21% lower penetration resistance following 3 years of repeated application, with no changes in texture or plant‐available water. Co‐application of organic amendments yielded no additional benefits compared to rock alone, but usually improved physical properties compared to the unamended control. Long‐term studies are needed to gauge the rate and persistence of these improvements. Core Ideas Enhanced rock weathering harnesses weathering reactions to remove atmospheric carbon dioxide via soil and water. The impacts of crushed silicate rock amendments on soil physical properties over time remain unclear. Rock‐amended soils showed evidence of structural and hydraulic improvement following three annual applications. Biochar enhanced soil physical quality alone and in combination with compost. Future work should assess co‐benefits and tradeoffs associated with silicate rock application on cropland soils. Plain Language Summary Crushed silicate rock is being used in agricultural systems to facilitate storage of atmospheric carbon and offset fossil fuel emissions. However, relatively little is known about how crushed silicate rock affects soil structure and water characteristics, especially alongside commonly used organic amendments like compost and biochar. This will be important to know for maintaining crop productivity and overall soil health, should this method be implemented widely. We studied how crushed silicate rock, compost, and biochar affected compaction, aggregate stability, soil water conductivity, and soil water‐holding capacity in a corn cropping system over a 2‐year drought period in Northern California. We found that crushed silicate rock increased aggregate stability and water conductivity, and decreased compaction when combined with biochar and compost. These preliminary results are promising for crushed silicate rock's effects on soil physical health, but long‐term studies are needed.