Keeping a Clean Surface under Water: Nanoscale Nipple Array Decreases Surface Adsorption and Adhesion Forces

While nanoscale nipple arrays are expected to reduce light reflection and/or dust contamination in some insects, similar structures have been reported in various marine invertebrates. To evaluate the anti-contamination property of the structure in aquatic regimes, we measured the adsorption and adhesion forces on the flat surface and MOSMITE™ (Mitsubishi Chemical Corporation, Tokyo, Japan), a synthetic material mimicking the nipple array, under water. A small force toward the surface occurred when the probe approached the substrate surface. This adsorption force was significantly smaller on MOSMITE™ than on the flat surface. The adhesion force toward the surface occurred when the probe was detached from the surface, and it was also significantly smaller on MOSMITE™ than on the flat surface. The adhesion force in the air was much greater than the force under water, and the force was also significantly smaller on MOSMITE™ than on the flat surface. In the aquatic regime, the nipple array provides less adsorption/adhesion properties for the surface and thus, the organisms would have less contamination of microparticles on their body surface. As the adsorption and adhesion forces are also involved in the attachment of cells, tissue, and larvae, less adhesive body surfaces should be beneficial for survival in aquatic environments, as well as land environments.

YAP/TAZ Promote Hematopoietic Regeneration Via Accelerating the Recovery of Bone Marrow Niche

Adult hematopoietic stem cells (HSCs) reside and are protected in a unique bone marrow (BM) microenvironment, termed the HSC niche, which consists mainly of vascular endothelial cells (EC) and EC-associated mesenchymal stromal cells (MSC). Myeloablative stresses, such as ionizing radiation (IR) and chemotherapy, induce not only depletion of hematopoietic cells but also disruption of HSC niche components, as exemplified by dilation and leakiness of BM vasculature and depletion and dysfunction of BM MSCs. These structural and functional changes in the HSC niche restrain efficient hematopoietic recovery, which often compromises the efficacy of HSC transplantation (HSCT) and chemotherapy. YAP/TAZ are the two transcriptional coactivators normally repressed by LATS kinases downstream of the Hippo pathway. Although cumulative evidence has established a critical role of YAP/TAZ activation in tissue regeneration of various solid organs, their role in BM regeneration remains poorly understood. Our quantitive RT-PCR revealed that YAP/TAZ are abundantly expressed in steady-state mouse ECs (CD45 -Ter119 -CD31 +Sca1 +CD105 hi) and MSCs (CD45 -Ter119 -CD31 -PDGFRα +CD51 +LepR +) but scarcely in hematopoietic cells including HSCs (Lin -cKit +Sca1 +Flk2 -CD150 +CD48 -CD34 lo), which was confirmed by reanalysis of the published single cell RNA-seq datasets (GSE128423). Immunofluorescent imaging of BM sections revealed that YAP/TAZ are distributed mainly in the cytoplasm of ECs but evenly in the cytoplasm and nuclei of MSCs, indicating their differential basal activity in these two HSC niche components. Kinetic transcriptome analysis revealed that YAP/TAZ activity is transiently activated in ECs at 24 hours and returns to a basal repressive state by day 3 after sublethal IR. This transient activation of endothelial YAP/TAZ was critical for vascular integrity, as conditional deletion of YAP/TAZ in ECs (Cdh5-Cre ERT2Yap1 f/fTaz f/f) caused 100% lethality of mice within 10 days following sublethal IR. In sharp contrast, the kinetic expression analysis of a YAP/TAZ target gene CTGF indicated their transient inhibition in MSCs after sublethal IR, and the conditional YAP/TAZ deletion in BM MSCs (Ebf3-Cre ERT2Yap1 f/fTaz f/f) led to their reduced colony forming ability when assessed by colony forming unit fibroblast (CFU-F) assay. Recently, we discovered a novel and potent LATS inhibitor GA-003 that selectively induces mouse and human YAP/TAZ activation in vitro (IC 50 against LATS1 = 1.06 ± 0.08 nM). To analyze the effect of pharmacological YAP/TAZ activation on BM regeneration in vivo, we treated mice with intraperitoneal injection of GA-003 (50 mg/kg per day, for 8 days) following sublethal IR. Remarkably, we observed an accelerated recovery of hematopoiesis, with the absolute numbers of BM cellularity, GMP (Lin -cKit +Sca1 -FcγR +CD34 +) and HSC EPCR (Lin -cKit +Sca1 +CD150 +EPCR +) on day 14 increased by 3.50-fold (p=0.0002), 6.49-fold (p=0.0022) and 11.41-fold (p=0.022), respectively in the GA-003-treated group compared to vehicle-treated group. In addition, GA-003 also promoted hematopoietic recovery after 5-FU injection (150 mg/kg) and HSCT. Nonetheless, consistent with the scarce expression of YAP/TAZ in hematopoietic stem and progenitor cells (HSPC), in vitro GA-003 treatment did not enhance HSPC growth, suggesting niche-mediated effects by GA-003. Indeed, in vitro tube formation assay indicated accelerated angiogenesis by GA-003-treated human umbilical vein ECs, and CFU-F assays revealed significant enhancement of colony formation by mouse BM-derived MSCs upon GA-003 treatment. To reveal the effect of GA-003 on the HSC niche components in vivo, we performed whole BM immunofluorescent imaging at various time points following sublethal IR and GA-003 treatment. We observed alleviated vascular dilation and leakiness and earlier restoration of vascular damage in GA-003-treated group compared to vehicle-treated group, which was associated with increased VE-Cadherin expression in ECs. These results suggest that reinforcing YAP/TAZ activity upon myelosuppression promotes HSC niche integrity and recovery and accelerates hematopoietic regeneration. Taken together, our results establish YAP/TAZ as novel regulators of HSC niche and highlight YAP/TAZ as promising therapeutic targets to boost hematopoietic recovery after myeloablative interventions such as chemotherapy and HSCT. Disclosures Aihara: Nissan Chemical Corporation: Current Employment. Iwawaki: Nissan Chemical Corporation: Current Employment. Nishino: Nissan Chemical Corporation: Current Employment. Iwama: Nissan Chemical Corporation: Research Funding.

Single Cell Analyses Reveal a Non-Canonical EZH2 Activity As a Main Driver of Retinoic Acid Resistance in PLZF/Rara Leukemia

Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. Acute Promyelocytic Leukemia (APL), the M3 subtype of AML, is a good model to illustrate these problematics. Indeed, APL driven by oncogenic fusion proteins such PML/RARA t(15;17) or PLZF/RARA t(11;17) behave differently to differentiation therapeutics. Both APLs differentiate in vivo upon Retinoic Acid (RA) treatment; however, while PML/RARA APL patients exhibit partial or complete remission, PLZF/RARA APL patients remain clinically resistant. In the present study we aim to decipher the transcriptional and epigenetic networks that is linked to t(11;17) APL resistance towards RA. We took advantage of the PLZF/RARA RA resistant murine APL model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. To validate the function of Ezh2 in APL physiology, we combined epigenomic studies with RA-treated and non-RA-treated bone marrow transplantation experiments. We revealed high Ezh2 activity that marks the relapse of RA-treated APL. However, targeting Ezh2 methyltransferase activity was not sufficient to achieve disease cure and, suggests an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight path to sensitize therapy-resistant leukemia cells. In addition, our study uncovers a dual role of Ezh2 in APL and suggests that targeting non-canonical Ezh2 activity could be a new promising therapeutic approach for RA resistant APL. Disclosures Iwama: Nissan Chemical Corporation: Research Funding.

A sales and operations planning application in the Brazilian subsidiary of a multinational chemical company

Goal: the goal of this paper is to investigate how Sales and Operations Planning (S&OP) is conducted in the Brazilian subsidiary of a global corporation of the chemical industry that manufactures and commercializes a variety of hygiene and cleaning consumer products. Design/Methodology/Approach: the case study approach was adopted. Data was gathered during four months by means of visits to the organization for direct observation, interviews with key executives, and internal and public documents, guaranteeing data triangulation. A well-known framework from the literature is applied to analyze the S&OP practices performed by the organization. Results: Findings contribute to aid in the understanding of the S&OP process. The case study indicates that S&OP has been a central process to organize and to align the enterprise’s efforts and deliver its business objectives. Limitations of the investigation: the research is conducted within one single company, a Brazilian subsidiary of a multinational chemical corporation, which limits the generalization of the findings. Practical implications: The research findings enhance the knowledge about S&OP providing practitioners with valuable information to understand better its phenomenon, such as how the process is performed, and the best practices and benefits. Originality/Value: S&OP has been an object of interest of scholars and practitioners for decades. However, the process is far from being completely understood and there is a call for more empirical studies. Thus the academic literature can benefit from this in-depth research that sheds light on an S&OP industry application.

Escalating the DDT Issue with More Court Cases

While HEW and USDA pondered these appellate court decisions, we turned our attention to several more local DDT problems. From a New York Times article (May 3, 1970), we learned that the Olin Chemical Corporation was manufacturing about 20% of the nation’s DDT in buildings owned by the federal government and leased to Olin on the site of the U.S. Army’s Redstone Arsenal near Huntsville, Alabama. A DDT-contaminated effluent from this plant was leaking into the Wheeler National Wildlife Refuge at concentrations known to inhibit reproduction of birds and fish. The refuge also served as a drinking water supply for the city of Decatur, implying a human health hazard as well. Downriver fisherman were also eating their catch, thus concentrating DDT to higher levels as well. In October 1969, the federal Water Quality Administration had recommended a stricter pollution control standard for the Olin plant. Olin said it could not meet that standard, and the Army then overruled the Water Quality Administration’s recommendation. So on June 5, 1970, EDF, along with the National Audubon Society and the National Wildlife Federation, sued in Federal District Court against Olin, the Department of the Army, and the Corps of Engineers seeking to stop the DDT-contaminated discharge. The complaint was written by EDF’s new attorney, Edward Lee Rogers. I supplied the scientific support, which was easy, since it was similar, although steadily expanding, to the Wisconsin hearings and the USDA and HEW cases. Only three days later Olin threw in the towel! On June 8 Olin decided to close its DDT plant and no longer make DDT. DDT apparently was not worth defending. They said they had reached that decision shortly before our case was filed. True or not, it was a quick and easy victory. We needed it. We had won by winning. Even as the legal briefs went back and forth between EDF, USDA, HEW, and the appeals court, another DDT battle was brewing in California. For years scientists had been puzzled by the extremely high levels of DDT contamination along the coast of Southern California compared with other marine environments.