A Phosphatidic Acid Binding/Nuclear Localization Motif Determines Lipin1 Function in Lipid Metabolism and Adipogenesis

A polybasic motif in the metabolic regulator lipin1 is both a membrane anchor and a nuclear localization sequence required for lipin1 function in phospholipid metabolism and adipogenesis

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Purpose: In chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably downmodulated in vivo and recover in vitro, suggesting a reversible influence of tissue-located antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.Experimental Design: We investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of patients with CLL.Results: At week 1, there was a significant increase of sIgM expression (64% increase from pretherapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, surface IgD (sIgD) and a range of other receptors did not change. SIgM levels remained higher than pretherapy in the following 3 months despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro The sIgM was fully capable of mediating phosphorylation of SYK, which lies upstream of BTK in the B-cell receptor pathway.Conclusions: This specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy

Advanced Undersea Warfare Systems

Includes supplementary materialOver the next twenty years, the proliferation of threats in the undersea environment will likely challenge the platform-centric model that the United States Navy uses to maintain dominance in Undersea Warfare (USW). Meanwhile, rapidly maturing technologies offer greater capabilities to potential adversaries around the world. Such a paradigm creates an imperative for the Navy to harness emerging technologies to maintain USW dominance amid a dynamic threat environment, while balancing cost, risk, and required performance. This systems engineering analysis develops Advanced Undersea Warfare Systems (AUWS) that provide a technological and tactical advantage based on the needs of the war-fighter. Following critical analysis of the numerous possible alternatives for performing the necessary Command, Control, Communications, Computers, Intelligence, Surveillance, and Reconnaissance (C4ISR) and prosecution and an objective screening process, four system architectures, and associated operational concepts, are selected for detailed analysis. From cost, risk, and performance analyses, superior AUWS concepts are shown to be flexible, scalable, and tailorable systems that balance critical need areas. This analysis highlights the need for new warfare systems that can meet future challenges to the traditional platform-centric model for USW dominance. Using the results and recommendations in this analysis will allow the Navy to deploy capabilities that effectively and efficiently meet future operational needs.http://archive.org/details/advancedundersew109456959Approved for public release; distribution is unlimited

Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL

15Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) immunoglobulin gene heavy-chain variable region (IGHV) displays different states of anergy, indicated by reduced surface immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca(2+) mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. sIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with +12, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, although the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo, and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset.nonenoneD'Avola, Annalisa; Drennan, Samantha; Tracy, Ian; Henderson, Isla; Chiecchio, Laura; Larrayoz, Marta; Rose-Zerilli, Matthew; Strefford, Jonathan; Plass, Christoph; Johnson, Peter W; Steele, Andrew J; Packham, Graham; Stevenson, Freda K; Oakes, Christopher C; Forconi, FrancescoD'Avola, Annalisa; Drennan, Samantha; Tracy, Ian; Henderson, Isla; Chiecchio, Laura; Larrayoz, Marta; Rose Zerilli, Matthew; Strefford, Jonathan; Plass, Christoph; Johnson, Peter W; Steele, Andrew J; Packham, Graham; Stevenson, Freda K; Oakes, Christopher C; Forconi, Francesc

High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in CLL patients

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progress more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 CLL patients (median follow-up of 66 months) and correlated it with pre-treatment sIgM levels and signaling characteristics. Pre-treatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r=0.70; p<0.0001). High sIgM levels/signaling strongly correlated with short TTNT (p<0.05), and 36% CLLhigh versus 8% CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pre-therapy sIgM levels (r=-0.68, p=0.01) or iCa2+ (r=-0.71, p=0.009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy, but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, while it was minimal when sIgM expression was low (p<0.05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction, able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches

Root architecture development in stony soils

Abstract Soils with high stone content represent a challenge to root development, as each stone is an obstacle to root growth. A high stone content also affects soil properties such as temperature or water content, which in turn affects root growth. We investigated the effects of all soil properties combined on root development in the field using both experiments and modeling. Field experiments were carried out in rhizotron facilities during two consecutive growing seasons (wheat [Triticum aestivum L.] and maize [Zea mays L.]) in silty loam soils with high (>50%) and low (<4%) stone contents. We extended the CPlantBox root architecture model to explicitly consider the presence of stones and simulated root growth on the plot scale over the whole vegetation period. We found that a linear increase of stone content resulted in a linear decrease of rooting depth across all stone contents and developmental stages considered, whereas rooting depth was only sensitive to cracks below a certain crack density and at earlier growth stages. Moreover, the impact of precipitation‐influenced soil strength had a relatively stronger impact on simulated root arrival curves during the vegetation periods than soil temperature. Resulting differences between stony and non‐stony soil of otherwise the same crop and weather conditions show similar trends as the differences observed in the rhizotron facilities. The combined belowground effects resulted in differences in characteristic root system measures of up to 48%. In future work, comparison of absolute values will require including shoot effects—in particular, different carbon availabilities