New methods of analysis and investigation of terpenoid indole alkaloids

Plant science

An ABS control logic based on wheel force measurement

The paper presents an anti-lock braking system (ABS) control logic based on the measurement of the longitudinal forces at the hub bearings. The availability of force information allows to design a logic that does not rely on the estimation of the tyre-road friction coefficient, since it continuously tries to exploit the maximum longitudinal tyre force. The logic is designed by means of computer simulation and then tested on a specific hardware in the loop test bench: the experimental results confirm that measured wheel force can lead to a significant improvement of the ABS performances in terms of stopping distance also in the presence of road with variable friction coefficien

A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis.

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes

SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity

Spalt-like transcription factor 1 (SALL1) is a critical regulator of organogenesis and microglia identity. Here we demonstrate that disruption of a conserved microglia-specific super-enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knockout mice, we provide evidence for functional interactions between SALL1 and SMAD4 required for microglia-specific gene expression. SMAD4 binds directly to the Sall1 super-enhancer and is required for Sall1 expression, consistent with an evolutionarily conserved requirement of the TGFβ and SMAD homologs Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Unexpectedly, SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in enhancer knockout microglia, thereby enforcing microglia-specific functions of the TGFβ–SMAD signaling axis.</p

Potential for Phototrophy in Venus' Clouds

We show that solar irradiances calculated across Venus clouds support the potential for Earth-like phototrophy and that treatment of Venus aerosols containing neutralized sulfuric acid favor a habitable zone. The phototrophic potential of Venus atmosphere was assessed by calculating irradiances (200-2000 nm, 15 deg solar zenith angle, local noon) using a radiative transfer model that accounted for absorption and scattering by the major and minor atmospheric constituents. Comparisons to Earths surface (46 W m-2, 280-400 nm) suggest that Venus middle and lower clouds receive 87% less normalized UV flux (6-7 W m-2) across 200-400 nm, yet similar normalized photon flux densities (4400-6200 micromol m2 s-1) across 350-1200 nm. Further, Venus signature phototrophic windows and subwindows overlap with the absorption profiles of several photosynthetic pigments, especially bacteriochlorophyll b from intact cells and phycocyanin. Therefore, Venus light, with limited UV flux in the middle and lower clouds, is likely quite favorable for phototrophy. We additionally present interpretations to refractive index and radio occultation measures for Venus aerosols that suggest the presence of lower sulfuric abundances and/or neutralized forms of sulfuric acid, such as ammonium bisulfate. Under these considerations, the aerosols in Venus middle clouds could harbor water activities (0.6) and buffered acidities (Hammett acidity factor, H0 -0.1 to -1.5) that lie within the limits of acidic cultivation (H0 -0.4) and are tantalizingly close to the limits of oxygenic photosynthesis (H0 0.1). Together, these photophysical and chemical considerations support a potential for phototrophy in Venus clouds

Hoxa9 Immortalizes a Granulocyte-Macrophage Colony-Stimulating Factor-Dependent Promyelocyte Capable of Biphenotypic Differentiation to Neutrophils or Macrophages, Independent of Enforced Meis Expression

The genes encoding Hoxa9 and Meis1 are transcriptionally coactivated in a subset of acute myeloid leukemia (AML) in mice. In marrow reconstitution experiments, coexpression of both genes produces rapid AML, while neither gene alone generates overt leukemia. Although Hoxa9 and Meis1 can bind DNA as heterodimers, both can also heterodimerize with Pbx proteins. Thus, while their coactivation may result from the necessity to bind promoters as heterodimers, it may also result from the necessity of altering independent biochemical pathways that cooperate to generate AML, either as monomers or as heterodimers with Pbx proteins. Here we demonstrate that constitutive expression of Hoxa9 in primary murine marrow immortalizes a late myelomonocytic progenitor, preventing it from executing terminal differentiation to granulocytes or monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3. This immortalized phenotype is achieved in the absence of endogenous or exogenous Meis gene expression. The Hoxa9-immortalized progenitor exhibited a promyelocytic transcriptional profile, expressing PU.1, AML1, c-Myb, C/EBP alpha, and C/EBP epsilon as well as their target genes, the receptors for GM-CSF, G-CSF, and M-CSF and the primary granule proteins myeloperoxidase and neutrophil elastase. G-CSF obviated the differentiation block of Hoxa9, inducing neutrophilic differentiation with accompanying expression of neutrophil gelatinase B and upregulation of gp91phox. M-CSF also obviated the differentiation block, inducing monocytic differentiation with accompanying expression of the macrophage acetyl-low-density lipoprotein scavenger receptor and F4/80 antigen. Versions of Hoxa9 lacking the ANWL Pbx interaction motif (PIM) also immortalized a promyelocytic progenitor with intrinsic biphenotypic differentiation potential. Therefore, Hoxa9 evokes a cytokine-selective block in differentiation by a mechanism that does not require Meisgene expression or interaction with Pbx through the PIM

A Unified Controller for Multi-State Operation of the Bi-Directional Buck-Boost DC-DC Converter

DC grid interfaces for supercapacitors (SCs) are expected to operate with a wide range of input voltages with fast dynamics. The class-C DC-DC converter is commonly used in this application because of its simplicity. However, it does not work if the output voltage (V2) becomes smaller than the input voltage (V1). The non-isolated bi-directional Buck-Boost DC-DC converter does not have this limitation. Its two half-bridges provide a means for controlling the power flow operating in the conventional dual-state mode, as well as multi-state, tri, and quad modes. These can be used for mitigating issues such as the Right Half Plane (RHP) zero that has a negative impact on the dynamic response of the system. Multi-state operation typically requires multi-variable control, which is not easy to realize with conventional PI-type controllers. This paper proposes a unified controller for multi-state operation. It employs a carrier-based modulation scheme with three modulation signals that allows the converter to operate in all four possible states and eight different modes of operation. A mathematical model is developed for devising a multi-variable control scheme using feedback linearization. This allows the design of control loops with simple PI controllers that can be used for all multi-state modes under a wide range of operating conditions with the same performance. The proposed scheme is verified by means of simulations

Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: Potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia

Hoxa9 and Meis1a are homeodomain transcription factors that heterodimerize on DNA and are down-regulated during normal myeloid differentiation. Hoxa9 and Meis1a cooperate to induce acute myeloid leukemia (AML) in mice, and are coexpressed in human AML. Despite their cooperativity in leukemogenesis, we demonstrated previously that retroviral expression of Hoxa9 alone—in the absence of coexpressed retroviral Meis1 or of expression of endogenous Meis genes—blocks neutrophil and macrophage differentiation of primary myeloid progenitors cultured in granulocyte–macrophage colony-stimulating factor (GM-CSF). Expression of Meis1 alone did not immortalize any factor-dependent marrow progenitor. Because HoxA9-immortalized progenitors still execute granulocytic differentiation in response to granulocyte CSF (G-CSF) and monocyte differentiation in response to macrophage CSF (M-CSF), we tested the possibility that Meis1a cooperates with Hoxa9 by blocking viable differentiation pathways unaffected by Hoxa9 alone. Here we report that Meis1a suppresses G-CSF-induced granulocytic differentiation of Hoxa9-immortalized progenitors, permitting indefinite self-renewal in G-CSF. Meis1a also reprograms Hoxa9-immortalized progenitors to proliferate, rather than die, in response to stem cell factor (SCF) alone. We propose that Meis1a and Hoxa9 are part of a molecular switch that regulates progenitor abundance by suppressing differentiation and maintaining self-renewal in response to different subsets of cytokines during myelopoiesis. The independent differentiation pathways targeted by Hoxa9 and Meis1a prompt a “cooperative differentiation arrest” hypothesis for a subset of leukemia, in which cooperating transcription factor oncoproteins block complementary subsets of differentiation pathways, establishing a more complete differentiation block in vivo