DELAYED HEADING DATE1 interacts with OsHAP5C/D,delays flowering time and enhances yield in rice

Heading date is an important agronomic trait affecting crop yield. The GRAS protein family is a plant‐specific super family extensively involved in plant growth and signal transduction. However, GRAS proteins are rarely reported have a role in regulating rice heading date. Here, we report a GRAS protein DHD1 (Delayed Heading Date1) delays heading and enhances yield in rice. Biochemical assays showed DHD1 physically interacts with OsHAP5C/D both in vitro and in vivo. DHD1 and OsHAP5C/D located in the nucleus and showed that rhythmic expression. Both DHD1 and OsHAP5C/D affect heading date by regulating expression of Ehd1. We propose that DHD1 interacts with OsHAP5C/D to delay heading date by inhibiting expression of Ehd1.     

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5^S163R/wt), and homozygous knock‐in (Ctrp5^S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5^S163R/S163R and Ctrp5^S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology.     

Actomyosin contraction during cellularization is regulated in part by Src64 control of Actin 5C protein levels

Src64 is required for actomyosin contraction during cellularization of the Drosophila embryonic blastoderm. The mechanism of actomyosin ring constriction is poorly understood even though a number of cytoskeletal regulators have been implicated in the assembly, organization, and contraction of these microfilament rings. How these cytoskeletal processes are regulated during development is even less well understood. To investigate the role of Src64 as an upstream regulator of actomyosin contraction, we conducted a proteomics screen to identify proteins whose expression levels are controlled by src64. Global levels of actin are reduced in src64 mutant embryos. Furthermore, we show that reduction of the actin isoform Actin 5C causes defects in actomyosin contraction during cellularization similar to those caused by src64 mutation, indicating that a relatively high level of Actin 5C is required for normal actomyosin contraction and furrow canal structure. However, reduction of Actin 5C levels only slows down actomyosin ring constriction rather than preventing it, suggesting that src64 acts not only to modulate actin levels, but also to regulate the actomyosin cytoskeleton by other means.     

An In Situ Interface Reinforcement Strategy Achieving Long Cycle Performance of Dual‐Ion Batteries

Dual‐ion batteries (DIBs) with high operation voltage offer promising candidates for low‐cost clean energy chemistries. However, there still exist tough issues, including structural collapse of the graphite cathode due to solvent co‐intercalation and electrolyte decomposition on the electrode/electrolyte interface, which results in unsatisfactory cyclability and fast battery failure. Herein, Li₄Ti₅O₁₂ (LTO) modified mesocarbon microbeads (MCMBs) are proposed as a cathode material. The LTO layer functions as a skeleton and offers electrocatalytic active sites for in situ generation of a favorable and compatible cathode electrolyte interface (CEI) layer. The synergetic LTO‐CEI network can change the thermodynamic behavior of the PF₆^? intercalation process and maintain the structural integrity of the graphite cathode, as a “Great Wall” to protect the cathode from structural collapse and electrolyte decomposition. Such LTO‐CEI reinforced cathode exhibits a prolonged cyclability with 85.1% capacity retention after 2000 cycles even at cut‐off potential of 5.4 V versus Li⁺/Li. Moreover, the LTO‐modified MCMB (+)//prelithiated MCMB (?) full cell exhibits a high energy density of ≈200 Wh kg^?1, remarkably enhanced cyclability with 93.5% capacity retention after 1000 cycles. Undoubtedly, this work offers in‐depth insight into interface chemistry, which can arouse new originality to boost the development of DIBs.     

Improving phosphorus sustainability of sugarcane production in Brazil

Phosphorus (P) use in global food and bioenergy production needs to become more efficient and sustainable to reduce environmental impacts and conserve a finite and critical resource (Carpenter & Bennett, Environmental Research Letters, 2011, 6, 014009; Springmann et al., Nature, 2018, 562, 519). Sugarcane is one crop with a large P footprint because production is centered on P‐fixing soils with low P availability (Roy et al., Nature Plants, 2016, 2, 16043; Withers et al., Scientific Reports, 2018, 8, 2537). As global demand for processed sugar and bioethanol continues to increase, we advocate that improving P efficiency could become a key sustainability goal for the sugarcane industry. Here, we applied the 5R global P stewardship framework (Withers et al., Ambio, 2015, 44, 193) to identify more sustainable options to manage P in Brazilian sugarcane production. We show that current inputs of P fertilizer to the current crop area could be reduced by over 305 Gg, or 63%, over the next three decades by reducing unnecessary P fertilizer use, better utilization of recyclable bioresources and redesigning recommendation systems. Adoption of these 5R options would save the sugarcane industry in Brazil 528 US$ million and help safeguard global food and energy security.     

Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes

The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.     

Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome

Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10–100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.     

Design and synthesis of novel 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4-thiadiazol- 2-yl)urea derivatives with potent anti-CML activity throughout PI3K/AKT signaling pathway

In this investigation, a series of 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea receptor tyrosine kinase inhibitors were synthesized by a simple and efficient structure-based design. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against human chronic myeloid leukemia (CML) cell line K562, but very weak or no cellular toxicity through monitoring the growth kinetics of K562 cell during a period of 72 h using the real-time live-cell imaging. Among these compounds, 1-(5-((6-((3-morpholinopropyl) amino)pyrimidin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (7) exhibited the least cellular toxicity and better biological activity in cellular assays (K562, IC₅₀: 0.038 μM). Compound 7 also displayed very good induced-apoptosis effect for human CML cell line K562 and exerted its effect via a significantly reduced protein phosphorylation of PI3K/Akt signal pathway by Human phospho-kinase array analysis. In vitro results indicate that 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea derivatives are lead molecules for further development as treatment of chronic myeloid leukemia and cancer.