PKM2 enters the morpheein academy.

In this issue of Molecular Cell, Gao et al. (2012) show that the glycolytic enzyme PKM2, in its dimeric form, possesses protein kinase activity and phosphorylates STAT3 in the nucleus, thereby driving expression of genes that promote transformation.

Targeting PAK1.

p21-Activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date, several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents. Given the central role of PAK1 in vital signaling pathways, future clinical development of PAK1 inhibitors will require careful investigation of their safety and efficacy.

Financial logistics models based on systematic approach improving management solutions.

Background: Some firms with good growth opportunities and additional funds could have difficulties accessing external finance. One possible way to enhance their financial inclusion could be an exciting approach to planning the money reserve collected on a firm's account. Methods: This article aims to disclose the introduction of financial logistics as the new theoretical field of management science. The authors present, in this paper, the key findings on the development of logistical models of an optimum money reserve calculation taking into account digital transformation and industry 4.0 technologies and optimization methods. Results: The monetary reserve models are analogies of models of storekeeping in supply chains. The specific area of the theoretical research of logistics is shown in this paper, which could be disclosed as the subject of financial logistics as a science. The authors consider the term "Financial Logistics" based on logistics theory and money demand. Conclusions: Authors suggest the methodology of studying the nature of both financial and material flows of resources by comparing the relevant formulas. From the researchers' points of view, financial logistics could be defined as the theory of managing the cash flows based on the logistical models for calculating a corporation's cash reserve. The authors find it interesting to expand the conditions for calculating financial flows since the uncertainty of external market conditions always influences actual commercial activity.

Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer.

The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function. SIGNIFICANCE: This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease.

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer.

PURPOSE: DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. EXPERIMENTAL DESIGN: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). RESULTS: Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. CONCLUSIONS: Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes.

EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition.

In response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.

Structural and molecular strategy of photosynthetic apparatus organisation of wild flora halophytes.

Structural and molecular parameters of photosynthetic apparatus in plants with different strategies for the accumulation of salts were investigated. CO2 gas exchange rate, content of pigments, mesostructure, chloroplast ultrastructure and the biochemical composition of the membrane structural components in leaves were measured. The objects of the study were euhalophytes (Salicornia perennans, Suaeda salsa, Halocnemum strobilaceum), crynohalophyte (Limonium gmelinii), glycohalophyte (Artemisia santonica). Euhalophytes S. perennans and S. salsa belong to the plants of the halosucculent type, three other species represent the xerophilic type. The highest photosynthetic activity estimated by the average parameters of CO2 gas exchange rate in the leaves was observed in S. perennans plants. Plants of the xerophyte type including both H. strobilaceum euhalophyte and cryno- and glycohalophytes are described by lower values of these characteristics. Larger cells with a great number of chloroplasts and a high content of membrane glycerolipids and unsaturated C18:3 fatty acid, but with smaller pigment and light-harvesting complexes size characterise the features of euhalophytes with a succulent leaf type. Thus, features of the mesostructure, ultrastructure, and supramolecular interactions of the halophyte PA were closely related to the functional parameters of gas exchange, and were characterised by the strategy of species in relation to the accumulation of salts, the life form of plants, and the attitude to the method of water regulation.

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1.

The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model. These data suggest that inhibitors of PP2A, as well as calcium channel blockers, might be used in broader MPNST preclinical studies as single agents or in combinatorial therapeutic strategies.

Mesophyll cell ultrastructure of wheat leaves etiolated by lead and selenium.

The ultrastructure of mesophyll cells was studied in leaves of the Triticum aestivum L. cv. "Trizo" seedlings after two weeks of growth on soil contaminated by Pb and/or Se. The soil treatments: control; (Pb1) 50mgkg-1; (Pb2) 100mgkg-1; (Se1) 0.4mgkg-1; (Se2) 0.8mgkg-1; (Pb1+Se1); (Pb1+Se2); (P2+Se1); and (Pb2+Se2) were used. Light and other conditions were optimal for plant growth. The (Se1)-plants showed enhanced growth and biomass production; (Pb1+Se1)-plants did not lag behind the controls, though O2 evolution decreased; chlorophyll content did not differ statistically in these treatments. Other treatments led to statistically significant growth suppression, chlorophyll content reduction, inhibition of photosynthesis, stress development tested by H2O2 and leaf etiolation at the end of 14-days experiment. The tops of etiolated leaves remained green, while the main leaf parts were visually white. Plastids in mesophyll cells of etiolated parts of leaves were mainly represented by etioplasts and an insignificant amount of degraded chloroplasts. Other cellular organelles remained intact in most mesophyll cells of the plants, except (Pb2+Se2)-plants. Ruptured tonoplast and etioplast envelope, swelled cytoplasm and mitochondria, and electron transparent matrix of gialoplasm were observed in the mesophyll cells at (Pb2+Se2)-treatment, that caused maximal inhibition of plant growth. The results indicate that Pb and Se effects on growth of wheat leaves are likely to target meristem in which the development of proplastids to chloroplasts under the light is determined by chlorophyll biosynthesis. Antagonistic effect of low concentration of Se and Pb in combination may retard etiolation process.

An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas, and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of FASN, suggesting new targeted strategies in the treatment of NF2-deficient tumors. Cancer Res; 77(18); 5026-38. ©2017 AACR.

Photochemical activity and the structure of chloroplasts in Arabidopsis thaliana L. mutants deficient in phytochrome A and B.

The reduced content of photoreceptors, such as phytochromes, can decrease the efficiency of photosynthesis and activity of the photosystem II (PSII). For the confirmation of this hypothesis, the effect of deficiency in both phytochromes (Phy) A and B (double mutant, DM) in 7-27-day-old Arabidopsis thaliana plants on the photosynthetic activity was studied in absence and presence of UV-A radiation as a stress factor. The DM with reduced content of apoproteins of PhyA and PhyB and wild type (WT) plants with were grown in white and red light (WL and RL, respectively) of high (130 µmol quanta m-2 s-1) and low (40 µmol quanta m-2 s-1) intensity. For DM and WT grown in WL, no notable difference in the photochemical activity of PSII was observed. However, the resistance of the photosynthetic apparatus (PA) to UV-A and the rate of photosynthesis under light saturation were lower in the DM compared to those in the WT. Growth in RL, when the photoreceptors of blue light-cryptochromes-are inactive, resulted in the significant decrease of the photochemical activity of PSII in DM compared to that in WT including amounts of QB-non-reducing complexes of PSII and noticeable enhancement of thermal dissipation of absorbed light energy. In addition, marked distortion of the thylakoid membrane structure was observed for DM grown in RL. It is suggested that not only PhyA and PhyB but also cryptochromes are necessary for normal functioning of the PA and formation of the mechanisms of its resistance to UV-radiation.

Biochemistry and cell ultrastructure changes during senescence of Beta vulgaris L. leaf.

The comparative study of biochemical and ultrastructure features in senescing sugar beet (Beta vulgaris L.) leaves was carried out. One group of plants was grown under normal conditions in washed river sand and poured in turn with nitrate-containing mineral solution or water (N plants). Another group of plants, after 1 month of normal growth, was further grown with nitrate omitted in the nutritive solution (defN plants). The starting point of normal leaf senescence in N plants was identified by the maximal content of soluble protein. Soluble carbohydrate pools were statistically constant in senescing N plants, whereas glucose pools varied noticeably. A decrease in the contents of soluble protein and chlorophyll (a + b) in the course of senescing was typical for N plant leaves. The cell membrane in N plant leaves remained mostly intact; the central vacuoles in the leaf cells were large, and their membranes remained intact. The chloroplasts and mitochondria in senescing N plant leaves became swollen. The vesicles that were present in the cytoplasm of N plant leaves were especially large in the oldest leaves. It was concluded that senescing of sugar beet leaves at sufficient nitrate nutrition occurs according to a "vacuolar" scenario. In the case of nitrate deficiency, the content of soluble carbohydrates in defN leaves first reached maximum and then decreased in older leaves; the protein and chlorophyll (a + b) contents were totally lower than those in normal leaves and continuously decreased during the experiments. Chloroplasts in mesophyll cells of defN plant leaves became more rounded; starch grains in chloroplasts degraded and the number and size of lipid globules increased. The multitude of membrane impairments and lots of large vesicles-"crystals" appeared during the experiment. The results showed the controlling action of nitrogen nutrition in the senescing of sugar beet leaves.

PAK signalling during the development and progression of cancer.

p21-Activated kinases (PAKs) are positioned at the nexus of several oncogenic signalling pathways. Overexpression or mutational activation of PAK isoforms frequently occurs in various human tumours, and recent data suggest that excessive PAK activity drives many of the cellular processes that are the hallmarks of cancer. In this Review, we discuss the mechanisms of PAK activation in cancer, the key substrates that mediate the developmental and oncogenic effects of this family of kinases, and how small-molecule inhibitors of these enzymes might be best developed and deployed for the treatment of cancer.

Effects of polyaromatic hydrocarbons on photosystem II activity in pea leaves.

The acute effects of three typical polyaromatic hydrocarbons (PAHs): naphthalene (Naph), phenanthrene (Phen) and fluoranthene (Flu) on photochemical activity of photosystem II (PSII) in detached leaves of 3-week-old pea plants were studied. The leaves were exposed in water with PAHs under white light for 0.5-72 h. The activity of PSII was examined by prompt and delayed chlorophyll a (Chl a) fluorescence. The effects of PAHs depended on their concentration and exposure time. This dependency was more significant in the presence of chemical stressors (Triton X-100 or acetone) or under high intensity irradiance. Increased content of PAHs and long-term exposure (24-72 h) led to significant reduction of the maximum photochemical quantum efficiency (Fv/Fm) of PS II, changes in the polyphasic fluorescence induction (OJIP), and to decreasing amplitudes of fast and slow components of delayed Chl a fluorescence. The damage of PSII depended on water solubility of a given type of PAHs, their concentration and exposure time. During short-time exposure the compound with highest water-solubility - naphthalene - revealed the strongest effect. During long-time exposure the compounds with low water-solubility -Phen, Flu-revealed the strongest effect as the corresponding PAH accumulates in the thylakoids especially when the solution is oversaturated containing a solid phase. The reduction of PSII activity at the presence of naphthalene (30 mg L(-1)) was accompanied by transient generation of H2O2 as well as swelling of thylakoids and distortion of cell plasma membranes, which was indicated by electron microscopy images. Distortion of thylakoid membranes due to accumulation of PAHs as well as the development of oxidative stress seems to be the main pathways of PAHs influencing the photochemical activity of PS II.

Structural features of the salt glands of the leaf of Distichlis spicata 'Yensen 4a' (Poaceae).

The epidermal salt glands of the leaf of Distichlis spicata 'Yensen 4a' (Poaceae) have a direct contact with one or two water-storing parenchyma cells, which act as collecting cells. A vacuole occupying almost the whole volume of the collecting cell has a direct exit into the extracellular space (apoplast) through the invaginations of the parietal layer of the cytoplasm, which is interrupted in some areas so that the vacuolar-apoplastic continuum is separated only by a single thin membrane, which looks as a valve. On the basis of ultrastructural morphological data (two shapes of the extracellular channels, narrow and extended, are found in basal cells), the hypothesis on the mechanical nature of the salt pump in the basal cell of Distichlis leaf salt gland is proposed. According to the hypothesis, a driving force giving ordered motion to salt solution from the vacuole of the collecting cell through the basal cell of the salt gland to cap cell arises from the impulses of a mechanical compression-expansion of plasma membrane, which penetrates the basal cell in the form of extracellular channels. The acts of compression-expansion of these extracellular channels can be realized by numerous microtubules present in the basal cell cytoplasm.

Characterization of the nature of photosynthetic recovery of wheat seedlings from short-term dark heat exposures and analysis of the mode of acclimation to different light intensities.

The nature of photosynthetic recovery was investigated in 10-d-old wheat (Triticum aestivum L., cv. Moskovskaya-35) seedlings exposed to temperatures of 40 and 42 degrees C for 20 min and to temperature 42 degrees C for 40 min in the dark. The aftereffect of heat treatment was monitored by growing the heat-treated plants in low/moderate/high light at 20 degrees C for 72h. The net photosynthetic rates (P(N)) and the fluorescence ratios F(v)/F(m) were evaluated in intact primary leaves and the rates of cyclic and non-cyclic photophosphorylation were measured in the isolated thylakoids. At least two temporally separated steps were identified in the path of recovery from heat stress at 40 and 42 degrees C in the plants growing in high and moderate/high light, respectively. Both photochemical activity of the photosystem II (PSII) and the activity of CO(2) assimilation system were lowered during the first step in comparison with the corresponding activities immediately after heat treatment. During the second step, the photosynthetic activities completely or partly recovered. Recovery from heat stress at 40 degrees C was accompanied by an appreciably higher rate of cyclic photophosphorylation in comparison with control non-heated seedlings. In pre-heated seedlings, the tolerance of the PSII to photoinhibition was higher than in non-treated ones. The mode of acclimation to different light intensities after heat exposures is analyzed.