Mean and variance of FST in a finite number of incompletely isolated populations

In the presence of migration F_ST in a finite number of incompletely isolated populations first increases, but after reaching a certain maximum value, it starts to decline and eventually becomes 0. The mean and variance of F_ST in this process are studied by using the recurrence formulas for the moments of gene frequencies in the island model of finite size as well as by using Monte Carlo simulation. The mean and variance in the early generations can be predicted by the approximate formulas developed. On the other hand, if we exclude the cases of an allele being fixed in all subpopulations, the mean of F_ST eventually reaches a steady-state value. This value is given by 1 − 2N_T(1 − λ) approximately, where N_T is the total population size and λ is the rate of decay of heterozygosity at steady state. It is shown that the mean and variance of F_ST depend on the initial gene frequency and when this is close to 0 or 1, Lewontin and Krakauer's test of the neutrality of polymorphic genes is not valid.     

Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.     

l-Acylimidazoles with Broad-spectrum Fungicidal Activity

The membrane lipids of six higher plants that differ in salt tolerance were analyzed and compared. The root lipids increased in a ratio of glycolipid/phospholipid with increasing salt- tolerance. A similar increase in the ratio was observed with increasing external salinity when halophytic orach and salt-sensitive cucumber were exposed to varying salinity, although the latter plant was limited to only a little increase. Measurements of ion-transport rates with artificial lipid membranes revealed that the root lipids from a salt-resistant plant formed a more permeable membrane than those from a salt-sensitive species. It was found that the membrane permeability was related to the glycolipid/phospholipid ratio in the membrane lipids, where the glycolipids were stimulative and the phospholipids were repressive for ion-flow. These different effects of the two lipid classes may be attributed to their molecular species and head groups.     

Lack of Plasma Kallikrein-Kinin System Cascade in Teleosts

The kallikrein-kinin system (KKS) consists of two major cascades in mammals: “plasma KKS” consisting of high molecular-weight (HMW) kininogen (KNG), plasma kallikrein (KLKB1), and bradykinin (BK); and “tissue KKS” consisting of low molecular-weight (LMW) KNG, tissue kallikreins (KLKs), and [Lys⁰]-BK. Some components of the KKS have been identified in the fishes, but systematic analyses have not been performed, thus this study aims to define the KKS components in teleosts and pave a way for future physiological and evolutionary studies. Through a combination of genomics, molecular, and biochemical methods, we showed that the entire plasma KKS cascade is absent in teleosts. Instead of two KNGs as found in mammals, a single molecular weight KNG was found in various teleosts, which is homologous to the mammalian LMW KNG. Results of molecular phylogenetic and synteny analyses indicated that the all current teleost genomes lack KLKB1, and its unique protein structure, four apple domains and one trypsin domain, could not be identified in any genome or nucleotide databases. We identified some KLK-like proteins in teleost genomes by synteny and conserved domain analyses, which could be the orthologs of tetrapod KLKs. A radioimmunoassay system was established to measure the teleost BK and we found that [Arg⁰]-BK is the major circulating form instead of BK, which supports that the teleost KKS is similar to the mammalian tissue KKS. Coincidently, coelacanths are the earliest vertebrate that possess both HMW KNG and KLKB1, which implies that the plasma KKS could have evolved in the early lobe-finned fish and descended to the tetrapod lineage. The co-evolution of HMW KNG and KLKB1 in lobe-finned fish and early tetrapods may mark the emergence of the plasma KKS and a contact activation system in blood coagulation, while teleosts may have retained a single KKS cascade.     

‘Tethering’ fragment-based drug discovery to identify inhibitors of the essential respiratory membrane protein type II NADH dehydrogenase

Energy generation is a promising area of drug discovery for both bacterial pathogens and parasites. Type II NADH dehydrogenase (NDH-2), a vital respiratory membrane protein, has attracted attention as a target for the development of new antitubercular and antimalarial agents. To date, however, no potent, specific inhibitors have been identified. Here, we performed a site-directed screening technique, tethering-fragment based drug discovery, against wild-type and mutant forms of NDH-2 containing engineered active-site cysteines. Inhibitory fragments displayed IC₅₀ values between 3 and 110?μM against NDH-2 mutants. Possible binding poses were investigated by in silico modelling, providing a basis for optimisation of fragment binding and improved potency against NDH-2.     

Synthesis and Inhibitory Activity Against Phosphatidylinositol 4-Kinase of Echiguanine Analogs

Abstract

N-Substituted-2-amino-4(3H)-7H-oxopyrrolo[2,3-d]pyrimidine-5-carboxamides and their ribofuranosyl and 2′,3′-dideoxyribofuranosyl derivatives were prepared as membrane permeable echiguanine analogs and tested for their ability to inhibit phosphatidylinositol (PI) 4-kinase. The ethylamide 5 and the corresponding ribofuranosyl compound 11 inhibited PI 4-kinase with IC₅₀ values of 0.02 and 2.4 μg/ml, respectively.     

Estimation of Aeration and Agitation Conditions in Respect to Oxygen Supply and Ventilation

In inosine fermentation, the yield of the product was closely related to the partial pressure of carbon dioxide in the culture system rather than the bicarbonate ion concentration in the culture liquid. The inhibitory effect of carbon dioxide was restored by the methods of reducing the partial pressure of carbon dioxide lower than a certain level. Both ventilation and chemical absorption were applicable for the restoration of the carbon dioxide inhibition, but ventilation had great advantages over the other method from an industrial view-point. In the estimation of aeration-agitation conditions for the scale-up of submerged fermentation in which carbon dioxide was inhibitory, the rate of aeration was to be established to make sufficient ventilation and overcome this inhibition. A scheme for the procedure for the estimation of aeration-agitation conditions under the consideration of influences of carbon dioxide on submerged fermentation was proposed in this paper.     

Extracellular Accumulation of Phospholipids,UDP-N-Acetylhexosamine Derivatives and L-Glutamic Acid by Penicillin-treated Corynebacterium alkanolyticum

The addition of penicillin to cells of Corynebacterium alkanolyticum No. 314 growing on n-paraffins medium caused the simultaneous excretion of phospholipids, UDP-N-acetylhexosamine derivatives and L-glutamic acid.

Among many antibiotics which inhibit cell wall synthesis, only the inhibitors of peptideglycan transpeptidase such as penicillin G and cephaloridine were effective for inducing the excretion of phospholipids, UDP-N-acetylhexosamine derivatives and L-glutamic acid, while the others promoted only the excretion of UDP-N-acetylhexosamine derivatives.

From the close relationship between the excretion of L-glutamic acid and the excretion of phospholipids, it was suggested that the action of penicillins and cephalosporins on the cell membrane resulted in the excretion of L-glutamic acid.     

Conformational Change of a Natto Mucin in Solution

The mucin obtained from a natto sample was found to be composed of 58 % of γ-polyglutamic acid and 40% of polysaccharide. The ratio of l- and d-glutamic acid was determined to be 58:42 using l-glutamic acid decarboxylase. The weight- and z-average molecular weight were 2.08 × 10⁵ and 2.22 × 10⁵, respectively. The distribution curve of the sedimentation coefficient showed a small heterogeneity. The mucin molecule was considered to be randomly coiled at pH 5.0 ~ 8.8 and to be a rod-like molecule in the lower pH region.