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Shooting darts: co-evolution and counter-adaptation in hermaphroditic snails.

BACKGROUND: Evolutionary conflicts of interest between the sexes often lead to co-evolutionary arms races consisting of repeated arisal of traits advantageous for one sex but harmful to the other sex, and counter-adaptations by the latter. In hermaphrodites, these antagonistic interactions are at least an equally important driving force. Here, we investigate the evolution of one of the most striking examples of sexual conflict in hermaphrodites, the so-called shooting of love-darts in land snails. Stabbing this calcareous dart through the partner's skin ultimately increases paternity. This tra

Crystal structure of tabtoxin resistance protein complexed with acetyl coenzyme A reveals the mechanism for beta-lactam acetylation.

Tabtoxin resistance protein (TTR) is an enzyme that renders tabtoxin-producing pathogens, such as Pseudomonas syringae, tolerant to their own phytotoxins. Here, we report the crystal structure of TTR complexed with its natural cofactor, acetyl coenzyme A (AcCoA), to 1.55A resolution. The binary complex forms a characteristic "V" shape for substrate binding and contains the four motifs conserved in the GCN5-related N-acetyltransferase (GNAT) superfamily, which also includes the histone acetyltransferases (HATs). A single-step mechanism is proposed to explain the function of three conserved resi

Replication origins: why do we need so many?

During the G1 phase of the cell cycle, replication origins are prepared to fire, a process that is referred to as origin licensing. It was often pondered what a cell's fate would be if not all of its replication origins were licensed and subsequently activated during S phase. One obvious prediction was that S phase would simply be prolonged. As it turns out, however, the consequences are much more complex. A short G1 phase enforced by premature entry into S phase, or other events that negatively affect origin licensing, will ultimately compromise the cell's ability to complete DNA replication

Cloning an iron-regulated metal transporter from rice.

Rice cDNA and genomic libraries were screened in order to clone an Fe(II) transporter gene. A cDNA clone highly homologous to the Arabidopsis Fe(II) transporter gene IRT1 was isolated from Fe-deficient rice roots. The cDNA clone was named OsIRT1. A genomic clone corresponding to the cDNA was also obtained, sequenced and analysed. When expressed in yeast cells, OsIRT1 cDNA reversed the growth defects of the yeast iron-uptake mutant. Northern blot analysis revealed that OsIRT1 mRNA was predominantly expressed in roots and was induced by Fe- and Cu-deficiency. This suggests that OsIRT1 is a funct

Identification of a novel family of putative methyltransferases that interact with human and Drosophila presenilins.

Mutations in the presenilin genes have been shown to cause the majority of cases of early-onset familial Alzheimer's disease (AD). In addition to their role in AD, presenilins are also known to function during development by interacting with the Notch pathway. To determine if presenilins have additional functions during development and AD we have used a yeast two-hybrid approach to search for proteins that can bind to presenilins. Here, we show the identification and characterization of a novel putative methyltransferase (Metl) that interacts with the loop region of Drosophila presenilin as we

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polyp

Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.

The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott-Aldrich syndrome protein (WASP) family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins. Here we report the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating comple

The novel analgesic compound OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimid ine) attenuates mechanical nociceptive responses in animal models of acute and peripheral neuropathic hyperalgesia.

We investigated the effects of OT-7100, a novel analgesic compound (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidi ne), on prostaglandin E2 biosynthesis in vitro, acute hyperalgesia induced by yeast and substance P in rats and hyperalgesia in rats with a chronic constriction injury to the sciatic nerve (Bennett model), which is a model for peripheral neuropathic pain. OT-7100 did not inhibit prostaglandin E2 biosynthesis at 10(-8)-10(-4) M. Single oral doses of 3 and 10 mg/kg OT-7100 were effective on the hyperalgesia induced by yeast. Single oral doses of 0.1, 0.3, 1 and 3

Candidacidal activity of salivary histatins. Identification of a histatin 5-binding protein on Candida albicans.

Candida albicans is the predominant species of yeast isolated from patients with oral candidiasis, which is frequently a symptom of human immunodeficiency virus infection and is a criterion for staging and progression of AIDS. Salivary histatins (Hsts) are potent in vitro antifungal agents and have great promise as therapeutic agents in humans with oral candidiasis. The molecular mechanisms by which Hsts kill yeast cells are not known. We report here, that unlike other antimicrobial proteins, Hsts do not display lytic activities to lipid membranes, measured by release and dequenching of the fl

Protein transport by purified yeast Sec complex and Kar2p without membranes.

Posttranslational protein translocation across the endoplasmic reticulum membrane of yeast requires a seven-component transmembrane complex (the Sec complex) in collaboration with the lumenal Kar2 protein (Kar2p). A translocation substrate was initially bound to the cytosolic face of the purified Sec complex in a signal-sequence-dependent but Kar2p- and nucleotide-independent manner. In a subsequent reaction, in which Kar2p interacted with the lumenal face of the Sec complex and hydrolyzed adenosine triphosphate, the substrate moved through a channel formed by the Sec complex and was released

Evidence that CYP2C19 is the major (S)-mephenytoin 4'-hydroxylase in humans.

The present study assesses the role of members of the human CYP2C subfamily in the 4'-hydroxylation of (S)-mephenytoin. When recombinant CYP2C proteins were expressed using a yeast cDNA expression system, 2C19 stereospecifically 4'-hydroxylated (S)-mephenytoin with a turnover number at least 10 times higher than that of human liver microsomes. 2C9 (both Ile359 and Leu359 alleles) and 2C18 (Thr385 and Met385 alleles) metabolized this substrate at a rate 100-fold lower than 2C19, and metabolism by these 2C proteins was not stereospecific for the S-enantiomer. 2C8 exhibited very little mephenytoi

What information do inhibitors provide about the structure of the hydroquinone oxidation site of ubihydroquinone: cytochrome c oxidoreductase?

The Q cycle mechanism of the bc1 complex requires two quinone reaction centers, the hydroquinone oxidation (QP) and the quinone reduction (QN) center. These sites can be distinguished by the specific binding of inhibitors to either of them. A substantial body of information about the hydroquinone oxidation site has been provided by the analysis of the binding of QP site inhibitors to the bc1 complex in different redox states and to preparations depleted of lipid or protein components as well as by functional studies with mutant bc1 complexes selected for resistance toward the inhibitors. The r

Fragile X-linked mental retardation and the difficulties of reverse genetics.

Fragile X-linked mental retardation is an enigmatic inheritable syndrome in which severe mental retardation, a cytogenetically detectable fragile site at Xq27.3 (FraX) and a number of dysmorphic features are associated. Genetic analysis shows that the mode of inheritance is more complex than a straightforward X-linked recessive trait and probably involves a two-step process for which several models have been proposed. Early attempts at 'cloning the fragile site' provided several DNA segments lying in its general vicinity, and large scale DNA mapping methods were extensively applied in an effor

Growth performance and physiometabolic safety of probiotic-Curcuma herbal supplementation in local female lambs of Indonesia.

BACKGROUND AND AIM: The escalating demand for animal protein in Indonesia underscores the imperative for efficacious nutritional strategies … he supplement comprised Lactobacillus sp. (1.00 × 107 CFU/mL), Aspergillus sp. (1.00 × 105 CFU/mL), Saccharomyces cerevisiae (5.25 × 107 CFU/mL), and Azotobacter sp. (8.20 × 106 CFU/mL), amalgamated with Curcuma longa and Curcuma xanthorrhiza (Herbal Farm, Sido Muncul, Semarang, Indonesia). The formulation was dispensed daily at 10 mL/L in drinking water over a …

Applications of synthetic biology in medical and pharmaceutical fields.

Synthetic biology aims to design or assemble existing bioparts or bio-components for useful bioproperties. During the past decades, progresses have been made to build delicate biocircuits, standardized biological building blocks and to develop various genomic/metabolic engineering tools and approaches. Medical and pharmaceutical demands have also pushed the development of synthetic biology, including integration of heterologous pathways into designer cells to efficiently produce medical agents, enhanced yields of natural products in cell growth media to equal or higher than that of the extract

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… Artemisic acid | A precursor of anti-malarial drug artemisinin | Terpenoids | Saccharomyces cerevisiae | 25 | 2013 | 23 Thebaine | Pain management and palliative care | Alkaloids | E. coli / Saccharomyces cerevisiae | 2.1 × 10 −3 /6.6 × 10 −5 | 2016/2015 | 323 , 324 Hydrocodone | Pain management and … and vincristine | Alkaloids | Saccharomyces cerevisiae | 2.7 × 10 −5 | 2022 | 405 Breviscapine | Treat cardio- and cerebrovascular diseases | Flavonoids | Saccharomyces cerevisiae | 0.2 | 2018 | 406 Scopolamine | Treat neuromuscular disorders | Alkaloids | Saccharomyces cerevisiae | 6 × 10 −2 | 2020 …

GC-MS profiling and in vitro antioxidant, cytotoxic and antimicrobial activities of Trianthema triquetra Rottl. ex Willed.

Trianthema triquetra Rottl. ex Willed is being used as a herbal remedy for various diseases in India and Pakistan. Still, no scientific data is available about therapeutic potential and phytochemistry of the plant. The aim of the current investigation is to perform GC-MS analysis, antioxidant (total phenolic and flavonoid content, DPPH assay), antimicrobial (disc diffusion assay) and cytotoxic (XTT and RBC's cellular membrane protection assay) studies. Methanolic extract and its fractions (n-hexane, ethyl-acetate, chloroform, n-butanol and water) were investigated for in vitro studies. Results

Halcyon days of TOR: Reflections on the multiple independent discovery of the yeast and mammalian TOR proteins.

The quest to elucidate the molecular mechanism of action of rapamycin in the early 1990s led to the discovery of the novel TOR (target of rapamycin) proteins in yeast and mammalian cells. This was a major breakthrough that resulted in the development of new rapamycin analogs as anti-cancer agents, and launched new research that revealed the pre-eminent biological role of mTOR (mammalian or mechanistic TOR). Beyond mediating rapamycin sensitivity, the TOR proteins are nutrient sensing protein kinases, conserved from yeast to man, with a core function in regulating cell growth, metabolism and ov

Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening.

The mitochondrial calcium uniporter complex is essential for calcium (Ca2+) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca2+ signal transduction. Despite its involvement in several human diseases, we currently lack pharmacological agents for targeting uniporter activity. Here we introduce a high-throughput assay that selects for human MCU-specific small-molecule modulators in primary drug screens. Using isolated yeast mitochondria, reconstituted with human MCU, its essential regulator EMRE, and aequorin, and exploiting a D-lactate- and m

Generation in yeast and antigenic characterization of hepatitis E virus capsid protein virus-like particles.

Hepatitis E is a globally distributed human disease caused by hepatitis E virus (HEV). In Europe, it spreads through undercooked pork meat or other products and with blood components through transfusions. There are no approved or golden standard serologic systems for HEV diagnostics. Commercially available HEV tests often provide inconsistent results which may differ among the assays. In this study, we describe generation in yeast and characterization of HEV genotype 3 (HEV-3) and rat HEV capsid proteins self-assembled into virus-like particles (VLPs) and the development of HEV-specific monocl

Cross-Neutralising Nanobodies Bind to a Conserved Pocket in the Hemagglutinin Stem Region Identified Using Yeast Display and Deep Mutational Scanning.

Cross-neutralising monoclonal antibodies against influenza hemagglutinin (HA) are of considerable interest as both therapeutics and diagnostic tools. We have recently described five different single domain antibodies (nanobodies) which share this cross-neutralising activity and suggest their small size, high stability, and cleft binding properties may present distinct advantages over equivalent conventional antibodies. We have used yeast display in combination with deep mutational scanning to give residue level resolution of positions in the antibody-HA interface which are crucial for binding.