Complete Genome Sequencing of Three Clade-1 Xanthomonads Reveals Genetic Determinants for a Lateral Flagellin and the Biosynthesis of Coronatine-Like Molecules in Xanthomonas.

Evolutionarily, early-branching xanthomonads, also referred to as clade-1 xanthomonads, include major plant pathogens, most of which colonize monocotyledonous plants. Seven species have been validly described, among them the two sugarcane pathogens Xanthomonas albilineans and Xanthomonas sacchari, as well as Xanthomonas translucens, which infects small-grain cereals and diverse grasses but also asparagus and pistachio trees. Single-gene sequencing and genomic approaches have indicated that this clade likely contains more, yet-undescribed species. In this study, we sequenced representative strains of three novel species using long-read sequencing technology. Xanthomonas campestris pv. phormiicola strain CFBP 8444 causes bacterial streak on New Zealand flax, another monocotyledonous plant. Xanthomonas sp. strain CFBP 8443 has been isolated from common bean, and Xanthomonas sp. strain CFBP 8445 originated from banana. Complete assemblies of the chromosomes confirmed their unique phylogenetic position within clade 1 of Xanthomonas. Genome mining revealed novel genetic features, hitherto undescribed in other members of the Xanthomonas genus. In strain CFBP 8444, we identified genes related to the synthesis of coronatine-like compounds, a phytotoxin produced by several pseudomonads, which raises interesting questions about the evolution and pathogenicity of this pathogen. Furthermore, strain CFBP 8444 was found to contain a second, atypical flagellar gene cluster in addition to the canonical flagellar gene cluster. Overall, this research represents an important step toward better understanding the evolutionary history and biology of early-branching xanthomonads.

The Prognostic Role of CYP Enzyme in Kidney Transplantation: A Single Centre Experience.

BACKGROUND: The main goal of immunosuppressive agents is to reach a balance of preserving allograft function while minimizing adverse effects. The purpose of our research is to corroborate the role of CYP3A enzyme in developing individual medication therapy via measuring medicine levels in patients' blood samples. METHODS: This retrospective analysis studies 15 kidney transplant recipients. We carried out genotyping (CYP3A5, CYP3A4) after isolating DNA and RNA in patient and donor blood samples; we also determined CYP3A4 messenger RNA expression in case of recipients. Tacrolimus blood levels, dosage, and tacrolimus concentration normalized by dose and the body weight (C0/D ratio) were evaluated. RESULTS: In this research, recipients were divided into 2 groups based on their CYP3A5 genotype. Those who carry CYP3A5*1 allele (*1/*1 or *1/*3) are CYP3A5 expressors, whereas those who are homozygous for the nonfunctional CYP3A5*3 allele are CYP3A5 nonexpressors. There were 3 patients with functioning CYP3A5 enzyme (patients with CYP3A5*1/*3 genotype) where increased tacrolimus metabolism was expected. Our data show that C0/D ratio of CYP3A5 nonexpressors was around 3 times higher than of CYP3A5 expressors. Looking at CYP3A4 enzyme, we found 1 patient carried CYP3A4*22/*22 genotype where we expected decreased CYP3A4 expression. It is clear that this patient had adequate therapy medication levels (9.50 µg/L) despite having received very low dosage of tacrolimus (0.03 mg/weight/d). CONCLUSIONS: Our results confirmed the importance of determining CYP status of recipients after a transplant because individual differences were observed in tacrolimus treatment that were partly influenced by CYP status of recipients.

Bacteriophage-Mediated Control of Phytopathogenic Xanthomonads: A Promising Green Solution for the Future.

Xanthomonads, members of the family Xanthomonadaceae, are economically important plant pathogenic bacteria responsible for infections of over 400 plant species. Bacteriophage-based biopesticides can provide an environmentally friendly, effective solution to control these bacteria. Bacteriophage-based biocontrol has important advantages over chemical pesticides, and treatment with these biopesticides is a minor intervention into the microflora. However, bacteriophages' agricultural application has limitations rooted in these viruses' biological properties as active substances. These disadvantageous features, together with the complicated registration process of bacteriophage-based biopesticides, means that there are few products available on the market. This review summarizes our knowledge of the Xanthomonas-host plant and bacteriophage-host bacterium interaction's possible influence on bacteriophage-based biocontrol strategies and provides examples of greenhouse and field trials and products readily available in the EU and the USA. It also details the most important advantages and limitations of the agricultural application of bacteriophages. This paper also investigates the legal background and industrial property right issues of bacteriophage-based biopesticides. When appropriately applied, bacteriophages can provide a promising tool against xanthomonads, a possibility that is untapped. Information presented in this review aims to explore the potential of bacteriophage-based biopesticides in the control of xanthomonads in the future.

Analysis of the acceptance practice of deceased donor kidneys in a single Hungarian transplant centre / A kadáverdonor-vesék elfogadási gyakorlatának vizsgálata a debreceni transzplantációs centrumban.

Összefoglaló. Bevezetés: A magyarországi vesetranszplantáció 2013 óta az Eurotransplant (ET) keretein belül zajlik. A debreceni vesetranszplantációs centrumhoz évente kb. 200 kadáverdonorvese-felajánlás érkezik, melyek 37%-a kerül a megismert adatok alapján elfogadásra. Nem minden elfogadott vese kerül beültetésre, aminek számos oka lehet. Célkituzés: A debreceni szakmai gyakorlat elemzése és bemutatása reprezentatív mintán. Módszer: A debreceni centrumhoz 2016. november és 2020. március között 624 vesefelajánlás érkezett. A felajánlott vesék 37%-a (n = 229) került elozetesen elfogadásra, késobb az elfogadott vesék 63%-a (n = 144) került beültetésre. Centrumunkban az ún. 'standard criteria', azaz tökéletes minoségu donorvesék szignifikánsan magasabb arányban kerültek elfogadásra, majd beültetésre, mint az 'extended criteria', azaz kompromisszummal vállalhatók. Az elfogadott és nem elfogadott veséket vizsgálva a KDPI (kidney donor profile index) és a KDRI (kidney donor risk index) értéke szignifikánsan magasabb volt az elutasított donorok esetében (p<0,001). Eredmények: Elemeztük, hogy a felajánlott, de a centrum által nem beültetett donorveséket más ET-centrumban elfogadták-e. Látható, hogy a felajánlott 624 donorvese közül 144 Debrecenben, 313 pedig más ET-centrumban került beültetésre, viszont 167 vese beültetése egyik ET-centrumban sem történt meg (discarded organ). A 36-85 KDPI-értékkel rendelkezo csoportból került beültetésre a legtöbb donorvese (180 vese) más ET-centrumban. A Debrecenben beültetett kadáverdonor-vesék KDPI- és KDRI-értéke szignifikánsan alacsonyabb volt a nekünk felajánlott, majd máshol beültetett vesékhez képest. Következtetés: Összességében elmondható, hogy a debreceni centrumban a magas rizikócsoportba tartozó donorszervek elutasításra kerültek, miközben más centrumban a nagy részüket beültették. Ez alapján a 36-85 KDPI-értéku csoport a transzplantációs esetszám bovítésének lehetséges forrása a recipiens ismeretében. Orv Hetil. 2021; 162(26): 1022-1028. INTRODUCTION: Kidney transplantation in Hungary is carried out via Eurotransplant (ET). Our centre in Debrecen receives around 200 kidney offers a year, of which 37% are accepted. Not all accepted kidneys are transplanted, which can be a result of a number of causes. Obejctive: A debreceni szakmai gyakorlat elemzése és bemutatása reprezentatív mintán. METHOD: Between November 2016 and March 2020, the centre of Debrecen received 624 kidney offers. 37% (n = 229) of the offered kidneys got preliminarily accepted, of which 63% (n = 144) were transplanted later. In our centre, standard criteria donor kidneys were accepted and transplanted in significantly higher rate, than extended criteria donor kidneys. Looking at accepted and rejected kidneys, KDPI and KDRI values were significantly higher in the case of the refused ones (p<0.001). RESULTS: Part of our assessment is to analyze whether kidneys offered to and refused by us got accepted in other transplant centres. In the examined period, of the 624 kidneys offered to our centre 144 were transplanted in Debrecen, 313 were transplanted in other ET centres, while 167 were not transplanted at all (discarded organ). The majority of transplanted kidneys in other ET centres had KDPI values between 36 and 85 (180 kidneys.) KDPI and KDRI values of kidneys transplanted in our centre were significantly lower than those that were offered to us, but got transplanted elsewhere. CONCLUSION: To summarize, we can say that high-risk donor organs are refused in the transplant centre of Debrecen, while the majority of them are being transplanted in other centres. Based on this, kidneys of KDPI value between 36 and 85 are a possible source of expanding the number of transplantations, with regards to the recipient. Orv Hetil. 2021; 162(26): 1022-1028.

T-cell Subset Profile in Kidney Recipients of Extended or Standard Donors.

INTRODUCTION: The usage of extended-criteria donors (ECD) became a routinely accepted manner in the last decade. ECD is a potential risk factor for antibody-mediated rejection. Analysis of lymphocyte subsets might be a complementary diagnostic toolkit because there is limited knowledge about this term. METHOD: Between May 12, 2016, and September 4, 2019, a total of 130 patients who had undergone kidney transplant were investigated. Patients were divided in ECD and standard criteria donor (SCD) groups. Blood samples were collected before the operation, then in the first week and after 30, 60, 180, and 365 days. Besides routine laboratory tests, multicolor flow cytometry was performed for lymphocyte subsets. RESULTS: ECD grafts were transplanted to older recipients. The number of CD4+ cells increased in the SCDs from the first week to until the end of first month, and then decreased. The number of CD4+ cells decreased from the beginning of the study until the end of first year to 66% of its original value in ECDs. At the first month, the number of CD19+ cells was higher in SCD compared with ECD cases; the number then decreased in both groups. T-regulatory cells had a drop at the first week that lasted until the first month. A bigger increase in SCD and a moderate increase in ECD group were then observed. The kinetics of CD19+ and CD19+ naive cells are similar in the ECD and SCD groups. In the SCD group, cell count decreased in both CD19+ (13%) and CD19+ naive (12%) between third and sixth month. The count of CD19+ cells decreased by 9%, but the count of CD19+ naive cells increased by 11% between the sixth month and first year. DISCUSSION: The prolonged postoperative uremic state caused by the poorer initial function, together with an aging immune system, explains the weaker immune response in ECD patients, which may be the cause of the decreased number of memory and regulatory T cells. Older patients with an ECD graft need a tailored, personalized, and less aggressive immunosuppressive treatment.

Quality Assessment of Donor Kidneys and the Tendency of Kidney Acceptance: A Single-Center Experience.

PURPOSE: The increasing age of donors and the increasing tendency of comorbidities requires an extension in acceptance criteria. In this review, the tendency for acceptance and refusal was analyzed by examining reasons for declining donor kidneys at the kidney transplantation center in Debrecen. This analysis aimed to assess the quality of donor kidneys and indicate why two-thirds of donated organs were refused. METHOD: Our center in Debrecen received 535 kidney offers (based on exclusion criteria) between November 2016 and August 2019, which were retrospectively analyzed. Donor kidneys were evaluated using expanded criteria donor, kidney donor profile index (KDPI), and kidney donor risk index criteria systems. RESULTS: Thirty-five percent (n = 189) of the kidneys offered to the center in Debrecen had been approved in advance, and later 63% (n = 119) were transplanted. Using the KDPI system, 41% of donors had a KDPI above 85, of which 23% were accepted, while acceptance of kidneys with a KDPI of 0 to 35 was around 70%. When examining causes of donor kidney refusal, 90% of the organs had donor quality problems, 13% had logistical cause (long cold ischemic time, large age difference between donor and recipient), and 10.5% had immunologic cause. In 13% of cases, the refusal of donor organs was due to the coexistence of several problems. CONCLUSION: Our data showed that high-risk donor organs were being refused in our center; however, they are being transplanted at a higher rate in other Eurotransplant centers. The decision to refuse or accept donor organs depends on several factors, including expected waiting time, patient's clinical characteristics, and quality of life.

Identification of a novel archaea virus, detected in hydrocarbon polluted Hungarian and Canadian samples.

Metagenomics is a helpful tool for the analysis of unculturable organisms and viruses. Viruses that target bacteria and archaea play important roles in the microbial diversity of various ecosystems. Here we show that Methanosarcina virus MV (MetMV), the second Methanosarcina sp. virus with a completely determined genome, is characteristic of hydrocarbon pollution in environmental (soil and water) samples. It was highly abundant in Hungarian hydrocarbon polluted samples and its genome was also present in the NCBI SRA database containing reads from hydrocarbon polluted samples collected in Canada, indicating the stability of its niche and the marker feature of this virus. MetMV, as the only currently identified marker virus for pollution in environmental samples, could contribute to the understanding of the complicated network of prokaryotes and their viruses driving the decomposition of environmental pollutants.

Complete Genome Sequences of 10 Xanthomonas oryzae pv. oryzae Bacteriophages.

Xanthomonas oryzae pv. oryzae is the causative agent of bacterial leaf blight of rice. The application of bacteriophages may provide an effective tool against this bacterium. Here, we report the complete genome sequences of 10 newly isolated OP2-like X. oryzae pv. oryzae bacteriophages.

Terrain uplift due to natural hydrologic overpressure in karstic conduits.

Water supply from karst sources is a worldwide natural resource and the exploitation is tied to the knowledge of the positions of the hydrologic channels. We show that surface deformation induced by flood events in karst conduits is observable, and consists in uplift and outward movement from the hydraulic channel. Precipitation events produce the natural occurrence of subsurface hydraulic overpressure up to 1 MPa. Numerical modeling shows that the stresses are so strong to uplift and dislocate the surface by several mm and induce tilts in the order of microradians. The naturally induced deformation is compatible with a transient internal pressure loading of a channel. The results can be used to find new channels with dense GNSS networks. Sea water incursion and channels accessed for tourism could be monitored. Seismicity has been shown to have a seasonal variation in some areas, which could be explained by the subsurface stresses induced by the natural subsurface overpressure. The pressure induced deformation is expected to be observed in all karstic systems worldwide.

[Clinical neurophysiological methods in diagnosis and treatment of cerebrovascular diseases]. / Klinikai neurofiziológiai módszerek a cerebrovascularis betegségek diagnózisában és kezelésében.

Neurophysiological methods are gaining ground in the diagnosis and therapy of cerebrovascular disease. While the role of the EEG (electroencephalography) in the diagnosis of post-stroke epilepsy is constant, quantitative EEG para-meters, as new indicators of early efficiency after thrombolysis or in prognosis of patient's condition have proved their effectiveness in several clinical studies. In intensive care units, continuous EEG monitoring of critically ill patients became part of neurointenzive care protocols. SSEP (somatosesnsory evoked potencial) and EEG performed during carotid endarterectomy, are early indicative intraoperativ neuromonitoring methods of poor outcome. Neurorehabilitation is a newly discovered area of neurophysiology. Clinical studies have demonstrated the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the rehabilitation of stroke patients. Brain computer interface mark the onset of modern rehabi-litation, where the function deficit is replaced by robotic tehnology.

Abcb1a (P-glycoprotein) limits brain exposure of the anticancer drug candidate seliciclib in vivo in adult mice.

Seliciclib displayed limited brain exposure in vivo in adult rats with mature blood-brain barrier (BBB). Selicilib was shown to be a specific substrate of human ABCB1 in vitro. To demonstrate that ABCB1/Abcb1 can limit brain exposure in vivo in mice we are showing that seliciclib is a substrate of mouse Abcb1a, the murine ABCB1 ortholog expressed in the BBB as LLC-PK-Abcb1a cells displayed an efflux ratio (ER) of 15.31±3.54 versus an ER of 1.44±0.10 in LLC-PK1-mock cells. Additionally, in the presence of LY335979, an ABCB1/Abcb1a specific inhibitor, the observed ER for seliciclib in the LLC-PK1-mMdr1a cells decreased to 1.05±0.25. To demonstrate in vivo relevance of seliciclib transport by Abcb1a mouse brain microdialysis experiments were carried out that showed that the AUCbrain/AUCblood ratio of 0.143 in anesthetized mice increased about two-fold to 0.279 in the presence of PSC833 another ABCB1/Abcb1a specific inhibitor. PSC833 also increased the brain exposure (AUCbrain) of seliciclib close to 2-fold (136 vs 242) in awake mice. In sum, Abcb1a significantly decreases seliciclib permeability in vitro and is partly responsible for limited brain exposure of seliciclib in vivo in mice.

Membrane Transporters in Physiological Barriers of Pharmacological Importance.

Membrane transporters expressed in barrier forming cell types provide a dual filtration system as unwanted xenobiotics are effluxed by ABC transporters, and compounds essential for the organism, such as nutrients or physiological substrates, are taken up by influx transporters. The majority of efflux transporters apically-localized in barrier forming cell types are ABC transporters that may limit absorption or distribution, and promote excretion. Pharmaceutical scientists are increasingly aware of the limitations these efflux transporters represent. Influx transporters are also critically important, as apically-located influx transporters may counteract the effect of co-localized efflux transporters, promoting absorption or reabsorption, as well as facilitating distribution of low passive permeability substrates into tissues that are otherwise heavily guarded by efflux transporters. In excretory organs, basolaterally-localized influx transporters cooperate with apically-localized efflux trransporters to efficiently drive transcellular movement of xenobiotics and their metabolites. Pharmacological inhibition of absorption or reabsorption of unwanted nutrients and endobiotics has become a great opportunity for pharmaceutical development. For drug developers, these transporters also offer the opportunity to target specific organs and cell types. Targeting drugs to cells and tissues harboring the pharmacological target not only makes drugs more efficient, but can also make them less toxic, as it allows for administration of lower doses and less distribution of drugs into non-target organs.

HupO, a Novel Regulator Involved in Thiosulfate-Responsive Control of HupSL [NiFe]-Hydrogenase Synthesis in Thiocapsa roseopersicina.

[NiFe]-hydrogenases are regulated by various factors to fulfill their physiological functions in bacterial cells. The photosynthetic purple sulfur bacterium Thiocapsa roseopersicina harbors four functional [NiFe]-hydrogenases: HynSL, HupSL, Hox1, and Hox2. Most of these hydrogenases are functionally linked to sulfur metabolism, and thiosulfate has a central role in this organism. The membrane-associated Hup hydrogenases have been shown to play a role in energy conservation through hydrogen recycling. The expression of Hup-type hydrogenases is regulated by H2 in Rhodobacter capsulatus and Cupriavidus necator; however, it has been shown that the corresponding hydrogen-sensing system is nonfunctional in T. roseopersicina and that thiosulfate is a regulating factor of hup expression. Here, we describe the discovery and analysis of mutants of a putative regulator (HupO) of the Hup hydrogenase in T. roseopersicina. HupO appears to mediate the transcriptional repression of Hup enzyme synthesis under low-thiosulfate conditions. We also demonstrate that the presence of the Hox1 hydrogenase strongly influences Hup enzyme synthesis in that hup expression was decreased significantly in the hox1 mutant. This reduction in Hup synthesis could be reversed by mutation of hupO, which resulted in strongly elevated hup expression, as well as Hup protein levels, and concomitant in vivo hydrogen uptake activity in the hox1 mutant. However, this regulatory control was observed only at low thiosulfate concentrations. Additionally, weak hydrogen-dependent hup expression was shown in the hupO mutant strain lacking the Hox1 hydrogenase. HupO-mediated Hup regulation therefore appears to link thiosulfate metabolism and the hydrogenase network in T. roseopersicina.

Evidence-based development and evaluation of mobile cognitive support apps for people on the autism spectrum: methodological conclusions from two R+D projects.

A growing body of evidence confirms that mobile digital devices have key potentials as assistive/educational tools for people with autism spectrum disorders. The aim of this paper is to outline key aspects of development and evaluation methodologies that build on, and provide systematic evidence on effects of using such apps. We rely on the results of two R+D projects, both using quantitative and qualitative methods to support development and to evaluate developed apps (n=54 and n=22). Analyzing methodological conclusions from these studies we outline some guidelines for an 'ideal' R+D methodology but we also point to important trade-offs between the need for best systematic evidence and the limitations on development time and costs. We see these trade-offs as a key issue to be resolved in this field.

Temperature-dependent transformation of biogas-producing microbial communities points to the increased importance of hydrogenotrophic methanogenesis under thermophilic operation.

Stability of biogas production is highly dependent on the microbial community composition of the bioreactors. This composition is basically determined by the nature of biomass substrate and the physical-chemical parameters of the anaerobic digestion. Operational temperature is a major factor in the determination of the anaerobic degradation process. Next-generation sequencing (NGS)-based metagenomic approach was used to monitor the organization and operation of the microbial community throughout an experiment where mesophilic reactors (37°C) were gradually switched to thermophilic (55°C) operation. Temperature adaptation resulted in a clearly thermophilic community having a generally decreased complexity compared to the mesophilic system. A temporary destabilization of the system was observed, indicating a lag phase in the community development in response to temperature stress. Increased role of hydrogenotrophic methanogens under thermophilic conditions was shown, as well as considerably elevated levels of Fe-hydrogenases and hydrogen producer bacteria were observed in the thermophilic system.

[The presence of callous/unemotional traits among students in different roles of bullying]. / A rideg/erzeketlen vonasok jelenlete a zaklatas szerepkoreiben levo diakok kozott.

BACKGROUND: The phenomenon of bullying in the schools is more frequent in our country and abroad too. The bullying behaviour is a persistent, intentional harm of others where the balance of power between the participants is uneven.Researches about school bullying has provided many useful information regarding prevention and treatment of bullying but only the few of them takes an interest in the personality traits in bullies which can increase the appearance of the aggressive, bullying behaviour.The callous/unemotional traits get a growing role in the explanation and understanding of aggressive behaviour. In case of the presence of callous/unemotional traits a special emotional (lack of guilt, shallow emotions) and interpersonal style (use of proactive aggression and absence of responsibility) can be observed in children. AIM: The purpose of our study was to measure the callous/unemotional traits between the different groups determined by the role they play in the bullying. We assume that the presence of callous/unemotional traits are significantly more typical within the group of Bullies than the other groups. SAMPLE: Our sample consisted of 117 elementary school students (6th-8th grade). METHOD: To examine the roles of bullying we used the Bullying Questionniare. The questionnaire consist 23 items, it was developed to determine the role of students and involvement in the process of bullying. To measure callous/ unemotional traits we used the Inventory of Callous Unemotional Traits (ICU) developed by Frick which measure the factors of callous unemotional traits along 24 items. RESULTS: According to our results the group of Bullies scored significantly higher in all three factors of the Inventory of Callous Unemotional Traits compared to other groups. Treatment of callous/unemotional features may reduce the occurrence of bullying.

Selective hydroboration of dieneamines. Formation of hydroxyalkylphenothiazines as MDR modulators.

N-dienylphenothiazines synthesized from tetrazolo[1,5-a]pyridinium salts by treatment with phenothiazine were subjected to catalytic hydrogenation to yield N-butylphenothiazines, whereas transformation of these dienes with borane dimethyl sulfide (BH(3) × Me(2)S) resulted in selective hydroboration of one double bond and full reduction of the other double bond to give 2-hydroxybutylphenothiazines. Position of the hydroxyl group was supported by NMR spectroscopy and verified by X-ray analysis. Comparison of MDR modulatory activity of the new derivatives revealed that the hydroxybutyl compounds are promising candidates for development of novel MDR inhibitors.

[The role of breastfeeding in the infant nourishment]. / Význam kojení ve výzive dítete.

Breastfeeding is a natural nutrition of newborns, infants and toddlers, which is best suited to their specific needs. Breast milk has evolved throughout the existence of the species that best match the specific needs of the newborn. The more we know about the nutritional, immunological and other beneficial properties of the breast milk and breast-feeding; the clearer is its importance. It is assumed that breastfeeding may be one of the factors that reduce the development of several diseases in a later age. Breastfeeding is a unique emotional experience. Closer contact with a child during breast-feeding creates the child a sense of security, love, and forms a strong emotional bond with mother and provides the child's sense of security and love.

A second soluble Hox-type NiFe enzyme completes the hydrogenase set in Thiocapsa roseopersicina BBS.

Three functional NiFe hydrogenases were previously characterized in Thiocapsa roseopersicina BBS: two of them are attached to the periplasmic membrane (HynSL and HupSL), and one is localized in the cytoplasm (HoxEFUYH). The ongoing genome sequencing project revealed the presence of genes coding for another soluble Hox-type hydrogenase enzyme (hox2FUYH). Hox2 is a heterotetrameric enzyme; no indication for an additional subunit was found. Detailed comparative in vivo and in vitro activity and expression analyses of HoxEFUYH (Hox1) and the newly discovered Hox2 enzyme were performed. Functional differences between the two soluble NiFe hydrogenases were disclosed. Hox1 seems to be connected to both sulfur metabolism and dark/photofermentative processes. The bidirectional Hox2 hydrogenase was shown to be metabolically active under specific conditions: it can evolve hydrogen in the presence of glucose at low sodium thiosulfate concentration. However, under nitrogen-fixing conditions, it can oxidize H(2) but less than the other hydrogenases in the cell.

Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.

Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.