Acid Position Research Articles

Novel Cyclic Lipopeptide Antibiotics: Effects of Acyl Chain Length and Position.

Multidrug-resistant bacteria are a global health problem. One of the last-resort antibiotics against Gram-negative bacteria is the cyclic lipopeptide colistin, displaying a flexible linker with a fatty acid moiety. The aim of the present project was to investigate the effect on antimicrobial activity of introducing fatty acid moieties of different lengths and in different positions in a cyclic peptide, S3(B), containing a flexible linker. The lipidated analogues of S3(B) were synthesized by 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis. Following assembly of the linear peptide by Fmoc solid-phase peptide synthesis, on-resin head-to-tail cyclization and fatty acid acylation were performed. The antimicrobial activity was determined against the ESKAPE pathogens, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. Furthermore, hemolytic activity was determined against human erythrocytes. A total of 18 cyclic lipopeptides were synthesized and characterized. It was found that introduction of fatty acids in positions next to the flexible linker was more strongly linked to antimicrobial activity. The fatty acid length altered the overall hydrophobicity, which was the driving force for both high antimicrobial and hemolytic activity. Peptides became highly hemolytic when carbon-chain length exceeded 10 (i.e., C10), overlapping with the optimum for antimicrobial activity (i.e., C8–C12). The most promising candidate (C8)5 showed antimicrobial activity corresponding to that of S3(B), but with an improved hemolytic profile. Finally, (C8)5 was further investigated in a time-kill experiment.

The outlier Pseudomonas aeruginosa strain ATCC 9027 harbors a defective LasR quorum-sensing transcriptional regulator.

Pseudomonas aeruginosa infections represent an important health problem that has been recognized by the World Health Organization as a research priority. A complex regulatory network called the quorum sensing (QS) regulates several P. aeruginosa virulence-related traits, including production of elastase, rhamnolipids and pyocyanin. The avirulent P. aeruginosa strain ATCC 9027 belongs to clade 3, which is the more distant phylogroup in relationship to the other four clades of this species. This strain does not produce QS-regulated virulence factors such as elastase and rhamnolipids when cultured in rich LB medium. We report here that ATCC 9027 harbors a defective LasR protein, presumably due to the presence of an aspartic acid in position 196 instead of a glutamic acid which is the amino acid present in this position in functional LasR proteins of the type strains PAO1 (clade 1) and PA7 (also belonging to clade 3), among others. In addition, we report that ATCC 9027 and PA7 strains present differences compared to the PAO1 strain in lasB which encodes elastase, and in the rhlR regulatory sequences that modify las-boxes, and that these mutations have a little effect in the expression of these genes by a functional LasR transcriptional regulator.

Detrimental Effects of Multiple Mutations in Position 240 of Fusarium graminearum β2-Tubulin.

Fusarium graminearum causes Fusarium head blight (FHB), a destructive disease of cereal crops worldwide. Carbendazim (methylbenzimidazol-2-ylcarbamate [MBC]) is widely used for controlling FHB. A previous study showed that the F240L mutation in the β2-tubulin of F. graminearum (Fgβ2-tubulin) confers hypersensitivity to MBC. Whether the substitution of phenylalanine by other amino acids in position 240 of the Fgβ2-tubulin gene also confers hypersensitivity to MBC is unknown. Moreover, the biological fitness of these mutants is poorly understood. In this study, we substituted position 240 of Fgβ2-tubulin with other amino acids. We found that the F240A, F240E, F240I, and F240Y mutations in Fgβ2-tubulin could also confer F. graminearum hypersensitivity to MBC, although the effective concentration resulting in 50% inhibition (EC50) differed among the mutations. The F240G mutation, in contrast, decreased the sensitivity to MBC. In addition, a molecular docking assay indicated that the binding affinity between Fgβ2-tubulin and MBC were increased by the F240A, F240E, F240I, and F240Y mutations but decreased by the F240G mutation. All mutants had normal conidial morphology, but the growth rates and pathogenicity of the F240A, F240E, F240G, F240I, and F240Y mutants were significantly decreased. Moreover, the F240A and F240G mutants produced twisted hyphae. In addition, microtubules were sparse and rarely observed in β2F240A-EGFP, β2F240E-EGFP, and β2F240G-EGFP. These results indicate that position 240 (phenylalanine) is not only vital to the function of Fgβ2-tubulin but also plays an important role in regulating the sensitivity of F. graminearum to MBC. Any mutation in this site would be detrimental to survival.

Asplenia in a 12 Year Old Boy with Sickle Beta Thalassemia

Sickle cell anemia is an inherited hemoglobin disease caused by the substitution of valine for glutamic acid in position 6 of the s chain of globin. It is the most common genetic disease in the world. Its severity is linked to its complications. Asplenia is a rare chronic complication due to repeated infarctions. The authors report a case of asplenia in a 12-year-old thalasso-sickle cell patient.

A single amino acid substitution in aromatic hydroxylase (HpaB) of Escherichia coli alters substrate specificity of the structural isomers of hydroxyphenylacetate

BackgroundA broad range of aromatic compounds can be degraded by enteric bacteria, and hydroxyphenylacetic acid (HPA) degrading bacteria are the most widespread. Majority of Escherichia coli strains can use both the structural isomers of HPA, 3HPA and 4HPA, as the sole carbon source, which are catabolized by the same pathway whose associated enzymes are encoded by hpa gene cluster. Previously, we observed that E. coli B REL606 grew only on 4HPA, while E. coli B BL21(DE3) grew on 3HPA as well as 4HPA.ResultsIn this study, we report that a single amino acid in 4-hydroxyphenylacetate 3-hydroxylase (HpaB) of E. coli determines the substrate specificity of HPA isomers. Alignment of protein sequences encoded in hpa gene clusters of BL21(DE3) and REL606 showed that there was a difference of only one amino acid (position 379 in HpaB) between the two, viz., Arg in BL21(DE3) and Cys in REL606. REL606 cells expressing HpaB having Arg379 could grow on 3HPA, whereas those expressing HpaB with Gly379 or Ser379 could not. Structural analysis suggested that the amino acid residue at position 379 of HpaB is located not in the active site, but in the vicinity of the 4HPA binding site, and that it plays an important role in mediating the entrance and stable binding of substrates to the active site.ConclusionsThe arginine residue at position 379 of HpaB is critical for 3HPA recognition. Information regarding the effect of amino acid residues on the substrate specificity of structural isomers can facilitate in designing hydoxylases with high catalytic efficiency and versatility.

A Replication-Defective Influenza Virus Vaccine Confers Complete Protection against H7N9 Viral Infection in Mice.

Avian influenza H7N9 viruses continue to pose a great threat to public health, which is evident by their high case-fatality rates. Although H7N9 was first isolated in humans in China in 2013, to date, there is no commercial vaccine available against this particular strain. Our previous studies developed a replication-defective influenza virus through mutation of the hemagglutinin (HA) cleavage site from a trypsin-sensitive to an elastase-sensitive motif. In this study, we report the development of a reassortant mutant influenza virus derived from the human isolate A/British Columbia/01/2015 (H7N9) [BC15 (H7N9)], which is the QVT virus. The HA gene of this virus possesses three mutations at the cleavage site, Lys-Gly-Arg were mutated to Gln-Thr-Val at amino acid (aa) positions 337, 338, and 339, respectively. We report this virus to rely on elastase in vitro, possess unaltered replication abilities when elastase was provided compared to the wild type virus in vitro, and to be non-virulent and replication-defective in mice. In addition, we report this virus to induce significant levels of antibodies and IFN-γ and IL-5 secreting cells, and to protect mice against a lethal challenge of the BC15 (H7N9) virus. This protection is demonstrated through the lack of body weight loss, 100% survival rate, and the prevention of BC15 (H7N9) viral replication as well as the reduction of proinflammatory cytokines induced in the mouse lung associated with the influenza disease. Therefore, these results provide strong evidence for the use of this reassortant mutant H7N9 virus as a replication-defective virus vaccine candidate against H7N9 viruses.

Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues

A structure–activity relationship (SAR) study of NOSO-95179, a nonapeptide from the Odilorhabdin class of antibacterials, was performed by systematic variations of amino acids in positions 2 and 5 of the peptide. A series of non-proteinogenic amino acids was synthesized in high enantiomeric purity from Williams’ chiral diphenyloxazinone by highly diastereoselective alkylation or by aldol-type reaction. NOSO-95179 analogues for SAR studies were prepared using solid-phase peptide synthesis. Inhibition of bacterial translation by each of the synthesized Odilorhabdin analogues was measured using an in vitro test. For the most efficient analogues, antibacterial efficacy was measured against two wild-type Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) and against an efflux defective E. coli strain (ΔtolC) to evaluate the impact of efflux on the antibacterial activity.

Dogs are resistant to prion infection, due to the presence of aspartic or glutamic acid at position 163 of their prion protein.

Unlike other species, prion disease has never been described in dogs even though they were similarly exposed to the bovine spongiform encephalopathy (BSE) agent. This resistance prompted a thorough analysis of the canine PRNP gene and the presence of a negatively charged amino acid residue in position 163 was readily identified as potentially fundamental as it differed from all known susceptible species. In the present study, the first transgenic mouse model expressing dog prion protein (PrP) was generated and challenged intracerebrally with a panel of prion isolates, none of which could infect them. The brains of these mice were subjected to in vitro prion amplification and failed to find even minimal amounts of misfolded prions providing definitive experimental evidence that dogs are resistant to prion disease. Subsequently, a second transgenic model was generated in which aspartic acid in position 163 was substituted for asparagine (the most common in prion susceptible species) resulting in susceptibility to BSE-derived isolates. These findings strongly support the hypothesis that the amino acid residue at position 163 of canine cellular prion protein (PrPC ) is a major determinant of the exceptional resistance of the canidae family to prion infection and establish this as a promising therapeutic target for prion diseases.

XPO1 Mutations May Identify Binet Α Chronic Lymphocytic Leukemia Patients with Shorter Time to First Treatment

Background. Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in western countries. CLL is a highly heterogeneous disease; some patients may never require treatment, whereas other relapse early after frontline therapy. In approximately 70% of newly diagnosed cases, CLL presents at an early clinical stage and is managed with a watch & wait strategy. Until now, few clinical and molecular predictors inform on the risk of treatment requirement and the impact of CLL gene mutations is not completely understood. Purpose. We aimed at identifying new molecular markers that may predict early treatment requirement and may help clinicians to better plan the watch & wait strategy in asymptomatic early stage CLL patients. Methods. This study includes 295 Binet A CLL patients referring at our institution who did not require treatment for at least 3 months after diagnosis. Tumor genomic DNA (gDNA) was isolated from peripheral blood mononuclear cells at the time of diagnosis. gDNA was analyzed in the coding exons plus splice sites of the most frequently mutated genes in CLL with a next-generation-sequencing (NGS) approach. NGS analysis was performed on the Illumina MiSeq instrument (coverage >2000x in >80% of the target region). The somatic function of VarScan2 was used for variant calling and a stringent bioinformatic pipeline was developed to protect against the false call of polymorphisms and sequencing errors. A threshold of 5% of variant allele frequency was set for variant calling. The primary endpoint was time to first treatment (TTFT) defined as the timeinterval between the date of CLL diagnosis and the date of first CLL treatment. Statistical analysis was performed using SPSS version 24.0. Results. The median age of the study cohort was 70.8 years old, 136 (46.1%) patients were female, 71 (24.1%) harbored unmutated IGHV genes, 44 (14.9%) had trisomy 12, 12 (4.1%) had 17p deletion, 15 (5.1%) had 11q deletion and 150 (50.8%) had 13q deletion. NGS mutational analysis showed that NOTCH1 was the most frequently mutated gene occurring in 25 (8.5%) patients, followed by ATM in 18 (6.1%), TP53 in 17 (5.8%), MYD88 in 12 (4.1%), SF3B1 in 10 (3.4%), XPO1 in 7 (2.4%), EGR2 in 6 (2.0%), NFKBIE in 4 (1.4%), POT1 in 2 (0.7%), and BIRC3 in 1 (0.3%) patients. After a median follow-up of 9.5 years, 80 (27.1%) patients required treatment. In univariate analysis, molecular characteristics associated with a shorter TTFT were trisomy 12 (HR: 2.42; 95% CI 1.43-4.15; p=0.001), unmutated IGHV genes (HR: 4.51; 95% CI 2.83-7.05; p<0.0001) and mutations of XPO1 (HR: 8.88; 95% CI 3.77-20.95; p<0.0001), NOTCH1 (HR: 3.02; 95% CI 1.66-5.51; p<0.001) and SF3B1 (HR: 2.65; 95% CI 1.15-6.10; p=0.022). Interestingly, neither 17p deletion nor TP53 mutations associated with a shorter TTFT, in line with the notion that TP53 disruption interacts with treatment but not with a watch & wait strategy. By multivariate analysis, XPO1 mutations (HR: 4.24; 95% CI 1.72-10.44; p=0.002) maintained an independent association with a shorter TTFT (Table 1). At 10 years, XPO1 mutated patients had a probability of remaining free from treatment of 0% compared to 69.3% for wild type cases (p<0.0001) (Figure 1). Conclusions. Mutations of the XPO1 gene, encoding for exportin 1 which mediates the nuclear export of proteins and RNA, are an independent predictor of shorter TTFT and, if validated, might help clinicians in a better management of the watch & wait strategy for Binet A CLL patients. Moreover, since most of mutations, approximately 90%, affect the glutamic acid in position 571, polymerase chain reaction based methods may be used to identify XPO1 mutations in a simple and time effective manner. Disclosures Rossi: Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria.

Spontaneous Isomerization of Long-Lived Proteins Provides a Molecular Mechanism for the Lysosomal Failure Observed in Alzheimer's Disease.

Proteinaceous aggregation is a well-known observable in Alzheimer’s disease (AD), but failure and storage of lysosomal bodies within neurons is equally ubiquitous and actually precedes bulk accumulation of extracellular amyloid plaque. In fact, AD shares many similarities with certain lysosomal storage disorders though establishing a biochemical connection has proven difficult. Herein, we demonstrate that isomerization and epimerization, which are spontaneous chemical modifications that occur in long-lived proteins, prevent digestion by the proteases in the lysosome (namely, the cathepsins). For example, isomerization of aspartic acid into l-isoAsp prevents digestion of the N-terminal portion of Aβ by cathepsin L, one of the most aggressive lysosomal proteases. Similar results were obtained after examination of various target peptides with a full series of cathepsins, including endo-, amino-, and carboxy-peptidases. In all cases peptide fragments too long for transporter recognition or release from the lysosome persisted after treatment, providing a mechanism for eventual lysosomal storage and bridging the gap between AD and lysosomal storage disorders. Additional experiments with microglial cells confirmed that isomerization disrupts proteolysis in active lysosomes. These results are easily rationalized in terms of protease active sites, which are engineered to precisely orient the peptide backbone and cannot accommodate the backbone shift caused by isoaspartic acid or side chain dislocation resulting from epimerization. Although Aβ is known to be isomerized and epimerized in plaques present in AD brains, we further establish that the rates of modification for aspartic acid in positions 1 and 7 are fast and could accrue prior to plaque formation. Spontaneous chemistry can therefore provide modified substrates capable of inducing gradual lysosomal failure, which may play an important role in the cascade of events leading to the disrupted proteostasis, amyloid formation, and tauopathies associated with AD.

Diffic ulties of diagnostics of epilepsy due to mol ybdenum cofactor deficienc y: a case report

The article presents a clinical study of an infant with rare inherited metabolism disorder – molybdenum cofactor deficiency, for the first time in Russian literature. The onset of disorder – in early neonatal period with a suppression syndrome and myoclonic seizures combined with a burstsuppression electroencephalographic patterns, followed by a reveal of psychomotor delay. Сraniofacial dystrophies were present, including craniostenosis and microcephaly. Somatic status was characterized by hepatolienomegaly, dysmetabolic changes of kidneys’ parenchyma (suggested by ultrasound) and crystalluria. Neuroimaging data were contradictory. Neurosonography results allowed diagnosing concomitant inborn brain development defect: true porencephalia of large hemispheres. However, brain magnetic resonance imaging revealed a picture of diffuse leukomalacia with pseudocyst formation, which were considered a consequence of perinatal brain damage. Magnetic resonance imaging revealed a picture of diffuse leukomalacia with pseudocyst formation, which were considered a consequence of perinatal brain damage. Differential diagnosis was held between the early infantile epileptic encephalopathy (Ohtahara syndrome) and early myoclonic encephalopathy (Aicardi syndrome). However, etiology of the disease remained unclear. To eliminate inherited metabolic disease accompanied by epilepsy, Inherited Epilepsy Panel DNA sequencing was used. The results showed a homozygotic mutation on the exon 6 of MOCS2 gene, leading to deletion of amino acid in position 158 of the protein, which was described before in patients with molybdenum cofactor deficiency (OMIM: 252160).

Re-investigating substrate specificity of dihydroflavonol 4-reductase with respect to the B-ring hydroxylation pattern of substrates

Dihydroflavonol 4-reductase (EC 1.1.1.219, DFR) catalyses the reduction of (2R,3R)-(+)-dihydroflavonols into (2R,3S,4S)-cis-3,4-leucoanthocyanidins. Depending on the plant species, DFR can be unspecific with regard to the B-ring hydroxylation pattern or selective, as in Petunia hybrida in which the DFR does not convert DHK, or in Fragaria species where a pair of DFRs are present that shows contrasting substrate specificity with regard to DHK. DFR substrate specificity has been largely investigated in many plant species. The amino acids determining DFR substrate specificity are not yet completely understood, but previous studies have identified a region of 26 amino acids putatively relevant and in particular, an aspartic acid in position 134, that seems to be responsible for the non-acceptance of DHK as substrates. The recently identified pair of Fragaria DFRs with contrasting substrate specificity was used to study putative regions responsible for the divergent substrate specificity. We demonstrate that neither the versatile C-terminus nor the DFR length nor two of three putative regions are of any relevance. In addition, we analyse previously published DFRs of Malus × domestica, Pyrus communis and Ginkgo biloba and the correlation between their substrate specificity and amino acid sequences. Technical constraints of DFR enzyme assays and potential putative substrate specificity bias is discussed.

The carrier state for sickle cell disease is not completely harmless.

Sickle cell disease (SCD) is a clinical syndrome caused by the presence of hemoglobin S (HbS), in which glutamic acid in position 6 of the β chain of hemoglobin is substituted by valine (βGlu6Val). It is generally recognized as an autosomal recessive disorder, in that individuals who have inherited one copy of the HbS allele and one normal HbA allele (i.e. have HbAS or sickle cell trait, SCT), are typically asymptomatic and spared the serious complications associated with possessing two copies of the mutant allele (i.e. HbSS). It is estimated that 300 million people (~5% of the world’s population) carry the HbS allele, and nearly 5.5 million births are affected annually.1 Individuals with SCD die prematurely, but the life expectancy of individuals with SCT is similar to that of people without the trait.2 However, early literature attributed a number of possible disease associations to this heterozygous state, partly as a result of unreliable diagnostic laboratory testing for hemoglobinopathies and partly due to questionable conclusions drawn from uncontrolled observational studies, individual case reports, and small case series.3,4 Nevertheless, while some of the associations historically attributed to SCT are unfounded, recent meta-analyses found high-quality evidence that SCT is indeed a risk factor for a handful of complications common to SCD.2

The STAT5b Linker Domain Mediates the Selectivity of Catechol Bisphosphates for STAT5b over STAT5a.

STAT family proteins are important mediators of cell signaling and represent therapeutic targets for the treatment of human diseases. Most STAT inhibitors target the protein-protein interaction domain, the SH2 domain, but specificity for a single STAT protein is often limited. Recently, we developed catechol bisphosphates as the first inhibitors of STAT5b demonstrated to exhibit a high degree of selectivity over the close homologue STAT5a. Here, we show that the amino acid in position 566 of the linker domain, not the SH2 domain, is the main determinant of specificity. Arg566 in wild-type STAT5b favors tight binding of catechol bisphosphates, while Trp566 in wild-type STAT5a does not. Amino acid 566 also determines the affinity for a tyrosine-phosphorylated peptide derived from the EPO receptor for STAT5a and STAT5b, demonstrating the functional relevance of the STAT5 linker domain for the adjacent SH2 domain. These results provide the first demonstration that a residue in the linker domain can determine the affinity of nonpeptidic small-molecule inhibitors for the SH2 domain of STAT proteins. We propose targeting the interface between the SH2 domain and linker domain as a novel design approach for the development of potent and selective STAT inhibitors. In addition, our data suggest that the linker domain could contribute to the enigmatically divergent biological functions of the two STAT5 proteins.

Characterization of Amino Acid Based Molecular Micelles with Molecular Modeling.

The enantiomers of chiral drugs often have different potencies, toxicities, and biochemical properties. Therefore, the FDA and other worldwide regulatory agencies require manufactures to test and prove the enantiomeric purity of chiral drugs. Amino acid based molecular micelles (AABMM) have been used in chiral CE separations since the 1990's because of their low environmental impact and because their properties can easily be tuned by changing the amino acids in the chiral surfactant headgroups. Using molecular dynamics simulations to investigate the structures and properties of AABMM is part of an ongoing study focusing on investigating and elucidating the factors responsible for chiral recognition with AABMM. The results will be useful for the proper design and selection of more efficient chiral selectors. The micelles investigated contained approximately twenty covalently linked surfactant monomers. Each monomer was in turn composed of an undecyl hydrocarbon chain bound to a dipeptide headgroup containing of all combinations of L-Alanine, L-Valine, and L-Leucine. These materials are of interest because they are effective chiral selectors in capillary electrophoresis separations. Molecular dynamics simulation analyses were used to investigate how the sizes and positions of the headgroup amino acid R-groups affected the solvent accessible surface areas of each AABMM chiral center. In addition, headgroup dihedral angle analyses were used to investigate how amino acid R-group size and position affected the overall headgroup conformations. Finally, distance measurements were used to study the structural and conformational flexibilities of each AABMM headgroup. All analyses were performed in the context of a broader study focused on developing structure-based predictive tools to identify the factors responsible for (a) self-assembly, (b) function, (c) higher ordered structure and (d) molecular recognition of these amino acid based molecular micelles.

Linguistic-Probabilistic and Quantum Understanding of Gene Operation

This paper introduces the hypothesis that during the biosynthesis of prion proteins, the ribosome works in the opposite direction and thus, it is a “prion-poly-anticodon-dependent mRNA polymerase”. And accordingly, in violation of the Central Dogma, information flows from protein to RNA. This requires dogma formula to be re-written as follows: DNARNA Protein. The idea of contextual orientations of the ribosome on mRNA during protein biosynthesis is introduced. This ensures the selection of the correct amino acid or stop position due to the strategic role of the “wobbling” off the 3’-codon nucleotide in non-synonymous codons. This leads to the transition of the genetic code from purely a physico-chemical level of its operation to mental-textual one. This is a representation of the fact of one of the levels of non-locality (continuity) of the genome. There are six such levels of nonlocality. Level 1—Organizational. Here, non-locality is expressed with the ability to regenerate, for example, in planarians. Level 2—Cellular. From every cell, and not just from zygotes, you can grow a whole organism. Level 3—Cellular-nuclear. Enucleation of nuclei from somatic and germinal cells with the subsequent introduction of other nuclei into them does not prevent the development of a normal organism. Level 4—Molecular: the ribosome “reads” the informational RNA not only for individual codons, but for the whole RNA, taking into account the context, that is, non-locally, continually. Level 5— Chromosome-holographic. The genome has a holographic memory, and this is a typically distributed (non-local) associative memory. At this and subsequent levels, non-locality acquires a new quality, a dualistic, material-wave character, since holograms as a substance are “read” by electromagnetic and/or acoustic fields that carry genome-wave information beyond the substance of chromosomes. Level 6—Quantum non-locality of the genome. Up to level 6, the non-locality of genetic information is realized in the space of the organism. Level 6 has a special character and a new quality. It manifests itself in one of the forms of quantum non-locality, namely, permissive, postulated in this work. In this case, the non-locality is realized both in the space of the biosystem and in its own, “compressible” to zero, time. Gene-wave programs that are instantly distributed in such ways, isomorphic to material ones, work in the body “here and there at the same time”, therefore, the semantic construction “first and then” loses its meaning. And this is a strategic factor, an extraordinary achievement for multicellular biosystems. We have obtained theoretical and experimental results confirming our ideas.

Catalyst-Controlled Regiodivergent C–H Arylation Site of Fluorinated 2-Arylpyridine Derivatives: Application to Luminescent Iridium(III) Complexes

Regiodivergent C–H bond arylation of fluorinated 2-arylpyridines and 2-arylquinolines has been developed. The use of Pd catalyst allows functionalization of the C–H bond of the aryl flanked by two fluorine atoms (most acidic position), while using Ru catalyst, the arylation takes place on the aryl unit at the ortho position of the heterocycle. Both reaction conditions exhibit a good functional group tolerance. The synthetically useful selectivity observed with Pd catalyst was applied to design C^N ligands for the preparation of luminescent cationic iridium(III) complexes. The influence of the incorporated aryl group onto the fluorinated phenyl unit and the fluorine position patterns on the photophysical properties is described.

Synthesis of Mesomorphic Derivatives of Methyl 2,4-Dihydroxybenzoate and Spectral and Luminescence Properties of Their Lanthanide Complexes

The derivatives of methyl 2,4-dihydroxybenzoate containing fragments of different organic acids in position 4 have been synthesized. Their mesomorphic properties have been investigated. Lanthanide complexes of the prepared compounds have been obtained. Their spectral properties have been studied.

Hepatitis B Virus Subtype Distribution in Bangladeshi Chronic Carriers

Background : Hepatitis B virus (HBV) infection is one of the major global health problems and this virus has many variants that differ from epidemiological distributions, transmission sources, clinical outcomes, diagnostic assays as well as therapeutic responses. HBV was also divided into 9 different subtypes which has distinct geographical distributions and important for the epidemiological studies and vaccine development.Objective : Bangladesh is an intermediate prevalence region for HBV infection, however, very little is known about the incidence of HBV subtypes in circulation. Therefore, we investigated the HBV subtype distribution in Bangladesh.Method : A small cohort was performed on between March 2014 and August 2017 with 172 HBV DNA positive patients from the BSMMU. From them, 29 HBV DNA samples were isolated for sequencing by Sanger method. HBsAg subtypes were determined by identifying of 226 amino acid (aa) positions in the small surface (S) gene.Result : Our study showed that HBV subtype adrq+ was in 17 (58.6%) isolates, ayw3 in 8 (27.5%), ayw2 in 2 (6.9%) and adw2 in 2 (6.9%) isolates.Conclusion : We conclude subtype adrq+ predominant in Bangladesh. This was followed by ayw3, while adw2 and ayw2 were least dominant. Subtype adw2 and adrq+ strains are found to be related with more complication, therefore, patients infected with these HBV strains need to be careful monitoring to assess their clinical outcome in future.Northern International Medical College Journal Vol.9(2) Jan 2018: 286-290

Effect of zeolite structure on light aromatics formation during upgrading of cellulose fast pyrolysis vapor

Promising technology for the conversion of cellulose to aromatics by catalytic fast pyrolysis (CFP) was investigated using five zeolite catalysts, i.e., 5A, SAPO-34, HY, BETA and HZSM-5. The relationship between the porosity and acidity of different zeolites with product selectivity was studied. The results showed that both the acidity and pore size of the zeolite significantly affected the production of aromatics and coke, especially the bio-oil composition. The bio-oils obtained over 5A or SAPO-34 (small pore<5.5 nm) have relatively high oxygen content. The BTEXN (benzene, toluene, ethylbenzene, xylenes and naphthalene) carbon yields over weak acidic zeolites of HY and BETA are only 6.5% and 9.0%, respectively. Due to the appropriate pore size distribution and acid position, HZSM-5 gave the highest BTEXN carbon yield of 21.1%. Moreover, the coke deposited on the spent zeolites was analyzed by temperature programmed oxidation. Furthermore, three possible mechanisms that the acid sites catalyze vapor towards non-condensable gases, aromatics and coke were also studied. HZSM-5 achieved satisfactory deoxygenation and aromatic production simultaneously, made it a potential catalyst for producing light aromatics from reforming the biomass pyrolytic vapors.