From Rational Design of Drug Crystals to Understanding of Nucleic Acid Structures: Lamivudine Duplex

A DNA-like duplex of nucleosides is probable to exist even without the 5`-phosphate groups needed to assemble the chain backbone. However, double-stranded helical structures of nucleosides are unknown. Here, we report a duplex of nucleoside analogs that is spontaneously assembled due to stacking of the neutral and protonated molecules of lamivudine, a nucleoside reverse transcriptase inhibitor (NTRI) widely used in anti-HIV drug combinatory medication. The left-handed lamivudine duplex has features similar to those of i-motif DNA, as the face-to-face base stacking and the helix rise per base pair. Furthermore, the protonation pattern on alternate bases expected for it DNA-like duplex stabilized by pairing of neutral and protonated cytosine fragments was observed for the first time in the lamivudine double-stranded helix. This structure demonstrates that hydrogen bonds can substitute for covalent phosphodiester linkage in the stabilization of the duplex backbone. This interesting example of spontaneous molecular self-organization indicates that the 5`-phosphate group could not be a requirement for duplex assembly.

A computational framework for nucleic acid sub-sequence identification

Identification of nucleic acid sub-sequences within larger background sequences is a fundamental need of the biology community. The applicability correlates to research studies looking for homologous regions, diagnostic purposes and many other related activities. This paper serves to detail the approaches taken leading to sub-sequence identification through the use of hidden Markov models and associated scoring optimisations. The investigation of techniques for locating conserved basal promoter elements correlates to promoter thus gene identification techniques. The case study centred on the TATA box basal promoter element, as such the background is a gene sequence with the TATA box the target. Outcomes from the research conducted, highlights generic algorithms for sub-sequence identification, as such these generic processes can be transposed to any case study where identification of a target sequence is required. Paths extending from the work conducted in this investigation have led to the development of a generic framework for the future applicability of hidden Markov models to biological sequence analysis in a computational context.

Nucleic acid vaccines: tasks and tactics

There are no adequate vaccines against some of the new or reemerged infectious scourges such as HIV and TB. They may require strong and enduring cell-mediated immunity to be elicited. This is quite a task, as the only known basis of protection by current commercial vaccines is antibody. As DNA or RNA vaccines may induce both cell-mediated and humoral immunity, great interest has been shown in them. However, doubt remains whether their efficacy will suffice for their clinical realization. We look at the various tactics to increase the potency of nucleic acid vaccines and divided them broadly under those affecting delivery and those affecting immune induction. For delivery, we have considered ways of improving uptake and the use of bacterial, replicon or viral vectors. For immune induction, we considered aspects of immunostimulatory CpG motifs, coinjection of cytokines or costimulators and alterations of the antigen, its cellular localization and its anatomical localization including the use of ligand-targeting to lymphoid tissue. We also thought that mucosal application of DNA deserved a separate section. In this review, we have taken the liberty to discuss these enhancement methods, whenever possible, in the context of the underlying mechanisms that might argue for or against these strategies.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

NUCLEIC ACID EXPRESSED IN THE HYPOTHALAMUS OR MUSCLE TISSUE IN OBESE ANIMALS

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a large r amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucle ic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

NUCLEIC ACID EXPRESSED IN THE HYPOTHALAMUS OR MUSCLE TISSUE IN OBESE ANIMALS

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

NUCLEIC ACID EXPRESSED IN THE HYPOTHALAMUS OR MUSCLE TISSUE IN OBESE ANIMALS

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies

Haematological malignancies result from a heterogeneous mix of genetic mutations and chromosome aberrations and translocations. Targeted therapies, such as the anti-CD20 antibody rituximab, or the BCR-ABL1 inhibitor imatinib, have proven to be effective treatments in the management of some of these malignancies, though relapsing or refractory disease is still common. Nucleic acid-based therapies have also entered the clinical arena, providing an alternative, complementary approach. The forerunner of these therapies were the antisense oligonucleotides, but their scope has expanded to include short-interfering RNA (siRNA), microRNA, decoy oligonucleotides and aptamers. These can be used either as monotherapeutics, in conjunction with current chemotherapy regimens, or in combination with each other to improve therapeutic efficacy. Not only can these nucleic acid-based therapies silence target genes, they also have the potential of restoring gene function. While challenges remain in delivering effective doses of nucleic acid in vivo, these are steadily being met, suggesting an optimistic future in the treatment of haematological malignancies. This review summarizes the application of nucleic acid-based therapeutics, particularly aptamers, in the diagnosis and treatment of haematological malignancies.