Hap2-Ino80-facilitated transcription promotes de novo establishment of CENP-A chromatin.

Centromeres are maintained epigenetically by the presence of CENP-A, an evolutionarily conserved histone H3 variant, which directs kinetochore assembly and hence centromere function. To identify factors that promote assembly of CENP-A chromatin, we affinity-selected solubilized fission yeast CENP-ACnp1 chromatin. All subunits of the Ino80 complex were enriched, including the auxiliary subunit Hap2. Chromatin association of Hap2 is Ies4-dependent. In addition to a role in maintenance of CENP-ACnp1 chromatin integrity at endogenous centromeres, Hap2 is required for de novo assembly of CENP-ACnp1 chromatin on naïve centromere DNA and promotes H3 turnover on centromere regions and other loci prone to CENP-ACnp1 deposition. Prior to CENP-ACnp1 chromatin assembly, Hap2 facilitates transcription from centromere DNA. These analyses suggest that Hap2-Ino80 destabilizes H3 nucleosomes on centromere DNA through transcription-coupled histone H3 turnover, driving the replacement of resident H3 nucleosomes with CENP-ACnp1 nucleosomes. These inherent properties define centromere DNA by directing a program that mediates CENP-ACnp1 assembly on appropriate sequences.

Centromere DNA Destabilizes H3 Nucleosomes to Promote CENP-A Deposition during the Cell Cycle.

Active centromeres are defined by the presence of nucleosomes containing CENP-A, a histone H3 variant, which alone is sufficient to direct kinetochore assembly. Once assembled at a location, CENP-A chromatin and kinetochores are maintained at that location through a positive feedback loop where kinetochore proteins recruited by CENP-A promote deposition of new CENP-A following replication. Although CENP-A chromatin itself is a heritable entity, it is normally associated with specific sequences. Intrinsic properties of centromeric DNA may favor the assembly of CENP-A rather than H3 nucleosomes. Here we investigate histone dynamics on centromere DNA. We show that during S phase, histone H3 is deposited as a placeholder at fission yeast centromeres and is subsequently evicted in G2, when we detect deposition of the majority of new CENP-ACnp1. We also find that centromere DNA has an innate property of driving high rates of turnover of H3-containing nucleosomes, resulting in low nucleosome occupancy. When placed at an ectopic chromosomal location in the absence of any CENP-ACnp1 assembly, centromere DNA appears to retain its ability to impose S phase deposition and G2 eviction of H3, suggesting that features within centromere DNA program H3 dynamics. Because RNA polymerase II (RNAPII) occupancy on this centromere DNA coincides with H3 eviction in G2, we propose a model in which RNAPII-coupled chromatin remodeling promotes replacement of H3 with CENP-ACnp1 nucleosomes.

Identification of a novel class of quinoline-oxadiazole hybrids as anti-tuberculosis agents.

A series of novel quinoline-oxadiazole hybrid compounds was designed based on stepwise rational modification of the lead molecules reported previously, in order to enhance bioactivity and improve druglikeness. The hybrid compounds synthesized were screened for biological activity against Mycobacterium tuberculosis H37Rv and for cytotoxicity in HepG2 cell line. Several of the hits exhibited good to excellent anti-tuberculosis activity and selectivity, especially compounds 12m, 12o and 12p, showed minimum inhibitory concentration values<0.5µM and selectivity index>500. The results of this study open up a promising avenue that may lead to the discovery of a new class of anti-tuberculosis agents.

Rational drug design based synthesis of novel arylquinolines as anti-tuberculosis agents.

A series of novel arylquinoline derivatives was designed retaining significant pharmacophoric features and three dimensional geometry of bedaquiline. In silico ADME study was performed to assess drug likeness and toxicity profiles of the designed molecules. The compounds were evaluated for activity against Mycobacterium tuberculosis H37Rv using Resazurin Microtitre Assay (REMA) plate method and cytotoxicity in VERO C1008 cell line. Several of the synthesized compounds exhibited good antituberculosis activity and selectivity, especially compounds, 12i (MIC: 5.18 µM and MIC/CC50: 152.86) and 12l (MIC: 5.59 µM and MIC/CC50: 160.57). The study opens up a new platform for the development of arylquinoline based drugs for treating tuberculosis.

Current opinion on the role of resection and liver transplantation for hepatocellular cancer.

Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC.

Effects of disorder on the optical properties of CVD grown polycrystalline graphene.

We explore the effects of crystallite size (L(a)) on the linear and non-linear optical properties of chemical vapor deposition grown polycrystalline graphene. The π-plasmon resonance present at ∼4.75 eV (∼260 nm) in the optical absorption spectrum of graphene follows the empirical relationship λ(π) = 250.5 nm + 89.5 nm(2)/L(a), where λ(π) represents the π-plasmon wavelength. Furthermore, our Z-scan studies reveal that the crystallite size significantly changes the saturation intensity in CVD grown graphene. Notably, in comparison to epitaxial graphene layers grown on SiC wafers which exhibit a photogenerated carrier lifetime of few picoseconds, we find that the photogenerated carriers in our CVD grown graphene can exhibit lifetimes as long as nanoseconds.