Export, Assembly-line FDI or FDI with the Possibility of Technology Diffusion: Optimal Entry Mode for Multinationals

The paper tries to evaluate the optimal entry mode of a Multinational Company that is choosing among export, fragmented production structure with assembly-line FDI in LDC or complete production in LDC with FDI. The results show that if the plant installation cost is sufficiently high then the firm will find it profitable to export the finished product to the LDC market and the Government will not exercise any IPR restriction. If plant installation cost is below a certain critical level the MNC chooses complete LDC production with FDI over assembly-line FDI if the IPR restriction is strong, where the model assumes that a fake producer can copy the product if complete production takes place in LDC. In such a situation government will choose to protect IPR if government earning exceeds the cost of IPR protection, otherwise no monitoring is the optimal strategy of the government and MNC will choose the strategy of fragmented production structure and assembly-line FDI will take place in LDC.Export, Assembly-line FDI, FDI with Complete Production, IPR Protection

Role of culture in the process of resource creation : a case study on Temple Town Bishnupur, district Bankura, West Bengal, India

The prerogative of cultural geography is to analyse how space, place and landscape are shaped by culture. It focuses on people’s relationship to the natural world and the modification of that natural landscape into cultural landscape. Cultural landscape is tangible outcome of the complex interaction between human groups with its own practice, preferences, values, aspirations and a natural or modified environment (Knox & Manston, 1987). This interaction is time and space specific. Thus each and every place has its own cultural identity. This identity may become a resource for the further development of that place. So is happen in case of the ‘temple town’ Bishnupur. Geographically it is located between 22057’15" N to 23012’32"N latitude and 87031’46"E to 87024’11"E longitude. The place significance of Bishnupur is historically rooted. It was the capital of Malla (local chieftain) dynasty. The Malla kings patronise many handloom and cottage industries including Silk, Tasar, Conch shell carvings, Bell metal, Patachitra etc. Along with this the Malla kings constructed many terracotta and brick made temples as religious symbols from locally available building materials. Malla reign faced many ups and downs for several times. Naturally many cultural practices imprinted their material and non material culture to the indigenous Bishnupur culture. The terracotta temples witnessed as piece of evidence of that acculturation process. The temples of Bishnupur and surrounding areas were constructed in 16th or 17th century. The temple architecture of neighbouring state Orissa has great impact on the temple of the study area. Incarnation of Mughal and South Indian style of temple can also be found (Santra, 1998). The Mughal, Parsic, Indo-Parsic, Hindu classics, Buddhist style and the mythological influences are prominent in terracotta ornamentation. Beside that the influence of Portuguese architecture is prominent (Dasgupta 1980). Thus mixture of tangible or natural resource and intangible resource in form of religious beliefs makes temples as a part of cultural environment which becomes a resource base for tourism

A Clinical Update on Employing Tocilizumab to Fight COVID-19

SARS-CoV-2 infection or COVID-19, currently regarded as ‘terror’ worldwide, has spread uncontrollably as a serious menace. Till date, limited effective medicines or treatments are available. The mortality and morbidity rates have increased considerably, which have been aggravated by acute respiratory distress syndrome (ARDS) and new and old cardiovascular injuries. To control COVID-19, many drugs have been taken into consideration, like ACE2 blockers, anti-inflammatory drugs, antibodies against IL-1 and anti-IL-6, Remdesivir, Dexamethasone, Hydroxychloroquine and vaccines. In this chapter, preference is given to Tocilizumab with the latest status of clinical research update available. Despite several clinical research attempts, some have yielded promising results, others are inconclusive

Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodeling

Nucleosomes, the fundamental units of chromatin structure, are regulators and barriers to transcription, replication and repair. Post-translational modifications (PTMs) of the histone proteins within nucleosomes regulate these DNA processes. Histone H3(T118) is a site of phosphorylation [H3(T118ph)] and is implicated in regulation of transcription and DNA repair. We prepared H3(T118ph) by expressed protein ligation and determined its influence on nucleosome dynamics. We find H3(T118ph) reduces DNA–histone binding by 2 kcal/mol, increases nucleosome mobility by 28-fold and increases DNA accessibility near the dyad region by 6-fold. Moreover, H3(T118ph) increases the rate of hMSH2–hMSH6 nucleosome disassembly and enables nucleosome disassembly by the SWI/SNF chromatin remodeler. These studies suggest that H3(T118ph) directly enhances and may reprogram chromatin remodeling reactions

Disparity in the DNA translocase domains of SWI/SNF and ISW2

An ATP-dependent DNA translocase domain consisting of seven conserved motifs is a general feature of all ATP-dependent chromatin remodelers. While motifs on the ATPase domains of the yeast SWI/SNF and ISWI families of remodelers are highly conserved, the ATPase domains of these complexes appear not to be functionally interchangeable. We found one reason that may account for this is the ATPase domains interact differently with nucleosomes even though both associate with nucleosomal DNA 17–18 bp from the dyad axis. The cleft formed between the two lobes of the ISW2 ATPase domain is bound to nucleosomal DNA and Isw2 associates with the side of nucleosomal DNA away from the histone octamer. The ATPase domain of SWI/SNF binds to the same region of nucleosomal DNA, but is bound outside of the cleft region. The catalytic subunit of SWI/SNF also appears to intercalate between the DNA gyre and histone octamer. The altered interactions of SWI/SNF with DNA are specific to nucleosomes and do not occur with free DNA. These differences are likely mediated through interactions with the histone surface. The placement of SWI/SNF between the octamer and DNA could make it easier to disrupt histone–DNA interactions

Heme Uptake in Group A Streptococcus: A Role in Physiology and Disease

The Group A streptococcus (GAS) produces millions of infections worldwide, leading to acute diseases, post-infection sequelae, and severe complications. This leading human pathogen requires iron for growth and relies on the heme-iron it obtains from host hemoproteins to fulfill its need for the metal during infection. Since heme is a critical nutrient for GAS within the host environment, the proteins involved in heme capture and metabolism could be targeted for the development of new modalities to treat and prevent GAS infections and their devastating complications. The 10-gene sia operon, which consists of two surface receptors (Shr and Shp), and an ABC transporter (SiaABC), is the best-described heme capture and import system in GAS. The function of the remaining siaDEFGH genes is not yet characterized. Mutants in the characterized heme uptake proteins (shr, shp, or siaABC) exhibit reduced ability to grow on heme iron, but the partial phenotype indicates other GAS genes contribute to heme metabolism. This dissertation addresses the knowledge gaps in the current understanding of heme uptake in GAS and investigates the potential of targeting the surface receptor, Shr, for the development of new therapy. The first chapter describes a new surface receptor, HupY, and demonstrates that HupY binds heme in vitro, contributes to iron acquisition from hemoglobin or serum, and GAS colonization of the mucosal surfaces in mice. The second chapter shows that the siaFGH genes encode a new type of heme importer that is vital for GAS growth on hemoglobin iron, colonization of the vaginal surface, and systemic infections in murine models. The third chapter describes high-affinity human monoclonal antibody against the surface receptor Shr, their efficacy in protecting from GAS infection in murine models, and investigate their defense mechanism. Altogether this dissertation significantly expands the current understanding of heme metabolism in GAS and lays the groundwork for the development of new therapeutic measures

SWI/SNF COMPLEXES COORDINATE WITH HISTONE MODIFICATIONS TO REGULATE CHROMATIN REMODELING

SWI/SNF, the founding member of ATP dependent chromatin remodelers and its paralog RSC in yeast perform similar yet distinct functions inside the cell. In vitro these complexes use ATP dependent DNA translocation to either mobilize or disassemble nucleosomes. However, how these complexes interact with nucleosomes and the mechanism by which chromatin remodeling is achieved is not fully understood. Further, it is not understood how they perform disparate roles in vivo despite their similar biochemical activities. To understand the fundamental differences between these complexes the substrate specificity of RSC and SWI/SNF and their interaction with different parts of the nucleosome were investigated. SWI/SNF and RSC exhibited almost identical nucleosome binding affinities (~7 nm) with a minimal requirement of 20 bp of extranucleosomal DNA for efficient binding. Hydroxical-radical footprinting of RSC-nucleosome complex showed that RSC, unlike SWI/SNF, interacts extensively with approximately 50 bp of extranucleosomal DNA near the nucleosome entry site. RSC also interacts, but not as strongly as SWI/SNF, with almost one gyre of nucleosomal DNA (SHL-2 to SHL-6) on the same side of the extranucleosomal DNA. Analogous to the previously observed SWI/SNF-footprint the second gyre of nucleosomal DNA had no protection and in fact enhanced cleavage was seen starting from 3-4 helical turns from the dyad axis up to the exit site where DNA leaves the nucleosome. The asymmetry of the DNA footprint pattern confirmed binding of RSC in one preferred orientation guided by the extranucleosomal DNA at one end of the nucleosome like ISW2 and also like SWI/SNF but only when recruited by transcription factors. DNA crosslinking revealed that most of the SWI/SNF contacts are with a small region spanning the DNA translocation start site near SHL2 and does not extend to the rest of the footprint. Further, the SWI/SNF contacts are primarily through its catalytic subunit Snf2 which is found to intercalate between the DNA gyre and the histone octamer at SHL2. Consistent with its DNA footprint, RSC however makes extensive contacts with both nucleosomal and extranucleosomal DNA through five major subunits Sth1, Rsc2, Rsc3, Rsc30 and Rsc4. Excepting the catalytic subunit Sth1 which is highly homologous to Snf2, the remaining four are unique to RSC. Sth1 contacts a much broader region in the nucleosomal DNA than Snf2 with the primary contact being at SHL2 where it wedges between the DNA and the histone octamer surface. The accessory subunits Rsc2, Rsc3 and Rsc30 mostly contribute to the extranucleosomal DNA contacts of RSC. These subunits also make a second major contact near the dyad, with those made by Rsc3 and Rsc30 being the strongest. The histone N-terminal tails that emanate out of the nucleosome structure are implicated in the regulation of chromatin remodeling, in general, and in the activation of several SWI/SNF dependent genes, in particular. Remodeling kinetics studies with tailless nucleosomes revealed that the histone H4 tail is required for nucleosome mobilization, H2A/H2B dimer displacement and nucleosome disassembly by both RSC and SWI/SNF. Further, the H4 tail modulates RSC and SWI/SNF remodeling without affecting ATP hydrolysis or nucleosome binding. These data suggest a similarity between SWI/SNF and ISWI class of chromatin remodelers based on their dependence on the H4 tail. Owing to the presence of acetyl-lysine binding bromodomains in these complexes and to a greater extent in RSC the differences in their remodeling activities, if any, were expected to be accentuated by histone acetylation. Studies with H3 and H4 tail acetylated nucleosomes provided evidence for two pathways that work synergistically to recruit SWI/SNF and RSC to chromatin. While one of the pathways involves transcription activators, the other pathway of SWI/SNF recruitment is dependent on covalent acetylation of histone H3 tail. Bromodomain mediated recognition of these acetyl marks not only facilitates SWI/SNF recruitment but also stimulates their catalytic activity to mobilize nucleosomes. Importantly, extensive conformational changes occur in SWI/SNF in response to H3 tail acetylation. Chromatin remodeling by SWI/SNF and RSC is also regulated to different degrees by H3 tail acetylation depending on the number of bromodomains. The higher responsiveness of RSC to H3 tail acetylation than SWI/SNF can provide additional regulatory mechanisms for RSC which might ultimately account for their different functional roles inside the cell. When these same acetyl marks are within the H3 globular core and reside near the dyad axis of symmetry they are found to act in synergy with RSC and SWI/SNF to facilitate nucleosome movement as well as nucleosome disassembly. Unlike H3 tail acetylation, the remodeling enhancement by H3 core acetylation occurs via an acetyl lysine-bromodomain recognition independent mechanism. Further, supporting this recognition-independent mechanism H3 core acetylation does not affect the recruitment of these complexes. These data illustrate how histone acetylation modulates RSC and SWI/SNF function, and provide a mechanistic insight into their collaborative efforts to remodel chromatin