Impact of Liquidity on the Futures–Cash Basis: Evidence from the Indian Market

The law of one price relies on enforcement by arbitragers who are expected to eliminate price differentials quickly. Arbitragers’ activities are constrained by liquidity of markets. However, large price differentials attract arbitrage activity enhancing the liquidity of markets. Using daily data on the NYSE index and related futures contracts, Roll, Schwartz, and Subrahmanyam (2007) document two-way Granger causality between the futures-cash basis and bid-ask spreads for stocks. We examine the issue using intra-day data on Indian single stock futures (SSF) contracts on Indian stocks and also consider the spread on the futures contracts. While the spreads in both the futures and cash markets affect futures-cash basis, we find that the futures-cash basis Granger-causes only the bid-ask spreads for SSFs but not the stocks.Futures-cash basis; Single stock futures; Indian stocks.

CLEVER-1 as an immune suppressive molecule

The immune response and immune suppression are equally essential for the immune system to protect the host against an infection and to protect self-molecules in different pathophysiological conditions. Pregnancy is one of the conditions where the maternal immune system remains resistant against microbes and yet attains tolerance to protect the fetus, whose genetic material differs partially from the mother’s. However, if the balance of immune suppression is not precise in the host it can favor conditions which lead to diseases, such as cancer and autoimmune disorders. This study was initiated to investigate the expression and functions of CLEVER-1/Stabilin-1, a multifunctional protein expressed on subsets of endothelial cells and type II macrophages, as an immune suppressive molecule. Firstly, the expression of CLEVER-1/stabilin-1 and its function in human placental macrophages were examined. Secondly, the expression profile and functional significance of stabilin-1 on healthy human monocytes was investigated. The results clarified the expression of CLEVER-1/stabilin-1 on placental macrophages, and verified that CLEVER-1/stabilin-1 functions as an adhesion and scavenging molecule on these cells. The data from normal monocytes revealed that the monocytes with low stabilin-1 expression carried a pro-inflammatory gene signature, and that stabilin-1 can directly or indirectly regulate pro-inflammatory genes in monocytes. Finally, it was shown that monocyte CLEVER-1/stabilin-1 dampens IFN production by T cells. To conclude, CLEVER-1/stabilin-1 is defined as an immune suppressive molecule on monocytes and macrophages. Strikingly, anti-stabilin-1 antibodies may have the potential to promote the Th1 dependent inflammatory response and counteract the tumor induced immune suppression.CLEVER-1 tulehdusreaktiota vaimentavana molekyylinä Elimistön puolustusjärjestelmä torjuu mikrobi-infektioita ja muita vieraita molekyylejä immuunivasteeksi kutsutun mekanismin avulla. Samalla immuunivasteen pitää kuitenkin suojella elimistön normaalisoluja ja kyetä palaamaan taas normaalitilaan uhkan torjumisen jälkeen. Raskaus on yksi esimerkki tilanteesta, jossa äidin immuunisysteemi säilyttää reagointikykynsä mikrobeja kohtaan samalla kun se sikiön suojelemiseksi sietää sikiön sisältämää vierasta geneettistä materiaalia. Immuuunireaktion tasapainon säätelyhäiriöt ovat osallisina syövän ja autoimmuunitautien synnyssä. CLEVER-1/stabilin-1 on tietyissä endoteelisoluissa ja makrofaageissa ilmentyvä molekyyli, joka osallistuu valkosolujen liikkumiseen ja vieraiden molekyylien tunnistamiseen. Tässä työssä selvitin CLEVER-1/stabilin-1:n ilmentymistä ja toimintaa ihmisen veren monosyyteissä ja istukan makrofageissa. Väitöskirjatyön tulokset osoittivat, että CLEVER-1/stabilin-1 ilmenee istukan kaikissa makrofageissa ja että se toimii näissä soluissa sekä tarttumismolekyylinä että ns. scavenging-molekyylinä. Normaaleilla monosyyteillä tehdyt tutkimukset paljastivat, että niukasti CLEVER-1/stabilin-1 molekyyliä ilmentävät solut olivat tulehduksellisesti aktiivisempia kuin runsaasti CLEVER-1/stabilin-1:tä ilmentävät solut. Lisäksi kokeissa pystyttiin osoittamaan, että monosyyttien CLEVER-1/Stabilin-1 säätelee tulehdusta vahvistavien geenien ilmentymistä monosyyteissä ja tulehduksen välittäjäaineiden (gamma-interferoni) tuottoa T-soluissa. Väitöskirjatyöni osoittaa, että CLEVER-1/stabilin-1 on immunosuppressiivinen molekyyli monosyyteissä ja makrofageissa. CLEVER-1/stabilin-1- vasta-aineilla voisikin olla mahdollista tehostaa interferoni-gamma riippuvaista tulehdusvastetta ja näin kumota syövän aiheuttamaa immunosuppressiota.Siirretty Doriast

Mechanisms of neutrophil recruitment in septic lung injury

Sepsis is one of leading cause of death despite aggressive surgical intervention and antibiotic therapies. Excessive neutrophil recruitment is a major feature in early phase with immune system dysfunction at later phase. Lung is the most vulnerable, critical and sensitive organ during sepsis process. The aim of thesis was to prevent excessive neutrophil accumulation in lung parenchyma on one hand, and to reinforcement of immune system at later phase of sepsis on other hand. We hypothesized that CD44 may have a role in mediating pulmonary recruitment of neutrophils along with Rho GTPase subfamily in more than one way for enhancing neutrophil stiffness and migration. Peptides are new evolutionary compound with multifunctional effects, especially during infection and sepsis but potential therapeutic effect of them in polymicrobial sepsis remains elusive. Polymicrobial sepsis was induced by cecal ligation and puncture, purified monoclonal antibody against CD44, Rho kinase inhibitor (Y-27632) and Rac1 inhibitor (NSC23766). Specific TDPs, GKY20 and GKY25 were injected after procedure. Edema formation, bronchoalveolar accumulation of neutrophils, myeloperoxidase activity, and CXC chemokine in lung measured after CLP. We observed that sepsis triggered clear-cut lung damage characterized by edema formation, neutrophil infiltration, and increased levels of MIP-2 in the lung. We demonstrate that immunoneutralization with anti-CD44 reduce neutrophil activation and accumulation as well as edema formation and lung injury. Pretreatment with Y-27632 reduced the CLP-induced pulmonary injury and MPO activity as well as Mac-1 on neutrophils along with clear reduction in F-actin formation. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. NSC23766 abolished the sepsis-evoked elevation of mRNA levels of CXC chemokines and TNF-α in alveolar macrophages. Moreover, TDPs maintain CD4 T-cells function in spleen by reducing T-cell apoptosis and clear reduction in sepsis-mediated T-regulatory production. TDPs abolished CLP- evoked HMGB1 and IL-6 production. Furthermore TDPs exerts clear cut bacterial clearance in the blood and spleen. Thus, this work show more details in neutrophil extravagation during sepsis. Our data may dig up the way for establishing more specific and effective treatments of sepsis

Interplay of Extrinsic and Intrinsic Cues in Cell-Fate Decisions

A cell’s decision making process is coordinated by dynamic interplay between its extracellular environment and its intracellular milieu. For example, during stem cell differentiation, fate decisions are believed to be ultimately controlled by differential expression of lineage-specific transcription factors, but cytokine receptor signals also play a crucial instructive role in addition to providing permissive proliferation and survival cues. Here, we present a minimal computational framework that integrates the intrinsic and extrinsic regulatory elements implicated in the commitment of hematopoietic progenitor cells to mature red blood cells (Chapter 2). Our model highlights the importance of bidirectional interactions between cytokine receptors and transcription factors in conferring properties such as ultrasensitivity and bistability to differentiating cells. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. We then experimentally test predictions from this lineage commitment model in a model system for studying erythropoiesis (Chapter 3). Our experiments show that hemoglobin synthesis is highly switch-like in response to cytokine and cells undergoing lineage commitment possess memory of earlier cytokine signals. We show that erythrocyte-specific receptor and transcription factor are indeed synchronously co-upregulated and the heterogeneity in their expression is positively correlated during differentiation, confirming the presence of autofeedback and receptor-mediated positive feedback loops. To evaluate the possibility of employing this minimal topology as a synthetic “memory module” for cell engineering applications, we constructed this topology synthetically in Saccharomyces cerevisiae by integrating Arabidopsis thaliana signaling components with an endogenous yeast pathway (Chapter 4). Our experiments show that any graded and unimodal signaling pathway can be rationally rewired to achieve our desired topology and the resulting network immediately attains high ultrasensitivity and bimodality without tweaking. We further show that this topology can be tuned to regulate system dynamics such as activation/deactivation kinetics, signal amplitude, switching threshold and sensitivity. We conclude with a computational study to explore the generality of this interplay between extrinsic and intrinsic cues in hematopoiesis. We extend our minimal model analysis in Chapter 2 to examine the more complex fate decisions in bipotent and multipotent progenitors, particularly how these cells can make robust decisions in the presence of multiple extrinsic cues and intrinsic noise (Chapter 5). Our model provides support to both the instructive and stochastic theories of commitment: cell fates are ultimately driven by lineage-specific transcription factors, but cytokine signaling can strongly bias lineage commitment by regulating these inherently noisy cell-fate decisions with complex, pertinent behaviors such as ligand-mediated ultrasensitivity and robust multistability. The simulations further suggest that the kinetics of differentiation to a mature cell state can depend on the starting progenitor state as well as on the route of commitment that is chosen. Lastly, our model shows good agreement with lineage-specific receptor expression kinetics from microarray experiments and provides a computational framework that can integrate both classical and alternative commitment paths in hematopoiesis that have been observed experimentally

Asymmetrical Information & Health Care Industry: A case study on Indian Drug stores

Health care systems are generally recognizing that information is an essential commodity, and the information is a key ingredient to being successful. Any absence of full information can lead to transactions that are ultimately disadvantageous for patients and physician and drugstores. An attempt is made in this study on information asymmetry with patients and drug stores with the principal component analysis of factor analysis and it was extracted 9 interpretable factors from 21 information variables that are possibly attributes the asymmetrical information. From the analysis, it is found that (a) expected role from Drug Store persons and (b) expected details about medicines purchased by the patients are the most important factors. This is because the price and the cost spent for the drugs and medicines are increasing day by day. Another important factor is related to patient “dependency” with drug stores persons and role of drug store persons in building the confidence in the minds of patients. A clear cut legal reforms on health care is required to be streamlined and right to avail the information from the agents of the health care sector viz., physicians and drug stores

Regulation of polyamine biosynthesis in Saccharomyces cerevisiae

Polyamines are essential organic cations with multiple cellular functions. Their synthesis is controlled by a feedback regulation whose main target is ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. In mammals, ODC has been shown to be inhibited and targeted for ubiquitin-independent degradation by ODC antizyme. The synthesis of mammalian antizyme was reported to involve a polyamine-induced ribosomal frameshifting mechanism. High levels of polyamine therefore inhibit new synthesis of polyamines by inducing ODC degradation. In this work, a previously unrecognized sequence in the genome of Saccharomyces cerevisiae encoding an orthologue of mammalian antizyme was identified. Synthesis of yeast antizyme (Oaz1) involves polyamine-regulated frameshifting. New elements, termed OFRE (OAZ1 frameshifting repressor element) and OPRE (OAZ1 polyamine responsive element) that are necessary for the polyamines to regulate frameshifting were mapped in the OAZ1 mRNA. Degradation of yeast ODC by the proteasome depends on Oaz1. Oaz1 mediates the degradation by binding to ODC thereby exposing a degradation signal at the N-terminus of ODC. Using the novel transplantable yeast ODC degradation signal (ODS) identified in this work a new possible role of the shuttle factor Rad23 in ODC degradation was identified. In addition, ODS is shown to interact with multiple 19S lid subunits in the proteasome. Using this novel model system for polyamine regulation another level of its control was discovered. Oaz1 itself is subject to ubiquitin-mediated proteolysis by the proteasome. Degradation of Oaz1, however, is efficiently inhibited by polyamines. I propose a model, in which polyamines inhibit their ODC-mediated biosynthesis by two mechanisms, the control of Oaz1 synthesis and inhibition of its degradation. In a second part of the work, peptide aptamers were isolated that inhibit the ubiquitin-dependent turnover of test substrates of the proteasome. These aptamers appear to either inhibit ubiquitylation or the proteasome and thereby lead to a stabilization of test substrates. I Propose that ODS due to its ubiquitin-independent mode of degradation can be used as a tool in aptamer screens that are aimed at identifying additional peptide inhibitors of the proteasome with potential clinical relevance

Making Graphical Information Accessible Without Vision Using Touch-based Devices

Accessing graphical material such as graphs, figures, maps, and images is a major challenge for blind and visually impaired people. The traditional approaches that have addressed this issue have been plagued with various shortcomings (such as use of unintuitive sensory translation rules, prohibitive costs and limited portability), all hindering progress in reaching the blind and visually-impaired users. This thesis addresses aspects of these shortcomings, by designing and experimentally evaluating an intuitive approach —called a vibro-audio interface— for non-visual access to graphical material. The approach is based on commercially available touch-based devices (such as smartphones and tablets) where hand and finger movements over the display provide position and orientation cues by synchronously triggering vibration patterns, speech output and auditory cues, whenever an on-screen visual element is touched. Three human behavioral studies (Exp 1, 2, and 3) assessed usability of the vibro-audio interface by investigating whether its use leads to development of an accurate spatial representation of the graphical information being conveyed. Results demonstrated efficacy of the interface and importantly, showed that performance was functionally equivalent with that found using traditional hardcopy tactile graphics, which are the gold standard of non-visual graphical learning. One limitation of this approach is the limited screen real estate of commercial touch-screen devices. This means large and deep format graphics (e.g., maps) will not fit within the screen. Panning and zooming operations are traditional techniques to deal with this challenge but, performing these operations without vision (i.e., using touch) represents several computational challenges relating both to cognitive constraints of the user and technological constraints of the interface. To address these issues, two human behavioral experiments were conducted, that assessed the influence of panning (Exp 4) and zooming (Exp 5) operations in non-visual learning of graphical material and its related human factors. Results from experiments 4 and 5 indicated that the incorporation of panning and zooming operations enhances the non-visual learning process and leads to development of more accurate spatial representation. Together, this thesis demonstrates that the proposed approach —using a vibro-audio interface— is a viable multimodal solution for presenting dynamic graphical information to blind and visually-impaired persons and supporting development of accurate spatial representations of otherwise inaccessible graphical materials

Principles and Guidelines for Advancement of Touchscreen-Based Non-visual Access to 2D Spatial Information

Graphical materials such as graphs and maps are often inaccessible to millions of blind and visually-impaired (BVI) people, which negatively impacts their educational prospects, ability to travel, and vocational opportunities. To address this longstanding issue, a three-phase research program was conducted that builds on and extends previous work establishing touchscreen-based haptic cuing as a viable alternative for conveying digital graphics to BVI users. Although promising, this approach poses unique challenges that can only be addressed by schematizing the underlying graphical information based on perceptual and spatio-cognitive characteristics pertinent to touchscreen-based haptic access. Towards this end, this dissertation empirically identified a set of design parameters and guidelines through a logical progression of seven experiments. Phase I investigated perceptual characteristics related to touchscreen-based graphical access using vibrotactile stimuli, with results establishing three core perceptual guidelines: (1) a minimum line width of 1mm should be maintained for accurate line-detection (Exp-1), (2) a minimum interline gap of 4mm should be used for accurate discrimination of parallel vibrotactile lines (Exp-2), and (3) a minimum angular separation of 4mm should be used for accurate discrimination of oriented vibrotactile lines (Exp-3). Building on these parameters, Phase II studied the core spatio-cognitive characteristics pertinent to touchscreen-based non-visual learning of graphical information, with results leading to the specification of three design guidelines: (1) a minimum width of 4mm should be used for supporting tasks that require tracing of vibrotactile lines and judging their orientation (Exp-4), (2) a minimum width of 4mm should be maintained for accurate line tracing and learning of complex spatial path patterns (Exp-5), and (3) vibrotactile feedback should be used as a guiding cue to support the most accurate line tracing performance (Exp-6). Finally, Phase III demonstrated that schematizing line-based maps based on these design guidelines leads to development of an accurate cognitive map. Results from Experiment-7 provide theoretical evidence in support of learning from vision and touch as leading to the development of functionally equivalent amodal spatial representations in memory. Findings from all seven experiments contribute to new theories of haptic information processing that can guide the development of new touchscreen-based non-visual graphical access solutions

Trading Profits in Closed-End Fund Tender Offers

Prior research has documented anomalous profits as high as 9% from participating in stock repurchase tender offers. The trading strategy is to buy shares in the market just before offer expiration and tender; it involves a trading horizon of just a few days. The large profits given a short trading horizon are puzzling, and this evidence raises serious questions about market efficiency. A possible reason inhibiting arbitragers from eliminating these profits is risk exposure. We examine whether trading profits are available in tender offer repurchases conducted by closed-end funds. Risk exposure concerns should be minimized for these offers, since the underlying assets of closed-end funds constitute a well-diversified portfolio of securities. We find significant tendering profits even in this sample, although the magnitude is much smaller at around 1%.Tender offer, closed-end fund

Modulation of apoptosis and signalling in cancer cells after treatment with epigenetic modulators

Krebs wurde lange Zeit als eine genetische Erkrankung angesehen. Inzwischen ist jedoch klar, dass auch epigenetische Veränderungen an der Krebsentstehung beteiligt sind. Eine wichtige epigenetische Modifikation ist die Histon-Acetylierung, deren Fehlregulierung das Krebswachstum stimulieren kann. Mit den Histondeacetylase-Inhibitoren (HDACi) lässt sich hier korrigierend eingreifen. In der vorliegenden Arbeit wurden Mechanismen untersucht, mit denen HDACi als Monosubstanzen oder in Kombination mit anderen Wirkstoffen gegen Krebszellen wirken. HDACi können einen Zellzyklus-Arrest in der G2/M-Phase induzieren. In der Untersuchung des zugrunde liegenden Mechanismus stellten wir fest, dass HDACi die Phosphorylierung von H2AX, einem Marker für DNA-Schädigung, und ATM, einem Schlüsselenzym in der zellulären Reaktion auf DNA-Schäden, bewirkten. In der weiteren Analyse der Faktoren, die an der Regulierung des Zellzyklus beteiligt sind, i. e. dem Proteasom, NF-κB und p53, beobachten wir, dass der Proteasom-Hemmstoff Bortezomib, NF-κB-Inhibitoren und der p53-Aktivator Nutlin-3 den G2/M-Arrest deutlich modulierten. Zudem führten diese Analysen eine kooperative antineoplastische Wirkung von HDACi und Nutlin-3 zu Tage. Nutlin-3 wird als ein aussichtsreicher Wirkstoff zur Behandlung von Tumoren mit Wildtyp-p53 (wt-p53) angesehen. In der Untersuchung der Kombination von Nutlin-3 und HDACi beobachteten wir, dass diese Kombination in wt-p53-Zellen, aber nicht in p53-Null-Zellen, synergistisch den Zelltod auslöste. Die Analysen zum Mechanismus des Nutlin-3/HDACi-Synergismus zeigten, dass HDACi die p53-Acetylierung induzierten und die Genexpression der p53-Inhibitor-Proteine MDM2 und MDM4 deutlich reduzierten. Das Ewing-Sarkom ist der zweithäufigste Knochenkrebs bei Kindern. Da Ewing-Sarkome in nur zehn Prozent der Fälle p53-Mutationen aufweisen, sollten 90 % auf p53-gerichtete Behandlungen ansprechen können. Wir überprüften darum die Wirksamkeit von Nutlin-3 in Ewing-Sarkom-Zelllinien und beobachteten, dass Nutlin-3 in wt-p53-Zellen p53 stabilisierte, die Expression von p53-regulierten Genen (MDM2, p21, PUMA) induzierte und die Apoptose auslöste. Unsere Befunde legen nahe, dass Nutlin-3 ein effektiver Wirkstoff zur Behandlung von Ewing-Sarkomen sein könnte