Regulation and Function of Neuronal Nicotinic Acetylcholine Receptors in Lung Cancer: A Dissertation

Lung cancer is the leading cause of cancer-related mortality worldwide. The main risk factor associated with lung cancer is cigarette smoking. Research through the years suggests that nicotine in cigarettes promotes lung cancer by activating signaling pathways that lead to cell proliferation, cell survival, angiogenesis, and metastasis. Nicotine’s cellular actions are mediated by its cognate receptors, nicotinic acetylcholine receptors (nAChRs). Here, I describe the expression levels of all known human nAChR subunit genes in both normal and lung cancer cells. Of note, the genes encoding the α5, α3, and β4 subunits (CHRNA5/A3/B4) are over-expressed in small cell lung carcinoma (SCLC), the most aggressive form of lung cancer. This over-expression is regulated by ASCL1, a transcription factor important in normal lung development and lung carcinogenesis. The CHRNA5/A3/B4 locus has recently been the focus of a series of genetic studies showing that polymorphisms in this region confer risk for both nicotine dependence and lung cancer. I show that CHRNA5/A3/B4 depletion results in decreased SCLC cell viability. Furthermore, while nicotine promotes SCLC cell viability and tumor growth, blockade of α3β4 nAChRs inhibits SCLC cell viability. These results suggest that increased expression and function of nAChRs, specifically the α3β4α5 subtype, potentiate the effects of nicotine in SCLC. This dual hit from the carcinogens in tobacco and the cancer-promoting effects of nicotine, may provide a possible mechanism for the increased aggressiveness of SCLC. In addition, nAChRs can be activated by the endogenous ligand, acetylcholine, which acts as an autocrine/paracrine growth factor in SCLC. Increased function of α3β4α5 nAChRs in SCLC could also potentiate acetylcholine’s mitogenic effects. This mechanism, combined with other known autocrine/paracrine growth loops in SCLC, may help explain the ineffectiveness of available therapies against SCLC. In an effort to add to the current arsenal against SCLC, I screened a 1280-compund library using a bioluminescence-based viability assay I developed for high-throughput applications. Primary screening, followed by secondary and tertiary verification, indicate that pharmacologically active compounds targeting neuroendocrine markers inhibit SCLC cell viability

Knowledge Management (KM) Practıces of the Retaıl Industry in Camarınes Norte, Phılıppınes: A Descrıptıve Quantıtatıve Analysıs

This study was conducted to ascertain the Knowledge Management (KM) practices of the retail industry, utilizing the quantitative descriptive research design. Using survey within the Philippines border the findings revealed that the majority of the retail industries in the province were highly understand the concept of Knowledge Management. Among its four major components the retail industries have the highest level of awareness towards the component of people, whereas, on the level of application, it is on the component of the strategy. While on customers' needs and satisfaction, KM strongly contributed to the retail industry and help uplift business operation and performance as well as long-term sustainability. It is concluded that by embracing Knowledge Management in business operations, the status of retail industry would rise up. The formulation of a centralized Knowledge Management system and collaboration to the government agency like the Department of Trade and Industry (DTI) will steadfast the growth of the retail industry in the province of Camarines Norte, Philippines

Sequence analysis of putative swrW gene required for surfactant serrawettin W1 production from Serratia marcescens

Serratia marcescens produces biosurfactant serrawettin, essential for its population migration behavior. Serrawettin W1 was revealed to be an antibiotic serratamolide that makes it significant for deoxyribonucleic acid (DNA) and protein sequence analysis. Four nucleotide and amino-acid sequences from local strains analyzed through bioinformatics showed high confidence prediction of serrawettin. Database comparison analysis resulted to high similarity of the nucleotide sequence to the swrW gene of 88 to 94%, the homologous protein sequence to the serrawettin W1 synthetase protein ranging from 85 to 89%, presence of condensation domain from the non-ribosomal peptide synthetase (NRPS) family that synthesize peptide antibiotics and strong relation to the predicted surfactin synthetase structure. Further protein analysis showed high identical multiple alignment having conserved regions and the predicted structure representation was identified as putative surfactin a synthetase c (srfa-c), a non-ribosomal peptide synthetase termination module with 100% confidence. These nucleotide and protein sequence analysis of the putative swrW gene provides vital information on the versatility of S. marcescens as a pathogen of diverse hosts and an impetus for further genetic manipulation for practical applications.Keywords: swrW gene, serrawettin W1, non-ribosomal peptide synthetase (NRPS

Electroweak radiative corrections to e+e−→ttˉhe^+e^- \to t \bar{t} h at linear colliders

We calculate the ${\cal O}(\alpha_{{\rm ew}})$ electroweak radiative corrections to $e^+ e^- \to t \bar{t} h$ at a electron-positron linear collider (LC) in the standard model. We analyze the dependence of the ${\cal O}(\alpha_{{\rm ew}})$ corrections on the Higgs boson mass $m_{h}$ and colliding energy $\sqrt{s}$, and find that the corrections significantly decrease or increase the Born cross section depending on the colliding energy. The numerical results show that the ${\cal O}(\alpha_{{\rm ew}})$ relative correction is strongly related to the Higgs boson mass when $\sqrt{s}=500 GeV$, and for $m_h = 150 GeV$ the relative correction ranges from -31.3% to 2.3% as the increment of the colliding energy from 500 GeV to 2 TeV.Comment: 16 pages, 7 figure

Substrate-controlled Michael additions of chiral ketones to enones

Substrate-controlled Michael additions of the titanium-(IV) enolate of lactate-derived ketone 1 to acyclic α,β-unsaturated ketones in the presence of a Lewis acid (TiCl4 or SnCl4) provide the corresponding 2,4-anti-4,5-anti dicarbonyl compounds in good yields and excellent diastereomeric ratios. Likely, the nucleophilic species involved in such additions are bimetallic enolates that may add to enones through cyclic transition states. Finally, further studies indicate that a structurally related β-benzyloxy chiral ketone can also participate in such stereocontrolled conjugate additions

Assessment of bone-regeneration using adipose-derived stem cells in critical-size alveolar ridge defects: an experimental study in a dog model

Purpose: To assess bone regeneration potential of a fibronectin- and adipose-derived stem cell-covered ceramic biomaterial in three-wall critical size alveolar ridge defects. Materials and methods: In 18 dogs, four dehiscence-type and critical size defects were created surgically in the edentulous alveolar ridge. Defects were randomly regenerated using biomaterials coated with particulate ß-tricalcium phosphate (ß-TCP), ß-TCP with fibronectin (Fn) (ß-TCP-Fn), and ß-TCP with a combination of Fn and autologous adipose-derived stem cells (ADSCs) (ß-TCP-Fn-ADSCs), leaving one defect as control. The animals were divided into three groups according to the time of euthanasia (1, 2, or 3 months of healing). Results: At the time of sacrifice, statistically significant differences between the four types of defects in the total area of bone regeneration, percentage of neoformed bone matrix, medullary space, or contact between particulate biomaterial and neoformed bone matrix were not found. All defects showed a significant increase in neoformed bone matrix as sacrifice was delayed, but a uniform pattern was not followed. Only defects treated with ß-TCP-Fn-ADSCs showed a significant increase in the bone regeneration area when animals sacrificed at 3 months were compared to those sacrificed at 1 month (P = .006). Conclusion: The use of ADSCs in bone regeneration processes of critical size defects of the alveolar ridge did not entail an advantage regarding greater bone regeneration as compared with other biomaterials. However, the use of ß-TCP coated with a combination of Fn and ADSCs appeared to favor stabilization of the regenerated area, allowing a more efficient maintenance of the space at 3 months of healing

VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications

Voltage-Dependent Anion selective Channels (VDAC) are pore-forming mitochondrial outer membrane proteins. In mammals VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed toward the intermembrane space. We find that cysteines in VDAC3 can stay in different oxidation states. This was preliminary observed when, in our experimental conditions, completely lacking any reducing agent, VDAC3 presented a pattern of slightly different electrophoretic mobilities. This observation holds true both for rat liver mitochondrial VDAC3 and for recombinant and refolded human VDAC3. Mass spectroscopy revealed that cysteines 2 and 8 can form a disulfide bridge in native VDAC3. Single or combined site-directed mutagenesis of cysteines 2, 8 and 122 showed that the protein mobility in SDS-PAGE is influenced by the presence of cysteine and by the redox status. In addition, cysteines 2, 8 and 122 are involved in the stability control of the pore as shown by electrophysiology, complementation assays and chemico-physical characterization. Furthermore, a positive correlation between the pore conductance of the mutants and their ability to complement the growth of porin-less yeast mutant cells was found. Our work provides evidence for a complex oxidation pattern of a mitochondrial protein not directly involved in electron transport. The most likely biological meaning of this behavior is to buffer the ROS load and keep track of the redox level in the intermembrane space, eventually signaling it through conformational change

Entrepreneurs’ Perspective in Coping with the New Normal: Basis for Business Model Development

This descriptive quantitative study was conducted to determine the entrepreneurs’ perspective in coping with the new normal using weighted and average mean as statistical tools in analyzing the data.  Findings revealed that the 22 restaurant owners had experienced challenges or business gaps in the new normal situation, which centered on the administrative, production, and financial aspects. Whereas, respondents' perspectives on the opportunity in the new normal situation are on working in flexibility, creating a more responsive business environment, and creating new needs as a break in restaurant business operations. To support the plight of the restaurant entrepreneurs, a business model named 3Ms Strategic Innovation Business Model is developed to reinvent and redesign its corporate strategies in response to the new normal situation. The study concluded that restaurant entrepreneurs in the province of Camarines Norte, Philippines need to adopt a business model suited to the new normal context in order to promote business growth, create competitive advantage, and generate value for their business, its customers, and other stakeholders, making them more empowered individuals in dealing with this crisis

Single production of the top partners at high energy colliders

The left-right twin $Higgs$ ($LRTH$) model is a concrete realization of the twin $Higgs$ mechanism, which predicts the existence of the top partner $T$. In this paper, we consider production of $T$ associated with the top quark $t$ at the high energy linear $e^{+}e^{-}$ collider ($ILC$) and the $LHC$ experiments, and its single production in future linac-ring type $ep$ collider experiment. To compare our results with those of the littlest $Higgs$ model with $T$-parity, we also estimate production of the $T$-even top partner $T_{+}$ via the corresponding processes in these high energy collider experiments. A simply phenomenological analysis is also given.Comment: 21 pages, 10 figures; to be published in Nucl. Phys.