Family businesses and their effects on organisational performance : Wealth View Industries Sdn. Bhd. as a case study

[Executive Summary] The aim of this management project is to identify the effects on organisational performance in the context of family businesses. In other words, do family businesses impede or support the performance of an organisation. Wealth View Industries Sdn. Bhd., a Malaysian pure lead manufacturing company was chosen as a case study to support the research. The organisation was chosen as it is wholly owned and managed by one family, with the third generation in midst of succession. These factors were in line with the objectives of the research. Data in the form of Interviews conducted with the participants from the organisation were obtained, transcribed, and analysed to identify categories that affect Wealth View Industries Sdn. Bhd.’s organisational performance. There were two categories identified as the supporting themes that promote the organisational performance at Wealth View Industries Sdn. Bhd., namely: The importance emphasised by the family management to maintain social capital and the positive effects of the newer generation entering the business. Two categories that impeded organisational performance at Wealth View Industries Sdn. Bhd. were the threat of operation delays and the lack of long-term plan communication. By analysing and providing backing from theoretical literature research, the author had recommended that Wealth View Industries Sdn. Bhd. need to enforce corporate governance, manage succession, and professionalise operation to ensure continuous growth of the company and superior organisational performance. It was then concluded that family businesses do affect organisational performance, both positively and negatively

Family businesses and their effects on organisational performance : Wealth View Industries Sdn. Bhd. as a case study

[Executive Summary] The aim of this management project is to identify the effects on organisational performance in the context of family businesses. In other words, do family businesses impede or support the performance of an organisation. Wealth View Industries Sdn. Bhd., a Malaysian pure lead manufacturing company was chosen as a case study to support the research. The organisation was chosen as it is wholly owned and managed by one family, with the third generation in midst of succession. These factors were in line with the objectives of the research. Data in the form of Interviews conducted with the participants from the organisation were obtained, transcribed, and analysed to identify categories that affect Wealth View Industries Sdn. Bhd.’s organisational performance. There were two categories identified as the supporting themes that promote the organisational performance at Wealth View Industries Sdn. Bhd., namely: The importance emphasised by the family management to maintain social capital and the positive effects of the newer generation entering the business. Two categories that impeded organisational performance at Wealth View Industries Sdn. Bhd. were the threat of operation delays and the lack of long-term plan communication. By analysing and providing backing from theoretical literature research, the author had recommended that Wealth View Industries Sdn. Bhd. need to enforce corporate governance, manage succession, and professionalise operation to ensure continuous growth of the company and superior organisational performance. It was then concluded that family businesses do affect organisational performance, both positively and negatively

The Cloning and Characterization of MADD-4, A Novel Guidance Cue in C. elegans

Directed cell migration is fundamental to the development of all multicellular organisms including humans. To investigate the molecular underpinnings of directed cell migration, our lab primarily exploits plasma membrane extensions called muscle arms, from the body wall muscles in the tiny nematode Caenorhabditis elegans. Through genetic screens for genes required for muscle arm extension, we found that the UNC-40/DCC netrin guidance receptor directs muscle arm extension to the midlines. Surprisingly, neither the UNC-6/netrin cue (the canonical ligand for UNC-40) nor other well-characterized guidance cues such as the slits, ephrins and semaphorins were found to be the primary cue for muscle arm extension. This suggested that muscle arms were likely responding to a novel guidance cue. In this thesis, I describe the cloning and characterization of MADD-4, a novel secreted cue that diffuses and attracts muscle arms and sensory axons along the dorsoventral axis in C. elegans. MADD-4 is a member of the non-enzymatic ADAMTSL family of proteins and is well conserved among animals. Very little is known about the biological role of any of MADD-4's orthologs. Together with Kevin Chan, I found that MADD-4's guidance function is dependent on an EVA-1-UNC-40 co-receptor complex. We found that MADD-4 interacts with both EVA-1 and UNC-40. Similarly, we found that EVA-1 and UNC-40 likely physically interact and this interaction is critical for the MADD-4 response. Furthermore, we found that the binding of EVA-1 to UNC-40 increases UNC-40's sensitivity to MADD-4. This enhanced sensitivity becomes especially meaningful within a field of other ligands capable of binding UNC-40 like UNC-6. In the absence of UNC-6, UNC-40's responsiveness to MADD-4 becomes less dependent on EVA-1. Hence, by regulating UNC-40's sensitivity to MADD-4, EVA-1 may increase the precision by which UNC-40-directed processes can reach MADD-4-expressing target cells. Collectively, the work discussed in this thesis recounts the first description of a novel guidance cue and its mechanism of action. Furthermore, since the biological role of any ADAMTSL family member outside of MADD-4 is largely unknown, it is very likely that my work on MADD-4 will broaden our understanding of the biological role of the ADAMTSL family of proteins.Ph.D.2018-06-17 00:00:0

Traction cytometry: regularization in the Fourier approach and comparisons with finite element method

Traction forces exerted by adherent cells are quantified using displacements of embedded markers on polyacrylamide substrates due to cell contractility. Fourier Transform Traction Cytometry (FTTC) is widely used to calculate tractions but has inherent limitations due to errors in the displacement fields; these are mitigated through a regularization parameter (g) in the Reg-FTTC method. An alternate finite element (FE) approach computes tractions on a domain using known boundary conditions. Robust verification and recovery studies are lacking but essential in assessing the accuracy and noise sensitivity of the traction solutions from the different methods. We implemented the L2 regularization method and defined a maximum curvature point in the traction with g plot as the optimal regularization parameter (g*) in the Reg-FTTC approach. Traction reconstructions using g* yield accurate values of low and maximum tractions (Tmax) in the presence of up to 5% noise. Reg-FTTC is hence a clear improvement over the FTTC method but is inadequate to reconstruct low stresses such as those at nascent focal adhesions. FE, implemented using a node-by-node comparison, showed an intermediate reconstruction compared to Reg-FTTC. We performed experiments using mouse embryonic fibroblast (MEF) and compared results between these approaches. Tractions from FTTC and FE showed differences of B92% and 22% as compared to Reg-FTTC. Selection of an optimum value of g for each cell reduced variability in the computed tractions as compared to using a single value of g for all the MEF cells in this study

Spike selection in SARS-CoV-2 variants across different geographical regions reveals unique signature patterns and differential stability with drug interaction

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected to be relatively neutral, mutations at the Spike region of the genome has shown to have a major impact on the viral transmission and infection in humans. Therefore, it is crucial to survey the structures of spike protein across the global virus population to contextualize the rate of therapeutic success against these variants. In this study, high-frequency mutational variants from different geographic regions were pooled in order to study the structural evolution of the spike protein through drug docking and MD simulations. We investigated the mutational burden in the spike sub regions and have observed that the different variants harbour unique signature patterns in the spike sub regions, with certain domains being highly prone to mutations. Further, the MD simulations and docking study revealed that different variants show differential stability when docked for the same set of drug targets. This work sheds light on the mutational burden and the stability landscape of the spike protein across the variants from different geographical regions

EVA-1 Functions as an UNC-40 Co-receptor to Enhance Attraction to the MADD-4 Guidance Cue in <i>Caenorhabditis elegans</i>

<div><p>We recently discovered a secreted and diffusible midline cue called MADD-4 (an ADAMTSL) that guides migrations along the dorsoventral axis of the nematode <i>Caenorhabditis elegans</i>. We showed that the transmembrane receptor, UNC-40 (DCC), whose canonical ligand is the UNC-6 (netrin) guidance cue, is required for extension towards MADD-4. Here, we demonstrate that MADD-4 interacts with an EVA-1/UNC-40 co-receptor complex to attract cell extensions. EVA-1 is a conserved transmembrane protein with predicted galactose-binding lectin domains. EVA-1 functions in the same pathway as MADD-4, physically interacts with both MADD-4 and UNC-40, and enhances UNC-40's sensitivity to the MADD-4 cue. This enhancement is especially important in the presence of UNC-6. In EVA-1's absence, UNC-6 interferes with UNC-40's responsiveness to MADD-4; in UNC-6's absence, UNC-40's responsiveness to MADD-4 is less dependent on EVA-1. By enabling UNC-40 to respond to MADD-4 in the presence of UNC-6, EVA-1 may increase the precision by which UNC-40-directed processes can reach their MADD-4-expressing targets within a field of the UNC-6 guidance cue.</p></div

Drug repurposing and sequence analysis in S-glycoprotein variants reveals critical signature patterns and destabilization of receptor-binding domain in omicron variant

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected to be relatively neutral, mutations at the Spike region of the genome have shown to have a major impact on the viral transmission and infection in humans. Therefore, it is crucial to survey the structures of spike protein across the global virus population to contextualize the rate of therapeutic success against these variants. In this study, high-frequency mutational variants from different geographic regions were pooled in order to study the structural evolution of the spike protein through drug docking and MD simulations. We investigated the mutational burden in the spike subregions and have observed that the different variants harbour unique signature patterns in the spike subregions, with certain domains being highly prone to mutations. Further, the MD simulations and docking study revealed that different variants show differential stability when docked for the same set of drug targets. This work sheds light on the mutational burden and the stability landscape of the spike protein across the variants from different geographical regions. Communicated by Ramaswamy H. Sarma</p

MADD-4 attracts extending AVM axons via EVA-1 and UNC-40.

<p><b>A</b>. A schematic illustrating the area of the worm shown in B-D. Anterior is to the right and dorsal is up. <b>B–D</b>. Three worms expressing MADD-4::YFP from the dorsal muscles (from the <i>trIs78</i> transgenic array) in which the AVM axon (green arrowhead) extends ventrally (B), laterally (C) or dorsally (D). The ALMR neuron (yellow arrowhead) is also seen in all three panels. The <i>muIs32</i> transgene is used to visualize the AVM and ALMR neurons <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#pgen.1004521-Chng1" target="_blank">[22]</a>. The scale bar represents 50 µM. <b>E</b>. A genetic analysis of the AVM axon guidance errors in the indicated genetic background without transgenic expression of MADD-4. In all of these loss-of-function mutant backgrounds, the misguided axons invariably extend laterally. <b>F & G</b>. An analysis of laterally (F) or dorsally (G) -directed AVM axon extension in response to dorsally-expressed MADD-4::YFP. Shown is the percentage of animals in which the AVM extends laterally or dorsally, respectively. Note that in the background of dorsally-expressed MADD- 4, the AVM axon already extends dorsally in more than half of the <i>eva-1; unc-6</i> double mutant animals and leaves no room for the expected enhancement of <i>eva-1'</i>s lateral axon guidance defects by <i>unc-6</i>. Statistical significance is documented as described for <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#pgen-1004521-g001" target="_blank">figure 1f</a>. The alleles used in this analysis are <i>madd-4(ok2854)</i>; <i>unc-40(n324), eva-1(ok1133), slt-1(ok255), and sax-3(ky200)</i>. Standard error of the mean is shown in all graphs.</p

EVA-1 functions cell-autonomously in muscles and interacts with MADD-4.

<p><b>A</b>. Muscle-expressed EVA-1::CFP rescues the muscle extension defects of <i>eva-1</i> mutants. <b>B</b>. A summary of EVA-1 domain function that is fully detailed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#pgen.1004521.s003" target="_blank">Figure S1</a>. <b>C&D</b>. FLAG-tagged receptors were expressed from HEK293 cells, bathed in conditioned media from other HEK293 cells that express HA- and Gaussia luciferase-tagged MADD-4 or SLT-1 ligands, and immunoprecipitated to determine the relative amounts of ligand that co-immunoprecipitates with the receptor (see the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#s4" target="_blank">materials and methods</a> section for more details). <b>C</b>. The western blot on the left shows the five immunoprecipitated FLAG-tagged receptors. The western blot on the right shows the two HA- and Gaussia luciferase-tagged ligands that were collected from cell culture. <b>D</b>. The normalized relative levels of luciferase signal that immunoprecipitated with each potential ligand-receptor complex. <b>E–I</b>. Shown are animals harbouring one of three different transgenes that drive the expression of either neuronally-expressed MADD-4::YFP (from the <i>trIs66</i> transgenic array) (<b>E</b>), muscle-expressed MADD-4::YFP (from the <i>trIs78</i> transgenic array) (<b>F</b>), or muscle-expressed EVA-1::CFP (from the <i>trIs89</i> transgenic array) (<b>G</b>), or animals harbouring two of the transgenes; <i>trIs66</i> and <i>trIs89</i> (<b>H</b>) and <i>trIs78</i> and <i>trIs89</i> (<b>I</b>). The relative levels of MADD-4::YFP expression from <i>trIs66</i> and <i>trIs78</i> is shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#pgen.1004521.s004" target="_blank">Figure S2a</a>. Images show either the CFP channel (top), YFP channel (middle) or a merged view (bottom). Arrows in ‘H’ indicate the localization of MADD-4::YFP to EVA-1::CFP expressing muscles; arrows in ‘I’ indicate the vesicularization of MADD-4::YFP and EVA-1::CFP in the muscle cells. <b>J</b>. The quantification of neuronally-secreted MADD-4::YFP localization to muscles over-expressing the indicated receptor. <b>K</b>. The quantification of CFP vesicles in animals that over-express the indicated CFP-tagged receptors (x-axis) in muscles in either the presence of MADD-4::YFP expressed from dorsal muscles (mMADD-4) or pan-neuronally (nMADD-4). The colocalization of MADD-4 and EVA-1 with the RAB-11 and RAB-5 endosomal markers are shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#pgen.1004521.s004" target="_blank">Figure S2b and S2c</a>. <b>L&M</b>. MADD-4::YFP fails to induce obvious vesicularization of UNC-40::CFP in a wild type background (L), but YFP-CFP vesicles are obvious in animals that lack UNC-6 (M). In A, J, and K, statistical significance (<i>p</i><0.05) is indicated with a solid asterisk which is matched with a dot above the data point to which the comparison was made. In all micrographs, the scale bar represents 50 micrometers. In all graphs, standard error of the mean is shown.</p

EVA-1 functions in a MADD-4 pathway to counteract UNC-6 interference.

<p><b>A</b>. An illustration of the worm that schematizes the muscle arms of ventral left distal body wall muscles. Anterior is to the left and dorsal is up. <b>B & C</b>. Micrographs showing a ventral view of a young adult worm of the indicated genotype with anterior to the left. The yellow arrowhead indicates the ventral cord, the white and green arrows indicates ventral left muscle numbers 11 and 19 (VL11 and VL19), respectively. The red arrowheads indicate the muscle arms of VL11 and VL19. The scale bar shows 50 µM. <b>D</b>. Quantification of muscle arm extension from VL11 and dorsal right muscle number 15 (DR15) in young adults of the indicated genotype. Dorsal muscle arm data is not shown for strains carrying the <i>unc-6</i> mutation because they lack motor neurons within the dorsal cord, which consequently confounds any interpretation of the resulting muscle arm phenotypes. In the last column, MADD-4 is over-expressed (O/E) pan-neuronally from the <i>trIs66</i> integrated transgenic array (see the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004521#s4" target="_blank">materials and methods</a> section for details). <b>E</b>. The average distance of the mid-proximal face of the indicated muscle to the ventral nerve cord in wild type animals (that also harbor the <i>trIs30</i> muscle arm and neuronal markers). <b>F</b>. Quantification of VL19 muscle arm extension in young adults of the indicated genotype. Statistical significance (<i>p</i><0.001) is indicated with a solid asterisk which is matched with a dot above the data point to which the comparison was made. Standard error of the mean is shown in all graphs.</p