Effectiveness of On-the-job Learning for Enterprises' Innovativeness

The mode of on-the-job learning – one of the methods of acquiring competencies still remains one of the main modes of acquiring workplace competencies in conventional industries in developing countries. This paper explores the impact of aforesaid mode of competency acquisition for enterprise innovativeness of an industry of Sri Lanka.  A structured questionnaire was used to gather primary data related to modes of acquiring competencies. Before data collection, it was reviewed by industry experts and piloted later on for validity. The paper analyses and presents the effectiveness of on-the-job learning on the innovativeness of enterprises in this industry.  The research has found that the main mode of acquiring enterprise competencies remains on-the-job learning. It has been found that the level of innovations in enterprises in the industry remains at low attributed to the traditional way of acquiring competencies. As a result, the industry stagnates and faces challenges for sustainability.  No similar research study was done before in this industry and this is an original work. The study has implications to policy, theoretical and practical aspects of the industry

Modulation Mechanism of Ionic Transport through Short Nanopores by Charged Exterior Surfaces

Short nanopores have various applications in biosensing, desalination, and energy conversion. Here, the modulation of charged exterior surfaces on ionic transport is investigated through simulations with sub-200 nm long nanopores under applied voltages. Detailed analysis of ionic current, electric field strength, and fluid flow inside and outside nanopores reveals that charged exterior surfaces can increase ionic conductance by increasing both the concentration and migration speed of charge carriers. The electric double layers near charged exterior surfaces provide an ion pool and an additional passageway for counterions, which lead to enhanced exterior surface conductance and ionic concentrations at pore entrances and inside the nanopore. We also report that charges on the membrane surfaces increase electric field strengths inside nanopores. The effective width of a ring with surface charges placed at pore entrances (Lcs) is considered as well by studying the dependence of the current on Lcs. We find a linear relationship between the effective Lcs and the surface charge density and voltage, and an inverse relationship between the geometrical pore length and salt concentration. Our results elucidate the modulation mechanism of charged exterior surfaces on ionic transport through short nanopores, which is important for the design and fabrication of porous membranes.Comment: 27 pages, 6 figure

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Expansions of preexisting polyglutamine (polyQ) tracts in at least nine different proteins cause devastating neurodegenerative diseases. There are many unique features to these pathologies, but there must also be unifying mechanisms underlying polyQ toxicity. Using a polyQ-expanded fragment of huntingtin exon-1 (Htt103Q), the causal protein in Huntington disease, we and others have created tractable models for investigating polyQ toxicity in yeast cells. These models recapitulate key pathological features of human diseases and provide access to an unrivalled genetic toolbox. To identify toxicity modifiers, we performed an unbiased overexpression screen of virtually every protein encoded by the yeast genome. Surprisingly, there was no overlap between our modifiers and those from a conceptually identical screen reported recently, a discrepancy we attribute to an artifact of their overexpression plasmid. The suppressors of Htt103Q toxicity recovered in our screen were strongly enriched for glutamine- and asparagine-rich prion-like proteins. Separated from the rest of the protein, the prion-like sequences of these proteins were themselves potent suppressors of polyQ-expanded huntingtin exon-1 toxicity, in both yeast and human cells. Replacing the glutamines in these sequences with asparagines abolished suppression and converted them to enhancers of toxicity. Replacing asparagines with glutamines created stronger suppressors. The suppressors (but not the enhancers) coaggregated with Htt103Q, forming large foci at the insoluble protein deposit in which proteins were highly immobile. Cells possessing foci had fewer (if any) small diffusible oligomers of Htt103Q. Until such foci were lost, cells were protected from death. We discuss the therapeutic implications of these findings.Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grant GM25874)National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374)G. Harold and Leila Y. Mathers FoundationBeckman Laser Institute FoundationEleanor Schwartz Charitable FoundationWhitehead Institute for Biomedical Researc

Fluorescence lifetime imaging microscopy: in vivo application to diagnosis of oral carcinoma

A compact clinically compatible fluorescence lifetime imaging microscopy (FLIM) system was designed and built for intraoperative disease diagnosis and validated in vivo in a hamster oral carcinogenesis model. This apparatus allows for the remote image collection via a flexible imaging probe consisting of a gradient index objective lens and a fiber bundle. Tissue autofluorescence (337 nm excitation) was imaged using an intensified CCD with a gate width down to 0.2 ns. We demonstrate a significant contrast in fluorescence lifetime between tumor (1.77±0.26 ns) and normal (2.50±0.36 ns) tissues at 450 nm and an over 80% intensity decrease at 390 nm emission in tumor versus normal areas. The time-resolved images were minimally affected by tissue morphology, endogenous absorbers, and illumination. These results demonstrate the potential of FLIM as an intraoperative diagnostic technique

Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by the MLL Partner TET1

DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.Chemistry and Chemical Biolog

Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34+ cells in a murine model of umbilical cord blood transplantation

Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six-to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34+ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received two hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34+ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood , and spleen (p=0.0293) retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34+ cell infusion significantly improves engraftment

Cell adhesion molecule CD166 drives malignant progression and osteolytic disease in multiple myeloma

Multiple myeloma (MM) is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

High-Affinity Accumulation of a Maytansinoid in Cells via Weak Tubulin Interaction

The microtubule-targeting maytansinoids accumulate in cells and induce mitotic arrest at 250- to 1000-fold lower concentrations than those required for their association with tubulin or microtubules. To identify the mechanisms of this intracellular accumulation and exceptional cytotoxicity of maytansinoids we studied interaction of a highly cytotoxic maytansinoid, S-methyl DM1 and several other maytansinoids with cells. S-methyl DM1 accumulated inside the cells with a markedly higher apparent affinity than to tubulin or microtubules. The apparent affinities of maytansinoids correlated with their cytotoxicities. The number of intracellular binding sites for S-methyl DM1 in MCF7 cells was comparable to the number of tubulin molecules per cell (~ 4–6 × 107 copies). Efflux of 3 [H]-S-methyl DM1 from cells was enhanced in the presence of an excess of non-labeled S-methyl DM1, indicating that re-binding of 3 [H]-S-methyl DM1 to intracellular binding sites contributed to its intracellular retention. Liposomes loaded with non-polymerized tubulin recapitulated the apparent high-affinity association of S-methyl DM1 to cells. We propose a model for the intracellular accumulation of maytansinoids in which molecules of the compounds diffuse into a cell and associate with tubulin. Affinities of maytansinoids for individual tubulin molecules are weak, but the high intracellular concentration of tubulin favors, after dissociation of a compound-tubulin complex, their re-binding to a tubulin molecule, or to a tip of a microtubule in the same cell, over their efflux. As a result, a significant fraction of microtubule tips is occupied with a maytansinoid when added to cells at sub-nanomolar concentrations, inducing mitotic arrest and cell death