ics based first year module. The survey is a standardised, self-evaluation tool originally developed by the University of Pretoria. It is also applied at the university where this study is conducted. The survey measures the preparedness of students in different areas and the empirical study shows that there is a statistically significant correlation between the perception of the students regarding their planning ability and the final mark obtained in the mathematics based module.The double-layered cell envelope of Gram-negative bacteria and active drug efflux present a formidable barrier for antimicrobial compounds to penetrate. Fluoroquinolones are among the few classes of antimicrobials that are clinically useful in the treatment of Gram-negative bacterial infection. Previous studies on fluoroquinolone accumulation measured total bacteria associated compounds, rather than the cytoplasmic accumulation. Fluoroquinolones target the type II topoisomerases in the cytoplasm. Thus, the cytoplasmic accumulation is expected to be more relevant to the potency of the drugs. Here, we fractionated and measured the concentration of nine fluoroquinolone compounds in the periplasm and the cytoplasm of two strains of E. coli cells, a parent strain and its isogenic efflux-deficient tolC knockout strain. The potency of the drugs was determined using the minimum inhibitory concentration (MIC) assay. We found that all fluoroquinolones tested accumulated at much higher concentrations in the periplasm than in the cytoplasm. The periplasmic concentrations were 2-15 folds higher than the cytoplasmic concentration, while the actual distribution ratio varies drastically among the compounds tested. Good correlation between the MIC and the cytoplasmic accumulation, but not whole cell accumulation, was observed using a pair of isogenic wild type and drug-efflux deficient strains.

Calcium signaling and membrane fusion play key roles in exocytosis of drug-containing vesicles through the blood-brain barrier (BBB). Identifying the role of synaptotagmin-like protein4-a (Slp4-a) in the presence of Ca

ions, at the pre-fusion stage of a vesicle with the basolateral membrane of endothelial cell, can reveal brain drug transportation across BBB.

We utilized molecular dynamics (MD) simulations with a coarse-grained PACE force field to investigate the behaviors of Slp4-a with vesicular and endothelial membranes at the pre-fusion stage of exocytosis since all-atom MD simulation or experiments are more time-consuming and expensive to capture these behaviors.

The Slp4-a pulls lipid membranes (vesicular and endothelial) into close proximity and disorganizes lipid arrangement at contact points, which are predictors for initiation of fusion. Our MD results also indicate that Slp4-a needs Ca

to bind with weakly-charged POPE lipids (phosphatidylethanolamine).

Slp4-a is an important trigger for membrane fusion in BBB exocytosis. It binds to lipid membranes at multiple binding sites and triggers membrane disruption for fusion in calcium-dependent case.

Understanding the prefusion process of the vesicle will help to design better drug delivery mechanisms to the brain through formidable BBB.

Understanding the prefusion process of the vesicle will help to design better drug delivery mechanisms to the brain through formidable BBB.Profound intratumoral genomic heterogeneity has limited the ability of targeted therapies to overcome therapy resistance in glioblastoma. We have defined purine metabolism as a key mediator of DNA repair and radiation resistance in glioblastoma. Because many glioblastoma oncogenic drivers activate purine metabolism, its inhibition may overcome therapy resistance despite intratumoral genomic heterogeneity.Epigenetic reprogramming is emerging as a key mechanism for metastasis development. Our study identified a novel regulatory mechanism whereby promoter methylation-mediated epigenetic silencing of the gene encoding the ubiquitin ligase subunit F-box/LRR-repeat protein 7 (FBXL7) induces accumulation of active c-SRC, which, in turn, activates epithelial-to-mesenchymal transition and supports cancer cell invasion and metastasis.Cell-cycle dependent redox changes result in increased protein oxidation in mitotic cells. We show that oxidative modifications of a conserved cysteine residue within Aurora A kinase (AURKA) can promote its activation during mitosis. Targeting redox-sensitive cysteine residues within AURKA may lead to the development of novel anti-cancer agents with improved clinical efficacy.Chemoresistance remains to be a common and significant hurdle with all chemotherapies. Tumors gain resistance by acquiring additional mutations. Some of the chemoresistance mechanisms are known and can be tackled. However, the majority of chemoresistance mechanisms are unknown. Our recent findings shed light on one such unknown mechanism. We identified a novel role for 5-hydroxymethycytosine (5hmC), an epigenetic mark on the DNA, in maintaining the integrity of stalled replication forks and its impact on genomic stability and chemoresistance.The physiological response to estrogen differs according to the developmental stage. We show, in the adult, estrogen-responsiveness is driven by ERK1/2 (extracellular signal-regulated kinase 1/2) whereas its downstream effector, RSK2 (p90 ribosomal S6 kinase 2), prevents continuous ERK1/2 activity through regulation of oxidative stress. Bioinformatic analysis revealed RSK2 association with breast cancer risk and oral contraceptives.KRAS-driven cancers acquire profound metabolic dependencies that are intimately linked to tumor growth. Our work revealed that colorectal cancers that harbor KRAS mutations are addicted to copper metabolism. This adaptation renders tumor cells critically dependent on the copper transporter ATP7A, which reveals copper metabolism as a promising therapeutic target for KRAS-driven colorectal cancers.The role of biophysical properties of protein condensates in regulating gene expression and tumorigenesis remains unclear. We recently discovered that A-kinase anchoring protein 8 (AKAP8, also known as AKAP95), a RNA splicing regulator, supports tumorigenesis by forming liquid-like condensates, and that perturbing the biophysical properties of the condensates impairs its activity in regulating splicing and tumorigenesis.p16INK4a (CDKN2A) is a central tumor-suppressor and activator of senescence. We recently found that prolonged expression of p16INK4a in epidermal cells induces hyperplasia and dysplasia through Wnt-mediated stimulation of neighboring keratinocytes. The study suggests a pro-tumorigenic function of p16INK4a in early epidermal lesions, which could potentially be targeted by senolytic therapy.Cancer cells are often resistant to necroptosis as well as apotosis, but the underlying mechanisms are not fully understood. We recently revealed an important crosstalk between MYC, a potent oncogene, and receptor-interacting protein kinase 3 (RIPK3), a pivotal factor in inducing necroptosis. Mechanistically, cytoplasmic MYC directly binds to RIPK3, inhibiting initial necrosome complex formation.Medulloblastoma (MB) often originate from cerebellar granule neuron precursors (GNPs). We recently found that medulloblastoma cells undergo differentiation as GNPs. Differentiated MB cells have permanently lost their proliferative capacity and tumorigenicity. The differentiation of MB cells is driven by the transcription factor NeuroD1 (Neurogenic differentiation 1), and NeuroD1 expression in MB cells is repressed by EZH2-mediated H3K27me3.The mechanism of acquisition of tumorigenic properties by somatic cells at the onset of cancer and later during relapse is a question of paramount importance in cancer biology. We have recently discovered a Muscleblind like-1 (MBNL1)-driven alternative-splicing mediated mechanism of tumorigenic de-differentiation that is associated with poor prognosis, relapse and metastasis in common cancer types.Small extracellular vesicles released by fibroblasts from young human donors diminish lipid peroxidation in senescent cells and in different old mice organs due to their enrichment in Glutathione-S-transferase Mu lipid antioxidant activity.We have uncovered a novel role for the nuclear receptor-binding SET domain protein 1 (NSD1) in human and murine erythroid differentiation. Mechanistically, we found that the histone methyltransferase activity of NSD1 is essential for chromatin binding, protein interactions and target gene activation of the erythroid transcriptional master regulator GATA1.Advanced sequencing techniques have helped unveil numerous new, potential cancer driver mutations. However, manual curation and analysis of gene and protein annotation are essential to verify such discoveries. Our recent study of STK19 (Serine Threonine Kinase 19), a previously identified melanoma driver, is a clear example of the importance of such detailed analysis, with both STK19 gene and protein annotations in frequently used databases having been proven incorrect.We recently demonstrated that glioblastoma, the most lethal brain cancer, upregulates diacylglycerol O-acyltransferase 1 (DGAT1) to store excess fatty acids into triglycerides to prevent lipotoxicity and promote tumor growth. Targeting DGAT1 resulted in marked tumor cell death by triggering extensive oxidative stress, indicating that DGAT1 could be a promising target for cancer therapy.Acquired drug resistance leads to poor clinical outcome in high grade serous ovarian cancer (HGSOC). We have demonstrated the efficacy of the novel drug CX-5461 in HGSOC is mediated through destabilization of DNA replication forks. The data highlights the potential of CX-5461 in overcoming a general mechanism of chemotherapeutic resistance.Loss of tumor protein p53 (p53) and RB transcriptional corepressor 1 (RB1) in developmental and small cell lung cancer models promotes primary cilia formation and hyper-responsiveness to Hedgehog ligand. This is mediated by impaired transcription of p53 and RB1 target genes involved in autophagic degradation of primary cilia.The transcription factor SOX2 is a well-established and important stem cell marker. Its role in cancer biology remains unclear, but it has been proposed to also be a marker of cancer stem cells. We investigated the role of SOX2 protein expression in women with high-grade serous ovarian cancer (HGSOC) to determine its potential prognostic and treatment predictive value. We constructed a tissue microarray of 130 advanced stage HGSOC tumors with an average of 6 cores each, stained for SOX2 protein expression and evaluated survival outcomes. We also treated two HGSOC cell lines with carboplatin and paclitaxel and measured SOX2 expression by RT-PCR and immunoblotting at different doses and time-points. Among patients with non-radical debulking surgery overall and progression-free survival were shorter for patients with SOX2 positive tumors (mean 26 vs. 39 months, log-rank test p = .0076, and mean 14 vs. 19 months, p = .055, respectively). Knockdown of SOX2 in cell lines did not affect growth inhibition following chemotherapy treatment. Our results show that SOX2 has a strong prognostic potential among HGSOC patients with residual tumor tissue after debulking surgery and suggest that SOX2 expressing cells remaining after non-radical debulking surgery may constitute a subpopulation of cancer stem cells with greater tumor-initiating potential.