The cross-talk of LDL-cholesterol with cell migration: Insights from the Niemann Pick Type C1 mutation

Cholesterol is considered indispensible for the recruitment and functioning of integrins in focal adhesions for cell migration. However, the physiological cholesterol pools that control integrin trafficking and focal adhesion assembly remain unclear. Using Niemann Pick Type C1 (NPC) mutant cells, which accumulate Low Density lipoprotein (LDL)-derived cholesterol in late endosomes (LE), several recent studies indicate that LDL-cholesterol has multiple roles in regulating focal adhesion dynamics. Firstly, targeting of endocytosed LDL-cholesterol from LE to focal adhesions controls their formation at the leading edge of migrating cells. Other newly emerging literature suggests that this may be coupled to vesicular transport of integrins, Src kinase and metalloproteases from the LE compartment to focal adhesions. Secondly, our recent work identified LDL-cholesterol as a key factor that determines the distribution and ability of several Soluble NSF Attachment Protein (SNAP) Receptor (SNARE) proteins, key players in vesicle transport, to control integrin trafficking to the cell surface and extracellular matrix (ECM) secretion. Collectively, dietary, genetic and pathological changes in cholesterol metabolism may link with efficiency and speed of integrin and ECM cell surface delivery in metastatic cancer cells. This commentary will summarize how direct and indirect pathways enable LDL-cholesterol to modulate cell motility.

Neighbourliness and Australia’s contribution to regional migration strategies for climate displacement in the Pacific

The prospect of widespread displacement in the Pacific as a result of climate change is becoming increasingly likely and it is possible that many will eventually need to relocate to other countries. Regional migration strategies not only offer the potential to minimise the harms of relocation, while acknowledging existing relationships of friendship and regional cooperation. This article examines the use of the language of ‘neighbourliness’ in Australia’s regional climate change strategies and argues that, while it expresses friendship, such language can also be employed to avoid the creation of stronger obligations. The article considers the international doctrine of good neighbourliness and concludes that, while international legal obligations may not yet exist, Australia should nonetheless begin planning for regional migration within the Pacific to allow people to migrate with dignity.

Professor age and research assistant ratings of passive-avoidant and proactive leadership: The role of age-related work concerns and age stereotypes

Recent research has shown that, in general, older professors are rated to have more passive-avoidant leadership styles than younger professors by their research assistants. The current study investigated professors' age-related work concerns and research assistants' favorable age stereotypes as possible explanations for this finding. Data came from 128 university professors paired to one research assistant each. Results show that professors' age-related work concerns (decreased enthusiasm for research, growing humanism, development of exiting consciousness and increased follower empowerment) did not explain the relationships between professor age and research assistant ratings of passive-avoidant and proactive leadership. However, research assistants' favorable age stereotypes influenced the relationships between professor age and research assistant ratings of leadership, such that older professors were rated as more passive-avoidant and less proactive than younger professors by research assistants with less favorable age stereotypes, but not by research assistants with more favorable age stereotypes.

The oxygen migration in the apatite-type lanthanum silicate with the cation substitution

A theoretical model is proposed to determine the effects of Si substitution with Al on the oxygen diffusion in apatite-type lanthanum silicates based on density-functional theory (DFT) calculations for La10(SiO 4)4(AlO4)2O2. Substitution changes the stable configuration for excess oxygen from the split interstitial to a new cluster form with the original cluster. Al doping completely changes the migration mechanism from the interstitialcy one, which was proposed for the La9.33(SiO4)6O2 starting material, to a mechanism which contains an interstitial process. Nevertheless, the migration barrier is calculated to be 0.81 eV, which indicates small changes in oxygen conduction and is consistent with the observations. The present study indicates that the cation substitution on silicon site alone does not promise the improvement of the oxide ion conduction in the lanthanum silicate.

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

Visual performance at passive level crossings with long sighting distances

The third edition of the Australian Standard AS1742 Manual of Uniform Traffic Control Devices Part 7 provides a method of calculating the sighting distance required to safely proceed at passive level crossings based on the physics of moving vehicles. This required distance becomes greater with higher line speeds and slower, heavier vehicles so that it may return quite a long sighting distance. However, at such distances, there are also concerns around whether drivers would be able to reliably identify a train in order to make an informed decision regarding whether it would be safe to proceed across the level crossing. In order to determine whether drivers are able to make reliable judgements to proceed in these circumstances, this study assessed the distance at which a train first becomes identifiable to a driver as well as their, ability to detect the movement of the train. A site was selected in Victoria, and 36 participants with good visual acuity observed 4 trains in the 100-140 km/h range. While most participants could detect the train from a very long distance (2.2 km on average), they could only detect that the train was moving at much shorter distances (1.3 km on average). Large variability was observed between participants, with 4 participants consistently detecting trains later than other participants. Participants tended to improve in their capacity to detect the presence of the train with practice, but a similar trend was not observed for detection of the movement of the train. Participants were consistently poor at accurately judging the approach speed of trains, with large underestimations at all investigated distances.