A conserved region in the EBL proteins Is implicated in microneme targeting of the malaria parasite Plasmodium falciparum

The proliferation of the malaria parasite Plasmodium falciparum within the human host is dependent upon invasion of erythrocytes. This process is accomplished by the merozoite, a highly specialized form of the parasite. Secretory organelles including micronemes and rhoptries play a pivotal role in the invasion process by storing and releasing parasite proteins. The mechanism of protein sorting to these compartments is unclear. Using a transgenic approach we show that trafficking of the most abundant micronemal proteins (members of the EBL-family: EBA-175, EBA-140/BAEBL, and EBA-181/JSEBL) is independent of their cytoplasmic and transmembrane domains, respectively. To identify the minimal sequence requirements for microneme trafficking, we generated parasites expressing EBAGFP chimeric proteins and analyzed their distribution within the infected erythrocyte. This revealed that: (i) a conserved cysteine-rich region in the ectodomain is necessary for protein trafficking to the micronemes and (ii) correct sorting is dependent on accurate timing of expression.

Role of nanomedicine in reversing drug resistance mediated by ATP binding cassette transporters and P-glycoprotein in melanoma

Multidrug resistance (MDR) is one of the most common complex phenomenons exhibited by cancer cells. It is a very common property of melanoma postchemotherapy. MDR transporters, ATP binding cassette (ABC) transporters, play a critical role in conferring this property to melanoma cells. miRNA are post-transcriptional regulators that regulate the expression of these ABC transporters. Targeting these miRNA, in turn targeting ABC transporters with the help of nanodelivery systems to overcome drug resistance, is the primary focus for attaining successful treatment methods for drug-resistant melanoma. These delivery systems are endocytosed by the cancer cells and do not require ABC transporters for their delivery, being a promising therapeutic measure for melanoma.

Socioeconomic variation in diet and activity-related behaviours of Australian children and adolescents aged 2–16 years

Background

Evidence for age-related variation in the relationship between obesity-related behaviours and socioeconomic position may assist in the targeting of dietary and physical activity interventions among children.
Objective

To investigate the relationship between different indicators of socioeconomic position and obesity-related behaviours across childhood and adolescence.
Methods

Data were from 4487 children aged 2 to 16 years participating in the cross-sectional 2007 Australian National Children's Nutrition and Physical Activity Survey. Socioeconomic position was defined by the highest education of the primary or secondary carer and parental income. Activity was assessed using recall methods with physical activity also assessed using pedometers. Intake of energy-dense drinks and snack foods, fruits and vegetables was assessed using 2 × 24-h dietary recalls.
Results

A socioeconomic gradient was evident for each dietary measure (although in age-specific analyses, not for energy-dense snacks in older children), as well as television viewing, but not physical activity. Whether each behaviour was most strongly related to parental income or education of the primary or secondary carer was age and sex dependent. The socioeconomic gradient was strongest for television viewing time and consumption of fruit and energy-dense drinks.
Conclusions

A strong socioeconomic gradient in eating behaviours and television viewing time was observed. Relationships for particular behaviours differed by age, sex and how socioeconomic position was defined. Socioeconomic indicators define different population groups and represent different components of socioeconomic position. These findings may provide insights into who should be targeted in preventive health efforts at different life stages.

Does practice make perfect? Results from a Chinese feasibility study of cognitive remediation in schizophrenia

Patients with schizophrenia often receive little by way of non-pharmacological interventions. Despite this, promising outcomes in programmes targeting cognitive deficits have been reported, suggesting that this is an area worthy of further investigation. The aim of the study was to implement and evaluate a brief computerised cognitive remediation programme designed to improve memory and attention in a male Chinese sample with chronic schizophrenia. Pre-testing was completed on a number of clinical and cognitive measures for intervention (n = 14) and treatment as usual (n = 17) participants. The intervention group then completed six weeks ( x no. of sessions = 12.78) of the computer-based cognitive remediation programme. Post-test measures for both groups were then collected again. Following the six week intervention, we found, contrary to our expectations, the intervention group improved on several of the clinical variables. The intervention group also performed better than the control group on the post-test measure of attention, but not verbal memory. These findings suggest that it is feasible to improve some aspects of cognitive abilities with a simple computerised training programme for people with serious mental illness.

Targeting cancer cells using LNA-modified aptamer-siRNA chimeras

Aptamers are chimerized with drug or antisense oligos or nanoparticles to generate targeted therapeutics for cancer. Aptamer chimerized siRNA rescues nonspecific delivery and, thereby, enhances the availability of siRNA to target cells. EpCAM RNA aptamer (EpApt or Ep) has potential for siRNA chimerization due to its secondary structure. Stathmin and survivin proteins are reported to aid oncogenicity in retinoblastoma (RB), breast cancer and other cancers. Thus, chimerization of EpCAM Apt with siRNA against survivin and stathmin, respectively, was performed by incorporating Locked Nucleic Acid (LNA) modification. The LNA-modified chimeric aptamers were stable until 96 h and got internalized into RB, WERI-Rb1 and breast cancer, MDAMB453 cell lines. The constructs were studied using the recombinant dicer enzyme for the siRNA generation. Quantitative polymerase chain reaction and immunofluorescence by microscopic analysis of chimeras in vitro exhibited silencing of stathmin and survivin in the RB and breast cancer model. The chimeric constructs showed significant inhibition of cell proliferation of breast cancer cells. Thus, LNA-modified aptamer-based siRNA delivery aids in cell targeting and necessitates further studies in animal models.

The effects of target length on the visual control of step length for hard and soft impacts

Adjustments to gait were examined when positioning the foot within a narrow target at the end of an approach for two impact conditions, hard and soft. Participants (6 M, 6 F) ran toward a target of three lengths along a 10-m walkway consisting of two marker strips with alternating black and white 0.5-m markings. Five trials were conducted for each target length and impact task, with trials block randomized between the 6 participants of each gender. A 50-Hz digital video camera panned and filmed each trial from an elevated position adjacent to the walkway. Video footage was digitized to deduce the gait characteristics. A linear speed/accuracy tradeoff between target length and approach time was found for both impact tasks (hard, r = 0.99, p < 0.01; soft, r = 0.96, p < 0.05). For the hard-impact task, visual control time increased linearly (r = 0.99, p < 0.05) when whole-body approach velocity decreased. Visual control time was unaffected by whole-body approach velocity in the soft-impact task. A constant tau-margin of 1.08 describes the onset of visual control when approaching a target while running, with the control of braking during visual control described by a tau-dot of –0.85. Further research is needed to examine the control of braking in different targeting tasks.

Identification of unprecedented anticancer properties of high molecular weight biomacromolecular complex containing bovine lactoferrin (HMW-bLf)

With the successful clinical trials, multifunctional glycoprotein bovine lactoferrin is gaining attention as a safe nutraceutical and biologic drug targeting cancer, chronic-inflammatory, viral and microbial diseases. Interestingly, recent findings that human lactoferrin oligomerizes under simulated physiological conditions signify the possible role of oligomerization in the multifunctional activities of lactoferrin molecule during infections and in disease targeting signaling pathways. Here we report the purification and physicochemical characterization of high molecular weight biomacromolecular complex containing bovine lactoferrin (≥250 kDa), from bovine colostrum, a naturally enriched source of lactoferrin. It showed structural similarities to native monomeric iron free (Apo) lactoferrin (∼78-80 kDa), retained anti-bovine lactoferrin antibody specific binding and displayed potential receptor binding properties when tested for cellular internalization. It further displayed higher thermal stability and better resistance to gut enzyme digestion than native bLf monomer. High molecular weight bovine lactoferrin was functionally bioactive and inhibited significantly the cell proliferation (p<0.01) of human breast and colon carcinoma derived cells. It induced significantly higher cancer cell death (apoptosis) and cytotoxicity in a dose-dependent manner in cancer cells than the normal intestinal cells. Upon cellular internalization, it led to the up-regulation of caspase-3 expression and degradation of actin. In order to identify the cutting edge future potential of this bio-macromolecule in medicine over the monomer, its in-depth structural and functional properties need to be investigated further.

Foot-targeting in reaching and grasping

Foot positioning was investigated when right-handed (Experiment One) and left handed adults (Experiment Two) stopped walking to grasp a stationary 70 mm ball at shoulder height. In both experiments centroid location formed by the toe and heel coordinates relative to the object was highly consistent within a target-location condition, demonstrating a foot-targeting phenomenon. Centroid location in the anterior-posterior direction was uninfluenced by grasping hand but the centroid shifted right for left hand grasps and left for right hand grasps. With the target either centrally located or on the same side as the dominant hand, foot positioning brought the grasping hand closer to the target in the medial-lateral direction. When the target object was aligned with the shoulder opposite the dominant hand both groups adopted foot positions to the left of the target. Thus, neither group adopted optimal foot position when the target was located opposite their dominant hand. Foot orientation angle relative to the target was also influenced by choice of grasping hand. Collectively, the findings demonstrate a close association between grasping hand and foot position when approaching to reach and grasp an object but also suggest that foot-dominance may influence medial-lateral centroid location.

A new instrument for targeting falls prevention interventions was accurate and clinically applicable in a hospital setting

Background and Objective: To describe the diagnostic accuracy and practical application of the Peter James Centre Falls Risk Assessment Tool (PJC-FRAT), a multidisciplinary falls risk screening and intervention deployment instrument.

Methods: In phase 1, the accuracy of the PJC-FRAT was prospectively compared to a gold standard (the STRATIFY) on a cohort of subacute hospital patients (n = 122). In phase 2, the PJC-FRAT was temporally reassessed using a subsequent cohort (n = 316), with results compared to those of phase 1. Primary outcomes were falls (events), fallers (patients who fell), and hospital completion rates of the PJC-FRAT.

Results: In phase 1, PJC-FRAT accuracy of identifying fallers showed  sensitivity of 73% (bootstrap 95% confidence interval CI = 55, 90) and specificity of 75% (95% CI = 66, 83), compared with the STRATIFY (cutoff ≥ 2/5) sensitivity of 77% (95% CI = 59, 92) and specificity of 51% (95% CI = 41, 61). This difference was not significant. In phase 2, accuracy of nursing staff using the PJC-FRAT was lower. PJC-FRAT completion rates varied among disciplines over both phases: nurses and physiotherapists, ≥90%; occupational therapists, ≥82%; and medical officers, ≥57%.

Conclusion: The PJC-FRAT was practical and relatively accurate as a predictor of falls and a deployment instrument for falls prevention interventions, although continued staff education may be necessary to maintain its accuracy.

Targeting Hsp90 with small molecule inhibitors induces the over-expression of the anti-apoptotic molecule, survivin, in human A549, HONE-1 and HT-29 cancer cells

Survivin is a dual functioning protein. It inhibits the apoptosis of cancer cells by inhibiting caspases, and also promotes cancer cell growth by stabilizing microtubules during mitosis. Since the molecular chaperone Hsp90 binds and stabilizes survivin, it is widely believed that down-regulation of survivin is one of the important therapeutic functions of Hsp90 inhibitors such as the phase III clinically trialed compound 17-AAG. However, Hsp90 interferes with a number of molecules that up-regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently enhance cancer anti-drug responses. The purpose of this study is to determine whether targeting Hsp90 can alter survivin expression differently in different cancer cell lines and to explore possible mechanisms that cause the alteration in survivin expression.

Targeting survivin in cancer : patent review

Importanceof the field: Survivin is a prominent anti-apoptotic molecule expressed widely in the majority of cancers. Overexpression of survivin leads to uncontrolled cancer cell growth and drug resistance. Efficient downregulation of survivin expression and its functions can sensitise the tumour cells to various therapeutic interventions such as chemotherapeutic agents leading to cell apoptosis.

Areas covered in this review: The article thoroughly analyses up-to-date information on the knowledge generated from the survivin patents. Various key areas of research in terms of understanding survivin biology and its targeting are discussed in detail.

What the reader will gain: The article clearly gives an insight on the recent developments undertaken to understand the roles of survivin in cancer and in validating various treatment paradigms that suppress survivin expression in cancer cells.

Take home message:  Most recent developments are helpful for effectively downregulating survivin expression by using various therapeutic platforms such as chemotherapeutic drugs, immunotechnology, antisense, dominant negative survivin mutant, RNA interference and peptide-based methods. However, selective and specific targeting of survivin in cancer cells still poses a major challenge. Nanotechnology-based platforms are currently under development to enable site-specific targeting of survivin in tumour cells.