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Byline: Pratibha. Ramani, George. Thomas, Shaheen. Ahmed PURPOSE: Tumour metastasis is the most clinically significant and enigmatic aspect of tumour behavior and is an unequivocal hallmark of malignancy. Until recent [...]

The blood–brain barrier (BBB) is an active and complex diffusion barrier that separates the circulating blood from the brain and extracellular fluid, regulates nutrient transportation, and provides protection against various toxic compounds and pathogens. Creating an in vitro microphysiological BBB system, particularly with relevant human cell types, will significantly facilitate the research of neuropharmaceutical drug delivery, screening, and transport, as well as improve our understanding of pathologies that are due to BBB damage. Currently, most of the in vitro BBB models are generated by culturing rodent astrocytes and endothelial cells, using commercially available transwell membranes. Those membranes are made of plastic biopolymers that are nonbiodegradable, porous, and stiff. In addition, distinct from rodent astrocytes, human astrocytes possess unique cell complexity and physiology, which are among the few characteristics that differentiate human brains from rodent brains. In this study, we established a novel human BBB microphysiologocal system, consisting of a three-dimensionally printed holder with a electrospun poly(lactic-co-glycolic) acid (PLGA) nanofibrous mesh, a bilayer coculture of human astrocytes, and endothelial cells, derived from human induced pluripotent stem cells (hiPSCs), on the electrospun PLGA mesh. This human BBB model achieved significant barrier integrity with tight junction protein expression, an effective permeability to sodium fluorescein, and higher transendothelial electrical resistance (TEER) comparing to electrospun mesh-based counterparts. Moreover, the coculture of hiPSC-derived astrocytes and endothielial cells promoted the tight junction protein expression and the TEER value. We further verified the barrier functions of our BBB model with antibrain tumor drugs (paclitaxel and bortezomib) and a neurotoxic peptide (amyloid β 1-42). The human microphysiological system generated in this study will potentially provide a new, powerful tool for research on human BBB physiology and pathology.

Yerkes-Dodson law suggests an optimal level of arousal for the best performance in learning tasks. Ideally, the instructors’ expectations should match the abilities and inabilities of students. This study proposes a theory that challenges students optimally and continually over the course of teaching and learning, with proofs using both theoretical and classroom examples. The theory of sustained optimal challenge facilitates student learning by achieving primarily three objectives: (1) continually adjusts the speed and content difficulty levels over the course of teaching and learning; (2) matches the instructors’ expectations with the students’ aptitudes (abilities and inabilities); and (3) finally, reduces the variation in student learning. The effect of central limit theorem, teaching and learning theories, learning outcomes, and student feedback supported the proposed theory in a wide range of disciplines, including, Statistics, Mechanics, Quality, and Ergonomics. Sustained optimal challenges were observed in most courses taught utilizing the proposed theory.

H5N1 influenza virus has the potential to become a significant global health threat, and next generation vaccine technologies are needed. In this work, the combined efficacy of two nanoadjuvant platforms (polyanhydride nanoparticles and pentablock copolymer-based hydrogels) to induce protective immunity against H5N1 influenza virus was examined. Mice received two subcutaneous vaccinations (day 0 and 21) containing 10 μg of H5 hemagglutinin trimer alone or in combination with the nanovaccine platforms. Nanovaccine immunization induced high neutralizing antibody titers that were sustained through 70 days postimmunization. Finally, mice were intranasally challenged with A/H5N1 VNH5N1-PR8CDC-RG virus and monitored for 14 days. Animals receiving the combination nanovaccine had lower viral loads in the lung and weight loss after challenge in comparison to animals vaccinated with each platform alone. These data demonstrate the synergy between polyanhydride nanoparticles and pentablock copolymer-based hydrogels as adjuvants in the design of a more efficacious influenza vaccine.

Research has shown that both workload and time are associated with fatigue; however, a functional rela-tionship does not exist. This study observed sixteen participants in their workplace (computer programming and simulation) to quantify the workload-time-fatigue relationship for sedentary tasks. Equal numbers of participants were observed in the morning and afternoon sessions. Workload was measured both subjec-tively and objectively; while fatigue was measured using the Swedish Occupational Fatigue Inventory (SOFI) and a modified Borg scale. Forward selection stepwise regression analysis was performed to deter-mine the underlying mathematical relationship between workload, time, and fatigue. Results indicate that for sedentary tasks, fatigue is a hyperbolic function of workload and time; meaning an inherent interaction-only relationship between workload, time, and fatigue exists. Therefore, an individual can work for longer periods of time if the workload is minimal, and vice versa.

Research has shown differences in working postures between experts and novices for lifting tasks, though there is limited research on upper extremity postural differences between experts and novices. This study quantified upper extremity postural differences between novices and experts while completing two simulated finished carpentry tasks: deck building and picket installation. A 16 camera, motion capture system was used to track upper extremity posture for 21 expert and 21 novice participants while performing 15 minute laboratory task simulations. A biomechanical model, built in AnyBody Modeling System, was used to extract seven different joint postures for wrist, elbow, and shoulder. In general, experts assumed more neutral postures, thereby reducing injury risk associated with non-neutral postures, though task, as expected, dictated the working posture assumed. The picket installation task imposed higher levels of non-neutral wrist and elbow postures; while the deck building imposed higher levels of non-neutral shoulder postures.

In our previous work, we showed that fractal-based texture features are effective in detection, segmentation and classification of posterior-fossa (PF) pediatric brain tumor in multimodality MRI. We exploited an information theoretic approach such as Kullback-Leibler Divergence (KLD) for feature selection and ranking different texture features. We further incorporated the feature selection technique with segmentation method such as Expectation Maximization (EM) for segmentation of tumor T and non tumor (NT) tissues. In this work, we extend the two class KLD technique to multiclass for effectively selecting the best features for brain tumor (T), cyst (C) and non tumor (NT). We further obtain segmentation robustness for each tissue types by computing Bay's posterior probabilities and corresponding number of pixels for each tissue segments in MRI patient images. We evaluate improved tumor segmentation robustness using different similarity metric for 5 patients in T1, T2 and FLAIR modalities.

Ergonomic solutions for the workplace are important for any employee but especially important for workers with disabilities. This project investigates the workstations of physically and cognitively impaired employees at a state funded work program. Two workstations, a sorting station for coat hangers and a sealing station for flatware packages, were analyzed for inefficiencies and ergonomic hazards. The hanger station was redesigned using anthropometric principles and workstation aids to improve the employees’ capability to distinguish and sort the coat hangers. The positioning of the hangers was modified to improve the efficiency of the employees’ movements by reducing reach lengths. The sealing station was altered by providing a new platform for aligning flatware packages and installing a lever to control the sealer such that the lever motion conforms better to reduce errors and force requirements. Field tests were performed and the redesigns were proven successful in improving the productivity of the employees.

Subjective discomfort ratings are a common assessment technique in human factors and ergonomics, and there exist a number of different methods for analyzing ratings (e.g., mean, median, maximum rating, etc.). The objective of this research was to evaluate multiple methods for analyzing body discomfort ratings. Perceived discomfort of eight participants was measured across ten body parts (buttock, left buttock, right buttock, lower back, upper back, neck, shoulder, eye, thigh and whole body) during 2-hour simulated driving tasks at 3 backrest angles (105°, 120°, 135°). Discomfort ratings were collected every 15 minutes using a modified Borg CR-scale. The time weighted discomfort (TWD) average of was found to be more sensitive to backrest angle changes than other measures considered. In addition, factor analysis revealed different methods provided different groupings of body parts, and the method selected for analyzing subjective discomfort ratings should be selected based on the objective of the study.

Different training delivery methods each have their own advantages and disadvantages. Method effectiveness is based on the characteristics of the trainees and the program itself. Voluntary programs require extra consideration as there is no direct obligation for volunteers to participate and interact with the system. This paper studies and compares three methods (online, video, and face-to-face) for delivering training in a voluntary program. Demographic characteristics affected trainees' preference for training delivery method. Also, the training delivery method significantly impacts trainees' performance, participation in the program, and trainees' perceptions regarding re-training. These issues should be considered when a volunteer training program is designed.

Mobile phone use during driving continues to remain a cause in vehicular accidents. The purpose of this study was to examine the effectiveness of a conceptual, in-vehicle warning design to increase public awareness of the consequences of mobile phone use while driving. Warning messages were designed for both the driver and incoming callers, and were presented to 24 potential users to assess their effectiveness. Survey responses provide preliminary support for the use of the in-vehicle phone warning system. Many of the respondents underestimated statistics relating to vehicular deaths and mobile phone use. Additionally, 54% of the respondents indicated that they would not call someone who is driving, 42% believed that these messages will increase public awareness of the risks of phone use during driving, and 28% indicated they would stop phone use while driving based on the suggested design.

Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inhibition studies, and molecular modeling. Mutation of the gatekeeper residue, a key structural determinant influencing inhibitor binding, rendered the fusion protein, NPM/ALK, sensitive to inhibition by SKI-606 in the nanomolar range, while PD173955 inhibited the NPM/ALK mutant at micromolar concentrations. In contrast, both wild type and mutant NPM/ALK were insensitive to imatinib. Computer modeling indicated that docking solutions obtained with a homology model representing the intermediate conformation of the ALK kinase domain reflected closely experimental data. The good agreement between experimental and virtual results indicate that the ALK molecular models described here are useful tools for the rational design of ALK selective inhibitors. In addition, 4-phenylamino-quinoline compounds may have potential as templates for ALK inhibitors.

Background In Bangladesh, as in other developing countries, protein–energy malnutrition is most prevalent among children during weaning. After weaning, children are often fed cereal-based diluted low-calorie porridge, resulting in growth-faltering.Objective To assess the effect on food intake of adding amylase-rich flour (ARF) from germinated wheat to supplementary food among children in nine rural Community Nutrition Centers under the Bangladesh Integrated Nutrition Project (BINP).Methods A total of 166 malnourished children of either sex, aged 6 to 24 months, received one of three diets randomly allocated to the Community Nutrition Centers. The composition of the diets was the same; however, the consistency and calorie density were altered by adding either ARF or water. Thirty-five children received the standard supplementary food of the BINP (S-SF), 65 received supplementary food with added ARF (ARF-SF), and 66 received supplementary food with added water (W-SF). The children were studied for six weeks.Results The mean ± SD intake of supplementary food from a single meal by children completing six weeks on the diets was higher for children receiving ARF-SF (33.91 ± 8.25 g) than for those receiving S-SF (25.66 ± 6.73 g) or W-SF (30.26 ± 8.39 g) (p < .05 for both comparisons). The weight of vomited food was significantly higher for children receiving W-SF than for children in the other two groups. Weight gain and increments in length and weight-for-height were higher for children who received ARF-SF than for children in the other two groups, but the differences were not statistically significant. The acceptability of ARF-SF was higher than that of the two other diets. The additional cost of adding 2 g of ARF to the diet was about Taka 0.25 (US$1 = Taka 48).Conclusions Addition of ARF to existing standard supplementary food, as used under the BINP program, is a simple and effective means to increase the intake of food by changing its consistency, thus making it easier for malnourished children to ingest.

The article discusses how the world's first human made forest Mulai Kathoni in Aruna Sapori , Assam, India is being sustained by an indigenous community in Assam despite a range of threats. Topics include Mulai Kathoni forest created by Jadav Payeng, a local resident, Payeng's ecological legacy being carried forward by Mishing community living on the island, and the community conserving the rich forest ecology, despite having little access to basic amenities.

Inflammatory bowel disease (IBD) and psoriasis are chronic inflammatory immune-mediated diseases. The interleukin-23- (IL23-) T helper (Th)17 pathway has been implicated in their pathogenesis, with multiple biologic therapies targeting this pathway. IL-17, the main proinflammatory cytokine produced by (TH)17, has been targeted by antibodies and IL-17 receptor blockers with favorable outcomes in treating psoriasis and psoriatic arthritis. However, their role in IBD is unpredictable as studies reported worsening of IBD with agents targeting IL-17 and rare case reports with new-onset IBD. We present a case of Crohn's-like severe terminal ileitis and worsening diverticulitis complicated by intestinal perforation requiring total parenteral nutrition shortly after being started on secukinumab.

Two letters to the editor and a correction notice are presented related to articles published in the August and September 2016 issue of the periodical including one related to teaching automotive engineering technology, "Six Sigma Can Estimate Custom Jobs" and correction notice for photo caption.

Resistance to imatinib represents an important scientific and clinical issue in CML and Ph+ ALL and is usually due to the selection of cells harbouring kinase point mutations of the BCR-ABL gene or presenting BCR-ABL gene amplification. In order to improve Bcr-Abl inhibition, several inhibitors with higher potency compared to imatinib have been identified including dasatinib and nilotinib, which show clinical activity in patients resistant to imatinib. In the present study the effects of the novel inhibitor SKI-606 on various models of resistance to imatinib were studied. SKI-606 is a selective dual Src/Abl inhibitor potently active against several CML cell lines and transfectants with IC50 values in the low nanomolar range, 2 logs lower than those obtained with imatinib. Cells expressing activated forms of c-KIT (HMC1560 and GIST882) or PDGFR (Ba/F3 Tel-PDGFRß) were unaffected by SKI-606, in contrast to imatinib and dasatinib. SKI-606 reduced proliferation rate of cells where resistance to imatinib was caused by BCR-ABL gene amplification, such as Lama84R and of imatinib-resistant K562R and KCL22R in which no known mechanism have been identified. D276G, Y253F and E255K kinase point mutants were affected by SKI-606, resulting in inhibition of cell proliferation with IC50 values of 25, 40 and 394 nM (imatinib:1147, 1888 and 3174 nM). No activity was observed against T315I mutant. These results were confirmed in in vivo experiments, in models where resistance was not caused by mutations, as well as in cells carrying the Y253F, E255K and D276G mutations. In the first one SKI-606 was able to eradicate tumors, while significant delay in tumor growth was observed using Ba/F3 transfectants. Modelling considerations attribute the superior activity of SKI-606 to its ability to bind the intermediate (1M52) conformation of Bcr-Abl, in contrast to imatinib. Excluding the T315 residue involved in direct hydrophilic interactions with both SKI-606 and imatinib, Y253 and E255 make electrostatic interactions stabilizing the inactive conformation of Abl nucleotide binding loop, thus affecting in a more pronounced way the binding of imatinib. Similar considerations have been made for the D276 residue affecting a-Helix C inactive conformation. The extended profile of activity performed here allows us to conclude that SKI-606 is a fairly active and specific inhibitor, with a very limited number of targets outside the Abl and Src families of TK.

Resistance to imatinib represents an important scientific and clinical issue in CML and Ph+ ALL and is usually due to the selection of cells harbouring kinase point mutations of the BCR-ABLgene or presenting BCR-ABLgene amplification. In order to improve Bcr-Abl inhibition, several inhibitors with higher potency compared to imatinib have been identified including dasatinib and nilotinib, which show clinical activity in patients resistant to imatinib. In the present study the effects of the novel inhibitor SKI-606 on various models of resistance to imatinib were studied. SKI-606 is a selective dual Src/Abl inhibitor potently active against several CML cell lines and transfectants with IC50values in the low nanomolar range, 2 logs lower than those obtained with imatinib. Cells expressing activated forms of c-KIT (HMC1560and GIST882) or PDGFR (Ba/F3 Tel-PDGFRβ) were unaffected by SKI-606, in contrast to imatinib and dasatinib. SKI-606 reduced proliferation rate of cells where resistance to imatinib was caused by BCR-ABLgene amplification, such as Lama84R and of imatinib-resistant K562R and KCL22R in which no known mechanism have been identified. D276G, Y253F and E255K kinase point mutants were affected by SKI-606, resulting in inhibition of cell proliferation with IC50values of 25, 40 and 394 nM (imatinib:1147, 1888 and 3174 nM). No activity was observed against T315I mutant. These results were confirmed in in vivoexperiments, in models where resistance was not caused by mutations, as well as in cells carrying the Y253F, E255K and D276G mutations. In the first one SKI-606 was able to eradicate tumors, while significant delay in tumor growth was observed using Ba/F3 transfectants. Modelling considerations attribute the superior activity of SKI-606 to its ability to bind the intermediate (1M52) conformation of Bcr-Abl, in contrast to imatinib.