A covalently crosslinked bioink for multi-materials drop-on-demand 3D bioprinting of three-dimensional cell cultures

In vitro three-dimensional (3D) cell models have been accepted to better recapitulate aspects of in vivo organ environment than 2D cell culture. Currently, the production of these complex in vitro 3D cell models with multiple cell types and microenvironments remains challenging and prone to human error. Here we report a versatile bioink comprised of a 4-arm PEG based polymer with distal maleimide derivatives as the main ink component and a bis-thiol species as the activator that crosslinks the polymer to form the hydrogel in less than a second. The rapid gelation makes the polymer system compatible with 3D bioprinting. The ink is combined with a drop-on-demand 3D bioprinting platform consisting of eight independently addressable nozzles and high-throughput printing logic for creating complex 3D cell culture models. The combination of multiple nozzles and fast printing logic enables the rapid preparation of many complex 3D structures comprising multiple hydrogel environments in the one structure in a standard 96-well plate format. The platform compatibility for biological applications was validated using pancreatic ductal adenocarcinoma cancer (PDAC) cells with their phenotypic responses controlled by tuning the hydrogel microenvironment

Aging and Urban Mobility in Bandar Sunway: A Holistic Approach

Human longevity is constantly changing the demographic outlook of the world’s population and older people are projected to double in the next 30 years from 11% to 22% of the world’s population. Malaysia is no exception and, like most western and developing nations, the number of Malaysians aged 60 years and above has been gradually rising from the 1970s onwards and is currently estimated to represent 10% of its population. This has created an urgent need to develop age-friendly cities, so that older individuals living in urban areas can have an improved life. It is important that the aging population continues to lead healthy and productive lives as far as possible. In this project, which is a work in progress, we surveyed a suburban community, aged 50 years and above, residing in Bandar Sunway and its vicinity in the state of Selangor Darul Ehsan, Malaysia. The aim was to assess their health and perceptions on mobility through targeted questionnaires, in-depth interviews and focus groups and identify the factors associated with healthy aging in a holistic manner. The overall goal is to promote a healthy mind in a healthy body despite the advancing years. In the preliminary phase we surveyed 73 participants aged between 52 – 85 years and compared responses and clinical parameters for individuals below (N = 36) and ≥ 65 years (N = 37) in age. Based on their Body Mass Index (BMI), the participants were generally healthy with a normal BMI (45%) or slightly overweight (41%) with a higher BMI and blood lipid levels. There were no significant differences in the cognitive assessments between the two age groups (p = 0.945). A majority (70%) of the participants were satisfied with their lives in Bandar Sunway, but some reported several health related issues and chronic diseases. However, this was not a factor that hindered their quality of life. Older adults in Bandar Sunway still preferred driving their own vehicles instead of taking public transports. This was due to several shortfalls in the transportation systems: pricing, schedules of transport, safety, and cleanliness. Preliminary results have identified several aspects of public transportation in urban areas that can be improved to better serve the aging community. In doing so, we anticipate the findings and recommendations will be applicable to a much wider community in Malaysia and other parts of the world. The project is aligned with the theme of improving health and well-being and will provide a model for understanding and dealing with aging in the local community

The distinct traits of the UNC13A polymorphism in amyotrophic lateral sclerosis

OBJECTIVE: The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. RESULTS: Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p < 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p < 0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p = 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p < 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p < 0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p = 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p = 0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p = 0.045 and p = 0.036). INTERPRETATION: Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796-806

Long-term outcomes of liver transplant recipients followed up in non-transplant centres: care closer to home

Introduction: Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this ‘hub and spoke’ healthcare model.Methods: A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa) was performed.Results: The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or de novo cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008).Conclusion: Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home, without compromising patient survival and long-term clinical outcomes

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

11 páginas, 4 figuras, 2 tablas. Datasets en su material suplementario. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2302720120/-/DCSupplemental.Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.Peer reviewe

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Designing an airline website incorporating usability guidelines: A case study on Philippine Airlines

The volume of passengers travelling via air has increased yearly. It is one of the fastest growing industries around the world. That is why airline companies need to know on how to market and sell their airline tickets to benefit from the growing volume of airline passengers. There are three ways on purchasing airline tickets, first, one can go to the ticketing office directly and purchase their airline ticket, another is to coordinate with the travel agency to help them book their flight, and third and largest is to purchase their airline tickets via online. The study involved the evaluation of the current airline website of Philippine Airlines using usability measure. In order to evaluate the website, a usability study was done with tasks required of the subjects with the use of Morae manager and recorder. The tasks that were given were chosen from the top results of a survey that evaluated the most important tasks in an airline website. The measures used were the efficiency, effectiveness and satisfaction. Efficiency in terms of web usability was measured by counting the total time spent. Effectiveness on the other hand was measured by errors committed in the task and its completion while satisfaction was measured by the total satisfaction by the user given in the after-scenario survey. The study viewed the behavior of the subjects and studied the errors and difficulties the subject experiences during the test. Single usability metric or SUM was used to evaluate the current PAL website. The current AL website has an overall sigma of 2.06. There are usability problems that were encountered in the current PAL website which were then categorized into the factors that were included in the study namely content organization, screen-based controls, text appearance and reversal of actions. Analysis of the test showed that the airline website of PAL had usability issues. From this observation and further usability testing, the problem statement was made that the current website is not usable with respect to the SUM standards. The current Philippine Airlines Website has a low SUM score of 2.06. This was a problem since the minimum SUM score of a usable website set should at least be 3.35. Usability issues for each factor that affected the PAL website were researched to know what were needed to be changed in order to attain a higher SUM. An iteration approach was used in this study. The initial design was designed using different usability guidelines that address the different issues found from the first user testing. The initial design was tested and analyzed to know if the changes were effective. Succeeding iterations were made until the SUM satisfied the minimum requirement for usable websites. After the 2nd iteration, the SUM was satisfied thus producing the final design. The final design utilized tab design for content organization, pop-up design for screen-based controls, had texts in Century Gothic with at least 12 in font size and allowed the user to do reversal of actions. Results showed that the sigma of the initial design is 2.73, first iteration design with 2.83, and second iteration design with 3.47. Compared with the sigma of the current PAL website, the 2nd iteration has a 67.63% improvement. It can be concluded from this study that for interactive/transactional websites such as airline to be usable, they must tab design for content organization, pop-up design as screen-based controls, permit of easy reversal of actions, and text appearance use of Century gothic with at least font size of 12. A new study can still be made to enhance and improve the proposed design. Designers could use other usability measures such as use of word labels, accessibility, etc. to attain the perfect sigma. To achieve the perfect sigma or as Jeff Sauro have termed it as for professionals would be the best case scenario. It would mean that the design is so good that even beginner could use the design perfectly as if a professional is using it

Geotechnical characterization of weathered limestones anapog from Consolacion, Cebu

In the Visayas, there is a type of weathered limestone called anapog , which is abundantly available in areas such as Cebu and Bohol. Preliminary studies conducted by the Department of Public Works and Highways strongly suggest that anapog contained from different areas have different properties, therefore there is a need to provide a geotechnical characterization of anapog in other areas like Cebu so that it can be safely and efficiently utilized in the engineering field. In this study, the physical properties, compaction behavior, shear strength properties, consolidation properties and load bearing capacity of anapog from Consolacion, Cebu were determined through a series of ASTM standard tests. Scanning electron microscopy (SEM) and energy dispersive x-ray (EDX) spectroscopy were also conducted to determine the microfabric details and chemical composition of anapog. The physical properties established in the study are specific gravity, maximum and minimum index density, grain size distribution and Atterberg limits. From the SEM-EDX, it was determined that anapog consists of subangular particles and elements such as carbon, oxygen, aluminum, silicon, calcium, and iron. Based on the compaction behavior obtained through the proctor test, it is anticipated that anapog will exhibit a fair to excellent performance as an embankment material. Consolidation properties obtained from the oedometer test indicate that Anapog is only slightly compressible when subjected to loads as high as 800 kPa. Pre-consolidation pressure was found to be 140 kPa. Shear strength properties obtained from the direct shear test suggest that anapog in saturated and dry condition exhibits ductile behavior when subjected to loads as high as 218 kPa. Values for angle of friction ranges from 30o-32o. Values of cohesion for anapog in dry condition is significantly higher than that of anapog in saturated condition. Based on anapog\u27s load bearing capacity, determined through the CBR test, pure anapog can be utilized as a subgrade in roa The characterization of anapog in this study may serve as a guide for engineers in fully understanding the behavior of anapog which they may use in engineering design and construction. Other researchers may also use these properties as a baseline for future studies that will involve anapog for other applications. The parameters determined guarantees anapog\u27s efficiency as a construction material. Thus, using it as an alternative for other construction materials would help in preventing the depletion of the natural resources currently being used in the construction industry. Moreover, the urbanization in the Philippines is widespread in the Visayas. Having a locally available material that may be used for construction will have a great impact on the economic and infrastructure growth in the region