J. E. Iglesias, J. Augustinack, Khoa Nguyen
et al.
Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra-high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.13 mm isotropic resolution (on average) using customized hardware. The images were manually segmented into 13 different hippocampal substructures using a protocol specifically designed for this study; precise delineations were made possible by the extraordinary resolution of the scans. In addition to the subregions, manual annotations for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo, T1-weighted MRI scans of the whole brain (1mm resolution). The manual labels from the in vivo and ex vivo data were combined into a single computational atlas of the hippocampal formation with a novel atlas building algorithm based on Bayesian inference. The resulting atlas can be used to automatically segment the hippocampal subregions in structural MRI images, using an algorithm that can analyze multimodal data and adapt to variations in MRI contrast due to differences in acquisition hardware or pulse sequences. The applicability of the atlas, which we are releasing as part of FreeSurfer (version 6.0), is demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results show that the atlas and companion segmentation method: 1) can segment T1 and T2 images, as well as their combination, 2) replicate findings on mild cognitive impairment based on high-resolution T2 data, and 3) can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1mm) T1 data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and classification based on whole hippocampal volume (82% accuracy).
Multipotent self-renewing haematopoietic stem cells (HSCs) regenerate the adult blood system after transplantation1, which is a curative therapy for numerous diseases including immunodeficiencies and leukaemias2. Although substantial effort has been applied to identifying HSC maintenance factors through the characterization of the in vivo bone-marrow HSC microenvironment or niche3–5, stable ex vivo HSC expansion has previously been unattainable6,7. Here we describe the development of a defined, albumin-free culture system that supports the long-term ex vivo expansion of functional mouse HSCs. We used a systematic optimization approach, and found that high levels of thrombopoietin synergize with low levels of stem-cell factor and fibronectin to sustain HSC self-renewal. Serum albumin has long been recognized as a major source of biological contaminants in HSC cultures8; we identify polyvinyl alcohol as a functionally superior replacement for serum albumin that is compatible with good manufacturing practice. These conditions afford between 236- and 899-fold expansions of functional HSCs over 1 month, although analysis of clonally derived cultures suggests that there is considerable heterogeneity in the self-renewal capacity of HSCs ex vivo. Using this system, HSC cultures that are derived from only 50 cells robustly engraft in recipient mice without the normal requirement for toxic pre-conditioning (for example, radiation), which may be relevant for HSC transplantation in humans. These findings therefore have important implications for both basic HSC research and clinical haematology. An albumin-free culture system for the long-term ex vivo expansion of mouse haematopoietic stem cells produces 236- to 899-fold expansion, and generates cultures that robustly engraft in recipient mice without toxic pre-conditioning.
Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25‐50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid‐base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.
Alexander S Cheung, David K. Y. Zhang, Sandeep T. Koshy
et al.
Therapeutic ex vivo T-cell expansion is limited by low rates and T-cell products of limited functionality. Here we describe a system that mimics natural antigen-presenting cells (APCs) and consists of a fluid lipid bilayer supported by mesoporous silica micro-rods. The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28, and interleukin-2, we show that the APC-mimetic scaffolds (APC-ms) promote two- to tenfold greater polyclonal expansion of primary mouse and human T cells compared with commercial expansion beads (Dynabeads). The efficiency of expansion depends on the density of stimulatory cues and the amount of material in the starting culture. Following a single stimulation, APC-ms enables antigen-specific expansion of rare cytotoxic T-cell subpopulations at a greater magnitude than autologous monocyte-derived dendritic cells after 2 weeks. APC-ms support over fivefold greater expansion of restimulated CD19 CAR-T cells than Dynabeads, with similar efficacy in a xenograft lymphoma model.
We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease. Measurement(s) nuclear magnetic resonance assay Technology Type(s) MRI Scanner Factor Type(s) flip angle Sample Characteristic - Organism Homo sapiens Measurement(s) nuclear magnetic resonance assay Technology Type(s) MRI Scanner Factor Type(s) flip angle Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.9958688
Asim Hussain, Fazeelat Rehman, Hamza Rafeeq
et al.
Nanotechnology, as an emerging science, has taken over all fields of life including industries, health and medicine, environmental issues, agriculture, biotechnology etc. The use of nanostructure molecules has revolutionized all sectors. Environmental pollution is a great concern now a days, in all industrial and developing as well as some developed countries. A number of remedies are in practice to overcome this problem. The application of nanotechnology in the bioremediation of environmental pollutants is a step towards revolution. The use of various types of nanoparticles (TiO2 based NPs, dendrimers, Fe based NPs, Silica and carbon nanomaterials, Graphene based NPs, nanotubes, polymers, micelles, nanomembranes etc.) is in practice to diminish environmental hazards. For this many In-situ (bioventing, bioslurping, biosparging, phytoremediation, permeable reactive barrier etc.) and Ex-situ (biopile, windrows, bioreactors, land farming etc.) methodologies are employed. Improved properties like nanoscale size, less time utilization, high adaptability for In-situ and Ex-situ use, undeniable degree of surface-region to-volume proportion for possible reactivity, and protection from ecological elements make nanoparticles ideal for natural applications. There are distinctive nanomaterials and nanotools accessible to treat the pollutants. Each of these methods and nanotools depends on the properties of foreign substances and the pollution site. The current designed review highlights the techniques used for bioremediation of environmental pollutants as well as use of various nanoparticles along with proposed In-situ and Ex-situ bioremediation techniques.
BACKGROUND Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODS We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTS Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONS Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
Oral administration is the most commonly used route for drug delivery owing to its cost-effectiveness, ease of administration, and high patient compliance. However, the absorption of orally delivered compounds is a complex process that greatly depends on the interplay between the characteristics of the drug/formulation and the gastrointestinal tract. In this contribution, we review the different preclinical models (in vitro, ex vivo and in vivo) from their development to application for studying the transport of drugs across intestinal barriers. This review also discusses the advantages and disadvantages of each model. Furthermore, the authors have reviewed the selection and validation of these models and how the limitations of the models can be addressed in future investigations. The correlation and predictability of the intestinal transport data from the preclinical models and human data are also explored. With the increasing popularity and prevalence of orally delivered drugs/formulations, the need of sophisticated preclinical models with higher predictive capacity for absorption of oral formulations used in clinical studies will be required.
Abstract The high intake of plastic materials for food packaging causes environmental problems due to the non-biodegradable properties of these materials. High, low and very low-density polyethylene, polyethylene terephthalate, polyvinyl chloride, polystyrene and polypropylene are the main materials used. Biodegradable polymers from natural sources are potential raw materials to develop novel food packaging. Bacterial cellulose is a material with extraordinary properties that is gaining special interest for applications in the Food Industry. The excellent mechanical properties, thermal stability and barrier to water vapor, oxygen and UV radiation of bacterial cellulose compared to other polysaccharides make this material very attractive and a potential alternative to non-biodegradable synthetic materials. Nevertheless, bacterial cellulose films are limited due to their lower elasticity. Therefore, the aim of this review is to provide an overview of the ex-situ and in-situ modifications of bacterial cellulose to improve its properties for the development of films for food packaging.
AbstractThe EIVIC project was launched in 2020, and the main goal was the organisation of a European intercomparison of in-vivo monitoring laboratories dealing with direct measurements of gamma-emitting radionuclides incorporated into the body of exposed workers. This project was organised jointly by members of EURADOS Working Group 7 on internal dosimetry (WG7), the Federal Office for Radiation Protection (BfS, Germany) and the Radioprotection and Nuclear Safety Institute (IRSN, France). The objective was to assess the implementation of individual-monitoring requirements in EU Member States on the basis of in-vivo measurements and to gain insight into the performance of in-vivo measurements using whole-body counters. In this context, a total of 41 in-vivo monitoring laboratories from 21 countries, together with JRC (EC) and IAEA participated. The results were submitted in terms of activity (Bq) of the radionuclides identified inside phantoms that were circulated to all participants. The measured data were compared with reference activity values to evaluate the corresponding bias according to the standards ISO 28218 and ISO 13528. In general, the results of the different exercises are good, and most facilities are in conformity with the criteria for the bias and z-scores in the ISO standards. Furthermore, information about technical and organisational characteristics of the participating laboratories was collected to test if they had a significant influence on the reported results.
Abstract This study investigated in-situ and ex-situ biological methanation strategies for biogas upgrading potential. The addition and circulation of hydrogen with a ceramic gas diffuser unit revealed positive effects on the methanogenic process. A short-term maximum methane productivity of 2.5 L CH4 per L reactor volume per day (LVR−1 d−1) was obtained in-situ. Adverse effects of elevated dissolved hydrogen concentrations on acetogenesis became evident. Ex-situ methanation in a reactor subjected to gas recirculation for recurrent 24 h periods achieved methane formation rates of 3.7 L CH4 LVR−1 d−1. A biomethane with methane concentrations in excess of 96% successfully demonstrated the potential for gas grid injection. A theoretic model supplying gases continuously into a sequential ex-situ reactor system and steadily displacing the upgraded biogas confirmed similar methane formation performance and was advanced to a full-scale concept. Gas conversion efficiency of 95% producing biomethane at 85% methane content was attained. A hybrid model, where an in-situ grass digester is followed by an ex-situ reactor, is proposed as a novel upgrading strategy.
Kidney transplantation remains the gold standard treatment for patients suffering from end-stage kidney disease. To meet the constantly growing organ demands grafts donated after circulatory death (DCD) or retrieved from extended criteria donors (ECD) are increasingly utilized. Not surprisingly, usage of those organs is challenging due to their susceptibility to ischemia-reperfusion injury, high immunogenicity, and demanding immune regulation after implantation. Lately, a lot of effort has been put into improvement of kidney preservation strategies. After demonstrating a definite advantage over static cold storage in reduction of delayed graft function rates in randomized-controlled clinical trials, hypothermic machine perfusion has already found its place in clinical practice of kidney transplantation. Nevertheless, an active investigation of perfusion variables, such as temperature (normothermic or subnormothermic), oxygen supply and perfusate composition, is already bringing evidence that ex-vivo machine perfusion has a potential not only to maintain kidney viability, but also serve as a platform for organ conditioning, targeted treatment and even improve its quality. Many different therapies, including pharmacological agents, gene therapy, mesenchymal stromal cells, or nanoparticles (NPs), have been successfully delivered directly to the kidney during ex-vivo machine perfusion in experimental models, making a big step toward achievement of two main goals in transplant surgery: minimization of graft ischemia-reperfusion injury and reduction of immunogenicity (or even reaching tolerance). In this comprehensive review current state of evidence regarding ex-vivo kidney machine perfusion and its capacity in kidney graft treatment is presented. Moreover, challenges in application of these novel techniques in clinical practice are discussed.
As the most powerful antigen-presenting cell type, dendritic cells (DCs) can induce potent antigen-specific immune responses in vivo, hence becoming optimal cell population for vaccination purposes. DCs can be derived ex vivo in quantity and manipulated extensively to be endowed with adequate immune-stimulating capacity. After pulsing with cancer antigens in various ways, the matured DCs are administrated back into the patient. DCs home to lymphoid organs to present antigens to and activate specific lymphocytes that react to a given cancer. Ex vivo pulsed DC vaccines have been vigorously investigated for decades, registering encouraging results in relevant immunotherapeutic clinical trials, while facing some solid challenges. With more details in DC biology understood, new theory proposed, and novel technology introduced (featuring recently emerged mRNA vaccine technology), it is becoming increasingly likely that ex vivo pulsed DC vaccine will fulfill its potential in cancer immunotherapy.
We study the problem of allocating indivisible goods among agents. When randomization is allowed, it is possible to achieve compelling fairness guarantees such as envy-freeness (Foley, 1967), which states that no agent should (in expectation) prefer any other agent's allocation to her own. For instance, we can simply allocate each good, independently of the other goods, to an agent chosen uniformly at random. However, while this scheme is fair ex-ante, it may produce outcomes that are very unfair ex-post, such as by chance assigning all the goods to a single agent. On the other hand, in the absence of randomization, some amount of ex-post unfairness is unavoidable. Nevertheless, it is possible to guarantee relaxations of envy-freeness that bound the maximum level of envy. One popular relaxation is envy-freeness up to one good (Lipton et al., 2004; Budish, 2011), which requires that the envy of any agent toward another agent can be removed by the elimination of at most one good from the envied agent's bundle. Our goal in this work is to develop algorithms for constructing randomized allocations that are simultaneously exactly fair ex-ante and approximately fair ex-post. We focus on additive valuations, under which an agent's value for the union of two disjoint sets of resources is the sum of her values for the two sets. The key question we address is whether there always exists an ex-ante envy-free (EF) distribution over deterministic allocations that each satisfy envy-freeness up to one good (EF1). We settle this positively by designing a novel algorithm, Recursive Probabilistic Serial, which is an adaptation of the classic Probabilistic Serial (PS) algorithm of Bogomolnaia and Moulin (2001) that inherits much of the desirable behavior of PS (in particular, ex-ante envy-freeness), while also allowing a simple and natural decomposition over EF1 allocations. While a naive interpretation of our algorithm yields a distribution over a possibly-exponential number of deterministic allocations, we show that a support size polynomial in the number of agents and goods is sufficient, thus yielding an efficient variant of Recursive Probabilistic Serial. In addition to ex-ante EF and ex-post EF1, one may want to achieve the economic efficiency notion of Pareto optimality, which states that it should be impossible to find an allocation that improves some agent's utility without reducing any other agent's. We show that it is impossible to achieve ex-ante Pareto optimality (that is, with respect to the randomized allocation) in conjunction with ex-ante EF and ex-post EF1. However, strong ex-ante guarantees --- in terms of both fairness and economic efficiency --- can be achieved if we are willing to compromise on the ex-post guarantee. In particular, we are able to achieve ex-ante group fairness (Conitzer et al., 2019), which generalizes both envy-freeness and Pareto optimality, in conjunction with two ex-post fairness properties that are incomparable but are both implied by EF1: proportionality up to one good or Prop1 (Conitzer et al, 2017) and envy-freeness up to one good more-and-less or $EF_1^1$ (Barman and Krishnamurthy, 2019). Our algorithm uses a rounding of the well-known Maximum Nash Welfare allocation, and by a novel characterization, we prove that this is the only allocation rule that can be used to achieve the desired properties. For more details, we refer the reader to the full version of the paper (Freeman et al., 2020).
Peter S. Arcidiacono, V. Hotz, Arnaud Maurel
et al.
Using data from Duke University undergraduates, we make three main contributions to the literature. First, we show that data on earnings beliefs and probabilities of choosing particular occupations are highly informative of future earnings and occupations. Second, we show how beliefs data can be used to recover ex ante treatment effects and their relationship with individual choices. We find large differences in expected earnings across occupations and provide evidence of sorting on expected gains. Finally, nonpecuniary factors play an important role, with a sizable share of individuals willing to give up substantial amounts of earnings by not choosing their highest-paying occupation.
Abstract This paper assesses farmers’ experiences with different climatic shocks as well as their ex-ante and ex-post coping strategies for climatic risks and shocks in rural Malawi. The paper is based on a comprehensive data set collected in 2013 from 1582 farm households located in three regions of Malawi (northern, central, and eastern). The study uses a bivariate probit model to examine the role of farm characteristics—including physical, human, social, and financial capital—in the household’s decision to adapt to climatic shocks. The results revealed that farmers in the study area experienced droughts, floods, and crop pests and diseases as key climatic shocks. Additionally, some indirect climatic shocks reported by farmers include crop damages, increases in input and output prices, and reductions in farm profit. Farmers adopted more on-farm work, drought-tolerant varieties, early planting, and intercropping as key ex-ante adaptation strategies to reduce the adverse impacts of extreme climate events. Farmers adopted drought and disease-tolerant crops, diversified their crops, planted earlier, did more on-farm work, and changed their eating habits as key ex-post climatic shock coping strategies. Furthermore, social networks and capital were found to be important factors influencing farmers’ adaptation decisions. The study suggests improving access to community resources, infrastructure, and information in order to improve household capacity to cope with climatic shocks.