Project description:Hematopoietic cell transplantation (HCT) remains an important and potentially curative option for most hematologic malignancies. As a form of immunotherapy, allogeneic HCT (allo-HCT) offers the potential for durable remissions but is limited by transplantation- related morbidity and mortality owing to organ toxicity, infection, and graft-versus-host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematologic malignancies as well. Clinical trials are now needed to address the relative roles of CART cells and HCT in the context of transplantation-eligible patients. In this review, we summarize the state of the art of the development of CART cell therapy for leukemia, lymphoma, and myeloma and discuss our perspective of how CART cell therapy can be applied in the context of HCT.
Project description:Although the question of animal welfare has been an important source of concern in the scientific community for several decades, many aspects are still under debate. On-farm assessments have to be rapid, acceptable to farmers and safe for both the assessors and animals. They are thus very demanding, with multiple decisions to make, such as the choice of appropriate indicators, sampling methods and scoring. Research has moved from resource-based to animal-based criteria, which reflects the subjective welfare state of an animal rather than relying upon external indices. In the present review, we describe two major (i.e., the most frequently/recently tested or disseminated) protocols: one in low-/middle-income countries, and the other in high-income countries, for on-farm assessments of horses, using animal-based resources; we evaluate their strengths and limitations, and then we compare their results with those obtained by various other studies. We propose lines of improvement, particularly in view of public dissemination, and offer suggestions for further refinement or new protocols. We emphasize the high risks of putting the cart before the horse, i.e., proposing protocols that rely upon indicators and sampling methods that need to be refined, as this could lead to under-evaluation (or less likely over-evaluation) of current welfare problems. Because welfare is a subjective experience, the true representation of an individual's actual welfare status has to be evaluated by using objective assessment tools (that are validated and have a scientific basis) used by well-trained observers.
Project description:This paper challenges assumptions that the health management of working equids among some of India's poorest communities is mainly dependent upon income, economic influence, or access to veterinary services. Using a mixed-methods approach, hierarchies of treatment practices are revealed through an examination of the 'lived experience' of equid owners in brick kilns and construction sites in northern India. Semi-structured interviews with 37 equid owners and corresponding livelihood surveys, combined with data from two focus groups with professional animal health practitioners and the welfare data of 63 working equids collected using the Equid Assessment, Research, and Scoping (EARS) tool, contributed to the findings of the study. Four principal influencing factors were found to affect the decision-making practices of equid owners. Infrastructural factors, community characteristics and experience, owners' characteristics and experience, and economic factors all impact the belief structures of equid owners. However, without verifying the validity of the treatment measures being employed, some animals are at risk from hazardous treatment behaviours. By understanding decision-making using the theory of planned behaviour, the findings of this study can provide a crucial contribution to informing future interventions involved in the health management and welfare of working equids.
Project description:Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products produced across all domains of life. The lasso peptides, a subclass of RiPPs with a lasso-like structure, are structurally and functionally unique compared to other known peptide antibiotics in that the linear peptide is literally "tied in a knot" during its post-translational maturation. This underexplored class of peptides brings chemical diversity and unique modes of action to the antibiotic space. To date, eight different lasso peptides have been shown to target three known molecular machines: RNA polymerase, the lipid II precursor in peptidoglycan biosynthesis, and the ClpC1 subunit of the Clp protease involved in protein homeostasis. Here, we discuss the current knowledge on lasso peptide biosynthesis as well as their antibiotic activity, molecular targets, and mechanisms of action.
Project description:Jumping take-off in birds is an explosive behaviour with the goal of providing a rapid transition from ground to airborne locomotion. An effective jump is predicated on the need to maintain dynamic stability through the acceleration phase. The present study concerns understanding how birds retain control of body attitude and trajectory during take-off. Cursory observation suggests that stability is achieved with relatively little cost. However, analysis of the problem shows that the stability margins during jumping are actually very small and that stability considerations play a significant role in the selection of appropriate jumping kinematics. We use theoretical models to understand stability in prehensile take-off (from a perch) and also in non-prehensile take-off (from the ground). The primary instability is tipping, defined as rotation of the centre of gravity about the ground contact point. Tipping occurs when the centre of pressure falls outside the functional foot. A contribution of the paper is the development of graphical tipping stability margins for both centre of gravity location and acceleration angle. We show that the nose-up angular acceleration extends stability bounds forward and is hence helpful in achieving shallow take-offs. The stability margins are used to interrogate simulated take-offs of real birds using published experimental kinematic data from a guinea fowl (ground take-off) and a diamond dove (perch take-off). For the guinea fowl, the initial part of the jump is stable; however, simulations exhibit a stuttering instability not observed experimentally that is probably due to the absence of compliance in the idealized joints. The diamond dove model confirms that the foot provides an active torque reaction during take-off, extending the range of stable jump angles by around 45°.
Project description:Second-generation sequencing platforms have revolutionized the field of ancient DNA, opening access to complete genomes of past individuals and extinct species. However, these platforms are dependent on library construction and amplification steps that may result in sequences that do not reflect the original DNA template composition. This is particularly true for ancient DNA, where templates have undergone extensive damage post-mortem. Here, we report the results of the first "true single molecule sequencing" of ancient DNA. We generated 115.9 Mb and 76.9 Mb of DNA sequences from a permafrost-preserved Pleistocene horse bone using the Helicos HeliScope and Illumina GAIIx platforms, respectively. We find that the percentage of endogenous DNA sequences derived from the horse is higher among the Helicos data than Illumina data. This result indicates that the molecular biology tools used to generate sequencing libraries of ancient DNA molecules, as required for second-generation sequencing, introduce biases into the data that reduce the efficiency of the sequencing process and limit our ability to fully explore the molecular complexity of ancient DNA extracts. We demonstrate that simple modifications to the standard Helicos DNA template preparation protocol further increase the proportion of horse DNA for this sample by threefold. Comparison of Helicos-specific biases and sequence errors in modern DNA with those in ancient DNA also reveals extensive cytosine deamination damage at the 3' ends of ancient templates, indicating the presence of 3'-sequence overhangs. Our results suggest that paleogenomes could be sequenced in an unprecedented manner by combining current second- and third-generation sequencing approaches.
Project description:Chemotherapy, a primary treatment for osteosarcoma (OS), has limited knowledge regarding its impact on tumor immune microenvironment (TIME). Here, tissues from 6 chemotherapy-naive OS patients underwent single-cell RNA sequencing (scRNA-seq) and were analyzed alongside public dataset (GSE152048) containing 7 post-chemotherapy OS tissues. CD45+ (PTPRC+) cells were used for cell clustering and annotation. Changes in immune cell composition pre- and post-chemotherapy were characterized. Totally, 28,636 high-quality CD45+ (PTPRC+) cells were extracted. Following chemotherapy, the proportions of regulatory T cells (Tregs) and activated CD8 T cells decreased, while CD8 effector T cells increased. GO analysis indicated that differentially expressed genes (DEGs) in T cells were associated with cell activation, adaptive immune response, and immune response to tumor cells. Furthermore, the proportions of plasma cells increased, while naive B cells decreased. B cell surface receptors expression was upregulated, and GO analysis revealed DEGs of B cells were mainly enriched in B cell-mediated immunity and B cell activation. Moreover, M2 polarization of macrophages was suppressed post-chemotherapy. Overall, this study elucidates chemotherapy remodels the OS TIME landscape, triggering immune heterogeneity and enhancing anti-tumor properties.
Project description:Multiple stable states, bifurcations and thresholds are fashionable concepts in the ecological literature, a recognition that complex ecosystems may at times exhibit the interesting dynamic behaviours predicted by relatively simple biomathematical models. Recently, several papers in Global Ecology and Biogeography, Proceedings of the National Academy of Sciences USA, Science and elsewhere have attempted to quantify the prevalence of alternate stable states in the savannas of Africa, Australia and South America, and the tundra-taiga-grassland transitions of the circum-boreal region using satellite-derived woody canopy cover. While we agree with the logic that basins of attraction can be inferred from the relative frequencies of ecosystem states observed in space and time, we caution that the statistical methodologies underlying the satellite product used in these studies may confound our ability to infer the presence of multiple stable states. We demonstrate this point using a uniformly distributed 'pseudo-tree cover' database for Africa that we use to retrace the steps involved in creation of the satellite tree-cover product and subsequent analysis. We show how classification and regression tree (CART)-based products may impose discontinuities in satellite tree-cover estimates even when such discontinuities are not present in reality. As regional and global remote sensing and geospatial data become more easily accessible for ecological studies, we recommend careful consideration of how error distributions in remote sensing products may interact with the data needs and theoretical expectations of the ecological process under study.
Project description:BackgroundMillions of working equids provide socio-economic support for many low-income communities worldwide. With the prevalence of harness-related wounds reported as higher than 60%, this study aims to describe the equipment used by working equids in three locations of the Ethiopian national regional state of Oromia (Fiche, Bishoftu and Shashamene), and the attitudes and practices of equid owners, users and harness makers regarding work equipment. This mixed-methods study consists of cross-sectional surveying of working equids used for taxi or transport of goods or water, as well as cart-driver questionnaires and focus groups (FG) with working equid stakeholders. Activities conducted with FG included participatory ranking of equipment attributes and equipment drawing exercises. Indicators of equipment design and assembly, as well as cart-driver attitudes and practices were described quantitatively. Associations between equipment characteristics and species, work-type and cart-driver indicators were investigated through univariable logistic regression models, whereas focus group discussions were transcribed and analysed thematically.ResultsIn total, 368 working equid surveys and cart-driver questionnaires were completed and 87 participants took part in nine FG. Equipment composition and characteristics differed considerably from ideal animal draught and harnessing principles described in the literature, with none of the observed harnesses adhering to all principles and thus not considered fully adequate. Various harness compositions were used, with only saddles and breast collars present in all. Donkey equipment had fewer components than that of horses, such as swingle trees (OR 0.02; 95% CI 0.01-0.06; p < 0.001) or girths (OR 0.09; 95%CI 0.02-0.4; p = 0.002). Horse equipment was more likely to have functional elements such as breeching (OR 7.8; 95% CI 2.9-20.9; p < 0.001). Of all equipment attributes, FG participants ranked cost, design and impact on animal wellbeing as having the highest importance. Thematic analysis identified motivations and priorities regarding equipment; awareness and knowledge of design and function; barriers to using ideal equipment; and consequences of equipment design and practices as key themes.ConclusionsVarious weaknesses of design, assembly and use of equid work equipment were identified. Promoting behavioural change through awareness and training could lead to a sustainable improvement of work equipment quality, access, and prevention of equipment-related problems.