Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions ...of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity. Provision of Foxp3-sufficient conventional T cells with nTreg cells reconstituted the iTreg pool and established tolerance. In turn, acute depletion of iTreg cells in rescued mice resulted in weight loss and inflammation. Whereas the transcriptional signatures of nTreg and in vivo-derived iTreg cells were closely matched, there was minimal overlap in their T cell receptor (TCR) repertoires. Thus, iTreg cells are an essential nonredundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses.
► iTreg cells are essential to the maintenance of peripheral tolerance ► nTreg and iTreg cells serve distinct nonredundant functions in vivo ► Distinct TCR specificities explain iTreg and nTreg cell nonredundancy
Display omitted
Powder bed fusion (PBF) is one of seven different classes of additive manufacturing (AM) technologies identified by ASTM and ISO. In polymer PBF, an infra-red energy source ...selectively fuses powder particles layer-by-layer into a three-dimensional structure. This enables the production of parts without the use of a mold, which is useful for prototyping and low-volume production. The early research in polymer PBF has focused largely on exploring the expanded design space afforded by the technology and modeling the heat transfer during fabrication. These are aspects that emphasize the manufacturing process and resultant quality in a material agnostic manner. Early investigations into structure-process-property relationships focused on the industrially dominant polyamide family. Only recently has research been conducted towards expanding the PBF material portfolio beyond nylon-12 and its composites. Guiding this research is the knowledge gained from studying the behavior of polyamides in PBF, which resulted in pervasive guidelines for material screening and process parameter development in polymer PBF, including the concepts of a “stable sintering region” and utilizing the “energy melt ratio” to set machine parameters. However, these guidelines are largely empirical and disproportionately focus on process parameter effects on the mechanical properties of the printed parts, instead of the intrinsic polymer properties and first principles of polymer science and engineering.
This review categorically compiles the PBF AM literature by the three process sub-functions: powder recoating, energy input, and coalescence and cooling. The literature outlining the governing physics, structure-property-processing relationships enabling printing, and the process-structure-property relationships enabling targeted final part properties are discussed within each sub-function. Establishing these polymer-manufacturing relationships, both for printability and for final part property prediction, is important to aid in the identification and adaptation of existing polymers, and development of novel polymers, for PBF AM.
Intensification of food production has the potential to drive increased disease prevalence in food plants and animals. Microsporidia are diversely distributed, opportunistic, and density-dependent ...parasites infecting hosts from almost all known animal taxa. They are frequent in highly managed aquatic and terrestrial hosts, many of which are vulnerable to epizootics, and all of which are crucial for the stability of the animal–human food chain. Mass rearing and changes in global climate may exacerbate disease and more efficient transmission of parasites in stressed or immune-deficient hosts. Further, human microsporidiosis appears to be adventitious and primarily associated with an increasing community of immune-deficient individuals. Taken together, strong evidence exists for an increasing prevalence of microsporidiosis in animals and humans, and for sharing of pathogens across hosts and biomes.
Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of ...patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
Display omitted
•Efficient generation of a biobank of patient-derived bladder cancer organoids•Organoids recapitulate the histological and molecular spectrum of human bladder cancer•Bladder tumor organoids display clonal evolution in culture and as xenografts•Drug response of organoids can be validated in xenografts
A biobank of patient-derived bladder tumor organoids faithfully recapitulates features of human cancer and enables analysis of clonal evolution and drug responses.
Abstract This review highlights the synthesis, properties, and advanced applications of synthetic and natural polymers 3D printed using stereolithography for soft tissue engineering applications. ...Soft tissue scaffolds are of great interest due to the number of musculoskeletal, cardiovascular, and connective tissue injuries and replacements humans face each year. Accurately replacing or repairing these tissues is challenging due to the variation in size, shape, and strength of different types of soft tissue. With advancing processing techniques such as stereolithography, control of scaffold resolution down to the μm scale is achievable along with the ability to customize each fabricated scaffold to match the targeted replacement tissue. Matching the advanced manufacturing technique to polymer properties as well as maintaining the proper chemical, biological, and mechanical properties for tissue replacement is extremely challenging. This review discusses the design of polymers with tailored structure, architecture, and functionality for stereolithography, while maintaining chemical, biological, and mechanical properties to mimic a broad range of soft tissue types.
Given the recent controversies in some neuroimaging statistical methods, we compare the most frequently used functional Magnetic Resonance Imaging (fMRI) analysis packages: AFNI, FSL and SPM, with ...regard to temporal autocorrelation modeling. This process, sometimes known as pre-whitening, is conducted in virtually all task fMRI studies. Here, we employ eleven datasets containing 980 scans corresponding to different fMRI protocols and subject populations. We found that autocorrelation modeling in AFNI, although imperfect, performed much better than the autocorrelation modeling of FSL and SPM. The presence of residual autocorrelated noise in FSL and SPM leads to heavily confounded first level results, particularly for low-frequency experimental designs. SPM's alternative pre-whitening method, FAST, performed better than SPM's default. The reliability of task fMRI studies could be improved with more accurate autocorrelation modeling. We recommend that fMRI analysis packages provide diagnostic plots to make users aware of any pre-whitening problems.
High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the ...generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.
Calnexin and calreticulin are related proteins that comprise an ER chaperone system that ensures the proper folding and quality control of newly synthesized glycoproteins. The specificity for ...glycoproteins is conferred by a lectin site that recognizes an early oligosaccharide processing intermediate on the folding glycoprotein, Glc₁Man₉GlcNAc₂. In addition, calnexin and calreticulin possess binding sites for ATP, Ca²⁺, non-native polypeptides and ERp57, an enzyme that catalyzes disulfide bond formation, reduction and isomerization. Recent studies have revealed the locations of some of these ligand-binding sites and have provided insights into how they contribute to overall chaperone function. In particular, the once controversial non-native-polypeptide-binding site has now been shown to function both in vitro and in cells. Furthermore, there is clear evidence that ERp57 participates in glycoprotein biogenesis either alone or in tandem with calnexin and calreticulin.
PDF
