1,469 research outputs found
A structural and physical study of sol-gel methacrylate-silica hybrids: intermolecular spacing dictates the mechanical properties
Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes
This is the final version. Available on open access from Springer via the DOI in this recordData availability:
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.Aims/hypothesis
Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31β72 years), followed up for 18β32 years.
Methods
Peripheral blood samples were obtained from slow progressors (nβ=β8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes.
Results
Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells.
Conclusions/interpretations
We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes.Diabetes UKJDR
Biodegradable zinc-containing mesoporous silica nanoparticles for cancer therapy
Triple-negative breast cancers are extremely aggressive with limited treatment options because of the reduced response of the cancerous cells to hormonal therapy. Here, monodispersed zinc-containing mesoporous silica nanoparticles (MSNPs-Zn) were produced as a tuneable biodegradable platform for delivery of therapeutic zinc ions into cells. We demonstrate that the nanoparticles were internalized by cells, and a therapeutic dose window was identified in which the MSNPs-Zn were toxic to breast cancer cells but not to healthy epithelial (MCF-10a) cells or to murine macrophages. A significant reduction in the viability of triple negative MDA-MB-231 and MCF-7 (ER+) breast cancer cells was seen following 24 h exposure to MSNPs-Zn. The more aggressive MDA-MB-231 cells, with higher metastatic potential, were more sensitive to MSNPs-Zn than the MCF-7 cells. MSNPs-Zn underwent biodegradation inside the cells, becoming hollow structures, as imaged by high-resolution transmission electron microscopy. The mesoporous silica nanoparticles provide a biodegradable vehicle for therapeutic ion release inside cells
Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request
The feasibility of a randomized controlled trial of esophagectomy for esophageal cancer - the ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open) study: protocol for a randomized controlled trial
Calpain system protein expression in carcinomas of the pancreas, bile duct and ampulla
Background: Pancreatic cancer, including cancer of the ampulla of Vater and bile duct, is very aggressive and has a
poor five year survival rate; improved methods of patient stratification are required.
Methods: We assessed the expression of calpain-1, calpain-2 and calpastatin in two patient cohorts using
immunohistochemistry on tissue microarrays. The first cohort was composed of 68 pancreatic adenocarcinomas
and the second cohort was composed of 120 cancers of the bile duct and ampulla.
Results: In bile duct and ampullary carcinomas an association was observed between cytoplasmic calpastatin
expression and patient age (P = 0.036), and between nuclear calpastatin expression and increased tumour stage
(P = 0.026) and the presence of vascular invasion (P = 0.043). In pancreatic cancer, high calpain-2 expression was
significantly associated with improved overall survival (P = 0.036), which remained significant in multivariate
Cox-regression analysis (hazard ratio = 0.342; 95% confidence interva l = 0.157-0.741; P = 0.007). In cancers of the
bile duct and ampulla, low cytoplasmic expression of calpastatin was significantly associated with poor overall
survival (P = 0.012), which remained significant in multivariate Cox-regression analysis (hazard ratio = 0.595; 95%
confidence interval = 0.365-0.968; P = 0.037).
Conclusion: The results suggest that calpain-2 and calpastatin expression is important in pancreatic cancers,
influencing disease progression. The findings of this study warrant a larger follow-up study.
Keywords: Calpain, Calpastatin, Pancreas, Ampulla, Bile duct, Cance
The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time
Peer reviewedPreprin
Composite Fermion Metals from Dyon Black Holes and S-Duality
We propose that string theory in the background of dyon black holes in
four-dimensional anti-de Sitter spacetime is holographic dual to conformally
invariant composite Dirac fermion metal. By utilizing S-duality map, we show
that thermodynamic and transport properties of the black hole match with those
of composite fermion metal, exhibiting Fermi liquid-like. Built upon
Dirac-Schwinger-Zwanziger quantization condition, we argue that turning on
magnetic charges to electric black hole along the orbit of Gamma(2) subgroup of
SL(2,Z) is equivalent to attaching even unit of statistical flux quanta to
constituent fermions. Being at metallic point, the statistical magnetic flux is
interlocked to the background magnetic field. We find supporting evidences for
proposed holographic duality from study of internal energy of black hole and
probe bulk fermion motion in black hole background. They show good agreement
with ground-state energy of composite fermion metal in Thomas-Fermi
approximation and cyclotron motion of a constituent or composite fermion
excitation near Fermi-point.Comment: 30 pages, v2. 1 figure added, minor typos corrected; v3. revised
version to be published in JHE
SILAC-based proteomic quantification of chemoattractant-induced cytoskeleton dynamics on a second to minute timescale
Cytoskeletal dynamics during cell behaviours ranging from endocytosis and exocytosis to cell division and movement is controlled by a complex network of signalling pathways, the full details of which are as yet unresolved. Here we show that SILAC-based proteomic methods can be used to characterize the rapid chemoattractant-induced dynamic changes in the actinβmyosin cytoskeleton and regulatory elements on a proteome-wide scale with a second to minute timescale resolution. This approach provides novel insights in the ensemble kinetics of key cytoskeletal constituents and association of known and novel identified binding proteins. We validate the proteomic data by detailed microscopy-based analysis of in vivo translocation dynamics for key signalling factors. This rapid large-scale proteomic approach may be applied to other situations where highly dynamic changes in complex cellular compartments are expected to play a key role
Recommended from our members
Output from VIP cells of the mammalian central clock regulates daily physiological rhythms
The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing
- β¦