Human memory B cells Seifert, M; Küppers, R
Leukemia,
12/2016, Letnik:
30, Številka:
12
Journal Article
Recenzirano
A key feature of the adaptive immune system is the generation of memory B and T cells and long-lived plasma cells, providing protective immunity against recurring infectious agents. Memory B cells ...are generated in germinal center (GC) reactions in the course of T cell-dependent immune responses and are distinguished from naive B cells by an increased lifespan, faster and stronger response to stimulation and expression of somatically mutated and affinity matured immunoglobulin (Ig) genes. Approximately 40% of human B cells in adults are memory B cells, and several subsets were identified. Besides IgG
and IgA
memory B cells, ∼50% of peripheral blood memory B cells express IgM with or without IgD. Further smaller subpopulations have additionally been described. These various subsets share typical memory B cell features, but likely also fulfill distinct functions. IgM memory B cells appear to have the propensity for refined adaptation upon restimulation in additional GC reactions, whereas reactivated IgG B cells rather differentiate directly into plasma cells. The human memory B-cell pool is characterized by (sometimes amazingly large) clonal expansions, often showing extensive intraclonal IgV gene diversity. Moreover, memory B-cell clones are frequently composed of members of various subsets, showing that from a single GC B-cell clone a variety of memory B cells with distinct functions is generated. Thus, the human memory B-cell compartment is highly diverse and flexible. Several B-cell malignancies display features suggesting a derivation from memory B cells. This includes a subset of chronic lymphocytic leukemia, hairy cell leukemia and marginal zone lymphomas. The exposure of memory B cells to oncogenic events during their generation in the GC, the longevity of these B cells and the ease to activate them may be key determinants for their malignant transformation.
To review the effects, adverse consequences, and extent of energy drink consumption among children, adolescents, and young adults.
We searched PubMed and Google using "energy drink," "sports drink," ..."guarana," "caffeine," "taurine," "ADHD," "diabetes," "children," "adolescents," "insulin," "eating disorders," and "poison control center" to identify articles related to energy drinks. Manufacturer Web sites were reviewed for product information.
According to self-report surveys, energy drinks are consumed by 30% to 50% of adolescents and young adults. Frequently containing high and unregulated amounts of caffeine, these drinks have been reported in association with serious adverse effects, especially in children, adolescents, and young adults with seizures, diabetes, cardiac abnormalities, or mood and behavioral disorders or those who take certain medications. Of the 5448 US caffeine overdoses reported in 2007, 46% occurred in those younger than 19 years. Several countries and states have debated or restricted energy drink sales and advertising.
Energy drinks have no therapeutic benefit, and many ingredients are understudied and not regulated. The known and unknown pharmacology of agents included in such drinks, combined with reports of toxicity, raises concern for potentially serious adverse effects in association with energy drink use. In the short-term, pediatricians need to be aware of the possible effects of energy drinks in vulnerable populations and screen for consumption to educate families. Long-term research should aim to understand the effects in at-risk populations. Toxicity surveillance should be improved, and regulations of energy drink sales and consumption should be based on appropriate research.
Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) ...in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals CIs, 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).
Research has shown that cognition often relies on simplified heuristics; however, few studies have explored the role of heuristics in design. We propose that designers utilize specific heuristics to ...explore the problem space of potential concepts, leading to the generation of novel and creative solutions. Design heuristic use in the early stages of product conception was examined through a case study of an expert industrial designer working on a real-world project. Sequences of exploratory concept sketches were analyzed for evidence of design heuristic use in generating concepts. This case study uncovers design heuristics that promote variation in concepts and alter existing solutions, supporting the claim that expertise incorporates the use of heuristics to maximize creativity and diversity in designs.
The retinal basis of vision in chicken Seifert, M.; Baden, T.; Osorio, D.
Seminars in cell & developmental biology,
October 2020, 2020-10-00, 20201001, Letnik:
106
Journal Article
Recenzirano
•The chicken retina is comparable to that of other birds regarding cell density and complexity.•Chicken have 6 different types of visual photoreceptors with narrow absorption spectra providing ...tetrachromatic vision.•The complexity of horizontal-. bipolar-, and ganglion cells is higher than in most mammalian species.•Due to a variety of established tools the chicken is an ideal model to study bird vision.
The Avian retina is far less known than that of mammals such as mouse and macaque, and detailed study is overdue. The chicken (Gallus gallus) has potential as a model, in part because research can build on developmental studies of the eye and nervous system. One can expect differences between bird and mammal retinas simply because whereas most mammals have three types of visual photoreceptor birds normally have six. Spectral pathways and colour vision are of particular interest, because filtering by oil droplets narrows cone spectral sensitivities and birds are probably tetrachromatic. The number of receptor inputs is reflected in the retinal circuitry. The chicken probably has four types of horizontal cell, there are at least 11 types of bipolar cell, often with bi- or tri-stratified axon terminals, and there is a high density of ganglion cells, which make complex connections in the inner plexiform layer. In addition, there is likely to be retinal specialisation, for example chicken photoreceptors and ganglion cells have separate peaks of cell density in the central and dorsal retina, which probably serve different types of behaviour.
Design Heuristics in Engineering Concept Generation DALY, SHANNA R.; YILMAZ, SEDA; CHRISTIAN, JAMES L. ...
Journal of engineering education (Washington, D.C.),
10/2012, Letnik:
101, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Innovation in design depends on successful concept generation. The ideation stage of design is intended to produce multiple, varied concepts from which to develop and choose. Often, instruction on ...idea generation methods is not offered in engineering classes; however, when taught, it is commonly through techniques like brainstorming, which lacks specific ways to generate designs. Further, existing ideation strategies are not based on evidence from designers or rigorous testing through empirical studies. This study investigated how engineering students and practitioners generated ideas. We focused on how designers used product characteristics to define concepts, and how previous concepts were transformed into new solutions by modifying their characteristics. Our methodology is based on our previous work identifying Design Heuristics in engineering solutions, defined as cognitive prompts that facilitate exploration of multiple designs during concept generation. Think-aloud recordings and concept sketches were collected from 36 engineering students and practitioners (with varying levels of experience) as they generated ideas for a novel design task in a laboratory setting. These data, along with retrospective interviews, were analyzed for the ideation strategies evident in the participants' solutions. This study revealed evidence for over 60 strategies for concept generation during the ideation stage. Participants generated novel concepts and proposed concept modifications, and specific Design Heuristics were observed in their designs. The results suggest instruction on Design Heuristics can aid in effective idea generation. This protocol study of engineering designers provides a collection of heuristics observed in practice that offers new methods for students and practitioners to explore design spaces. The Design Heuristics identified in this and previous work can potentially be learned and then incorporated into the practice of engineering students and practitioners.
T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8
and Th1-polarized CD4
T cell infiltration is associated with prolonged survival in human ...pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3
T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.
In this article, we propose variable-period diffraction gratings for terahertz frequencies. The design, fabrication and characterization of such devices are presented. Our measurements show the ...possibility to actively shift of the deflection angle for each frequency using this device. We also demonstrated that, when driven by a speaker, these variable gratings can be used for active beam steering with potential application in terahertz communications.
These final results from ABCSG-12 confirm that twice-yearly ZOL safely enhances the efficacy of adjuvant endocrine therapy. Tamoxifen together with Goserelin for now remains the endocrine standard of ...care. In general, overall survival of more than 95% at 8 years' median follow-up supports the efficacy of endocrine-only regimens in this premenopausal patient population.
Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months.
Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points.
After 94.4-month median follow-up (range, 0–114 months), relative risks of disease progression hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60–0.99; P = 0.042 and of death (HR = 0.66; 95% CI 0.43–1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05–1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw.
These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term.
NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).
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