4,790 research outputs found
Cellular maturation defects in Bruton's tyrosine kinase-deficient immature B cells are amplified by premature B cell receptor expression and reduced by receptor editing
In the mouse, Bruton's tyrosine kinase (Btk) is essential for efficient
developmental progression of CD43(+)CD2(-) large cycling into
CD43(-)CD2(+) small resting pre-B cells in the bone marrow and of
IgM(high) transitional type 2 B cells into IgM(low) mature B cells in the
spleen. In this study, we show that the impaired induction of cell surface
changes in Btk-deficient pre-B cells was still noticeable in kappa(+)
immature B cells, but was largely corrected in lambda(+) immature B cells.
As lambda gene rearrangements are programmed to follow kappa
rearrangements and lambda expression is associated with receptor editing,
we hypothesized that the transit time through the pre-B cell compartment
or receptor editing may affect the extent of the cellular maturation
defects in Btk-deficient B cells. To address this issue, we used 3-83 mu
delta transgenic mice, which prematurely express a complete B cell
receptor and therefore manifest accelerated B cell development. In
Btk-deficient 3-83 mu delta mice, the IgM(+) B cells in the bone marrow
exhibited a very immature phenotype (pre-BCR(+)CD43(+)CD2(-)) and were
arrested at the transitional type 1 B cell stage upon arrival in the
spleen. However, these cellular maturation defects were largely restored
when Btk-deficient 3-83 mu delta B cells were on a centrally deleting
background and therefore targeted for receptor editing. Providing an
extended time window for developing B cells by enforced expression of the
antiapoptotic gene Bcl-2 did not alter the Btk dependence of their
cellular maturation. We conclude that premature B cell receptor expression
amplifies the cellular maturation defects in Btk-deficient B cells, while
extensive receptor editing reduces these defects
Fermentation of animal components in strict carnivores: a comparative study with cheetah fecal inoculum
The natural diet of felids contains highly digestible animal tissues but also fractions resistant to small intestinal digestion, which enter the large intestine where they may be fermented by the resident microbial population. Little information exists on the microbial degradability of animal tissues in the large intestine of felids consuming a natural diet. This study aimed to rank animal substrates in their microbial degradability by means of an in vitro study using captive cheetahs fed a strict carnivorous diet as fecal donors. Fresh cheetah fecal samples were collected, pooled, and incubated with various raw animal substrates (chicken cartilage, collagen, glucosamine-chondroitin, glucosamine, rabbit bone, rabbit hair, and rabbit skin; 4 replicates per substrate) for cumulative gas production measurement in a batch culture technique. Negative (cellulose) and positive (casein and fructo-oligosaccharides; FOS) controls were incorporated in the study. Additionally, after 72 h of incubation, short-chain fatty acids (SCFA), including branched-chain fatty acids (BCFA), and ammonia concentrations were determined for each substrate. Glucosamine and glucosamine-chondroitin yielded the greatest OM cumulative gas volume (OMCV) among animal substrates (P < 0.05), whereas total SCFA production was greatest for collagen (P < 0.05). Collagen induced an acetate production comparable to FOS and a markedly high acetate-to-propionate ratio (8.41:1) compared to all other substrates (1.67:1 to 2.97:1)
Waste Management and Minimisation Strategies
Waste minimisation can potentially decrease the amount of waste to landfill by approximately 80%, using readily available means. This project examines ways in which a similar reduction could be achieved at the Australian Technology Park (ATP) and put the ATP at the forefront of waste reduction in NSW. The limitations of the current solid waste management system at the ATP include the lack of recycling services and the poor location of the communal waste facilities
Free surface cusp formation as a failure mechanism for hard disk drives with fluid dynamic bearings
Impaired precursor B cell differentiation in Bruton's tyrosine kinase-deficient mice
Bruton's tyrosine kinase (Btk) is a cytoplasmic signaling molecule that is
crucial for precursor (pre-B) cell differentiation in humans. In this
study, we show that during the transition of large cycling to small
resting pre-B cells in the mouse, Btk-deficient cells failed to
efficiently modulate the expression of CD43, surrogate L chain, CD2, and
CD25. In an analysis of the kinetics of pre-B cell differentiation in
vivo, Btk-deficient cells manifested a specific developmental delay within
the small pre-B cell compartment of about 3 h, when compared with
wild-type cells. Likewise, in in vitro bone marrow cultures, Btk-deficient
large cycling pre-B cells showed increased IL-7 mediated expansion and
reduced developmental progression into noncycling CD2(+)CD25(+) surrogate
L chain-negative small pre-B cells and subsequently into Ig-positive B
cells. Furthermore, the absence of Btk resulted in increased proliferative
responses to IL-7 in recombination-activating gene-1-deficient pro-B
cells. These findings identify a novel role for Btk in the regulation of
the differentiation stage-specific modulation of IL-7 responsiveness in
pro-B and pre-B cells. Moreover, our results show that Btk is critical for
an efficient transit through the small pre-B cell compartment, thereby
regulating cell surface phenotype changes during the developmental
progression of cytoplasmic mu H chain expressing pre-B cells into immature
IgM(+) B cells
The conduction pathway of potassium channels is water free under physiological conditions.
Ion conduction through potassium channels is a fundamental process of life. On the basis of crystallographic data, it was originally proposed that potassium ions and water molecules are transported through the selectivity filter in an alternating arrangement, suggesting a "water-mediated" knock-on mechanism. Later on, this view was challenged by results from molecular dynamics simulations that revealed a "direct" knock-on mechanism where ions are in direct contact. Using solid-state nuclear magnetic resonance techniques tailored to characterize the interaction between water molecules and the ion channel, we show here that the selectivity filter of a potassium channel is free of water under physiological conditions. Our results are fully consistent with the direct knock-on mechanism of ion conduction but contradict the previously proposed water-mediated knock-on mechanism
Decoding the genetic and epigenetic basis of asthma
Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility is strongly influenced by genetics. Given its high prevalence and our incomplete understanding of the mechanisms underlying disease susceptibility, asthma is frequently studied in genome-wide association studies (GWAS), which have identified thousands of genetic variants associated with asthma development. Virtually all these genetic variants reside in non-coding genomic regions, which has obscured the functional impact of asthma-associated variants and their translation into disease-relevant mechanisms. Recent advances in genomics technology and epigenetics now offer methods to link genetic variants to gene regulatory elements embedded within non-coding regions, which have started to unravel the molecular mechanisms underlying the complex (epi)genetics of asthma. Here, we provide an integrated overview of (epi)genetic variants associated with asthma, focusing on efforts to link these disease associations to biological insight into asthma pathophysiology using state-of-the-art genomics methodology. Finally, we provide a perspective as to how decoding the genetic and epigenetic basis of asthma has the potential to transform clinical management of asthma and to predict the risk of asthma development.</p
The importance of genetic parenthood for infertile men and women
STUDY QUESTION: Do men and women beginning to attend a fertility clinic prefer genetic over non-genetic parenthood? SUMMARY ANSWER: Nearly, all infertile men and women prefer genetic parenthood. WHAT IS KNOWN ALREADY: Clinicians assume that all infertile couples prefer genetic parenthood over non-genetic parenthood and, therefore, consider treatments with donor gametes an option of last resort. Previous studies of the desire for parenthood identified 30 motivations for genetic parenthood, and 51 motivations for which having a genetically related child is not strictly necessary but might be deemed required. The exact strength of the preference of infertile men and women for genetic parenthood remains unclear, as does the importance of the various motivations. STUDY DESIGN, SIZE, DURATION: A questionnaire was developed based on a literature review. It was assessed by professionals and pilot tested among patients. The coded paper-pencil questionnaire was disseminated among both partners of 201 heterosexual infertile couples after their first consultation at one of two Belgian fertility clinics between October 2015 and May 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The survey addressed: (i) the preference for genetic parenthood for themselves and for their partner, (ii) the importance of 30 motivations for genetic parenthood and (iii) the importance of 51 other motivations for parenthood and whether these motivations require being the genetic parent of their child to be fulfilled. To simplify presentation of the results, all 81 motivations were grouped into reliable categories of motivations using psychometric analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The survey was completed by 104 women and 91 men (response rate: 49%). Almost all respondents (98%) favored genetic over non-genetic parenthood for both their partner and themselves. One-third of the respondents stated they only wanted to parent their own genetically related child. Achieving genetic parenthood for their partner was considered significantly more important than achieving genetic parenthood for themselves. Within couples, men had a stronger preference for genetic parenthood (P = 0.004), but this was not significant after correction for educational level, which was significantly associated with the preference of both men and women. The 30 motivations for becoming a genetic parent clustered into 11 categories of which 'to experience a natural process' was deemed most important. The 51 motivations for becoming a parent for which having a genetically related child is not strictly necessary clustered into 14 categories of which 'to contribute to a child's well-being' and 'to experience the love of a child' were most important. Respondents deemed they would need to be the genetic parent of their child to fulfill nearly all their motivations for parenthood. LIMITATIONS REASONS FOR CAUTION: We included couples that visited the fertility clinic for the first time, and the preference for genetic parenthood might change throughout a fertility treatment trajectory. Moreover, what prospective parents expect to be important for their future well-being might not really define parents' well-being. WIDER IMPLICATIONS OF THE FINDINGS: The presumed preference of couples for genetic parenthood was confirmed. Resistance against using donor gametes is more likely among lower educated individuals. Researching whether non-genetic parents actually feel they cannot fulfill the 51 motivations for parenthood, could be a basis for developing patient informatio
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