Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 (-/-)) mice lacking brain serotonin and serotonin transporter (SERT)-deficient (SERT(-/-)) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 (-/-) mice, whereas no significant changes were observed in SERT(-/-) mice. Furthermore, BDNF levels were increased in the prefrontal cortex of Tph2 (-/-) but not of SERT(-/-) mice. Our results emphasize the interaction between serotonin signaling and BDNF. Complete lack of brain serotonin induces BDNF expression

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease

Thermodynamic State Ensemble Models of cis-Regulation

A major goal in computational biology is to develop models that accurately predict a gene's expression from its surrounding regulatory DNA. Here we present one class of such models, thermodynamic state ensemble models. We describe the biochemical derivation of the thermodynamic framework in simple terms, and lay out the mathematical components that comprise each model. These components include (1) the possible states of a promoter, where a state is defined as a particular arrangement of transcription factors bound to a DNA promoter, (2) the binding constants that describe the affinity of the protein–protein and protein–DNA interactions that occur in each state, and (3) whether each state is capable of transcribing. Using these components, we demonstrate how to compute a cis-regulatory function that encodes the probability of a promoter being active. Our intention is to provide enough detail so that readers with little background in thermodynamics can compose their own cis-regulatory functions. To facilitate this goal, we also describe a matrix form of the model that can be easily coded in any programming language. This formalism has great flexibility, which we show by illustrating how phenomena such as competition between transcription factors and cooperativity are readily incorporated into these models. Using this framework, we also demonstrate that Michaelis-like functions, another class of cis-regulatory models, are a subset of the thermodynamic framework with specific assumptions. By recasting Michaelis-like functions as thermodynamic functions, we emphasize the relationship between these models and delineate the specific circumstances representable by each approach. Application of thermodynamic state ensemble models is likely to be an important tool in unraveling the physical basis of combinatorial cis-regulation and in generating formalisms that accurately predict gene expression from DNA sequence

A self-organized model for cell-differentiation based on variations of molecular decay rates

Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of this dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.Comment: 16 pages, 5 figure

Test of a Novel Streptococcus pneumoniae Serotype 6C Type Specific Polyclonal Antiserum (Factor Antiserum 6d) and Characterisation of Serotype 6C Isolates in Denmark

<p>Abstract</p> <p>Background</p> <p>In 2007, Park <it>et al. </it>identified a novel serotype among <it>Streptococcus pneumoniae </it>serogroup 6 which they named serotype 6C. The aim of this study was to evaluate with the Neufeld test a novel <it>S. pneumoniae </it>serotype 6C type specific polyclonal antiserum. In addition, serotype 6C isolates found in Denmark in 2007 and 2008 as well as eight old original serotype 6A isolates were characterised.</p> <p>Methods</p> <p>In this study, 181 clinical <it>Streptococcus pneumoniae </it>isolates from Denmark 2007 and 2008 were examined; 96 isolates had previously been typed as serotype 6A and 85 as serotype 6B. In addition, eight older isolates from 1952 to 1987, earlier serotyped as 6A, were examined. Serotype 6C isolates were identified by PCR and serotyping with the Neufeld test using the novel type specific polyclonal antiserum, factor antiserum 6 d, in addition to factor antisera 6b, 6b* (absorbed free for cross-reactions to serotype 6C) and 6c. All antisera are commercially available and antiserum 6b obtained from the supplier after 1 January 2009 is antiserum 6b*. All serotype 6C isolates were further characterised using multi-locus sequence typing.</p> <p>Results</p> <p>When retesting all 96 original serotype 6A isolates by PCR and the Neufeld test, 29.6% (24 of 81) of the invasive isolates in Denmark from 2007 and 2008 were recognised as serotype 6C. In addition, three of eight old isolates originally serotyped as 6A were identified to be serotype 6C. The oldest serotype 6C isolate was from 1962. The serotype 6C isolates belonged to eleven different sequence types (ST) and nine clonal complexes (CC), ST1692 (CC395), ST386 (CC386) and ST481 (CC460) were the predominant types.</p> <p>Conclusions</p> <p>We tested a novel polyclonal antiserum 6 d, as well as modified antiserum 6b*, provided a scheme for the serotyping of <it>S. pneumoniae </it>serogroup 6 using the Neufeld test and compared the serotyping method with PCR based methods. The two types of methods provided the same results. In future, it will, therefore, be possible to test also serotype 6C in accordance to the standard method for serotyping of <it>S. pneumoniae </it>recommended by WHO.</p> <p>Among all invasive isolates from Denmark 2007 and 2008, serotype 6C constituted 29.6% of the original serotype 6A isolates. The serotype 6C isolates were found to be diverse belonging to a number of different STs and CCs of which most have been observed in other countries previously. Serotype 6C is regarded as an "old" serotype being present among <it>S. pneumoniae </it>isolates in Denmark for at least 48 years. The genetic diversity of serotype 6C isolates and their genetic relationship to other serotypes suggested that serotype 6C strains may have arisen from several different independent recombination events involving different parental strains such as serotypes 6A, 6B, 23F and 4.</p

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4–15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstrom's macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O2 therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O2/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O2 hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health