Miracle-dz/UniFAR-FTUs huggingface dataset:
Four common glomulin mutations cause two thirds of glomuvenous malformations (“familial glomangiomas”): evidence for a founder effect

Background: Glomuvenous malformation (GVM) (“familial glomangioma”) is a localised cutaneous vascular lesion histologically characterised by abnormal smooth muscle-like “glomus cells” in the walls of distended endothelium lined channels. Inheritable GVM has been linked to chromosome 1p21-22 and is caused by truncating mutations in glomulin. A double hit mutation was identified in one lesion. This finding suggests that GVM results from complete localised loss of function and explains the paradominant mode of inheritance. Objective: To report on the identification of a mutation in glomulin in 23 additional families with GVM. Results: Three mutations are new; the others have been described previously. Among the 17 different inherited mutations in glomulin known up to now in 43 families, the 157delAAGAA mutation is the most common and was present in 21 families (48.8%). Mutation 108C→A was found in five families (11.8%), and the mutations 554delA+556delCCT and 1179delCAA were present together in two families (4.7% each). Polymorphic markers suggested a founder effect for all four mutations. Conclusions: Screening for these mutations should lead to a genetic diagnosis in about 70% of patients with inherited GVM. So far, a mutation in glomulin has been found in all GVM families tested, thus demonstrating locus homogeneity.
Cerebrospinal Fluid in a Small Cohort of Patients with Multiple Sclerosis Was Generally Free of Microbial DNA

Multiple sclerosis (MS) is a common cause of non-traumatic neurologic disability with high incidence in many developed countries. Although the etiology of the disease remains elusive, it is thought to entail genetic and environmental causes, and microbial pathogens have also been envisioned as contributors to the phenotype. We conducted a metagenomic survey in cerebrospinal fluid (CSF) from 28 MS patients and 15 patients suffering other type of neurological conditions. We detected bacterial reads in eight out of the 15 non-MS patients and in a single MS patient, at an abundance >1% of total classified reads. Two patients were of special interest: one non-MS patient harbored ~73% bacterial reads, while an MS patient had ~83% bacterial reads. In the former case, Veillonella parvula, a bacterium occasionally found associated with meningitis was the predominant species, whilst Kocuria flava, apparently an environmental bacterium, predominated in the latter case. Thirty-four out of 43 samples contained <1% bacterial reads, which we regard as cross- or environmental contamination. A few viral reads corresponding to Epstein-Barr virus, cytomegalovirus, and parvovirus were also identified. Our results suggest that CSF of MS patients is often (but not always) free of microbial DNA.
Prenatal testosterone exposure is related to sexually dimorphic facial morphology in adulthood

Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21–24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a ‘gender score’ was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together (n = 183; r = −0.59), as well as when males (n = 86; r = −0.55) and females (n = 97; r = −0.48) were examined separately (p-values < 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology (n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure.
Appendicular skeletal muscle mass, physical activity, and cognitive status in patients with Alzheimer's disease

Objective: To examine the interrelations among appendicular skeletal muscle mass and physical activity, energy intake, and cognitive status in free-living patients with AD. Background: Increasing disease severity in AD patients may contribute to poor nutritional status and loss of skeletal muscle mass. This may lead to impaired physical function and loss of functional independence. Methods: Participants in our study were 30 noninstitutionalized AD patients (74 ± 8 years) and 30 healthy age- and body mass index-matched control subjects (73 ± 7 years). We measured appendicular skeletal muscle mass by dual-energy X-ray absorptiometry, energy expenditure by doubly labeled water, and energy intake by food diaries. Results: As expected, the AD group had lower Mini-Mental State Examination scores than the control subjects (p < 0.05). No differences in energy intake or energy expenditure and its components were noted between the groups. Higher levels of appendicular muscle mass in AD patients were associated with increased energy expenditure of physical activity (r = 0.52, p < 0.01) and daily energy intake (r = 0.49, p = 0.01). Cognitive status was not related to appendicular muscle mass, daily energy intake, or energy expenditure of physical activity in AD patients. Conclusions: Higher levels of physical activity and energy intake are associated with higher appendicular skeletal muscle mass in AD patients. Nutritional and physical activity interventions may represent practical and inexpensive strategies in their therapeutic management.
Motivation zum Kauf von Fahrerassistenzsystemen

Die psychologische Marktforschung dreht sich um die zentrale Frage, warum sich ein Kunde so verhaelt, wie er sich verhaelt, warum er das eine kauft und das andere nicht, warum er sich an bestimmte Marken bindet und andere ablehnt, warum er fuer manche Produkte viel und fuer andere wenig Geld ausgibt, etc. Es geht jedoch nicht nur um eine Erklaerung des Kundenverhaltens, sondern es geht auch um das Ausloten von Moeglichkeiten wie Kunden motiviert werden koennten, das gewuenschte Verhalten zu zeigen. Attraktive Produkte sind reich an Bedeutungen; es muss deshalb gefragt werden, welche Bedeutungen Fahrerassistenzsysteme vermitteln koennen und an welche Wuensche und Beduerfnisse sie appellieren. Sie nur ueber ihre technische Leistungen und nur ueber den Aspekt der Sicherheit vorzustellen erscheint nicht ausreichend, da vorrangig an das Verantwortungsbewusstsein der Fahrer appelliert wird. Andere Strategien der Vermarktung muessen erprobt werden; so zum Beispiel auf der einen Seite die Akzenturierung ihrer Erlebniskomponenten beziehungsweise auf der anderen Seite ihre Distinktionsleistung, ihr Prestigegewinn. Auch muessen bestimmte Gruppen von Autofahrern (beispielsweise aeltere Fahrer und bestimmte Typen von Frauen) staerker in den Blickpunkt genommmen werden. Plenarvortrag zur 24. VDI/VW-Gemeinschaftstagung "Integrierte Sicherheit und Fahrerassistenzsysteme, Wolfsburg, 29. und 30. Oktober 2008. Siehe auch Gesamtaufnahme der Tagung, ITRD-Nummer D364581.
Transient coupling between subplate and subgranular layers to L1 neurons before and during the critical period

Cortical layer 1 (L1) contains a diverse population of interneurons which can modulate processing in superficial cortical layers but the intracortical sources of synaptic input to these neurons and how these inputs change over development is unknown. We here investigated the changing intracortical connectivity to L1 in primary auditory cortex (A1) in slices of mouse A1 across development using laser-scanning photostimulation. Before P10 L1 cells receive most excitatory input from within L1, L2/3, L4 and L5/6 as well as the subplate. Excitatory inputs from all layers increase and peak during P10-P16, the peak of the critical period. Inhibitory inputs followed a similar pattern. Functional circuit diversity in L1 emerges after P16. In adult, L1 neurons receive ascending inputs from superficial L2/3 and subgranular L5/6, but only few inputs from L4. A subtype of L1 neurons, NDNF+ neurons, follow a similar pattern, suggesting that transient hyperconnectivity is a universal feature of developing cortical circuits. Our results demonstrate that deep excitatory and superficial inhibitory circuits are tightly linked in early development and might provide a functional scaffold for the layers in between. These results suggest that early thalamic driven spontaneous and sensory activity in subplate can be relayed to L1 from the earliest ages on, that the critical period is characterized by high transient columnar hyperconnectivity, and that in particular circuits originating in L5/6 and subplate might play a key role.
Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus1

Systemic lupus erythematosus (SLE) is characterized by a systemic autoimmune response with profound and diverse T cell changes. Dendritic cells (DCs) are important orchestrators of immune responses and have an important role in the regulation of T cell function. The objective of this study was to determine whether myeloid DCs from individuals with SLE display abnormalities in phenotype and promote abnormal T cell function. Monocyte-derived DCs and freshly isolated peripheral blood myeloid DCs from lupus patients displayed an abnormal phenotype characterized by accelerated differentiation, maturation, and secretion of proinflammatory cytokines. These abnormalities were characterized by higher expression of the DC differentiation marker CD1a, the maturation markers CD86, CD80, and HLA-DR, and the proinflammatory cytokine IL-8. In addition, SLE patients displayed selective down-regulation of the maturation marker CD83 and had abnormal responses to maturation stimuli. These abnormalities have functional relevance, as SLE DCs were able to significantly increase proliferation and activation of allogeneic T cells when compared with control DCs. We conclude that myeloid DCs from SLE patients display significant changes in phenotype which promote aberrant T cell function and could contribute to the pathogenesis of SLE and organ damage.
A novel lentivirus vector derived from apathogenic simian immunodeficiency virus.

The improvement of gene transfer efficiency in growth-arrested cells using human immunodeficiency virus type 1 (HIV-1)-derived vectors led to the development of vectors derived from other members of the lentivirus family. Here we report the generation of a lentiviral vector derived from the apathogenic molecular virus clone SIVagm3mc of the simian immunodeficiency virus from African green monkeys (Cercocebus pygerythrus). Upon pseudotyping with the G-protein of vesicular stomatitis virus (VSV-G), the SIVagm-derived vector was shown to transduce proliferating and growth-arrested mammalian cell lines, including human cells. After in vivo inoculation into the striatum of the adult rat brain, the vector was shown to transduce terminally differentiated neurons and oligodendrocytes as well as quiescent and reactive astrocytes. Moreover, SIVagm transfer vector mRNA was efficiently packaged by HIV-1 vector particles. Homologous [SIV(SIV)] vectors generated by using the SIVagm-derived envelope glycoproteins allowed selective gene transfer into human CD4(+)/CCR5(+) cells. Thus, the SIVagm3mc-derived vector is a useful alternative to HIV-1-derived lentiviral vectors in somatic gene therapy.
Cellular crowding imposes global constraints on the chemistry and evolution of proteomes

In living cells, functional protein–protein interactions compete with a much larger number of nonfunctional, or promiscuous, interactions. Several cellular properties contribute to avoiding unwanted protein interactions, including regulation of gene expression, cellular compartmentalization, and high specificity and affinity of functional interactions. Here we investigate whether other mechanisms exist that shape the sequence and structure of proteins to favor their correct assembly into functional protein complexes. To examine this question, we project evolutionary and cellular abundance information onto 397, 196, and 631 proteins of known 3D structure from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens, respectively. On the basis of amino acid frequencies in interface patches versus the solvent-accessible protein surface, we define a propensity or “stickiness” scale for each of the 20 amino acids. We find that the propensity to interact in a nonspecific manner is inversely correlated with abundance. In other words, high abundance proteins have less sticky surfaces. We also find that stickiness constrains protein evolution, whereby residues in sticky surface patches are more conserved than those found in nonsticky patches. Finally, we find that the constraint imposed by stickiness on protein divergence is proportional to protein abundance, which provides mechanistic insights into the correlation between protein conservation and protein abundance. Overall, the avoidance of nonfunctional interactions significantly influences the physico-chemical and evolutionary properties of proteins. Remarkably, the effects observed are consistently larger in E. coli and S. cerevisiae than in H. sapiens, suggesting that promiscuous protein–protein interactions may be freer to accumulate in the human lineage.
A slowly activating voltage‐dependent K+ current in rat pituitary nerve terminals.

1. A novel slowly activating voltage‐dependent K+ current was observed in isolated nerve terminals from rat neurohypophysis using the whole‐cell configuration of the patch‐clamp technique. 2. The activation kinetics of the slow current could be fitted assuming Hodgkin‐‐Huxley‐type kinetics, an exponential, n, of 1.3 and activation time constants decreasing from 4 s at ‐50 mV to 0.7s at +40 mV. 3. A positive shift of reversal potential was observed when [K+] was increased in the bath solution. The current is carried mainly but not exclusively by K+ ions. 4. When intracellular free [Mg2+] was low (approximately 60 microM), average current density was 74 pA pF‐1 at membrane potentials around 0 mV. In 83% of nerve terminals current amplitude was > 10 pA pF‐1. 5. The slow current was never observed when the pipette contained 4.6 mM free Mg2+. At a physiological level of free Mg2+ (0.5 mM) the average current density was 16 pA pF‐1. 6. When nerve terminals were analysed after patch‐clamp experiments for vasopressin content by immunodetection, no difference in current amplitude was found between the terminals containing vasopressin and all analysed terminals. 7. The voltage dependence of activation was fitted by a Boltzmann equation giving a half‐activation potential of ‐37 mV and a slope factor of about 9 mV. 8. Tail current deactivation kinetics was biexponential with time constants of 0.12 and 1.5s. Kinetics was dependent on the duration of the activating pulse. 9. Noise analysis of the slow current indicated a single‐channel current of 0.33 pA at +6 mV, corresponding to a single‐channel conductance of 4.3 pS. 10. This is the first demonstration of a current similar to the slow K+ current, IKs, in a neurone, suggesting that a protein similar to the IKs‐inducing channel protein IsK (minK) may be present in peptidergic nerve terminals. 11. The activation properties are consistent with a role of the slow current in inhibition of excitability, at least at the level of the nerve terminal.
Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus–specific immune response

Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. CD4+CD25+ regulatory T cells (Treg) are present in increased numbers in the peripheral blood of chronic HBV patients, and these Treg are capable of suppressing the HBV‐specific immune response. The aim of this study was to abrogate Treg‐mediated suppression of the HBV‐specific immune response. Therefore, Treg and a Treg‐depleted cell fraction were isolated from peripheral blood of chronic HBV patients. Subsequently, the suppressive effect of Treg on the response to HBV core antigen (HBcAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF‐α), interleukin‐1‐beta (IL‐1β), or neutralizing antibodies against interleukin‐10 (IL‐10) or transforming growth factor beta (TGF‐β) on Treg‐mediated suppression was determined. The results show that Treg of chronic HBV patients had a more potent suppressive effect on the response to HBcAg compared with the response to tetanus toxin. Neutralization of IL‐10 and TGF‐β or exogenous IL‐1β had no effect on Treg‐mediated suppression of the anti‐HBcAg response, whereas exogenous TNF‐α partially abrogated Treg‐mediated suppression. Preincubation of Treg with TNF‐α demonstrated that TNF‐α had a direct effect on the Treg. No difference was observed in the type II TNF receptor expression by Treg from chronic HBV patients and healthy controls. Conclusion: Treg‐mediated suppression of the anti‐HBV response can be reduced by exogenous TNF‐α. Because chronic HBV patients are known to produce less TNF‐α, these data implicate an important role for TNF‐α in the impaired antiviral response in chronic HBV. (HEPATOLOGY 2007.)
The selective removal of phosphorus from soil: is event size important?

Data from the Woburn Erosion Reference Experiment (Bedfordshire, UK) were used to test the hypothesis that losses of phosphorus (P) in small erosion events are as great as those in infrequent large events, and to examine the effect of storm characteristics on the selective enrichment of P in eroded sediment. For almost every plot event in the period 1988 to 1994, the clay-sized fraction of the sediment was enriched compared with the soil of the plots. There was more variation in clay enrichment for smaller erosion events than for larger ones. The clay and P contents of the sediment were strongly correlated (p < 0.01), and there was a wider range of P concentrations in the sediment derived from small events than in that from large events. However, individual events resulting in small soil losses (< 100 kg) did not account for greater P losses than larger events (> 100 kg). The greater frequency of smaller events, combined with the likelihood of higher P concentrations in the sediment, therefore accounted for a greater proportion of the P lost over the 6-yr period than the infrequent large events. Phosphorus concentrations generally increased with increasing peak discharge and decreased with increasing event duration. For the same return period, P losses were generally greater from plots cultivated up and down the slope than from those cultivated across the slope. Overall, our results suggest that small erosion events should be controlled to prevent P contamination of surface waters and that the most effective means of doing this are by the introduction of minimal tillage techniques and across-slope cultivations.
Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line.

Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein that contributes to neoplastic cell expansion primarily by promoting cell survival through interference with "programmed cell death" (PCD), also termed "apoptosis. " Because many chemotherapeutic drugs are capable of initiating pathways leading to apoptosis, we determined whether deregulated bcl-2 expression could render cells resistant to several drugs commonly used in the treatment of non-Hodgkin's lymphomas, including dexamethasone (DEX), methotrexate (MTX), 1-beta-D-arabinofuranosyl-cytosine (Ara-C), etoposide (VP-16), vincristine (VC), cisplatin (CP), and hydroperoxycyclophosphamide (4-HC). For these experiments, we achieved high levels of p26-Bcl-2 protein production in a human pre-B-cell leukemia line 697 by stable infection with a recombinant bcl-2-containing retrovirus and then compared these cells with control virus-infected 697 cells. Control 697 cells were induced to undergo apoptosis by all drugs tested as defined by DNA degradation into oligonucleosomal-length fragments, cell shrinkage, and subsequent cell death. In contrast, 697 cells with elevated Bcl-2 protein levels exhibited strikingly prolonged cell survival and markedly reduced DNA fragmentation when cultured in the presence of these antineoplastic agents. Although high levels of Bcl-2 protein protected 697 cells from the acute cytotoxic effects of DEX and the other drugs tested, Bcl-2 did not prevent these drugs from suppressing the proliferation of 697 cells. However, when 697 cells were treated with DEX or MTX for 3 days, then washed and cultured in semisolid media without drugs, bcl-2-virus-infected cells gave rise to colonies at much higher frequencies than 697 cells stably infected with control virus. These results indicate that by protecting 697 leukemic cells from the acute cytotoxicity of DEX and some other chemotherapeutic drugs, high levels of p26-Bcl-2 can create the opportunity for re-initiation of cell growth when drugs are withdrawn. The findings may be relevant to clinical correlative studies of non-Hodgkin's lymphoma patients that have found an association between worse prognosis and bcl-2 gene rearrangements or t[14;18] translocations.
Butyrate‐induced histone hyperacetylation in human and mouse cells: estimation of putative sites of histone acetylation in vivo

Human and mouse cells in culture were treated with various concentrations of sodium butyrate. Acid‐extracted histones of control and butyrate‐treated cells were analyzed by two‐dimensional gel electrophoresis. All core histones of the control cells contained modified forms. All core histones of the butyrate‐treated cells were hyperacetylated. Depending on the number of acetylation sites per molecule, each histone or histone variant exhibited a characteristic number of acetylated forms. This number was the same for each histone common in human and mouse cells treated with butyrate. Histones 2A.1, 2A.2, and 2A.X have two sites of inner acetylation; 2A.Z has 3; 2B's have 5; and each one of the H3 variants as well as H4 have 4.