Miracle-dz/UniFAR-FTUs huggingface dataset:
Update of the molecular basis of familial hypercholesterolemia in The Netherlands

Autosomal‐dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low‐density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high‐throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non‐LDLR/non‐APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening. Hum Mutat 26(6), 550–556, 2005. © 2005 Wiley‐Liss, Inc.
Extracellular ATP counteracts the ERK1/2‐mediated death‐promoting signaling cascades in astrocytes

Oxidative stress is the main cause of neuronal death in pathological conditions. Hydrogen peroxide (H2O2), one of the reactive oxygen species, activates many intracellular signaling cascades including src family and mitogen‐activated protein kinases (MAPKs), some of which are critically involved in the induction of cellular damage. We previously showed that H2O2‐induced cell death in astrocytes and adenosine 5′‐triphosphate (ATP), acting on P2Y1 receptors, had a protective effect. Here, we examined the H2O2‐induced changes in intracellular signaling cascades that promote cell death in astrocytes, showing the molecular mechanisms by which the activation of P2Y1 receptors counteracts such signals. Although H2O2 activated three MAPKs including ERK1/2, p38, and JNK, only the activation of ERK1/2 participated in the H2O2‐evoked cell death. H2O2 induced a sustained activation of ERK1/2 mainly in the nucleus region, which was well in accordance with the H2O2‐induced cell death. H2O2 also activated the src tyrosine kinase family, which was an upstream signal for ERK1/2. Activation of P2Y1 receptors by 2methylthio‐ADP (2MeSADP) inhibited the H2O2‐evoked activation of src tyrosine kinase, resulting in the inhibition of the phosphorylated‐ERK1/2 accumulation in the nucleus. 2MeSADP enhanced the gene expression and activity of protein tyrosine phosphatase (PTP), which was responsible for the inhibition of src tyrosine kinase. Thioredoxin reductase, another cytoprotective gene we previously showed to be upregulated by 2MeSADP, also controlled the activity of PTP. Taken together, ATP, acting on P2Y1 receptors, upregulates the PTP expression and its activity, which counteracts the H2O2‐promoted death signaling cascades including ERK1/2 and its upstream signal src tyrosine kinase in astrocytes. © 2006 Wiley‐Liss, Inc.
A Pilot Study of the Application of the Transtheoretical Model During Strength Training in Older Women

A Transtheoretical Model (TTM) goal-setting tool was used during strength training in women. Volunteers (mean age = 69, N = 27) were assigned to a strength training only or strength training/behavior change 12-week intervention. A pre/posttest, quasiexperimental design assessed TTM constructs, Health-Related Quality of Life, and functional fitness measurements. Multiple ANCOVAs revealed significant differences between groups on lower body strength (p = .001), upper body flexibility (p = .002), Decisional Balance (p = .024,) and Stage of Change for Exercise (p = .010). Stage of change progression may be enhanced using a goal-setting tool during strength training in older women.
Quorum sensing Escherichia coli regulators B and C (QseBC): a novel two‐component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli

Quorum sensing is a cell‐to‐cell signalling mechanism in which bacteria secrete hormone‐like compounds called autoinducers. When these auto‐inducers reach a certain threshold concentration, they interact with bacterial transcriptional regulators, thereby regulating gene expression. Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 as well as E. coli K‐12 produces the autoinducer‐2 (AI‐2), which is synthesized by the product of the luxS gene, and previous work from our laboratory has shown that genes encoding the EHEC type III secretion system were activated by quorum sensing. Recently, by hybridizing an E. coli K‐12 gene array with cDNA synthesized from RNA extracted from EHEC strain 86‐24 and its isogenic luxS mutant, we observed that other potential virulence‐associated factors, such as genes encoding the expression and assembly of flagella, motility and chemotaxis, were also activated by quorum sensing. The array data also indicated that several genes encoding putative E. coli regulators were controlled by quorum sensing. In this report, we describe a two‐component system regulated by quorum sensing that shares homology with Salmonella typhimurium PmrAB, which we have named quorum sensing E. coli regulator B and C (QseBC). The qseBC genes, previously identified only as open reading frames b3025 and b3026, are organized in an operon in the E. coli chromosome, with qseB encoding the response regulator and qseC the sensor kinase. We confirmed the regulation of qseBC by quorum sensing using qseB::lacZ transcriptional fusions and characterized the phenotypes of an isogenic qseC mutation in EHEC. This mutant expressed less flagellin and had reduced motility compared with the wild‐type and complemented strains. Transcription of flhD, fliA, motA and fliC::lacZ fusions was decreased in the qseC mutant, suggesting that qseBC is a transcriptional regulator of flagella genes. A qseC mutant was also generated in E. coli K‐12 strain MC1000 that showed the same phenotypes as the EHEC mutant, indicating that qseBC regulates flagella and motility by quorum sensing in both EHEC and K‐12. QseBC activates transcription of flhDC, which is the master regulator for the flagella and motility genes and, in the absence of flhD, QseBC failed to activate the transcription of fliA. Motility of a luxS, but not of a qseC, mutant can be restored by providing AI‐2 exogenously as preconditioned media, suggesting that the qseC mutant is unable to respond to AI‐2. However, QseC has no effect on the expression of other quorum sensing‐controlled genes such as those encoding for the type III secretion system. These data indicate that QseBC is one component of the quorum‐sensing regulatory cascade in both EHEC and K‐12 that is involved in the regulation of flagella and motility genes, but that additional regulators in this cascade remain to be characterized.
Cosmology with the Sunyaev-Zel'dovich Effect

▪ Abstract The Sunyaev-Zel'dovich effect (SZE) provides a unique way to map the large-scale structure of the universe as traced by massive clusters of galaxies. As a spectral distortion of the cosmic microwave background, the SZE is insensitive to the redshift of the galaxy cluster, making it well-suited for studies of clusters at all redshifts, and especially at reasonably high redshifts (z > 1) where the abundance of clusters is critically dependent on the underlying cosmology. Recent high signal-to-noise detections of the SZE have enabled interesting constraints on the Hubble constant and on the matter density of the universe using small samples of galaxy clusters. Upcoming SZE surveys are expected to find hundreds to thousands of new galaxy clusters, with a mass selection function that is remarkably uniform with redshift. In this review we provide an overview of the SZE and its use for cosmological studies, with emphasis on the cosmology that can, in principle, be extracted from SZE survey yields. We .
Genetic risk of rhegmatogenous retinal detachment: a familial aggregation study.

OBJECTIVE To investigate the magnitude of the genetic risk of nonsyndromic rhegmatogenous retinal detachments (RRDs) in a familial aggregation study. DESIGN Two hundred three consecutive patients with RRD and 461 controls without RRD were ascertained at the Department of Ophthalmology of the University Medical Centre Nijmegen in Nijmegen, the Netherlands. Data on family composition, history of RRD, and presence of other risk factors in siblings and offspring were collected by means of a questionnaire. Diagnosis of RRD was confirmed by evaluation of medical records. RESULTS One hundred eighty-one patients (89.2% of those eligible) and 408 controls (88.5% of invited controls) with 1090 and 2345 relatives, respectively, were included in the analysis. Thirteen familial RRDs (1.2%) were diagnosed in 10 case probands and 9 RRDs (0.4%) in 8 control probands. Siblings and offspring of cases had a higher incidence of RRD independent of age, sex, and myopia. The cumulative lifetime risk of RRD was 7.7% for relatives of cases and 3.0% for relatives of controls, yielding a risk ratio of 2.6 (95% confidence interval, 1.1-6.2). CONCLUSIONS Familial occurrence of RRD is a risk factor for RRD. Genetic factors apart from myopia may explain the increased familial risk.
Seeking Safer Sexual Spaces: Queer and Trans Young People Labeled with Intellectual Disabilities and the Paradoxical Risks of Restriction

Young lesbian, gay, bisexual, and transgender (LGBT) people labeled with intellectual disabilities have unique sexual health needs that are not being met. Denial by others of their right to pleasure and the exercise of heightened external control over their sexuality are commonplace. Current research indicates that these youth are at heightened risk for compromised sexual health. This study aimed to explore the ways in which social and environmental conditions influence vulnerability to adverse sexual health outcomes for this population. We used a community-based research approach to conduct qualitative interviews and focus groups with 10 young LGBT people (aged 17–26) labeled with intellectual disabilities. Participants reported multiple limitations on their autonomy that resulted in having sex in places where they did not feel comfortable and were unlikely to practice safer sex. Attempts by authority figures to protect youth through limits on their autonomy may be unintentionally leading to negative sexual health outcomes.
c‐Jun N‐terminal kinases (JNKs) mediate pro‐inflammatory actions of microglia

The activation and function of c‐Jun N‐terminal kinases (JNKs) were investigated in primary microglia cultures from neonatal rat brain, which express all three JNK isoforms. Lipopolysaccharide (LPS), tumor necrosis factor‐α (TNF‐α), and thrombin preparations induced a rapid and lasting activation of JNKs in the cytoplasm. In the nucleus, the activation patterns were rather complex. In untreated microglia, the small pool of nuclear JNKs was strongly activated, while the high‐affinity JNK substrate c‐Jun was only weakly phosphorylated. Stimulation with LPS increased the total amount of nuclear JNKs and the phosphorylation of the transcription factor c‐Jun. Levels of activated JNKs in the nucleus, however, rapidly decreased. Analysis of the nuclear JNK isoforms revealed that the amount of JNK1 declined, while JNK2 increased, and the weakly expressed JNK3 did not vary. This observation suggests that JNK2 is mainly responsible for the activation of c‐Jun in this context. Upstream of JNKs, LPS induced a lasting activation of the constitutively present JNK kinase MKK4. The function of JNKs in LPS‐triggered cellular reactions was investigated using SP600125 (0.5–5 μM), a direct inhibitor of JNKs. Inhibition of JNKs reduced the LPS‐induced metabolic activity and induction of the AP‐1 target genes cyclooxygenase‐2 (Cox‐2), TNF‐α, monocyte chemoattractant protein‐1 (MCP‐1), and interleukin‐6 (IL‐6) in response to LPS, while ERK1/2 and p38α had a more pronounced effect on LPS‐induced cellular enlargement than JNKs. In summary, JNKs are essential mediators of relevant pro‐inflammatory functions in microglia with different contributions of the JNK isoforms. © 2005 Wiley‐Liss, Inc.
MHC Class II-Restricted Interaction between Thymocytes Plays an Essential Role in the Production of Innate CD8+ T Cells

We have recently shown that MHC class II-dependent thymocyte–thymocyte (T–T) interaction successfully generates CD4+ T cells (T–T CD4+ T cells), and that T–T CD4+ T cells expressing promyelocytic leukemia zinc finger protein (PLZF) show an innate property both in mice and humans. In this article, we report that the thymic T–T interaction is essential for the conversion of CD8+ T cells into innate phenotype in the physiological condition. CD8+ T cells developed in the presence of PLZF+ CD4+ T cells showed marked upregulation of eomesodermin (Eomes), activation/memory phenotype, and rapid production of IFN-γ on ex vivo stimulation. Their development was highly dependent on the PLZF expression in T–T CD4+ T cells and the IL-4 secreted by PLZF+ T–T CD4+ T cells. The same events may take place in humans, as a substantial number of Eomes expressing innate CD8+ T cells were found in human fetal thymi and spleens. It suggests that PLZF+ T–T CD4+ T cells in combination with Eomes+ CD8+ T cells might actively participate in the innate immune response against various pathogens, particularly in human perinatal period.
Comparison of three-dimensional echocardiographic software packages for assessment of left ventricular mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy.

AIMS We directly compared TomTec and QLAB software packages for the three-dimensional echocardiographic (3DE) assessment of left ventricular (LV) dyssynchrony including their ability to predict response to cardiac resynchronization therapy (CRT) in patients with ischaemic and non-ischaemic cardiomyopathy. METHODS AND RESULTS A total of 140 heart failure patients with the LVEF ≤35% and 60 healthy volunteers underwent 3DE. A subgroup of 60 patients underwent CRT and were evaluated before and 6-12 months after implantation. The systolic dyssynchrony index (SDI) was derived from the dispersion of time to minimum regional volume for all 16 LV segments and measured with both software packages and compared using Pearson's correlation and Bland-Altman analysis. Measurements of SDI were significantly higher using TomTec compared with QLAB in both patients (10.9 ± 3.8 vs. 9.7 ± 3.9, P < 0.001) and healthy volunteers (4.1 ± 0.8 vs. 2.4 ± 1, P < 0.001), with large biases and wide limits of agreement. A moderate correlation (r = 0.65, P < 0.001) was observed between both software packages in patients while their inter-observer and intra-observer reliability were good. Of the 60 patients undergoing CRT, reverse remodelling as a measure of response was observed in 41 patients (68%). The optimal SDI cut-off value to predict response to CRT was higher for TomTec than for QLAB (8.8 vs.7.3%, P < 0.001) and demonstrated better sensitivity and specificity (93 and 61%, respectively) compared with QLAB (88 and 33%, respectively). Response prediction in patients with non-ischaemic cardiomyopathy was excellent with a sensitivity and specificity of 95 and 100% for TomTec and 70 and 83% for QLAB using similar cut-off values of 9.1 and 9.2%, respectively. CONCLUSION Different 3DE software packages for the assessment of mechanical dyssynchrony should not be used interchangeably until better software standardization is achieved. Dyssynchrony assessment with 3DE for the prediction of response to CRT seems particularly useful in patients with non-ischaemic cardiomyopathy.
Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine

Molecular “go” signals reveal their secrets Chemokines are proteins that direct how cells move within the body. For instance, chemokines help immune cells locate invading pathogens and ensure that cells position themselves correctly within a developing organ. Cells detect chemokines through G protein–coupled receptors on their surface; however, the molecular details of how these proteins interact remain unclear (see the Perspective by Standfuss). Qin et al. solved the crystal structure of the chemokine receptor CXCR4 bound to the viral chemokine vMIP-II. Burg et al. solved the crystal structure of a viral chemokine receptor bound to the chemokine domain of CX3CL1. Given the role of chemokines in a number of diseases, these results may help in future drug design. Science, this issue p. 1117, p. 1113; see also p. 1071 The crystal structure of the chemokine receptor CXCR4 bound to a viral chemokine provides insights into chemokine recognition. [Also see Perspective by Standfuss] Chemokines and their receptors control cell migration during development, immune system responses, and in numerous diseases, including inflammation and cancer. The structural basis of receptor:chemokine recognition has been a long-standing unanswered question due to the challenges of structure determination for membrane protein complexes. Here, we report the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1 angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic two-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.
Assessment of the effect of salinity on the early growth stage of soybean plants (Glycine max L.)

The effects of different salt concentration treatment of soybean plants and the occurrence of salinity stress have been assessed from a comparative analysis of remotely sensed ground-based spectral reflectance data and biochemical parameters. The contents of phenols, proline, malondialdehid, hydrogen peroxide, thiol groups, and chlorophyll a and b have been determined. The soybean plants were grown under controlled conditions as water cultures on Helrigel nutrient solution. Salinity was performed at the stage of 2nd to 4th trifoliate expanded leaves by adding of NaCl in the nutrient solution in concentrations 40 mM and 80 mM. The leaf spectral reflectance was measured in laboratory in the visible and near infrared spectral ranges using a fibre-optic multichannel spectrometer. An algorithm based on multivariate statistical analysis of the leaf reflectance spectra was developed. It includes Student's t-criterion, discriminant analysis and derivative analysis. The spectral intervals of interest were the green, red, red-edge and near infrared ranges of the spectrum. Statistically significant differences at p≪0.05 were found between the leaf spectral reflectance data of control and treated plants at 80 mM NaCl in all of the ranges examined with the exception of the near infrared range. No statistically significant differences were established at 40 mM NaCl treatment. Some of the biochemical parameters (proline, malondialdehid, thiol groups) were found at salinity treatment by 40 mM NaCl to increase in value more than 10% while the chlorophyll a and b concentrations decreased more than 20%. This trend was preserved for the 80 mM NaCl treatment as the corresponding parameters changed by about 45% on average, which is symptomatic for the stressed plants.
GPs' perceptions of patient influence on prescribing.

BACKGROUND Controlling prescribing costs is an issue of concern to many GPs. OBJECTIVE AND METHODS This paper is based on interviews with 21 GPs in which they were asked about influences on prescribing budgets. RESULTS The results presented relate specifically to GPs' perceptions of the influence of patients on prescribing. Perceptions of patient demand were described both in terms of a general demand and demand by patients with specific health beliefs or particular social characteristics. Generally, GPs reported that decisions to prescribe were informed by a concern to maintain a good relationship with their patients, and not to risk the relationship by not prescribing when they believed a prescription was expected. CONCLUSIONS Although information was available about whether practices had a 'high' or 'low' budget, and whether they were under- or overspent, there did not appear to be any relationship between GPs' beliefs that patient expectations affected their prescribing and whether they were under or over budget. This paper suggests that patient demand for prescriptions may not only be overestimated but also perpetuated by GPs' belief in its existence and a wish to maintain a good doctor-patient relationship.
Staple line leak with peritonitis after laparoscopic sleeve gastrectomy – a solution in one to six steps

Introduction Laparoscopic sleeve gastrectomy (LSG) is one of the most efficient bariatric interventions in morbidly obese patients. The most severe risk of this procedure seems to be the staple line leak, and the management of this complication can be very arduous. Aim To share our experience in managing the staple line leak after LSG and to help to find the best procedure that should be preferred. Material and methods In the 2010–2015 period we performed 223 LSG, with about 5 demonstrating severe complications – two patients with severe bleeding requiring revision surgery, and three patients with resection surface leak. Results We always primarily treated the staple line leak with a laparoscopic revision. Once the fistula did not spontaneously close after this treatment. A series of other methods were then indicated for this patient and only the sixth one resulted in the desirable therapeutic success. At first, our team opted for laparoscopic revision with drainage. The next procedure involved applying Ovesco and Boston clips. As a third method we performed abscess drainage through a nasobiliary tube inserted via gastroscopy. Due to failure we performed the second laparoscopic revision with staple line resuture, the next intervention was an open revision with fistula excision and suture, and finally we opted for the application of a self-expanding metallic stent, which proved to be definitely curative. Conclusions Without any guidelines it is very difficult to determine the right procedure addressing the staple line leak after LSG. It depends mainly on the clinician’s experience and is lengthy and often untraditional.