Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic anticipation in Swedish Lynch syndrome families

Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990–2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM–MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.
Tsallis Wavelet Entropy and Its Application in Power Signal Analysis

As a novel data mining approach, a wavelet entropy algorithm is used to perform entropy statistics on wavelet coefficients (or reconstructed signals) at various wavelet scales on the basis of wavelet decomposition and entropy statistic theory. Shannon wavelet energy entropy, one kind of wavelet entropy algorithm, has been taken into consideration and utilized in many areas since it came into being. However, as there is wavelet aliasing after the wavelet decomposition, and the information set of different-scale wavelet decomposition coefficients (or reconstructed signals) is non-additive to a certain extent, Shannon entropy, which is more adaptable to extensive systems, couldn’t do accurate uncertainty statistics on the wavelet decomposition results. Therefore, the transient signal features are extracted incorrectly by using Shannon wavelet energy entropy. From the two aspects, the theoretical limitations and negative effects of wavelet aliasing on extraction accuracy, the problems which exist in the feature extraction process of transient signals by Shannon wavelet energy entropy, are discussed in depth. Considering the defects of Shannon wavelet energy entropy, a novel wavelet entropy named Tsallis wavelet energy entropy is proposed by using Tsallis entropy instead of Shannon entropy, and it is applied to the feature extraction of transient signals in power systems. Theoretical derivation and experimental result prove that compared with Shannon wavelet energy entropy, Tsallis wavelet energy entropy could reduce the negative effects of wavelet aliasing on accuracy of feature extraction and extract transient signal feature of power system accurately.
A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification

Mammalian development is regulated by the interplay of tissue-specific and ubiquitously expressed transcription factors, such as Sp1. Sp1 knockout mice die in utero with multiple phenotypic aberrations, but the underlying molecular mechanism of this differentiation failure has been elusive. Here, we have used conditional knockout mice as well as the differentiation of mouse ES cells as a model with which to address this issue. To this end, we examined differentiation potential, global gene expression patterns and Sp1 target regions in Sp1 wild-type and Sp1-deficient cells representing different stages of hematopoiesis. Sp1−/− cells progress through most embryonic stages of blood cell development but cannot complete terminal differentiation. This failure to fully differentiate is not seen when Sp1 is knocked out at later developmental stages. For most Sp1 target and non-target genes, gene expression is unaffected by Sp1 inactivation. However, Cdx genes and multiple Hox genes are stage-specific targets of Sp1 and are downregulated at an early stage. As a consequence, expression of genes involved in hematopoietic specification is progressively deregulated. Our work demonstrates that the early absence of active Sp1 sets a cascade in motion that culminates in a failure of terminal hematopoietic differentiation and emphasizes the role of ubiquitously expressed transcription factors for tissue-specific gene regulation. In addition, our global side-by-side analysis of the response of the transcriptional network to perturbation sheds a new light on the regulatory hierarchy of hematopoietic specification.
Acute host-mediated endothelial injury after adenoviral gene transfer in normal rabbit arteries: impact on transgene expression and endothelial function.

Acute injury after adenoviral vascular gene transfer remains incompletely characterized. Here, we describe the early response (< or =days) in 52 New Zealand White rabbits undergoing gene transfer (beta-galactosidase or empty vector) or sham procedures to both carotid arteries. After gene transfer, arteries were either left in vivo for 1 hour to 3 days (in vivo arteries) or were excised immediately after gene transfer and cultured (ex vivo arteries). Within 1 hour, in vivo arteries receiving infectious titers of > or = 4X10(9) plaque-forming units (pfu)/mL showed endothelial activation, with an acute inflammatory infiltrate developing by 6 hours. Ex vivo arteries showed endothelial activation but no inflammatory infiltrate. There were also significant differences in transgene expression between in vivo and ex vivo arteries. Ex vivo arteries showed titer-dependent increases in beta-galactosidase expression through 2X10(10) pfu/mL, whereas in in vivo arteries, titers above 4X10(9) pfu/mL merely increased acute inflammatory response, without increasing transgene expression. In vivo arteries showed significant time- and titer-dependent impairment in endothelium-dependent relaxation, with no effect on contraction or nitroprusside-induced relaxation. Interestingly, however, if rabbits were made neutropenic with vinblastine, their arteries maintained full endothelium-dependent relaxation, even after very high titer vascular infection (up to 1X10(11) pfu/mL). These findings show that recombinant adenovirus triggers an early inflammatory response, and it is the inflammatory response that in turn causes functional endothelial injury. This occurs at much lower titers than previously appreciated (though the precise threshold will undoubtedly vary between laboratories). However, titers below the inflammatory threshold produce excellent transgene expression without inflammation or vascular injury.
The Ornibactin Biosynthesis and Transport Genes of Burkholderia cenocepacia Are Regulated by an Extracytoplasmic Function σ Factor Which Is a Part of the Fur Regulon

ABSTRACT Burkholderia cenocepacia mutants that fail to produce the siderophore ornibactin were obtained following mutagenesis with mini-Tn5Tp. These mutants were shown to be growth restricted under conditions of iron depletion. In eight of the mutants, the transposon had integrated into one of two genes, orbI and orbJ, encoding nonribosomal peptide synthetases. In the other mutant, the transposon had inserted into an open reading frame, orbS, located upstream from orbI. The polypeptide product of orbS exhibits a high degree of similarity to the Pseudomonas aeruginosa extracytoplasmic function (ECF) σ factor PvdS but possesses an N-terminal extension of approximately 29 amino acids that is not present in PvdS. Three predicted OrbS-dependent promoters were identified within the ornibactin gene cluster, based on their similarity to PvdS-dependent promoters. The iron-regulated activity of these promoters was shown to require OrbS. Transcription of the orbS gene was found to be under the control of an iron-regulated σ70-dependent promoter. This promoter, but not the OrbS-dependent promoters, was shown to be a target for repression by the global regulator Fur. Our results demonstrate that production of ornibactin by B. cenocepacia in response to iron starvation requires transcription of an operon that is dependent on the Fur-regulated ECF σ factor gene orbS. A mechanism is also proposed for the biosynthesis of ornibactin.
Rhabdomyolysis-related renal tubular damage studied by proton nuclear magnetic resonance spectroscopy of urine.

Rhabdomyolysis is a common clinical and laboratory syndrome, resulting from skeletal muscle injury, that leads to the release of potentially toxic muscle cell contents, specifically myoglobin, into the plasma (1)(2). Rhabdomyolysis can be induced by many different mechanisms and has been implicated as a major cause of acute renal failure. However, when correct treatment is provided, it is usually reversible. Acute tubular necrosis after rhabdomyolysis does not always appear to parallel the degree of muscle damage, but it may be related to other factors that potentiate the effects of myoglobinuria, such as hypotension, acidosis, and volume depletion. The pathophysiology of the renal injury is not fully understood, but it probably includes a combination of hypoperfusion/ischemia, iron tubular cytotoxicity, and cast formation potentially leading to proximal tubular necrosis and acute renal failure. The combination of fibrates plus 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) is an effective and generally well-tolerated treatment for high-risk patients with mixed dyslipidemias, and side effects, mainly hepatic and muscular disorders, are rare. However, when they do occur, muscular damage may be severe, leading to rhabdomyolysis (3)(4). High-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy is a nondestructive and noninvasive technique that can provide complete structural analysis of a wide range of organic molecules in complex mixtures. NMR spectroscopy has been used for the detection of low-molecular-weight metabolites present in biological fluids as a result of changes in physiologic status, toxic insult, or disease processes (5). NMR provides quantitative information on the low-molecular-weight metabolites present in the specimen studied and allows the detection of unexpected constituents related to disease or tissue damage. Urinalysis by NMR spectroscopy has led to detailed investigation of the excretion pattern in various physiologic and pathologic situations, such as inborn errors of metabolism, organ transplantation, and renal damage produced by acute …
New impedance reshaping algorithm for grid-connected DGs

This paper proposes a new control algorithm for optimally reshaping distributed generation (DG) output impedance so that the system damping and bandwidth are maximized. Such impedance reshaping is essential for managing variations in grid impedance and changes in DG operating conditions. The proposed control algorithm involves two design stages. First, the multivariable DG output impedance is derived mathematically. The grid impedance is also estimated to formulate the impedance stability criterion. Second, a multi-objective programming is formulated to maximize the system damping and bandwidth. Real-time simulations are performed to investigate the effectiveness and robustness of the proposed control algorithm.
Network maps beyond connectivity

Knowing network topology is becoming increasingly important for a number of applications such as server placement (E. Cronin et al., 2002) and traceback of DDoS attacks (D. Song and A. Perrig, 2001), Recent works in modeling the Internet topology and constructing network maps have focused on the connectivity aspect. This paper describes our study on incorporating connectivity, latency, and routing information all into a network map based on a large set of traceroute data. We introduce a model for constructing such a network map. We evaluate our network map based on various Internet routing models proposed in the literature. The evaluation shows that, for those traceroute data that we are able to evaluate, at least 85% of computed hop-counts and latencies are within a factor of two of the actual values. Furthermore, we show that a flat routing model based on hop-count performs as well as more complicated routing models
Statistical correction of central Southwest Asia winter precipitation simulations

Severe drought is a notable feature of the hydrology of central Southwest (CSW) Asia. Although studies have linked the region's interannual precipitation variability to remote forcings that include East Asia jet stream variability and western Pacific tropical convection, atmospheric general circulation models (GCMs) forced by observed sea‐surface temperatures demonstrate little skill in simulating interannual precipitation variability in this region. Here, statistical methods of correcting systematic errors in GCM simulations of CSW Asia precipitation are investigated. Canonical correlation analysis is used to identify model fields related to observed precipitation anomaly patterns. These relationships are then used to predict observed precipitation anomalies. This approach is applied to the ECHAM 4.5 GCM using regional precipitation, upper‐level winds and western Pacific tropical precipitation as predictors of observed CSW Asia precipitation anomalies. The statistical corrections improve the GCM precipitation simulations, resulting in modest, but statistically significant, cross‐validated skill in simulating CSW Asia precipitation anomalies. Applying the procedure to hindcasts with persisted sea‐surface temperatures gives lower, but statistically significant, precipitation correlations in the region along the Hindu Kush mountain range. Copyright © 2003 Royal Meteorological Society
Information Triage using Prospective Criteria

In many applications, large volumes of time-sensitive textual information require triage: rapid, approximate prioritization for subsequent action. In this paper, we explore the use of prospective indications of the importance of a time-sensitive document, for the purpose of producing better document filtering or ranking. By prospective, we mean importance that could be assessed by actions that occur in the future. For example, a news story may be assessed (retrospectively) as being important, based on events that occurred after the story appeared, such as a stock-price plummeting or the issuance of many follow-up stories. If a system could anticipate (prospectively) such occurrences, it could provide a timely indication of importance. Clearly, perfect prescience is impossible. However, sometimes there is sufficient correlation between the content of an information item and the events that occur subsequently. We describe a process for creating and evaluating approximate information-triage procedures that are based on prospective indications. Unlike many information-retrieval applications for which document labeling is a laborious, manual process, for many prospective criteria it is possible to build very large, labeled, training corpora automatically. Such corpora can be used to train text classification procedures that will predict the (prospective) importance of each document. This paper illustrates the process with two case studies, demonstrating the ability to predict whether the stock price of one or more companies mentioned in a news story will move significantly following the appearance of that story. We conclude by discussing that the comprehensibility of the learned classifiers can be critical to success.
Conversational Markers of Constructive Discussions

Group discussions are essential for organizing every aspect of modern life, from faculty meetings to senate debates, from grant review panels to papal conclaves. While costly in terms of time and organization effort, group discussions are commonly seen as a way of reaching better decisions compared to solutions that do not require coordination between the individuals (e.g. voting)---through discussion, the sum becomes greater than the parts. However, this assumption is not irrefutable: anecdotal evidence of wasteful discussions abounds, and in our own experiments we find that over 30% of discussions are unproductive. We propose a framework for analyzing conversational dynamics in order to determine whether a given task-oriented discussion is worth having or not. We exploit conversational patterns reflecting the flow of ideas and the balance between the participants, as well as their linguistic choices. We apply this framework to conversations naturally occurring in an online collaborative world exploration game developed and deployed to support this research. Using this setting, we show that linguistic cues and conversational patterns extracted from the first 20 seconds of a team discussion are predictive of whether it will be a wasteful or a productive one.
The Effects of Functional Polymorphisms in the TGFβ1 Gene on Nasopharyngeal Carcinoma Susceptibility

Objective. Transforming growth factor β1 (TGFβ1) promotes tumor growth and metastasis in the later stage of cancer development. In this study, we explored whether TGFβ1 polymorphisms were associated with increased risk of nasopharyngeal carcinoma (NPC) in a Chinese population. Design. Case-control study. Setting. Hospitals of the Department of Otorhinolaryngology–Head and Neck Surgery. Subjects and Methods. Two single nucleotide polymorphisms of TGFβ1 gene promoter -509C/T (rs1800469) and 869T/C (Leu 10 Pro, rs1800470) at exon 1 were analyzed in 522 NPC patients and 712 age- and sex-matched controls in a Chinese population, using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis. Functional relevance of the polymorphism was determined by biochemical assays. Results. The -509T allele carriers were associated with a significantly reduced risk of NPC as compared with the noncarriers (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.53-0.89 and OR, 0.50; 95% CI, 0.31-0.67, respectively). Moreover, -509C-containing TGFβ1 promoter drove an ~1.7-fold increase in reporter expression, compared with the -509T-containing counterpart in both CNE-1 and CNE-2 cell lines. The TGFβ1 -509 CC genotype carriers had a higher TGFβ1 mRNA level than the TGFβ1 -509TT genotype carriers did (P < .01). However, no significant association was observed between the 869T/C polymorphism and risk of NPC. Conclusion. These findings indicate that the -509C/T polymorphism in TGFβ1 may play a vital role in mediating individual susceptibility to NPC.
N-methyl-N-nitrosourea-induced cerebellar hypoplasia in rats: Effect of arachidonic acid supplementation during the gestational, lactational and post-weaning periods

Arachidonic acid (AA) is a fatty acid that is important for visual and brain development and is commonly added as a functional food ingredient to commercial infant formulas worldwide. However, few studies have examined whether AA supplementation during neonatal life has an effect on neuronal abnormalities. In the present study, the effect of dietary AA supplementation in dams during gestation and lactation was investigated by examining N-methyl-N-nitrosourea (MNU)-induced cerebellar hypoplasia in young Lewis rats. Dams were fed a 2.0% AA diet or a basal diet (<0.01% AA). At birth (postnatal day 0), male and female pups received a single intraperitoneal injection of 35 mg/kg MNU or vehicle. Brain weights were measured and a morphological analysis of macroscopic and histological specimens was conducted after 7, 14, 21, 28 and 60 days. Irrespective of whether the rats had been fed an AA diet, the brain weights of the MNU-treated rats, particularly the weights of the cerebellum, were decreased compared with those of the MNU-untreated rats from the 14th day following the MNU injection. Macroscopic reductions in the cerebellar length and/or width and histologically observed reductions in cerebellar vertex height and/or cortex width were also detected in the MNU-treated rats, irrespective of whether the rats had been fed with AA. Histopathologically, the MNU-treated rats (irrespective of AA supplementation) exhibited disorganization of the cerebellar cortex and disarrangement of the cortical layers (loss and/or disturbance of the molecular, Purkinje and granular cell layers). There were no significant differences in any parameters among the MNU-treated rats, irrespective of whether the rats had been fed an AA diet. In conclusion, an AA-rich diet for dams during gestation and lactation did not modify MNU-induced cerebellar hypoplasia in their offspring.
Improvement of renal function after the switch from a calcineurin inhibitor to everolimus in liver transplant recipients with chronic renal dysfunction

Chronic renal dysfunction is a frequent and severe complication in solid‐organ transplant recipients. Calcineurin inhibitors (CNIs) are the main pathogenic factors of renal dysfunction. Switching from CNIs to nonnephrotoxic drugs, such as mammalian target of rapamycin inhibitors (everolimus and sirolimus), can improve renal function in these patients, but available data about the efficacy and safety of everolimus in liver transplant recipients are scarce. Twenty‐one liver transplant recipients (19 males, mean age = 60.6 ± 7.8 years) with chronic renal dysfunction (creatinine ≥ 1.5 mg/dL) were prospectively included. The basal creatinine values were 1.79 ± 0.39 mg/dL (range = 1.50–2.90 mg/dL). The basal creatinine clearance, evaluated with the Cockroft‐Gault formula, was 54.64 ± 12.47 mL/minute. Everolimus was initiated at a dosage of 0.75 mg twice daily, with target levels of 3 to 8 ng/mL. The withdrawal of CNIs was initiated after the target levels of everolimus were reached. Periodic controls of the weight, arterial pressure, liver function tests, serum creatinine, everolimus levels, proteinuria, creatinine clearance, and glomerular filtration rate at days 30, 90, 180, and 360 were made. After a median follow‐up of 19.8 months, the respective creatinine values at 30, 90, 180, and 360 days were 1.68 ± 0.40 (P = 0.012 with respect to basal values), 1.67 ± 0.34 (P = 0.107), 1.70 ± 0.41 (P = 0.521), and 1.57 ± 0.30 mg/dL (P = 0.047). The respective creatinine clearance values at 30, 90, 180, and 360 days were 58.64 ± 16.50 (P = 0.013 with respect to basal values), 59.49 ± 13.27 (P = 0.028), 59.82 ± 16.83 (P = 0.124), and 64.46 ± 16.79 mL/minute (P = 0.025). CNIs were withdrawn in 20 recipients (95.2%). Rejection was not detected in any case. In conclusion, the application in liver transplant recipients with chronic renal dysfunction of an immunosuppressive protocol with everolimus and the withdrawal of CNIs was associated with an initial improvement of renal function tests without an increase in the risk of rejection. Liver Transpl 15:1792–1797, 2009. © 2009 AASLD.