Miracle-dz/UniFAR-FTUs huggingface dataset:
Functionality of sequence variants in the genes coding for the low‐density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia

Patients with familial hypercholesterolemia (FH) have elevated LDL‐C levels, usually above the 90th percentile (P90) for age and gender. However, large‐scale genetic cascade screening for FH showed that 15% of the LDL‐receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL‐C levels below P75. Nonpathogenicity of sequence changes may explain this phenomenon. To assess pathogenicity of a mutation we proposed three criteria: (1) mean LDL‐C >P75 in untreated mutation carriers; (2) higher mean LDL‐C level in untreated carriers than in untreated noncarriers; and (3) higher percentage of medication users in carriers than in noncarriers at screening. We considered a mutation nonpathogenic when none of the three criteria were met. We applied these criteria to mutations that had been determined in more than 50 untreated adults. Segregation analysis was performed to confirm nonpathogenicity. Forty‐six mutations had been tested in more than 50 untreated subjects, and three were nonpathogenic according to our criteria: one in LDLR (c.108C>A, exon 2) and two in APOB (c.13154T>C and c.13181T>C, both in exon 29). Segregation analysis also indicated nonpathogenicity. According to our criteria, three sequence variants were nonpathogenic. The criteria may help to identify nonpathogenic sequence changes in genetic cascade screening programs. Hum Mutat 31:752–760, 2010. © 2010 Wiley‐Liss, Inc.
Renal function preservation with the mTOR inhibitor, Everolimus, after lung transplant

Chronic kidney disease (CKD) is a common complication of calcineurin inhibitors (CNIs) in solid organ transplantation. Previous data suggest that the use of everolimus as an immunosuppressant drug leads to improvement in renal function. The aim of our study was to establish the effect of everolimus in combination with lower doses of CNIs on renal function among lung transplant recipients. Data regarding renal function and pulmonary function were collected from 41 lung transplanted patients in whom treatment was converted to a combination of everolimus with lower doses of CNIs. Patients transferred to everolimus and low dose CNIs showed an improvement in renal function. Patients who continued treatment with everolimus showed improvement in renal function, as opposed to patients who discontinued the treatment. Subjects without proteinuria at baseline showed a better improvement compared with subjects with proteinuria. The incidence of graft rejection did not increase. We concluded that a protocol that includes everolimus and lower doses of CNIs is effective for preserving renal function in lung transplant recipients with CKD. We also believe that an early implementation of everolimus, before proteinuria occurs or creatinine clearance is reduced, could lead to better outcomes.
Improvement of Basal Hepatic Glucose Production ana Fasting Hyperglycemia of Type I Diabetic Patients Treated With Human Recombinant Ultralente Insulin

OBJECTIVE To test whether a suppertime injection of human ultralente insulin in patients with type I diabetes would result in a larger inhibition of basal hepatic glucose production (HGP) and improvement in fasting and mean daily plasma glucose levels. RESEARCH DESIGN AND METHODS We studied 16 type I diabetic patients (41 ± 4 years of age; body mass index [BMI] = 23.3 ± 0.3 kg/m2; diabetes duration >3 years) with a crossover protocol of therapy with an intermediate and ultralente insulin. All patients were already treated with three injections per day of regular insulin in addition to intermediate-acting (NPH) insulin at suppertime. After a 14-day run-in period, patients were randomly assigned to treatment with equivalent doses (10.8 ± 0.8 U, at 1900) of intermediate (Humulin 1) or ultralente (Humulin U) insulin. After 1 month of treatment, patients were crossed over. No change of the insulin dosage was performed during the study period. Basal HGP was measured by β-glucose infusion. Plasma glucose concentration was measured in the fasting state and monitored during the day. RESULTS Before starting the study period, fasting plasma glucose was 13.4 ±1.1 mM and plasma free-insulin was 48.0 ± 4.8 pM. Daily plasma glucose concentration averaged 10.3 ± 0.3 mM and the area under the curve (AUC) was 1.41 ± 0.05 mol/14 h. NPH insulin, given at suppertime for a month, did not induce significant changes in fasting plasma insulin (40.2 ± 4.8 pM), glucose concentration (14.0 ± 0.9 mM) or HGP (20.2 ± 2.2 jamol · kg–1 · min–1). Accordingly, no change occurred in the average daily plasma glucose (10.3 ± 0.3 mM) or AUC (1.41 ± 0.9 mol/14 h). Glycated hemoglobin also was not affected (8.2 ± 0.4 vs. 8.2 ± 0.3%). On the contrary, a 4-week treatment with ultralente insulin, also given at suppertime, was associated with a decline in the basal HGP (16.0 ±1.3 /Ltmol · kg–1 · min–1), fasting (11.3 ± 0.9 mM) and average daily (9.4 ± 0.3 mM) plasma glucose concentrations, and AUC (1.29 ± 0.07 mol/14 h) of plasma glucose level (all P < 0.05). Glycated hemoglobin was reduced (7.9 ± 0.4%). In each condition, fasting plasma glucose concentration was correlated with the average daily plasma glucose level (basal = 0.78; intermediate = 0.89; ultralente = 0.62; all P < 0.05), which suggests that ultralente insulin likely induces the improvements of metabolic control through reducing fasting plasma glucose. CONCLUSIONS Our results suggest that treating type I diabetic patients with ultralente insulin at suppertime provides a better modulation of basal HGP so that lower fasting plasma glucose levels are ensured. The reduction of fasting hyperglycemia is likely to affect positively aily plasma glucose control.
Neuroanatomical organization of the cholinergic system in the central nervous system of a basal actinopterygian fish, the senegal bichir Polypterus senegalus

Polypterid bony fishes are believed to be basal to other living ray‐finned fishes, and their brain organization is therefore critical in providing information as to primitive neural characters that existed in the earliest ray‐finned fishes. The cholinergic system has been characterized in more advanced ray‐finned fishes, but not in polypterids. In order to establish which cholinergic neural centers characterized the earliest ray‐finned fishes, the distribution of choline acetyltransferase (ChAT) is described in Polypterus and compared with the distribution of this molecule in other ray‐finned fishes. Cell groups immunoreactive for ChAT were observed in the hypothalamus, the habenula, the optic tectum, the isthmus, the cranial motor nuclei, and the spinal motor column. Cholinergic fibers were observed in both the telencephalic pallium and the subpallium, in the thalamus and pretectum, in the optic tectum and torus semicircularis, in the mesencephalic tegmentum, in the cerebellar crest, in the solitary nucleus, and in the dorsal column nuclei. Comparison of the data within a segmental neuromeric context indicates that the cholinergic system in polypterid fishes is generally similar to that in other ray‐finned fishes, but cholinergic‐positive neurons in the pallium and subpallium, and in the thalamus and cerebellum, of teleosts appear to have evolved following the separation of polypterids and other ray‐finned fishes. J. Comp. Neurol. 521:24–49, 2013. © 2012 Wiley Periodicals, Inc.
A clinical comparison of two chemically-cured adhesives used for indirect bonding.

OBJECTIVE To compare and evaluate the clinical failure rates of the chemically-cured composite bonding resins Sondhi Rapid Set (SD) and Maximum Cure (MC) when used in an indirect bonding technique. SETTING In vivo study in the private orthodontic practice of a solo practitioner. MATERIALS AND METHODS Forty consecutive patients meeting the inclusion criteria were assigned to alternating groups in a split-mouth study design. Group 1 had the maxillary right and mandibular left quadrants indirectly bonded using SD adhesive, while the contralateral quadrants were bonded using MC adhesive. Group 2 had the opposite sides bonded to Group 1. One patient was lost from each group. Over a 6-month observation period, all loose brackets were recorded and the data compared with a Wilcoxon sign-rank test. RESULTS Of the 363 brackets placed in each group, 36 with the SD adhesive came loose (9.9 per cent failure rate) compared with five from the MC group (1.4 per cent failure rate, P = 0.0001). In the maxillary arch, seven brackets from the SD quadrants came loose versus one for the MC (P = 0.109). In the mandibular arch 29 brackets from the SD quadrants came loose during the 6-month observation period compared with four from the MC quadrants (P = 0.001). CONCLUSIONS Both chemically-cured adhesives (SD and MC) examined in this study were suitable for the indirect bonding of brackets. The SD adhesive had seven times the number of breakages than the MC adhesive in both arches (P = 0.0001).
How well do CMIP5 climate simulations replicate historical trends and patterns of meteorological droughts?

Assessing the uncertainties and understanding the deficiencies of climate models are fundamental to developing adaptation strategies. The objective of this study is to understand how well Coupled Model Intercomparison‐Phase 5 (CMIP5) climate model simulations replicate ground‐based observations of continental drought areas and their trends. The CMIP5 multimodel ensemble encompasses the Climatic Research Unit (CRU) ground‐based observations of area under drought at all time steps. However, most model members overestimate the areas under extreme drought, particularly in the Southern Hemisphere (SH). Furthermore, the results show that the time series of observations and CMIP5 simulations of areas under drought exhibit more variability in the SH than in the Northern Hemisphere (NH). The trend analysis of areas under drought reveals that the observational data exhibit a significant positive trend at the significance level of 0.05 over all land areas. The observed trend is reproduced by about three‐fourths of the CMIP5 models when considering total land areas in drought. While models are generally consistent with observations at a global (or hemispheric) scale, most models do not agree with observed regional drying and wetting trends. Over many regions, at most 40% of the CMIP5 models are in agreement with the trends of CRU observations. The drying/wetting trends calculated using the 3 months Standardized Precipitation Index (SPI) values show better agreement with the corresponding CRU values than with the observed annual mean precipitation rates. Pixel‐scale evaluation of CMIP5 models indicates that no single model demonstrates an overall superior performance relative to the other models.
Effects on Photosystem II Function, Photoinhibition, and Plant Performance of the Spontaneous Mutation of Serine-264 in the Photosystem II Reaction Center D1 Protein in Triazine-Resistant Brassica napus L

Wild-type and an atrazine-resistant biotype of Brassica napus, in which a glycine is substituted for the serine-264 of the D1protein, were grown over a wide range of constant irradiances in a growth cabinet. In the absence of serine-264, the function of photosystem II (PSII) was changed as reflected by changes in chlorophyll fluorescence parameters and in photosynthetic oxygen-evolving activity. The photochemical quenching coefficient was lower, showing that a larger proportion of the primary quinone acceptor is reduced at all irradiances. At low actinic irradiances, the nonphotochemical quenching coefficient was higher, showing a greater tendency for heat emission. Decreased rates of light-limited photosynthesis (quantum yield) and lower oxygen yields per single-turnover flash were also observed. These changes were observed even when the plants had been grown under low irradiances, indicating that the changes in PSII function are direct and not consequences of photoinhibition. In spite of the lowered PSII efficiency under light-limiting conditions, the light-saturated photosynthesis rate of the atrazine-resistant mutant was similar to that of the wild type. An enhanced susceptibility to photoinhibition was observed for the atrazine-resistant biotype compared to the wild type when plants were grown under high and intermediate, but not low, irradiance. We conclude that the replacement of serine by glycine in the D1 protein has a direct effect on PSII function, which in turn causes increased photoinhibitory damage and increased rates of turnover of the D1 protein. Both the intrinsic lowering of light-limited photosynthetic efficiency and the increased sensitivity to photoinhibition probably contribute to reduced crop yields in the field, to different extents, depending on growth conditions.
Other complications and associated conditions with diabetes in children and adolescents

aChildren’s Hospital auf der Bult, Hannover, Germany; bthe Children’s Hospital at Westmead, NSW, Australia; cUniversity of Helsinki, Finland; dMedical University Vienna, Austria; eUniversity of Genova, Italy; fUniversitat Ulm, Uni West, Germany; gUniversity of Sydney, Australia Corresponding author: Prof. Dr. med. Olga Kordonouri Diabetes Center for Children and Adolescents Children’s Hospital auf der Bult Hannover, Germany Tel: +49 511/8115-3340; fax: +49 511/8115-3334; e-mail: kordonouri@hka.de
Business Process Change: A Study of Methodologies, Techniques, and Tools

Growth in Business Process Reengineering (BPR) consulting services has led to a proliferation of methods for conducting BPR. Sifting through vendor promotional hype and identifying a set of techniques and tools that best meets a particular project's needs can be a daunting task. This article investigates BPR Methods, Techniques, and Tools (MTTs) and places them within an empirically derived reference framework. A comprehensive picture of BPR emerges that includes MTTs that help in reengineering strategy, people, management, structure, and technology dimensions of business processes. A BPR planning approach for customizing this framework based on unique project characteristics is then offered to assist in selecting those BPR project activities and techniques to be emphasized. This flexible framework and comprehensive survey of commonly used BPR techniques and tools forms a knowledge base to improve business process change practice and provides a basis for future BPR research.
Special Issue: Knowledge, Knowing, and Organizations: Knowledge Partitioning in the Interfirm Division of Labor: The Case of Automotive Product Development

Drawing on an empirical study on automakers' management of supplier involvement in product development in Japan, this paper shows that when the design of a component is outsourced to a supplier, how much automakers know about the component matters for them to gain a better outcome. While the actual tasks of designing and manufacturing components could be out-sourced, automakers should retain the relevant knowledge to obtain better component design quality. The paper argues that knowledge partitioning should be distinguished from task partitioning, and provides some implications for the knowledge-based theory of the firm.The results indicate that effective pattern of knowledge partitioning differs by the nature of component development project in terms of technological newness. For regular projects, it is more important for the automaker to have a higher level of architectural knowledge (how to coordinate various components for a vehicle) than of component-specific knowledge, which is supposed to be provided by the supplier. However, when the project involves new technology for the supplier, it is important for the automaker to have a higher level of component-specific knowledge to solve unexplored engineering problems together with the supplier. In innovative projects, effective knowledge partitioning seems to demand some overlap between an automaker and a supplier, rather than efficient and clear-cut boundaries that are optimal for regular projects. Such "fluid" nature of knowledge boundaries contingent on the project types poses a challenge for firms seeking both technological leadership and efficiency in established products.Developing and maintaining knowledge about an outsourced component is by no means easy. When the actual design tasks are outsourced, automakers miss substantial opportunities to gain relevant knowledge through learning by doing. Also, obtained knowledge may be diffused among competitors through shared suppliers. Another problem for automakers is that component-specific knowledge is important for only limited cases (innovative projects). Even worse, component-specific knowledge has a trade off relationship with architectural knowledge.Such an inherent dilemma of managing knowledge, however, may provide some automakers with the opportunity to achieve sustainable competitive advantage. Additional analysis shows that one automaker managed both types of knowledge better than others in a manner that deals effectively with the dilemma. Its organizational mechanisms include career development policies, extensive documentation of technological information, internal training programs, and incentive schemes. The difficulty in implementing those mechanisms in a consistent and complementary manner seems to explain why there was a significant variance among automakers in knowledge level, even when the actual tasks were carried out by a shared supplier.
Which complementary and alternative therapies benefit which conditions? A survey of the opinions of 223 professional organizations.

UNLABELLED With the increasing demand and usage of complementary/alternative medicine (CAM) by the general public, it is vital that healthcare professionals can make informed decisions when advising or referring their patients who wish to use CAM. Therefore they might benefit from advice by CAM-providers as to which treatment can be recommended for which condition. AIM The primary aim of this survey was to determine which complementary therapies are believed by their respective representing professional organizations to be suited for which medical conditions. METHOD 223 questionnaires were sent out to CAM organizations representing a single CAM therapy. The respondents were asked to list the 15 conditions they felt benefited most from their CAM therapy, the 15 most important contra-indications, the typical costs of initial and any subsequent treatments and the average length of training required to become a fully qualified practitioner. The conditions and contra-indications quoted by responding CAM organizations were recorded and the top five of each were determined. Treatment costs and hours of training were expressed as ranges. RESULTS Of the 223 questionnaires sent out, 66 were completed and returned. Taking undelivered questionnaires into account, the response rate was 34%. Two or more responses were received from CAM organizations representing twelve therapies: aromatherapy, Bach flower remedies, Bowen technique, chiropractic, homoeopathy, hypnotherapy, magnet therapy, massage, nutrition, reflexology, Reiki and yoga. The top seven common conditions deemed to benefit by all twelve therapies, in order of frequency, were: stress/anxiety, headaches/migraine, back pain, respiratory problems (including asthma), insomnia, cardiovascular problems and musculoskeletal problems. Aromatherapy, Bach flower remedies, hypnotherapy, massage, nutrition, reflexology, Reiki and yoga were all recommended as suitable treatments for stress/anxiety. Aromatherapy, Bowen technique, chiropractic, hypnotherapy, massage, nutrition, reflexology, Reiki and yoga were all recommended for headache/migraine. Bowen technique, chiropractic, magnet therapy, massage, reflexology and yoga were recommended for back pain. None of the therapies cost more than ł60 for an initial consultation and treatment. No obvious correlation between length of training and treatment cost was apparent. CONCLUSION The recommendations by CAM organizations responding to this survey may provide guidance to health care professionals wishing to advise or refer patients interested in using CAM.
Hybrids of Two Closely Related Tropical Sea Urchins (Genus Echinometra): Evidence Against Postzygotic Isolating Mechanisms

A series of cross-fertilization experiments were conducted with two unnamed, sympatric species of sea urchins in the Echinometra mathaei species complex, Echinometra sp. A (Ea) and Echinometra sp. C (Ec). Heterogametic fertilization success was high when eggs of Ec and sperm of Ea were involved, and low with eggs of Ea and sperm of Ec. Hybrids produced from crosses in either direction developed normally to sexually mature adults; Ea × Ea were largest in test size, followed by Ec (ova) × Ea (sperm), Ea (ova) × Ec (sperm), and Ec × Ec, respectively. Color patterns of the hybrids were closer to the maternal coloration, whereas other characters such as relative test dimensions and spine lengths, morphology of tubefoot and gonad spicules, and gamete sizes were intermediate. Fertilization rates in F1 backcrosses were high, minimizing the possibility that hybrid infertility is a postzygotic mechanism of reproductive isolation. On the other hand, intensive surveys failed to find individuals with hybrid characteristics in the field, suggesting that natural hybridization between the two species is rare. Prezygotic isolating mechanisms, such as microhabitat separation and gamete incompatibility, at least between Ea eggs and Ec sperm, most likely maintain the genetic integrity of these two closely related species.
HEPATIC TRANSPORT OF PKI166, AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR OF THE PYRROLO-PYRIMIDINE CLASS, AND ITS MAIN METABOLITE, ACU154

PKI166, a specific inhibitor of the tyrosine kinase activity of two epidermal growth factor receptors, was under development for the treatment of cancer. In preclinical studies PKI166 was mainly cleared by metabolism, and its metabolites were eliminated by biliary excretion, emphasizing the role of liver transport processes for its disposition. Here the transport properties of [14C]PKI166 and its main metabolite [14C]ACU154, an O-glucuronide, were analyzed using 1) Madin-Darby canine kidney II (MDCKII) cells stably transfected with human multidrug resistance-associated protein 2 (MRP2) and/or human organic anion-transporting peptide 2 (OATP2) and 2) liver canalicular membrane vesicles (CMVs) prepared from Wistar and mrp2-deficient TR- rats. Analysis of transport through MDCKII cells revealed that [14C]ACU154 was a substrate of MRP2 and OATP2. Rat mrp2 was shown to transport [14C]ACU154 with a Km of approximately 1 μM. [14C]PKI166 efficiently crossed MDCKII cells, particularly toward the apical side, but expression of MRP2 and/or OATP2 did not increase the flux. The effect of PKI166 and ACU154 on transport of [3H]estradiol-17β-d-glucuronide (EG; via mrp2/MRP2 and OATP2) or [3H]taurocholic acid (TCA; via bile salt export pump (bsep) was analyzed. PKI166 inhibited the transport of [3H]EG by OATP2. ACU154 did strongly inhibit [3H]TCA uptake into CMVs from Wistar but not from TR- rats, demonstrating a dependence of bsep inhibition on mrp2 activity. ATP-dependent uptake of [3H]EG into CMVs from Wistar rats was inhibited by ACU154 but up to 4-fold increased by PKI166. In conclusion, OATP2 and MRP2/mrp2 were identified as transporters involved in ACU154 transport into bile. Both PKI166 and its O-glucuronide ACU154 affected mrp2/MRP2-, OATP2-, and/or bsep-mediated transport processes.