Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Cloning and Functional Characterization of a Novel Mitogen-activated Protein Kinase Phosphatase, MKP-4*

Extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38/RK/CSBP (p38) mitogen-activated protein (MAP) kinases are target enzymes activated by a wide range of cell-surface stimuli. Recently, a distinct class of dual specificity phosphatase has been shown to reverse activation of MAP kinases by dephosphorylating critical tyrosine and threonine residues. By searching the expressed sequence tag data base (dbEST) for homologues of known dual specificity phosphatases, we identified a novel partial human sequence for which we isolated a full-length cDNA (termed MKP-4). The deduced amino acid sequence of MKP-4 is most similar to MKP-X/PYST2 (61% identity) and MKP-3/PYST1 (57% identity), includes two N-terminal CH2 domains homologous to the cell cycle regulator Cdc25 phosphatase, and contains the extended active site sequence motif VXVHCXAGXSRSXTX3AYLM (where X is any amino acid) conserved in dual specificity phosphatases. MKP-4 produced in Escherichia coli catalyzes vanadate-sensitive breakdown of p-nitrophenyl phosphate as well as in vitro inactivation of purified ERK2. When expressed in COS-7 cells, MKP-4 blocks activation of MAP kinases with the selectivity ERK > p38 = JNK/SAPK. This cellular specificity is similar to MKP-3/PYST1, although distinct from hVH-5/M3-6 (JNK/SAPK = p38 >>> ERK). Northern analysis reveals a highly restricted tissue distribution with a single MKP-4 mRNA species of approximately 2.5 kilobases detected only in placenta, kidney, and embryonic liver. Immunocytochemical analysis showed MKP-4 to be present within cytosol although punctate nuclear staining co-localizing with promyelocytic protein was also observed in a subpopulation (10-20%) of cells. Chromosomal localization by analysis of DNAs from human/rodent somatic cell hybrids and a panel of radiation hybrids assign the human gene for MKP-4 to Xq28. The identification and characterization of MKP-4 highlights the emergence of an expanding family of structurally homologous dual specificity phosphatases possessing distinct MAP kinase specificity and subcellular localization as well as diverse patterns of tissue expression.
Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) Is Required for Branching Morphogenesis in the Chorioallantoic Placenta

ABSTRACT Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-associated Kunitz-type serine proteinase inhibitor that was initially identified as a potent inhibitor of hepatocyte growth factor activator. HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase. HAI-1 is expressed predominantly in epithelial cells in the human body. Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts. In order to address the precise roles of HAI-1 in vivo, we generated HAI-1 mutant mice by homozygous recombination. Heterozygous HAI-1+/− mice underwent normal organ development. However, homozygous HAI-1−/− mice experienced embryonic lethality which became evident at embryonic day 10.5 postcoitum (E10.5). As early as E9.5, HAI-1−/− embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function. Histological analysis revealed severely impaired formation of the labyrinth layer, in contrast all other placental layers, such as the spongiotrophoblast layer and giant cell layer, which were formed. Our results indicate that mouse HAI-1 is essential for branching morphogenesis in the chorioallantoic placenta and lack of HAI-1 function may result in placental failure.
The protective effects of high amylose maize (amylomaize) starch granules on the survival of Bifidobacterium spp. in the mouse intestinal tract

The possibility of using high amylose maize starch granules as a delivery system for probiotic bacteria has been investigated using Bifidobacterium spp. LaftiTM 8B and LaftiTM 13B which were isolated from a healthy human. The Bifidobacterium cells were able to adhere to the amylomaize starch granules and were also able to hydrolyse the starch during growth. Initially, in vitro studies were carried out by studying the survival of strains Bifidobacterium LaftiTM 8B and LaftiTM 13B when exposed to pH 2·3, 3·5 and 6·5 as well as 0·03 and 0·05% w/v bile acids. Both strains were grown either in the absence or presence of high amylose maize starch granules, then mixed with the high amylose maize starch granules and exposed to acidic buffers or bile acid solutions. It was shown that growth in and the presence of high amylose maize starch granules led to enhanced survival of strains LaftiTM 8B and LaftiTM 13B. Subsequently, survival in vivo was monitored by measuring the faecal level of Bifidobacterium LaftiTM 8B after oral administration of the strain to mice. A sixfold better recovery of strain LaftiTM 8B from mice faeces after oral dosage was noted for cells grown in amylose‐containing medium compared with controls. It was concluded that high amylose maize starch granules contributed to enhanced survival of Bifidobacterium sp. LaftiTM 8B and LaftiTM 13B.
Pharmacodynamic Effects of Acamprosate on Markers of Cerebral Function in Alcohol-Dependent Subjects Administered as Pretreatment and during Alcohol Abstinence

Animal studies suggested that acamprosate modulates neuronal hyperexcitability of acute alcohol withdrawal, acting through the glutamatergic neurotransmission. In the present study, we further investigated whether treatment with acamprosate could attenuate the post-alcohol withdrawal hyperexcitability or hyperarousal in humans using brain magnetoencephalography mapping of spontaneous fields. A double-blind, randomised, placebo-controlled study with a parallel group design comparing 2,000 mg/day of acamprosate versus placebo was conducted in alcohol-dependent subjects meeting DSM-IV criteria for alcohol dependence. Treatments were initiated 8 days before alcohol withdrawal and prolonged during the 15 following (abstinence) days. The study demonstrated that during alcohol withdrawal, acamprosate decreased the arousal level as reflected by alpha slow-wave index (ASI) measurement. This effect was mostly evidenced in left parietotemporal regions and, to a lesser extent, in the contiguous anterior, posterior and right-sided regions. In the placebo group, on the contrary, ASI measures increased between day 2 (acute withdrawal) and day 14 (prolonged withdrawal). The present results suggest a sustained effect of acamprosate on the hyperexcitability state due to alcohol withdrawal in alcohol-dependent patients and that acamprosate may have a protective effect when administered 8 days before alcohol withdrawal.
The association between continuity of care and outcomes: a systematic and critical review.

BACKGROUND Numerous studies have tried to determine the association between continuity and outcomes. Studies doing so must actually measure continuity. If continuity and outcomes are measured concurrently, their association can only be determined with time-dependent methods. OBJECTIVE To identify and summarize all methodologically studies that measure the association between continuity of care and patient outcomes. METHODS We searched MEDLINE database (1950-2008) and hand-searched to identify studies that tried to associate continuity and outcomes. English studies were included if they: actually measured continuity; determined the association of continuity with patient outcomes; and properly accounted for the relative timing of continuity and outcome measures. RESULTS A total of 139 English language studies tried to measure the association between continuity and outcomes but only 18 studies (12.9%) met methodological criteria. All but two studies measured provider continuity and used health utilization or patient satisfaction as the outcome. Eight of nine high-quality studies found a significant association between increased continuity and decreased health utilization including hospitalization and emergency visits. Five of seven studies found improved patient satisfaction with increased continuity. CONCLUSIONS These studies validate the belief that increased provider continuity is associated with improved patient outcomes and satisfaction. Further research is required to determine whether information or management continuity improves outcomes.
SPERM CASPASES BECOME MORE ACTIVATED IN INFERTILITY PATIENTS THAN IN HEALTHY DONORS DURING CRYOPRESERVATION

The programmed cell death (PCD, the apoptosis) is associated with the activation of the “death enzymes” caspases and very likely plays a role in the decrease of sperm vitality during cryopreservation. The activation of pan-caspases was examined in fresh and cryostored sperm by fluorescence microscopy applying a cell permeable and noncytotoxic carboxy-fluorescein labelled caspase inhibitor. Cryopreservation increased significantly the percentage of spermatozoa with activated pan-caspases (aCP) from 21 ± 2.6 to 47 ± 5.8 % (mean ± SEM). Quantitative Western blot analyses confirmed the activation of caspase-1, -8, and -9 in detail on protein level after cryopreservation, whereas, the caspases of sperm of infertility patients showed a higher activation status than donors' sperm. This effect raised with increasing glycerol concentration from 7–14 %. The higher level in activation of caspases in cryostored spermatozoa of infertility patients may indicate that these cells have a lower cryotolerance and a higher susceptibility to caspase activation than does the sperm of donors.
A cohort study of women with a Fontan circulation undergoing preconception counselling

Objective To describe outcomes for women with a Fontan circulation attending preconception counselling (PCC). Exploring (1) impact of counselling on decision to become pregnant; (2) pregnancy rates in those opting for pregnancy and (3) short-term and long-term outcome of those who succeeded in becoming pregnant. Methods Retrospective review of women aged 16–45 years with a Fontan circulation from 1994 to 2014. Results 58 women were offered PCC, 3 declined and 55 received PCC. Following PCC, 15 opted against conception, 16 decided to delay pregnancy, 19 attempted pregnancy and 5 were lost to follow-up. Of the 19 women, 14 succeeded, becoming pregnant a total of 43 times (median 1, range 1–9). Of these, 6 miscarried all pregnancies. 8 carried 14 pregnancies to viability. Baseline hypoxaemia and cardiac disease in pregnancy (CARPREG) score was similar in those opting for and against pregnancy, but CARPREG score was better in those delaying conception. Women exclusively miscarrying or unable to conceive were more likely to have baseline hypoxaemia and greater CARPREG score. Cardiac complications included arrhythmia requiring treatment (n=4) and one thromboembolism. Obstetric complications were greater in women with a Fontan circulation, 10 preterm births (<37 weeks) and 8 small for gestational age babies (<10th centile). There was one neonatal death. At follow-up, there was no deterioration in clinical status as determined by echo. Conclusions Most women accept PCC and decided to pursue pregnancy; in some cases, this was despite being advised of a poor prognosis. Pregnancy outcome was related to baseline hypoxia and CARPREG scores.
Continuous Covariates in Mark‐Recapture‐Recovery Analysis: A Comparison of Methods

Summary Time varying, individual covariates are problematic in experiments with marked animals because the covariate can typically only be observed when each animal is captured. We examine three methods to incorporate time varying, individual covariates of the survival probabilities into the analysis of data from mark‐recapture‐recovery experiments: deterministic imputation, a Bayesian imputation approach based on modeling the joint distribution of the covariate and the capture history, and a conditional approach considering only the events for which the associated covariate data are completely observed (the trinomial model). After describing the three methods, we compare results from their application to the analysis of the effect of body mass on the survival of Soay sheep (Ovis aries) on the Isle of Hirta, Scotland. Simulations based on these results are then used to make further comparisons. We conclude that both the trinomial model and Bayesian imputation method perform best in different situations. If the capture and recovery probabilities are all high, then the trinomial model produces precise, unbiased estimators that do not depend on any assumptions regarding the distribution of the covariate. In contrast, the Bayesian imputation method performs substantially better when capture and recovery probabilities are low, provided that the specified model of the covariate is a good approximation to the true data‐generating mechanism.
Modular Gene Dynamics and Network Theory at Mesoscopic Scale

Complex dynamical systems are often modeled as networks, with nodes representing dynamical units which interact through the network's links. Gene regulatory networks, responsible for the production of proteins inside a cell, are an example of system that can be described as a network of interacting genes. The behavior of a complex dynamical system is characterized by cooperativity of its units at various scales, leading to emergent dynamics which is related to the system's function. Among the key problems concerning complex systems is the issue of stability of their functioning, in relation to different internal and external interaction parameters. In this Thesis we study two-dimensional chaotic maps coupled through non-directed networks with different topologies. We use a non-symplectic coupling which involves a time delay in the interaction among the maps. We test the stability of network topologies through investigation of their collective motion, done by analyzing the departures from chaotic nature of the isolated units. The study is done on two network scales: (a) full-size networks (a computer generated scalefree tree and a tree with addition of cliques); (b) tree's characteristic sub-graph 4-star, as a tree's typical dynamical motif which captures its topology in smallest possible number of nodes and is suitable for time-delayed interaction. We study the dynamical relationship between these two network structures, examining the emergence of cooperativity on a large scale (trees) as a consequence of mesoscale dynamical patterns exhibited by the 4-star. (FULL ABSTRACT INSIDE THE TEXT)
Hard-tissue alterations following immediate implant placement in extraction sites.

BACKGROUND The marginal gap that may occur following implant installation in an extraction socket may be resolved by hard-tissue fill during healing. OBJECTIVE To study dimensional alterations of hard tissues that occur following tooth extraction and immediate placement of implants. MATERIAL AND METHODS Eighteen subjects with a total of 21 teeth scheduled for extraction were included. Following flap elevation and the removal of a tooth and implant installation, clinical measurements were made to characterize the dimension of the surrounding bone walls, as well as the marginal defect. No membranes or filler material was used. The flaps were subsequently replaced and secured with sutures in such a way that the healing cap of the implant was exposed to the oral environment. After 4 months of healing a re-entry procedure was performed and the clinical measurements were repeated. RESULTS Fifty-two marginal defects exceeding 3 mm were present at baseline: 21 at buccal, 17 at lingual/palatal, and 14 at approximal surfaces. At the re-entry eight defects exceeding 3.0 mm remained. During the 4 months of healing, the bone walls of the extraction underwent marked change. The horizontal resorption of the buccal bone dimension amounted to about 56%. The corresponding resorption of the lingual/palatal bone was 30%. The vertical bone crest resorption amounted to 0.3+/-0.6 mm (buccal), 0.6+/-1.0 mm (lingual/palatal), 0.2+/-0.7 mm (mesial), and 0.5+/-0.9 mm (distal). CONCLUSION The marginal gap that occurred between the metal rod and the bone tissue following implant installation in an extraction socket may predictably heal with new bone formation and defect resolution. The current results further documented that marginal gaps in buccal and palatal/lingual locations were resolved through new bone formation from the inside of the defects and substantial bone resorption from the outside of the ridge.
Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis.

Salmeterol (SM) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients. In the present study, evaluating efficacy and possible development of tachyphylaxis after SM, 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15% to 200 micrograms salbutamol (SB) or 20% to 500 micrograms SB. At inclusion all patients were receiving treatment with inhaled beta 2-agonists, and 11 of the 12 patients were also receiving inhaled corticosteroids. The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day, following a double-blind, double-dummy, randomized design. The treatment periods were separated by a washout period of 1 wk. Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period. On each of these days, basal FEV1, tremor, heart rate, and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve. During the treatment periods, as well as during the washout week after each treatment, the patients recorded their morning and evening peak expiratory flow (PEF) each day before the inhalation of the study drug. Subjective asthma symptoms were monitored by a visual analog scale after each treatment period. The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments, but significant increases in basal FEV1 and FVC were seen after the SM period (p less than 0.05). (ABSTRACT TRUNCATED AT 250 WORDS)
Dendritic cell targeted liposomes–protamine–DNA complexes mediated by synthetic mannosylated cholestrol as a potential carrier for DNA vaccine

To construct mannosylated liposomes/protamine/DNA (LPD) carriers for DNA vaccine targeting to dendritic cells (DCs), a mannosylated cholesterol derivative (Man-C6-Chol) was synthesized via simple ester linkage and amide bonds. Then, the Man-C6-Chol was applied to LPD formulation as a synthetic ligand. The physicochemical properties of mannosylated LPD (Man-LPD) were first evaluated, including the size and zeta potential, morphology and the ability to protect DNA against DNase I degradation. Man-LPD showed a small size with a stable viral-like structure. In comparison to non-mannose liposomes/LPD (Man-free liposomes/LPD), mannosylated liposomes/LPD (Man-liposomes/Man-LPD) exhibited higher efficiency in both intracellular uptake (2.3-fold) and transfection (4.5-fold) in vitro. Subsequent MTT assays indicated that the LPD carriers had low toxicity on the tested cells. Afterwards, the investigation into the maturation activation on primary bone marrow-derived DCs (BMDCs) showed that both Man-LPD and Man-free LPD induced remarkable up-regulation of CD80, CD86 and CD40 on BMDCs. Inspired by these studies, we can conclude that the synthetic mannosylated LPD targeting to DCs was a potential carrier for DNA vaccine.
A comparison of lanreotide and octreotide LAR for treatment of acromegaly

Two long‐acting depot somatostatin analogues have recently been licensed for the treatment of acromegaly. We wished to assess the effectiveness of both these drugs in suppressing mean GH to a target of < 5 mU/l in patients with acromegaly unselected for responsiveness to octreotide, and also to compare the effects of both drugs
Validation of questionnaire-based long-term dietary exposure to polychlorinated biphenyls using biomarkers.

SCOPE The health consequences of lifelong low-level exposure to polychlorinated biphenyls (PCBs) via food are largely unknown, mainly due to the lack of large population-based prospective studies addressing this issue. We validated long-term food frequency questionnaire (FFQ)-based dietary PCB exposure against concentrations of six PCB congeners in serum. METHODS AND RESULTS Dietary PCB exposure was estimated in the Swedish Mammography Cohort by constructing a recipe-based database of CB-153, an indicator for total PCBs in food. The Spearman rank correlation (adjusted for within-person variability) was assessed between concurrent (2004-2006), past (1997), and long-term (mean of 1997 and 2004-2006) FFQ-based dietary PCB exposure, respectively, and the following serum PCB congeners, CB-118, CB-138, CB-153, CB-156, CB-170, and CB-180, in women (56-85 years of age, n = 201). The correlation between FFQ-based dietary PCB exposure and serum CB-153 was 0.41 (p < 0.001) for the concurrent (median 1.6 ng/kg body weight) and 0.34 (p < 0.05) for the past (median 2.6 ng/kg body weight) exposure assessment. Long-term validity of FFQ-based PCB estimates and the six serum PCB congeners ranged from 0.30 to 0.58 (p < 0.05). CONCLUSION FFQ-based PCB exposure estimates show acceptable validity in relation to PCB concentrations in serum, justifying their use in large-scale epidemiological studies.
Clinical experience of TiUnite implants: a 5-year cross-sectional, retrospective follow-up study.

BACKGROUND Little is known of the long-term clinical and radiographic performance of moderately rough surface implants. PURPOSE The aim of the present retrospective investigation was to study two pioneer cohorts of patients, that is, the first patients to receive Brånemark System implants with a moderately rough surface (TiUnite, Nobel Biocare AB, Göteborg, Sweden) at the present clinic. TiUnite implants were inserted either in compromised bone sites in a mixed-mouth concept together with turned implants or used solely. Patients were followed up over a period of 5 years with regard to implant survival and the marginal bone response. MATERIALS AND METHODS Patients who received both implant types (mixed group) comprised 41 subjects, and the second group (TiUnite group) comprised 70 subjects. A total of 110 turned and 68 TiUnite implants were placed in the mixed group, and 212 TiUnite implants in the TiUnite group. Follow-up radiographs were obtained at prosthesis placement and at the 1- and 5-year check-ups, and examined by independent observers. RESULTS One turned (0.9%) and two TiUnite (2.9%) implants failed in the mixed group, and three implants (1.6%) failed in the TiUnite group, indicating no significant differences between surfaces or groups (p < .05). The mean marginal bone loss at 5 years was 0.6 mm to 0.8 mm, also indicating no significant differences for the two implant types tested in the mixed group. CONCLUSIONS Cumulative survival rates for the two implant surfaces were favorable at 5 years, and the marginal bone loss was low and similar for both implant surfaces.