Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical pharmacokinetic characterization of an adipose tissue-targeting monoclonal antibody in obese and non-obese animals

ABSTRACT Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho. To understand the PK/PD relationship in non-obese and obese animals, we evaluated the adipose tissue distribution of the antibody, serum exposures, and an associated PD marker (high-molecular-weight adiponectin), in both non-obese and obese mice and monkeys. Antibody uptake into fat tissue was found to be higher on a per gram basis in non-obese animals compared to obese animals. Since obesity has been reported to be associated with reduced expression of FGFR1 and βKlotho receptor in white adipose tissues in mice, our results suggest that the distribution in adipose tissues was influenced by target expression levels. Even so, the overall dose-normalized serum exposures were comparable between non-obese and obese mice and monkeys, suggesting that adipose tissue uptake plays a limited role in overall systemic PK determination. It remains to be determined if and how obesity and receptor expression in humans influence the PK and PD profile of this novel therapeutic candidate.
Lower Physical Activity Is Associated With Higher Intermuscular Adipose Tissue in People With Type 2 Diabetes and Peripheral Neuropathy

Background Increased lipid accumulation in skeletal muscle has been linked to insulin resistance, impaired muscle performance, and impaired physical function. It is unclear whether physical activity is associated with lipid content in skeletal muscle, muscle performance, or overall physical function. Objective The purpose of this study was to characterize physical activity levels (average daily step count) in a sample of people with diabetes and peripheral neuropathy and to determine the relationship among step count, intermuscular adipose tissue volume (IMAT), muscle performance (peak torque, power), and physical function. Design A cross-sectional design was used in this study. Methods Twenty-two people with diabetes and peripheral neuropathy (15 men and 7 women, mean age=64.5 years [SD=12.7], and mean body mass index=33.2 kg/m2 [SD=6.4]) participated. Average daily step count, glycosylated hemoglobin, modified 9-item Physical Performance Test scores, Six-Minute Walk Test distance, calf intermuscular adipose tissue volume (via magnetic resonance imaging), and isokinetic dynamometry of the ankle muscles were recorded. Results Average daily step count was 7,754 (SD=4,678; range=3,088–20,079). Five participants had an average daily step count greater than 10,000. Average IMAT volume was 84 cm3 (SD=88). Greater average daily step count was associated with younger age (r=−.39, P<.05) and with lower IMAT volume in the calf (r=−.44, P<.05). Lower IMAT volume was associated with greater muscle performance (r=−.45) and physical function (r=−.43 to −.48). Limitations The sample in this study may be biased toward people with high levels of activity because participants were recruited for an exercise study. The results should not be generalized to people taking fewer than 3,000 steps/day or to those with a current foot ulcer, peripheral arterial disease, or severe foot deformity or amputation or who weigh more than 136 kg (300 lb). Conclusions Average daily step count was inversely related to IMAT, and IMAT was inversely related to muscle performance and overall physical function. In addition, we found that people with diabetes and peripheral neuropathy and without severe foot deformity appear to be able to take a large number of steps per day.
Corporate Strategy and Gendered Professional Identities: Reorganization and the Struggle for Recognition and Positions

Will decentralization of responsibilities in services give women service workers at the lower levels of the organization better and more ‘professional’ jobs and a recognition of their importance in the organization? This article looks at the valuation of so-called women's skills in services in reorganization processes involving dehierarchization and decentralization of responsibilities. Through four cases of reorganized private and public services in Norway it is shown that more focus on customers and decentralization of responsibilities for the services may lead to recognition of gendered skills and an improved position for women service workers at the lowest levels of the organization. When the tasks of the workers are closely linked to the core function of the organization and not dominated by the organization's ‘dirty work’, the women at the lowest levels may obtain a more ‘professional’ work role and their work be recognized as important for the organization.
Analysis of Half-Quadratic Minimization Methods for Signal and Image Recovery

We address the minimization of regularized convex cost functions which are customarily used for edge-preserving restoration and reconstruction of signals and images. In order to accelerate computation, the multiplicative and the additive half-quadratic reformulation of the original cost-function have been pioneered in Geman and Reynolds [IEEE Trans. Pattern Anal. Machine Intelligence, 14 (1992), pp. 367--383] and Geman and Yang IEEE Trans. Image Process. , 4 (1995), pp. 932--946]. The alternate minimization of the resultant (augmented) cost-functions has a simple explicit form. The goal of this paper is to provide a systematic analysis of the convergence rate achieved by these methods. For the multiplicative and additive half-quadratic regularizations, we determine their upper bounds for their root-convergence factors. The bound for the multiplicative form is seen to be always smaller than the bound for the additive form. Experiments show that the number of iterations required for convergence for the multiplicative form is always less than that for the additive form. However, the computational cost of each iteration is much higher for the multiplicative form than for the additive form. The global assessment is that minimization using the additive form of half-quadratic regularization is faster than using the multiplicative form. When the additive form is applicable, it is hence recommended. Extensive experiments demonstrate that in our MATLAB implementation, both methods are substantially faster (in terms of computational times) than the standard MATLAB Optimization Toolbox routines used in our comparison study.
Adaptation of the E-model for satellite internet protocol radio calls in air traffic control

This paper proves that voice over Internet protocol (IP) technology can be combined with satellite transmission in air traffic control (ATC) applications provided that the systems used to implement this approach have been meticulously designed to meet the end-to-end delay requirements and to certify the quality of service they offer under strenuous conditions.We propose a modified E-model and prove it can be used as a radio network planning tool, because once the requirements that were drawn from it were fulfilled, the users of the resulting service accepted it as sufficient in terms of call quality. The approach has been applied on the SATWAYS system, cofunded by the European Space Agency, and designed and implemented to extend the coverage of radio frequencies within airspaces when the commonly used landline communication infrastructure is either too costly or impossible to install and maintain. The paper provides evidence that the way to an all-IP ATC network is wide open.
Reproductive Biology and Endocrinology Open Access Uterine and Placental Expression of Trpv6 Gene Is Regulated via Progesterone Receptor-or Estrogen Receptor-mediated Pathways during Pregnancy in Rodents

Transient receptor potential cation channel, subfamily V, member 6 (TRPV6) is an epithelial Ca 2+ channel protein expressed in calcium absorbing organs. In the present study, we investigated the expression and regulation of uterine and placental TRPV6 during gestation in rodents. Uterine TRPV6 peaked at pregnancy day (P) 0.5, P5.5 and, P13.5 and was detected in uterine epithelium and glands of rats, while placental TRPV6 mRNA levels increased in mid-gestation. Uterine and placental TRPV6 mRNA levels in rats appear to cyclically change during pregnancy, suggesting that TRPV6 may participate in the implantation process. In addition, uterine TRPV6 mRNA is only expressed in placenta-unattached areas of the uterus, and uterine TRPV6 immunoreactivity was observed in luminal and glandular epithelial cells. In the placenta, TRPV6 was detected in the labyrinth and spongy zone. These results may indicate that TRPV6 has at least two functions: implantation of the embryo and maintenance of pregnancy. To investigate the pathway(s) mediating TRPV6 expression in rodents, anti-steroid hormone antagonists were injected prior to maximal TRPV6 expression. In rats, TRPV6 expression was reduced by RU486 (an anti-progesterone) through progesterone receptors, and ICI 182,780 (an anti-estrogen) blocked TRPV6 expression via estrogen receptors in mice. The juxtaposition of uterine and placental TRPV6 expressed in these tissues supports the notion that TRPV6 participates in transferring calcium ions between the maternal and fetal compartments. Taken together, TRPV6 gene may function as a key element in controlling calcium transport in the uterus between the embryo and the placenta during pregnancy.
Dropping Out of High School: The Influence of Race, Sex, and Family Background

This paper examines the extent of the high school dropout problem in 1979 and investigates both the stated reasons students leave school and some of the underlying factors influencing their decision. Particular attention is focused on differences by sex, race, and family background. Data for this research come from a new, national sample of youth who were 14 to 21 years of age in 1979. A multivariate model is developed to estimate the effects of family background and other factors on the decision to drop out of school. Several results emerge from the study: The reasons students cite for leaving school vary widely, with women more likely to leave because of pregnancy or marriage and men more likely to leave to go to work; family background strongly influences the propensity to drop out of school and accounts for virtually all the racial differences in dropout rates; various other factors, including ability and aspirations, also influence this decision.
Relationship between Perceived Risk, Evaluation, Satisfaction, and Behavioral Intention: A Case of Local-Festival Visitors

ABSTRACT This study analyzes the relationship between perceived risk, evaluation, satisfaction, and behavioral intention of tourists attending a local festival. Based on a survey with a sample of 465 respondents attending a local festival in South Korea, a structural equation model (SEM) is proposed that involves festival-related perceived risk, perceptual evaluation, overall satisfaction, and behavioral intention for future attendance at this and other festivals. Firstly, the results show that while risk may lead to a negative perception of a festival, it has no effect on satisfaction or subsequent behavioral intention. Secondly, the results show that direct causality exists between perception, satisfaction and future intention. Thirdly, a demand for diversity in programs determines perceptions of risk, which in turn permits a segmentation of visitors based on these characteristics. The findings of this study contribute to successful planning and marketing strategies to meet the demands of psychologically segmented tourists, especially in festival studies.
Turner Syndrome: A Review of Genetic and Hormonal Influences on Neuropsychological Functioning

Turner syndrome (TS) is a gene tic disorder affecting mainly females that arises from a loss of X chromosome material, most usually one of the two X chromosomes. TS is associated with a number of characteristic physical features such as short stature and absent ovaries as well as a set of common neuropsychological deficits and social and behavioral features. This paper will serve to review the cognitive, social, and psychoeducational abilities of individuals with TS as well as neuroimaging findings. Several putative genetic mechanisms contributing to their particular neurocognitive deficits will also be described including candidate genes. In addition, the available evidence on how hormones affect specific abilities in TS will be reviewed. It will be concluded that the TS neurobehavioral profile arises from an atypical cerebral organization caused by the complex interplay of insufficient expression of certain (unknown) genes on the X chromosome and by abnormal hormonal levels; however, it is still not clear exactly how the specific genes affect broader cognitive abilities. Future research needs to identify the elemental processes that are disturbed in TS and map these both to events in early brain development and subsequent brain function and to specific gene and hormonal contributions.
Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy

A common process associated with oxidative stress and severe mitochondrial impairment is the opening of the mitochondrial permeability transition pore, as described in many neurodegenerative diseases. Thus, inhibition of mitochondrial permeability transition pore opening represents a potential target for inhibiting mitochondrial-driven cell death. Among the mitochondrial permeability transition pore components, cyclophilin D is the most studied and has been found increased under pathological conditions. Here, we have used in vitro and in vivo models of X-linked adrenoleukodystrophy to investigate the relationship between the mitochondrial permeability transition pore opening and redox homeostasis. X-linked adrenoleukodystrophy is a neurodegenerative condition caused by loss of function of the peroxisomal ABCD1 transporter, in which oxidative stress plays a pivotal role. In this study, we provide evidence of impaired mitochondrial metabolism in a peroxisomal disease, as fibroblasts in patients with X-linked adrenoleukodystrophy cannot survive when forced to rely on mitochondrial energy production, i.e. on incubation in galactose. Oxidative stress induced under galactose conditions leads to mitochondrial damage in the form of mitochondrial inner membrane potential dissipation, ATP drop and necrotic cell death, together with increased levels of oxidative modifications in cyclophilin D protein. Moreover, we show increased expression levels of cyclophilin D in the affected zones of brains in patients with adrenomyeloneuropathy, in spinal cord of a mouse model of X-linked adrenoleukodystrophy (Abcd1-null mice) and in fibroblasts from patients with X-linked adrenoleukodystrophy. Notably, treatment with antioxidants rescues mitochondrial damage markers in fibroblasts from patients with X-linked adrenoleukodystrophy, including cyclophilin D oxidative modifications, and reverses cyclophilin D induction in vitro and in vivo. These findings provide mechanistic insight into the beneficial effects of antioxidants in neurodegenerative and non-neurodegenerative cyclophilin D-dependent disorders.
Effects of doxycycline on clinical, microbiological and immunological parameters in well-controlled diabetes type-2 patients with periodontal disease: a randomized, controlled clinical trial.

AIM To evaluate the clinical, microbiological and immunological effects of systemic doxycycline as an adjunct to scaling and root planing (SRP) in chronic periodontitis patients with well-controlled type 2 diabetes. MATERIALS AND METHODS Sixty-six patients compliant to oral hygiene (Hygiene Index <20%) allocated to either a test (systemic doxycycline for 21 days) or a control (placebo) group participated in the present randomized controlled trial (RCT). Clinical assessments were recorded at baseline, 3 and 6 months after therapy and included clinical attachment level (CAL), set as the primary outcome of the study, probing pocket depth (PPD), recession (RE) and bleeding on probing (BOP). At the same time points, counts of 15 subgingival species were evaluated by "checkerboard" DNA-DNA hybridization, gingival crevicular fluid samples were analysed for matrix metalloproteinase-8 (MMP-8) by ELISA and HbA1c levels were determined. Comparisons between and within groups were performed by non-parametric tests (Mann-Whitney, Wilcoxon signed-ranks and z-test for proportions with Bonferroni corrections) at the 0.05 level. RESULTS No major differences were noticed in clinical and microbiological parameters of periodontal disease or levels of MMP-8 between the two groups. CONCLUSIONS Adjunctive systemic doxycycline does not seem to significantly enhance the effects of SRP in well-controlled diabetes type 2 patients.
The Impact of Innovation Offshoring on Organizational Adaptability

We analyze the effects of captive off-shoring of innovation activities on the firms’ ability to adapt their organizational processes and structures. Starting from complexity theory, we use three consecutive waves of the German part of the Community Innovation Survey to test our hypotheses. We find an inverted u-shape of innovation off-shoring on the effectiveness of organizational adaptability, implying an optimal threshold value of innovation off-shoring. This value is 11% for share of off-shored R&D, 15% for downstream innovation activities such as local market adaptation, and 34% for design activities. We also analyze several contingency variables. In particular we show that the costs of innovation off-shoring in terms of reduced organizational adaptability are exacerbated by a strong focus on R&D and a strong embeddedness in on-shore networks. Smaller firms find it easier to deal with the management complexity induced by geographical dispersion of innovation activities because of their greater flexibility.
De l'étude des interactions parents-enfants dans un contexte muséal scientifique à une proposition d'intervention innovante auprès des parents

A partir de la prise en consideration de l'importance du role des parents accompagnant leurs enfants dans la decouverte d'une exposition interactive a caractere scientifique et technique, deux etudes ont ete conduites : la premiere propose une typologie des modes d'intervention des parents en fonction de leur caractere plus ou moins adapte au contexte des activites et aux capacites des enfants. A partir de cette etude la seconde etude vise a evaluer si une action de sensibilisation prealable des parents a leur role de tuteur a un impact sur la maniere dont ils accompagnent leur enfant. Le dispositif de formation des parents est un dispositif original dont les caracteristiques essentielles sont presentees.
Distinct Neural Suppression and Encoding Effects for Conceptual Novelty and Familiarity

Like yin and yang, novelty and familiarity are typically described as separate-yet-complementary aspects of an experience, two ends of a single continuum. However, novelty and familiarity are also multifaceted. For instance, novelty can sometimes result in enhanced mnemonic performance, whereas at other times familiarity is better remembered. As previous investigations focused primarily on the experimental aspect of novelty, the mechanisms supporting conceptual novelty (the novel combination of two previously unrelated existing concepts) remain unclear. Importantly, conceptual novelty can be recognized as such only when compared with preexperimental familiar knowledge, regardless of experimental status. Here we applied a combined repetition suppression/subsequent memory fMRI paradigm, focusing on the conceptual aspect of novelty and familiarity as the subject matter. Conceptual novelty was characterized by sustained neural activity; familiarity, on the other hand, exhibited repetition effects in multiple cortical regions, a subset of which was modulated by successful encoding. Subsequent memory of novelty was associated only with activation differences in a distinct set of regions, including the hippocampus and medial cortical regions. These results suggest that conceptual novelty (a) does not (easily) trigger the repetition suppression phenomenon but requires sustained neural recruitment and (b) activates dedicated encoding mechanisms. Conceptual familiarity, in contrast, allows rapid neural processing that depends upon existing neural representations. Overall, these findings challenge the definition of novelty as a unitary concept. Furthermore, they bear important implications for research into the neural bases of knowledge representation and recognition memory.
Preventability of pre-hospital trauma deaths in southern New Zealand.

AIM To assess the preventability of pre-hospital trauma deaths in the Otago and Southland regions of New Zealand. METHODS A retrospective audit was carried out of all post-mortems from trauma deaths that occurred in these regions between January 2000 and December 2004. The injuries documented in the post-mortem reports were scored using the Abbreviated Injury Scale (AIS) 2005 and from this an Injury Severity Score (ISS) derived. Based on the ISS groupings of Sampalis et al, a probability of the preventability of death was then determined. RESULTS A total of 362 deaths were identified. Post-mortems were available for 245; 54 were excluded and 191 had their post-mortems scored according to the AIS 2005 with derivation of an ISS. Of these, 19 (10%) were classified as having survivable injuries, 66 (35%) potentially survivable injuries and 106 (55%) non-survivable injuries. The majority were aged 35 years or younger (51%), male (71%) and suffered significant injuries to multiple regions (76% to two regions, 51% three or more regions) and were the result of a motor vehicle accident (70%). CONCLUSIONS In trauma-related deaths in southern New Zealand, the majority of patients who die before reaching hospital do so from non-survivable injuries; however, a significant proportion has either potentially survivable or survivable injuries. These results are very similar to comparable international studies and suggest that there should be further attempts at improving pre-hospital care while also aiming to improve primary prevention. Further research is required.