Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanisms of inhibition of endothelial cell migration by taxanes

Several antiangiogenic mechanisms have been proposed for the widely‐used cancer chemotherapeutic drugs taxotere (docetaxel) and taxol (paclitaxel), but none has been definitively identified. We analyzed their effects at a range of concentrations on migration and mitosis of human umbilical vein endothelial cells (HUVECs) on microtubule and focal adhesion morphology and microtubule dynamic instability during migration. Both taxanes inhibited migration by inhibiting both maintenance of the forward direction of the cell and by slowing migration over the entire contorted path length. At low (but not all) taxane concentrations that inhibit HUVEC migration, the shortening rates and shortening lengths of microtubules at the leading edge were strongly inhibited; peripheral microtubules were reduced in number and fewer targeted focal adhesions; focal adhesions doubled in length and became ring‐shaped, elongate, and reduced in number; and an increase in stabilized microtubules occurred centrally. HUVEC migration was 13–19‐fold more sensitive to taxanes than was mitosis confirming that taxanes exhibit significant effects in addition to mitotic arrest that may contribute to their overall antitumor effects. No relationship was detected between centrosome position and migration characteristics. The data suggest that taxanes inhibit migration, at least in part, by inhibiting the dynamic instability of microtubules that possibly interact with guanine nucleotide exchange factors and thus with the focal adhesion–associated G‐proteins that then lead to disruption of the regulated formation and turnover of focal adhesions. A mechanism is presented by which subcytotoxic concentrations of taxanes might stabilize dynamic instability of a few microtubules and thereby inhibit migration and angiogenesis. © 2013 Wiley Periodicals, Inc.
Differential inductions of small heat shock protein 27 and 1‐Cys peroxiredoxin in reactive astrocytes in sulfatide‐deficient mouse spinal cord

In myelinated fibers, various interactions among axons, oligodendrocytes, and astrocytes are present, particularly around the node of Ranvier. In the present study, we examined the protein composition of cerebroside sulfotransferase knockout (CST KO) mouse spinal cord by two‐dimensional gel electrophoresis to examine the molecular changes resulting from the disruption of paranodal junctions in addition to the sulfatide‐deficient condition. Interestingly, heat shock protein 27 (Hsp27) and 1‐cys peroxiredoxin (1‐Cys Prx) were both elevated in CST KO mice. Hsp27 was increased specifically in reactive astrocytes in the white matter, and the elevation was well correlated to the progression of neurologic symptoms. In contrast, 1‐Cys Prx was elevated both in white and gray matter astrocytes in CST KO mice. These results suggest that astrocytes do not always respond stereotypically, as they display differences in their activation in these two regions. To determine whether these changes are specific to the sulfatide‐deficient condition, spinal cords from CST KO mice and the hypomyelinating mutant shiverer mice were compared. The same distribution patterns of Hsp27 and 1‐Cys Prx were found in reactive astrocytes in both CST KO and shiverer mice, suggesting that paranodal disruption with progressive nodal changes may underlie the similar reaction of white matter astrocytes. In contrast, CST KO and shiverer mice showed distinctly different localization patterns of connexin 43 and connexin 47, suggesting that intercellular communication between astrocytes and oligodendrocytes was different in these mutants. These results suggest that astrocytes may respond differentially to individual white matter abnormalities and may modulate specific axonal functions. © 2007 Wiley‐Liss, Inc.
Effects of Pinacidil on Serotonin‐Induced Contractions and Cyclic Nucleotide Levels in Isolated Rat Aortae: Comparison with Nitroglycerin, Minoxidil, and Hydralazine

Pinacidil is a novel, clinically effective vasodilator used for the treatment of hypertension whose mechanism of action has not been precisely defined. In vitro, pinacidil (ED50 = 0.3 μM) was ∼30-fold less potent than nitroglycerin and 700-fold more potent than minoxidil or hydralazine in relaxing rat aortic strip preparations. Aortic relaxations produced by nitroglycerin and acetylcholine were dramatically antagonized by methylene blue (10-5 M), an inhibitor of soluble guanylate cyclase. In contrast, relaxation to hydralazine or minoxidil was unaffected and relaxation to pinacidil was only modestly inhibited (∼threefold) by methylene blue (10-5 M). Furthermore, aortic relaxation to pinacidil was similar in preparations with and without an intact endothelium. Relaxation induced by pinacidil (10-7-10-4 M) was not associated with any elevation in either cyclic AMP (cAMP) or cyclic GMP (cGMP) levels in vitro, although nitroglycerin (10-6 M) but not minoxidil (10-3 M) or hydralazine (10-3 M) significantly elevated cGMP levels. Thus, pinacidil was a potent relaxant agonist in vitro, in contrast to minoxidil and hydralazine, which were considerably weaker in this regard. Vascular relaxation produced by pinacidil was independent of an intact endothelium and was not associated with elevations in either cAMP or cGMP. These data are consistent with the proposal that the antihypertensive activity of pinacidil is due to nonspecific arterial vasodilation.
Assessing the facilitators and barriers of interdisciplinary team working in primary care using normalisation process theory: An integrative review

Background Interdisciplinary team working is of paramount importance in the reform of primary care in order to provide cost-effective and comprehensive care. However, international research shows that it is not routine practice in many healthcare jurisdictions. It is imperative to understand levers and barriers to the implementation process. This review examines interdisciplinary team working in practice, in primary care, from the perspective of service providers and analyses 1 barriers and facilitators to implementation of interdisciplinary teams in primary care and 2 the main research gaps. Methods and findings An integrative review following the PRISMA guidelines was conducted. Following a search of 10 international databases, 8,827 titles were screened for relevance and 49 met the criteria. Quality of evidence was appraised using predetermined criteria. Data were analysed following the principles of framework analysis using Normalisation Process Theory (NPT), which has four constructs: sense making, enrolment, enactment, and appraisal. The literature is dominated by a focus on interdisciplinary working between physicians and nurses. There is a dearth of evidence about all NPT constructs apart from enactment. Physicians play a key role in encouraging the enrolment of others in primary care team working and in enabling effective divisions of labour in the team. The experience of interdisciplinary working emerged as a lever for its implementation, particularly where communication and respect were strong between professionals. Conclusion A key lever for interdisciplinary team working in primary care is to get professionals working together and to learn from each other in practice. However, the evidence base is limited as it does not reflect the experiences of all primary care professionals and it is primarily about the enactment of team working. We need to know much more about the experiences of the full network of primary care professionals regarding all aspects of implementation work. Systematic review registration International Prospective Register of Systematic Reviews PROSPERO 2015: CRD42015019362.
A Prospective Study of the Consequences of Marital Disruption for Adolescents: Predisruption Family Dynamics and Postdisruption Adolescent Adjustment

This study employed data from the National Longitudinal Study of Adolescent Health to examine the consequences of marital disruption for youth prospectively. Using a diverse sample of 6,416 youth, we examined pre- and postdisruption group differences among youth in subsequently disrupting and continuously intact homes. We also examined the extent to which predisruption family dynamics (e.g., marital discord) accounted for both pre- and postdisruption group differences in youth functioning and examined the interaction between level of marital discord and marital disruption. Group differences in adjustment emerged at both time-points and were better explained by family-level variables than by marital disruption. Further, level of marital discord interacted with marital disruption, predicting differential youth outcomes. The implications of these findings for understanding and explaining the heterogeneity of divorce outcomes are discussed.
Probing diversity within subpopulations of locomotor‐related V0 interneurons

The V0 interneuronal population is derived from Dbx1 expressing progenitors. Initial studies on these interneurons in the mouse spinal cord demonstrated that they project commissural axons and are involved in coordinating left‐right alternation during locomotion. Subsequent work has indicated that the V0 population can be divided into genetically distinct ventral (V0V) and dorsal (V0D) subpopulations, and experimental evidence suggests that each is responsible for left‐right alternation at different locomotor speeds. In this study, we perform a series of experiments to probe the location and connectivity of these subpopulations in neonatal mice and demonstrate that they are more diverse than previously predicted. While the distribution of either subpopulation remains consistent along the extent of the lumbar spinal cord, a cluster of V0D cells lateral to the central canal receive substantial input from primary afferents. Retrograde tracing and activity dependent labeling experiments demonstrate that a group of V0 interneurons located in this same region preferentially project axons towards contralateral motoneurons via an oligosynaptic pathway, and are active during fictive locomotion. Our results suggest that this subset of V0 interneurons may be primarily responsible for coordination of left‐right alternation during locomotion. Furthermore these experiments indicate that while genetic identity is one determinant of the function of a neuron during locomotion, the specific position in which the cell is located may also play a key role. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1189–1203, 2015
Genetic and Environmental Factors Shape Infant Sleep Patterns: A Study of 18-Month-Old Twins

OBJECTIVE: Between 25% and 30% of children and adolescents experience sleep disorders. These disorders are complex phenotypes that are regulated by many genes, the environment, and gene-environment interactions. The objective of this study was to evaluate the contribution of genetic and environmental factors to sleep behaviors in early childhood and to contribute to the knowledge on appropriate therapeutic approaches, using a twin design. PATIENTS AND METHODS: Data on sleeping behavior were collected from 314 18-month-old twin pairs (127 monozygotic and 187 dizygotic)using a parent-rated questionnaire. We used structural equation modeling to estimate genetic and environmental variance components for different sleep behaviors (cosleeping, sleep duration, and night awakenings). RESULTS: Shared environment explained almost all (98.3%) of the total variance in cosleeping. Sleep duration was substantially influenced by shared environmental factors (64.1% nocturnal sleep and 61.2% diurnal sleep), with a moderate contribution of additive genetic effects (30.8% and 36.3% for nocturnal and diurnal sleep, respectively). For nocturnal waking episodes, we found a shared environmental contribution of 63.2% and a heritability estimate of 35.3%. CONCLUSIONS: Most sleep disturbances during early childhood are explained by common shared environmental factors, and behavioral interventions adopted by parents and focused on modifying sleep behavior could contribute to solving sleep disturbances in this age group. However, the influence of genetic factors should not be underestimated, and research in this area could clarify the physiologic architecture of sleeping and contribute to selecting appropriate personalized therapeutic approaches.
The Influence of the CYP3A4*22 Polymorphism on Serum Concentration of Quetiapine in Psychiatric Patients

Background Besides dietary, hormonal, or pathological factors, mutations in cytochrome P450 enzymes are thought to be responsible for the interindividual differences in serum concentrations of cytochrome P450 (CYP450)–dependent drugs. Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, a new single-nucleotide polymorphism (SNP) was found (CYP3A4*22), which results in a decreased enzyme activity, in contrast to the other known SNPs in CYP3A4. We investigated to which degree the CYP3A4*22 SNP affects serum concentrations of patients receiving quetiapine, a drug exclusively metabolized by CYP3A4. Methods Two hundred thirty-eight adult patients receiving quetiapine were included in this study, based on availability of DNA, serum quetiapine levels, and information on dose. Patients were genotyped for CYP3A4*22 using allele-specific polymerase chain reaction, and, as a control, restriction fragment length polymorphism analysis. Results Carriers of the CYP3A4*22 allele (*1/*22 and *22/*22, n = 31) had 2.5-fold higher serum levels of quetiapine than did wild-type patients (n = 207; P = 0.03) when using a comparable dose (median, 300 mg/d for both wild-type and carriers; P = 0.67). The dose-corrected serum concentration (C/D) was 67% higher in carriers than in wild-type patients (P = 0.01). The number of patients who achieved serum levels above the therapeutic range (>500 µg/L) was also higher in *22-allele carriers (16.1% vs 2.9%; P = 0.007). Conclusion Being a carrier of the CYP3A4*22 allele increases the serum concentration of quetiapine at comparable doses.
Comparing Touchscreen and Mouse Input Performance by People With and Without Upper Body Motor Impairments

Controlled studies of touchscreen input performance for users with upper body motor impairments remain relatively sparse. To address this gap, we present a controlled lab study of mouse vs. touchscreen performance with 32 participants (16 with upper body motor impairments and 16 without). Our study examines: (1) how touch input compares to an indirect pointing device (a mouse); (2) how performance compares across a range of standard interaction techniques; and (3) how these answers differ for users with and without motor impairments. While the touchscreen was faster than the mouse overall, only participants without motor impairments benefited from a lower error rate on the touchscreen. Indeed, participants with motor impairments had a three-fold increase in pointing (tapping) errors on the touchscreen compared to the mouse. Our findings also highlight the high frequency of spurious touches for users with motor impairments and update past accessibility recommendations for minimum touchscreen target sizes to at least 18mm.
Human Fc Receptor–Like 5 Binds Intact IgG via Mechanisms Distinct from Those of Fc Receptors

Fc receptor–like (FCRL) 5 regulates B cell Ag receptor signaling and has been reported to bind aggregated IgG. Using surface plasmon resonance, we analyzed the interaction of native IgG samples with FCRL5, revealing a complex binding mechanism, where isotype is just one factor. FCRL5 bound IgG1 and IgG4 with ∼1 μM KD, whereas the interaction with IgG3 was a magnitude weaker. However, IgG2 samples displayed a wide range of affinities, indicating that additional factors affect binding. We used a panel of 19 anti-FCRL5 mAbs with defined reactivity to identify domains involved in ligand binding. Six mAbs blocked IgG binding, indicating critical roles of FCRL5 domains 1 and 3, as well as epitopes at the domain 1/2 and domain 2/3 boundaries. We found that only glycosylated IgG containing both Fab arms and the Fc region bound with high affinity. Furthermore, the presence of sialic acid in the IgG carbohydrate altered FCRL5 binding. The interaction of IgG and FCRL5 consisted of two kinetic components, suggesting a complex binding mechanism. We established that the IgG-Fc and IgG-F(ab′)2 fragments bind FCRL5 independently but with low affinity, revealing the mechanism behind the two-step binding of whole IgG. This complex binding mechanism is distinct from that of Fc receptors, which bind through the Fc. We propose that FCRL5 is a new type of receptor that recognizes intact IgG, possibly enabling B cells to sense Ig quality. Recognition of undamaged IgG molecules by FCRL5 could allow B cells to engage recently produced Abs.
Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients.

OBJECTIVE Cerebral gray matter volume reductions have been found to progress over time in schizophrenia, with larger decreases related to poorer outcome, which has also been associated with cannabis use in schizophrenia patients. Progressive gray matter changes in patients who use cannabis may be more extensive than in those who do not. METHOD Patients with recent-onset schizophrenia (N=51) and matched healthy subjects (N=31) were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion (T0) and at 5-year follow-up (T5). Nineteen patients used cannabis but no other illicit drugs; 32 patients did not use any drugs during the 5-year follow-up. At T5, clinical outcome was measured. Cumulative amount of antipsychotic medication during the interval was calculated. At T0 and T5, total brain, gray and white matter, and lateral and third ventricle volumes were measured. Univariate analysis of covariance and pairwise comparisons were performed. RESULT Schizophrenia patients showed a larger gray matter volume decrease over time than healthy subjects. They also showed larger increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis during follow-up. This decrement was significantly more pronounced in the patients who continued to use cannabis. These differences could not be attributed to outcome or baseline characteristics. CONCLUSIONS First-episode schizophrenia patients who use cannabis show a more pronounced brain volume reduction over a 5-year follow-up than patients with schizophrenia who do not use cannabis. These results may help explain some of the detrimental effects of cannabis use in schizophrenia.
Maternal understanding of infant diabetes risk: Differential effects of maternal anxiety and depression

Purpose: This study describes maternal understanding of infant risk associated with newborn genetic screening for type 1 diabetes.Methods: Mothers of at-risk infants (n = 195), identified through the Prospective Assessment of Newborns for Diabetes Autoimmunity study, were notified of risk status by standardized script. Mothers participated in structured telephone interviews 1 and 3.5 months after notification that assessed understanding of infant risk and psychologic response to the news.Results: Most mothers (78.5%) were accurate in their understanding of infant risk at the initial interview, with a slight decline at the follow-up interview (73%). There was a significant increase in underestimation of risk from the initial (12%) to the follow-up interview (19%) (χ2 (1) = 6.0, P = . 01). Mothers with less education, those from ethnic minority backgrounds, and those who were not married tended to be less accurate. Further, mothers who experienced more anxiety and fewer depressive symptoms in response to the news were more likely to be accurate. Likewise, underestimation of risk was associated with fewer anxiety and more depressive symptoms.Conclusion: This study highlights the complex picture of factors promoting maternal understanding of infant diabetes risk in a sample of mothers whose newborns had been identified as at increased risk for type 1 diabetes.
How Does Fiscal Policy Affect GDP and Inflation in Ukraine?

In this study, we apply the Blanchard-Perotti approach to estimating the impact of fiscal policy on GDP and inflation in Ukraine. By disaggregating fiscal data, we were able to determine which items of the budget have the most influence on real GDP and inflation. Our results show that fiscal multipliers in Ukraine in absolute values are higher for budget expenditures than for taxes. In addition, both budget expenditures and taxes have a positive impact on inflation.
Nutritional assessment and diet quality of visually impaired Spanish children

Background: The visually impaired represents a fairly numerous group in Spain although no data on their nutritional status has previously been published. Aim: This work aims to assess the nutritional state of a sample of visually impaired children and the quality of their diet. Subjects and methods: The sample comprised 229 boys and girls aged between 8 and 18 years (mean = 14, SD = 2.6), all of whom had a visual discapacity and were students of the Centros de Recursos Educativos (CREs; Educational Resources Centres) of the Organización Nacional de Ciegos de España (ONCE; Spanish National Organization for the Blind). Results: This sample featured a high prevalence of overweight (25.8%) and obesity (11.8%) according to the international standard. The mean daily energy consumption and the quantity of carbohydrates, fats, proteins and fibre were greater in boys (2604 kcal day−1; 290 g of carbohydrates, 126 g of fats and 90 g of proteins) than in girls (2159 kcal day−1, 232 g of carbohydrates, 107 g of fats and 80 g of proteins). No differences in diet intake according to degree of visual impairment were found. Their diet was unbalanced in comparison with the nutritional objectives for the Spanish population, since consumption of carbohydrates was low and that of fats was very high. The results relating to the quality of the diet reveal quite large deviations from the Mediterranean model. Only 11.9% of the whole sample had a value corresponding to a good quality diet. Conclusion: The pattern of dietary consumption was the same as that observed in non visually impaired children in Spain in quantity and quality, nevertheless the prevalence of overweight and obesity is higher than in children without visual handicaps.
An analysis of demand uncertainty in the hotel market

This study proposes a two-step approach to investigate the impact of certain environmental variables on demand uncertainty within the hotel sector. Adopting a simultaneous-equation model and using the operation data of international tourist hotels in Taiwan, this study shows that chained hotels face less demand uncertainty than independent hotels. Additionally, hotels that are more distant from the airport or located in metropolitan areas face a significantly higher degree of demand uncertainty.
Unilateral limited scleroderma‐like changes following formation of an arteriovenous fistula

A 55‐year‐old man presented with a 1‐year history of progressive skin thickening involving the right hand associated with Raynaud’s phenomenon, sclerodactyly and painful cutaneous ulcers. An arteriovenous fistula for haemodialysis had been formed on the same arm 2 years previously. There were no symptoms or signs of systemic sclerosis or involvement of the contralateral arm. The limb was clinically ischaemic, attributed to a vascular steal phenomenon from the arteriovenous fistula, superimposed on occlusive arterial disease. A revascularization procedure was performed, which resulted in substantial improvement in the sclerodactyly, Raynaud’s phenomenon and hand function. Tissue hypoxia is believed to be a contributing factor in the pathogenesis of scleroderma, and this case demonstrates scleroderma‐like changes in the setting of limb ischaemia.