Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of Molecular Therapies for Venous Malformations

Vascular anomalies are localized defects of morphogenesis that can affect lymphatic and blood vessels. They are generally called birthmarks, typically observed soon after birth and occurring in up to 10% of children. Based on their clinical and histological characteristics, they are classified into vascular tumours and vascular malformations. The most common malformations are venous malformations (VMs) resulting in chronic vascular diseases that can be associated with significant morbidity necessitating often demanding and repeating clinical management. The current treatment is based on surgical resection and sclerotherapy, which can be impossible due to the size or location of lesions or ineffective due to the regrowth of malformed vessels. Therefore, medical therapies for VMs are highly desired. Recent studies have identified genetic defects that result in the constantly active endothelial cell receptor tyrosine kinase TIE2/phosphoinositide 3-kinase PI3K signalling pathway as a frequent cause for VMs. The first treatment to inhibit this pathway with sirolimus indicated that molecular treatment can be effective against VMs. In addition, certain VM 'hotspot' mutations have been previously found in tumours, providing the rationale for the exploration and repurposing of existing and investigational cancer drugs for VMs. Finally, discoveries of molecular and cellular abnormalities that characterize a large proportion of VMs and the generation of pre-clinical VM mouse models provide the necessary basis for the development of the targeted molecular treatment strategies we discuss in this MiniReview.
Optimization of intravenous contrast media at computed tomography

The administration of intravenous contrast media (IV CM) is essential for detecting lesions at most computed tomography (CT) examinations. The overall aim of this thesis is to investigate different aspects of IV CM administration that may affect the quality of the CT examination. In Study I a comparison was made between a low osmolar contrast media (LOCM) iomperol and the iso osmolar contrast media (IOCM) iodixanol, focusing on how they may affect heart rate, heart rate variability, experienced patient heat sensation and image quality at coronary computed angiography (CCTA) in 100 patients. No significant difference in terms of heart rate interfering with the imaging protocol was observed. However, a greater number of arrhythmic heart beats (hb) was observed with the use of LOCM than with IOCM (P< 0.001). There was no difference in subjective image quality between the two CM. The experienced heat sensation was stronger when receiving LOCM than when receiving IOCM (visual analogue scale = 36 mm and 18 mm respectively, P< 0.05). In Study II the enhancement of liver and aorta was related to different measures of body size and to the use of two different CM (LOCM iomeprol and IOCM iodixanol) in 100 patients undergoing thoraco-abdominal CT. Three parameters had a stronger correlation to the CM enhancement in liver and aorta; Body weight (BW, r= -0.51 and 0.64), body surface area (BSA, r= -0.54 and -0.65) and lean body mass (LBM, r= -0.54 and -0.59), but there was no statistically significant difference between those. The parameters body height (BH), body mass index (BMI) and ideal body weight (IBW) had weaker correlations to CM enhancement of liver and aorta. When adjusting for differences in weight, height, age and sex between the two groups there was a stronger liver enhancement after injection of the IOCM iodixanol than after injection of the LOCM iodixanol (mean difference 6 HU, p < 0.01). Conclusion: The iso osmolar contrast media iodixanol causes less arrhythmic hb and less heat sensation than the low osmolar contrast media iomeprol, but this does not significantly influence the quality at CCTA. The CM enhancement is affected by body size. There is no statistically significant better parameter than BW to adjust for, why this parameter is recommended for dose adjustments. When performing hepatic imaging the IOCM iodixanol might be preferred to the LOCM iomeprol due to a stronger CM enhancement, but confirming studies are required. LIST OF PUBLICATIONS
Chemical modification of metallic implant surfaces with biofunctional proteins (Part 1). Molecular structure and biological activity of a modified NiTi alloy surface.

Human plasma fibronectin (pFN), an adhesive protein, was covalently immobilized onto an alkylaminosilane derivative of a NiTi substrate with glutaraldehyde through Schiff's base formation. The surface at different stages of the modification was characterized by X-ray photoelectron spectroscopy (XPS), and the amount of immobilized pFN was determined by a fluorometric method. The spreading behavior of human gingival fibroblasts was examined on the modified surface. The XPS spectra suggested that gamma-aminopropyltriethoxysilane (gamma-APS) was bonded to the surface through metallosiloxane bonds (Ti-O-Si) formed via a condensation reaction between the silanol end of gamma-APS and the surface hydroxyl group, with a highly cross-linked siloxane network formed after heat treatment of the silanized surface at 100 degrees C. The pFN was immobilized at the surface density of 1.1 micrograms.cm-2, and significantly promoted fibroblast spreading, suggesting that this chemical modification offers an effective means of controlling metal/cell interactions. These results may contribute to the development of bioactive metallic implants.
Hybrid Silicon Photonic – Lithium Niobate Electro-Optic Mach-Zehnder Modulator Beyond 100 GHz

Hybrid Silicon Photonic – Lithium Niobate Electro-Optic Mach-Zehnder Modulator Beyond 100 GHz Peter O. Weigel1,*, Jie Zhao1, Kelvin Fang1, Hasan Al-Rubaye1, Douglas Trotter2, Dana Hood2, John Mudrick2, Christina Dallo2, Andrew T. Pomerene2, Andrew L. Starbuck2, Christopher T. DeRose2, Anthony L. Lentine2, Gabriel Rebeiz1 and Shayan Mookherjea1,* 1 University of California, San Diego, Electrical & Computer Engineering, La Jolla, California 92093-0407, USA 2 Sandia National Laboratories, Applied Microphotonic Systems, Albuquerque, New Mexico, 87185, USA
Shifting paradigm: From “No Code” and “Do-Not-Resuscitate” to “Goals of Care” policies

Policies addressing limitations of medical therapy in patients with advanced medical conditions are typically referred to as Code Status (No Code) policies or Do-Not-Resuscitate (DNR) status polices. Inconsistencies in implementation, understanding, decision-making, communication and management of No Code or DNR orders have led to delivery of poorer care to some patients. Several experts have called for a change in the current approach. The new approach, Goals of Care paradigm, aims to contextualize the decisions about resuscitation and advanced life support within the overall plan of care, focusing on choices of treatments to be given rather than specifically on treatments not to be given. Adopting “Goals of Care” paradigm is a big step forward on the journey for optimizing the care for patients with advanced medical conditions; a journey that requires collaborative approach and is of high importance for patients, community and healthcare systems.
A Split Model to Deal with Semantic Anomalies in the Task of Word Prediction

On the task of predicting the range of possible next words in a sentence, many networks (e.g. Elman, 1990) that have been proposed are capable of displaying a certain degree of systematicity, but fail in recognizing grammatically correct but semantically anomalous sentences. Based on an expansion of Hadley’s model (Hadley et al, 2001), I present a competitive network, which employs two sub-networks that discern coarsegrained and fine-grained categories respectively, by being trained via different parameter settings. Hence, one of the sub-networks will have a greater capacity for recognizing the syntactic structure of the preceding words, while the other will have a greater capacity for recognizing the semantic structure. This corresponds to the recent suggestion about specialization of the two hemispheres in the human brain (Beeman, 1998). Also, a mechanism to switch attention between the predictions from the two sub-networks is employed in order to make the global network more closely approximate human behavior. The results show that the network is able to deal with grammatically correct but semantically anomalous sentences.
Temporal Dynamics of Acute Stress‐Induced Dendritic Remodeling in Medial Prefrontal Cortex and the Protective Effect of Desipramine

Abstract Stressful events are associated with increased risk of mood disorders. Volumetric reductions have been reported in brain areas critical for the stress response, such as medial prefrontal cortex (mPFC), and dendritic remodeling has been proposed as an underlying factor. Here, we investigated the time‐dependent effects of acute stress on dendritic remodeling within the prelimbic (PL) region of the PFC, and whether treatment with the antidepressant desipramine (DMI) may interfere. Rodents were subjected to foot‐shock stress: dendritic length and spine density were analyzed 1 day, 7 days, and 14 days after stress. Acute stress produced increased spine density and decreased cofilin phosphorylation at 1 day, paralleled with dendritic retraction. An overall shift in spine population was observed at 1 day, resulting in a stress‐induced increase in small spines. Significant atrophy of apical dendrites was observed at 1 day, which was prevented by chronic DMI, and at 14 days after stress exposure. Chronic DMI resulted in dendritic elaboration at 7 days but did not prevent the effects of FS‐stress. Collectively, these data demonstrate that 1) acute stressors may induce rapid and sustained changes of PL neurons; and 2) chronic DMI may protect neurons from rapid stress‐induced synaptic changes.
Sympathetic neural recruitment patterns during the Valsalva maneuver

Sympathetic nerve activity is an important regulator of blood pressure and blood flow in humans. Our understanding about how sympathetic neurons are recruited during baroreflex stress is limited. This paper investigates the sympathetic neural recruitment patterns during the Valsalva maneuver. Using microneurography, muscle sympathetic nerve activity was recorded in seven healthy subjects during baseline and the Valsalva maneuver. A new algorithm for detection and classification of action potentials was employed to study the differences between the recruitment of sympathetic neurons during baseline and the Valsalva maneuver. The data suggests that the Valsalva maneuver increases the number of spikes per sympathetic bursts and also recruits at least one additional new cluster of larger, faster conducting neurons. Also, action potential's latencies (i.e., inverse of conduction velocity) were shifted downward for all action potential clusters during this maneuver.
A Neural Mechanism for Nonconscious Activation of Conditioned Placebo and Nocebo Responses

Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of conditioned pain responses, using functional magnetic resonance imaging in healthy participants. Nonconscious compared with conscious activation of conditioned placebo analgesia was associated with increased activation of the orbitofrontal cortex, a structure with direct connections to affective brain regions and basic reward processing. During nonconscious nocebo, there was increased activation of the thalamus, amygdala, and hippocampus. In contrast to previous assumptions about conditioning in humans, our results show that conditioned pain responses can be elicited independently of conscious awareness and our results suggest a hierarchical activation of neural pathways for nonconscious and conscious conditioned responses. Demonstrating that the human brain has a nonconscious mechanism for responding to conditioned cues has major implications for the role of associative learning in behavioral medicine and psychiatry. Our results may also open up for novel approaches to translational animal-to-human research since human consciousness and animal cognition is an inherent paradox in all behavioral science.
Behavioral Characteristics of Pharmacologically Selected Lines of Rats: Relevance to Depression

This brief review discusses the behavioral consequences of two pharmacologically selected lines of rats. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential hypothermic and behavioral responses to the anticholinesterase, diisopropylfluorophosphate (DFP). FSL rats are more sensitive to the hypothermic effects of cholinergic, serotonergic, and dopaminergic agonists but less sensitive to the locomotor or stereotypic effects of dopamine agonists. FSL rats exhibit greater immobility in the forced swim test and reduced social interaction compared with FRL rats, but do not differ in saccharin intake, behavior in the elevated plus maze, or responses for rewarding brain self-stimulation. The exaggerated immobility and reduced social interaction are counteracted by chronic treatment with antidepressants. Because FSL rats were more sensitive to 5-HT1A receptor agonists, high (HDS) and low (LDS) 8-OH-DPATsensitive lines were selectively bred for differential hypothermic responses to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT). HDS rats were also more sensitive to the hypothermic effects of oxotremorine, a cholinergic agonist, but selection for this response did not diverge with later selection. HDS rats exhibited greater immobility in the forced swim test than LDS rats and this correlated response could be seen early in selection (generation 3). HDS rats also showed reduced social interaction compared to LDS rats, but did not differ in behavior in the elevated plus maze. These findings confirm that selection for hypothermic responses to pharmacological agents do have behavioral consequences, notably the production of depressive-like phenotypes, which can be counteracted by chronic antidepressant treatment. Because increased 5-HT1A receptor sensitivity was common to both selected lines (FSL and HDS), neurobiological processes dependent on this receptor could contribute to the abnormal behaviors that manifest in these rat lines and thus suggesting a mechanism underlying depressive behaviors in humans. However, available human data are inconsistent with this hypothesis and suggest that other mechanisms underlie these behavioral abnormalities in HDS and FSL rats. These mechanisms as well as additional behavioral testing in these rat lines will be discussed.
How long does the pharmacokinetic interaction between carbamazepine and quetiapine last after carbamazepine withdrawal?

OBJECTIVES Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. METHODS In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal. RESULTS No serum quetiapine was detected during concurrent use of carbamazepine and was lower than the therapeutic range almost 2 weeks after carbamazepine withdrawal. The patient suffered from sedation when her serum level of quetiapine was 181 ng/ml and because she was quiet we started slowly to decrease to a quetiapine dose of 600 mg. Her serum level (45 ng/ml) was again below therapeutic levels after 3 weeks of carbamazepine withdrawal. CONCLUSION We hypothesize that induction of CYP3A lasts even after carbamazepine withdrawal. Our hypothesis was confirmed during the next treatment of mania. The patient had been off carbamazepine for 1 year and her serum level was four times higher (210 ng/ml) on 600 mg of quetiapine than 3 weeks after carbamazepine withdrawal. The influence of carbamazepine on CYP3A enzymes lasted at least 3 weeks after carbamazepine withdrawal which is in accordance with CYP3A de-induction lasting 3 weeks. This could be important information for psychiatrists to know that in some patients it is better to use a minimum washout period of 3 weeks for carbamazepine before new treatment with quetiapine.
Exceptional longevity is associated with decreased reproduction

A number of leading theories of aging, namely The Antagonistic Pleiotropy Theory (Williams, 1957), The Disposable Soma Theory (Kirkwood, 1977) and most recently The Reproductive-Cell Cycle Theory (Bowen and Atwood, 2004, 2010) suggest a tradeoff between longevity and reproduction. While there has been an abundance of data linking longevity with reduced fertility in lower life forms, human data have been conflicting. We assessed this tradeoff in a cohort of genetically and socially homogenous Ashkenazi Jewish centenarians (average age ~100 years). As compared with an Ashkenazi cohort without exceptional longevity, our centenarians had fewer children (2.01 vs 2.53, p < 0.0001), were older at first childbirth (28.0 vs 25.6, p < 0.0001), and at last childbirth (32.4 vs 30.3, p < 0.0001). The smaller number of children was observed for male and female centenarians alike. The lower number of children in both genders together with the pattern of delayed reproductive maturity is suggestive of constitutional factors that might enhance human life span at the expense of reduced reproductive ability.
Effect-dependent transformations for concurrent programs

We describe a denotational semantics for an abstract effect system for a higher-order, shared-variable concurrent language. The semantics validates general effect-based program equivalences, including sufficient conditions for replacing sequential composition with parallel composition. Effect annotations refer to abstract locations, specified by contracts, rather than physical footprints, allowing us to also show soundness of some transformations involving fine-grained concurrent data structures, such as Michael-Scott queues. We build on a trace-based semantics for first-order programs due to Brookes. By moving from concrete to abstract locations, and adding type refinements capturing possible side-effects of both expressions and their environments, we can validate many equivalences that do not hold in an unrefined model. Refined types are interpreted using a game-based logical relation over sets of traces.
Incidence and risk factors for psoriasis in the general population.

OBJECTIVES To study the clinical spectrum of psoriasis and the incidence in the general population and to identify risk factors associated with the occurrence of psoriasis. DESIGN Prospective cohort study with nested case-control analysis. SETTING The data source was the United Kingdom General Practice Research Database containing computerized clinical information entered by general practitioners (GPs). PATIENTS The study population comprised patients receiving a first-ever diagnosis of psoriasis between January 1, 1996, and December 31, 1997, and free of cancer. INTERVENTIONS Diagnosis of psoriasis was validated in a random sample of 14% of all ascertained cases requesting confirmation by the GPs. Nested case-control analysis included 3994 cases of psoriasis and a random sample of 10 000 controls frequency matched to cases by age, sex, and calendar year. MAIN OUTCOME MEASURES Incidence rate of psoriasis and estimates of the odds ratio (OR) and 95% confidence interval (CI) for psoriasis as associated with selected risk factors. RESULTS The incidence rate of psoriasis was 14 per 10 000 person-years. Patients with antecedents of skin disorders and skin infection within the last year carried the highest risk of developing psoriasis (OR, 3.6 [95% CI, 3.2-4.1], and OR, 2.1 [95% CI, 1.8-2.4], respectively). Also, smoking was found to be an independent risk factors for psoriasis (OR, 1.4 [95% CI, 1.3-1.6]). We did not find an association between risk of psoriasis and antecedents of stress, diabetes, hypertension, hyperlipidemia, cardiovascular disease, or rheumatoid arthritis. CONCLUSIONS The incidence rate in our study was higher than those published in other studies, probably owing to our case definition that considered cases recorded by the GPs independently of a specialist confirmation. Our results confirm the association between psoriasis, skin disorders, and smoking.
Integrin α2 marks a niche of trophoblast progenitor cells in first trimester human placenta

ABSTRACT During pregnancy the trophoblast cells of the placenta are the only fetal cells in direct contact with maternal blood and decidua. Their functions include transport of nutrients and oxygen, secretion of pregnancy hormones, remodelling of the uterine arteries, and communicating with maternal cells. Despite the importance of trophoblast cells in placental development and successful pregnancy, little is known about the identity, location and differentiation of human trophoblast progenitors. We identify a proliferative trophoblast niche at the base of the cytotrophoblast cell columns in first trimester placentas that is characterised by integrin α2 (ITGA2) expression. Pulse-chase experiments with 5-iodo-2′-deoxyuridine indicate that these cells might contribute to both villous (VCT) and extravillous (EVT) lineages. These proliferating trophoblast cells can be isolated by flow cytometry using ITGA2 as a marker and express genes from both VCT and EVT. Microarray expression analysis shows that ITAG2+ cells display a unique transcriptional signature, including genes involved in NOTCH signalling, and exhibit a combination of epithelial and mesenchymal characteristics. ITGA2 thus marks a niche allowing the study of pure populations of trophoblast progenitor cells. Summary: ITGA2 marks a proliferative trophoblast progenitor compartment in first trimester human placenta that appears to be regulated by NOTCH signalling and exhibits a unique combination of epithelial and mesenchymal expression characteristics.
Detecting and Identifying Industrial Gases by a Method Based on Olfactory Machine at Different Concentrations

Gas sensors have been widely reported for industrial gas detection and monitoring. However, the rapid detection and identification of industrial gases are still a challenge. In this work, we measure four typical industrial gases including CO2, CH4, NH3, and volatile organic compounds (VOCs) based on electronic nose (EN) at different concentrations. To solve the problem of effective classification and identification of different industrial gases, we propose an algorithm based on the selective local linear embedding (SLLE) to reduce the dimensionality and extract the features of high-dimensional data. Combining the Euclidean distance (ED) formula with the proposed algorithm, we can achieve better classification and identification of four kinds of gases. We compared the classification and recognition results of classical principal component analysis (PCA), linear discriminate analysis (LDA), and PCA + LDA algorithms with the proposed SLLE algorithm after selecting the original data and performing feature extraction. The experimental results show that the recognition accuracy rate of the SLLE reaches 91.36%, which is better than the other three algorithms. In addition, the SLLE algorithm provides more efficient and accurate responses to high-dimensional industrial gas data. It can be used in real-time industrial gas detection and monitoring combined with gas sensor networks.