Miracle-dz/UniFAR-FTUs huggingface dataset:
Aging and Economic Competitiveness in the Core of “North Euro-Zone

The paper addresses the problem of aging in close relationship with the changes produced by this phenomenon in the economic structure of countries. Two of the channels through which an aging population can influence the sectoral structure of an economy are the demand for specific products and services and the offer of a labour force with certain characteristics (related to age, skills, culture and so on). This article is founded on the success stories of some of the most affected by the phenomenon countries (Germany, Netherlands, Austria and Finland) that seem to have managed preserving a positive correlation between productivity and the aging workforce, in recent years. The originality of the paper is given by the comparative perspective from which these most attractive economies are analysed, with the main purpose to identify the driving factors of their long-term competitiveness. In addition, modern econometric analysis using Dynamic OLS (DOLS) and ARDL models based on panel data on five economic sectors and 19 years scientifically fundaments some solutions possibly to be adopted by other countries facing the same demographic challenges. DOI: http://dx.doi. org/10.5755/j01.ee. 27.3. 14028
Hsp90 Regulates p50 cdc37 Function during the Biogenesis of the Active Conformation of the Heme-regulated eIF2α Kinase*

Recent studies indicate that p50 cdc37 facilitates Hsp90-mediated biogenesis of certain protein kinases. In this report, we examined whether p50 cdc37 is required for the biogenesis of the heme-regulated eIF2α kinase (HRI) in reticulocyte lysate. p50 cdc37 interacted with nascent HRI co-translationally and this interaction persisted during the maturation and activation of HRI. p50 cdc37 stimulated HRI's activation in response to heme deficiency, but did not activate HRI per se. p50 cdc37 function was specific to immature and inactive forms of the kinase. Analysis of mutant Cdc37 gene products indicated that the N-terminal portion of p50 cdc37 interacted with immature HRI, but not with Hsp90, while the C-terminal portion of p50 cdc37 interacted with Hsp90. The Hsp90-specific inhibitor geldanamycin disrupted the ability of both Hsp90 and p50 cdc37 to bind HRI and promote its activation, but did not disrupt the native association of p50 cdc37 with Hsp90. A C-terminal truncated mutant of p50 cdc37 inhibited HRI's activation, prevented the interaction of Hsp90 with HRI, and bound to HRI irrespective of geldanamycin treatment. Additionally, native complexes of HRI with p50 cdc37 were detected in cultured K562 erythroleukemia cells. These results suggest that p50 cdc37 provides an activity essential to HRI biogenesis via a process regulated by nucleotide-mediated conformational switching of its partner Hsp90.
Terahertz imaging of paraffin-embedded epithelial cell of rat using pulsed and CW THz systems

To investigate the response of cell to the terahertz wave, both the pulsed and CW THz wave systems are employed. The THz wave systems include TDS broadband pulsed THz system(0.3-3 THz), narrowband CW BWO vacuum THz generator, (0.5 THz)and narrowband CW Gunn diode THz generator(0.3 THz). THz imaging of a ratpsilas paraffin-embedded epithelial cell with tumor is studied.
Emerging drugs for major depressive disorder

Most current pharmacologic antidepressant treatments target either or both serotonin and norepinephrine systems in the brain to alleviate depressive symptoms. However, ≥ 30% of patients with major depressive disorder fail to respond to these antidepressants, inciting a need for alternative treatment strategies. In the past decade, there has been extensive research into improving the mechanism of action for monoamine agents as well as identifying novel treatment targets for depression. For monoamines, drugs that increase serotonin, norepinephrine, melatonin or dopamine have been explored as putative antidepressants and in some cases approved (agomelatine and desvenlafaxine). Novel drugs that act on amino acid receptors, neurotrophic factors, cytokines, neuropeptides and acetylcholine are also in development. This review will discuss the scientific rationale for these targets, as well as highlight the current status of drugs in development.
LOVD v.2.0: the next generation in gene variant databases

Locus‐Specific DataBases (LSDBs) store information on gene sequence variation associated with human phenotypes and are frequently used as a reference by researchers and clinicians. We developed the Leiden Open‐source Variation Database (LOVD) as a platform‐independent Web‐based LSDB‐in‐a‐Box package. LOVD was designed to be easy to set up and maintain and follows the Human Genome Variation Society (HGVS) recommendations. Here we describe LOVD v.2. 0, which adds enhanced flexibility and functionality and has the capacity to store sequence variants in multiple genes per patient. To reduce redundancy, patient and sequence variant data are stored in separate tables. Tables are linked to generate connections between sequence variant data for each gene and every patient. The dynamic structure allows database managers to add custom columns. The database structure supports fast queries and allows storage of sequence variants from high‐throughput sequence analysis, as demonstrated by the X‐chromosomal Mental Retardation LOVD installation. LOVD contains measures to ensure database security from unauthorized access. Currently, the LOVD Website (http://www.LOVD.nl/) lists 71 public LOVD installations hosting 3,294 gene variant databases with 199,000 variants in 84,000 patients. To promote LSDB standardization and thereby database interoperability, we offer free server space and help to establish an LSDB on our Leiden server.
Endocrine-mediated mechanisms of fatigue during treatment with interferon-alpha.

Fatigue occurs in more than 70% of patients treated with interferon-alpha (IFN-alpha) and is the most problematic toxicity associated with IFN-based immunotherapy. Abundant evidence suggests that immune-mediated endocrine disease occurs during IFN-alpha therapy, which may contribute to the etiology of fatigue. Autoimmune thyroid disease is a well-recognized consequence of IFN-alpha therapy and may be mediated by the induction of IFN-gamma production by lymphocytes. Administration of exogenous IFN-gamma has been associated with upregulation of class II major histocompatibility antigens in the thyroid and the development of thyroiditis. Interferon-alpha also stimulates the production of interleukin-6; both interleukin-6 and IFN-gamma have specific effects on thyrocyte function. There also is evidence suggesting that IFN-alpha initiates a cytokine cascade that effects the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, thus affecting regulation of glucocorticoid and sex steroid hormone secretion, but the clinical significance of these observations has not been established. Although endocrine disease will not explain the occurrence of fatigue symptoms in all patients, there is clear evidence that hormonal deficiency syndromes occur in a relatively large portion of patients receiving systemic IFN-alpha therapy. Most importantly, the possibility of hypothyroidism must be considered; however, diagnosis of hypothyroidism in cancer patients is complicated by the occurrence of the "sick euthyroid syndrome. " Clinical recommendations for assessment and treatment of IFN-alpha-induced fatigue are offered. Most importantly, measurements of thyroid-stimulating hormone and antithyroid autoantibodies should be used to evaluate thyroid status. Acknowledging the limitations of current clinical data, adrenal- and gonadal-axis dysfunction also must be considered in patients with IFN-alpha-induced fatigue.
The ryanodine receptor agonist 4‐chloro‐3‐ethylphenol blocks ORAI store‐operated channels

Depletion of the Ca2+ store by ryanodine receptor (RyR) agonists induces store‐operated Ca2+ entry (SOCE). 4‐Chloro‐3‐ethylphenol (4‐CEP) and 4‐chloro‐m‐cresol (4‐CmC) are RyR agonists commonly used as research tools and diagnostic reagents for malignant hyperthermia. Here, we investigated the effects of 4‐CEP and its analogues on SOCE.
Minimized Extracorporeal Circulation Cannot Prevent Acute Kidney Injury but Attenuates Early Renal Dysfunction After Coronary Bypass Grafting

We studied the impact of minimized extracorporeal circulation (MECC) on acute kidney injury (AKI) after coronary bypass grafting. A retrospective, observational study with 1,685 patients with MECC and 3,046 patients with conventional bypass was done. Primary outcome was AKI defined as a decline ≥50% in estimated glomerular filtration rate (eGFR) within 48 hours after surgery. Secondary outcome was temporary dialysis. MECC exerts beneficial hemodynamic effects but does not prevent AKI. Fewer patients developed a decline in eGFR <60 mL/min/1.73 m2 (MECC) compared with conventional extracorporeal circulation (ECC) (30.7% versus 45.5%, p < 0.001). The incidence of eGFR decrease by ≥50% did not differ (1.8% versus 2.7%, p = 0.20). Temporary dialysis was required in 61 patients with ECC (2%) and in 16 patients with MECC (0.9%, p < 0.001). A preoperative eGFR <60 mL/min/1.73 m2 increased in both groups the risk for mortality compared with patients with an eGFR >60 mL/min/1.73 m2 (ECC: odds ratio 3.6, 95% confidence interval 2.6–4.9; MECC: odds ratio 4.9, 95% confidence interval 2.8–8.6). MECC is renoprotective in the early postoperative period but cannot prevent AKI. An impaired preoperative eGFR increases the risk for mortality irrespective of the cardiopulmonary bypass system used.
Reconstructing the Voice of an Individual Following Laryngectomy

This case study describes the generation of a synthetic voice resembling that of an individual before she underwent a laryngectomy. Recordings of this person (6–7 min) speaking prior to the operation were used to create the voice. Synthesis was based on statistical speech models and this method allows models pre-trained on many speakers to be adapted to resemble an individual voice. The results of a listening test in which participants were asked to judge the similarity of the synthetic voice to the pre-operation (target) voice are reported. Members of the patient's family were asked to make a similar judgment. These experiments show that, for most listeners, the voice is quite convincing despite the low quality and small quantity of adaptation data.
Pharmacology of GPR55 in Yeast and Identification of GSK494581A as a Mixed-Activity Glycine Transporter Subtype 1 Inhibitor and GPR55 Agonist

GPR55 is a G protein-coupled receptor activated by l-α-lysophosphatidylinositol and suggested to have roles in pain signaling, bone morphogenesis, and possibly in vascular endothelial cells. It has affinity for certain cannabinoids (molecules that interact with the cannabinoid CB1 and CB2 receptors), but investigation of its functional role in cell-based systems and in tissue has been limited by a lack of selective pharmacological tools. Here, we present our characterization of GPR55 in the yeast Saccharomyces cerevisiae and in human embryonic kidney (HEK293) cells. We describe GSK494581A (1-{2-fluoro-4-[1-(methyloxy)ethyl]phenyl}-4-{[4′-fluoro-4-(methylsulfonyl)-2-biphenylyl]carbonyl}piperazine), a selective small-molecule ligand of GPR55 identified through diversity screening. GSK494581A is one of a series of benzoylpiperazines originally identified and patented as inhibitors of the glycine transporter subtype 1 (GlyT1). The structure–activity relationship between GPR55 and GlyT1 is divergent across this series. The most GPR55-selective example is GSK575594A (3-fluoro-4-(4-{[4′-fluoro-4-(methylsulfonyl)-2-biphenylyl]carbonyl}-1-piperazinyl)aniline), which is approximately 60-fold selective for GPR55 (pEC50 = 6.8) over GlyT1 (pIC50 = 5.0). Several exemplars with activity at GPR55 and GlyT1 have been profiled at a broad range of other molecular targets and are inactive at cannabinoid receptors and all other targets tested. The benzoylpiperazine agonists activate human GPR55 but not rodent GPR55, suggesting that the relatively low level of sequence identity between these orthologs (75%) translates to important functional differences in the ligand-binding site.
Role of the combination spironolactone-norgestimate-estrogen in Hirsute women with polycystic ovary syndrome.

OBJECTIVE To compare the combination spironolactone-norgestimate-ethinyl estradiol in hirsutism with other protocols including the same dose of estrogen. STUDY DESIGN In this open prospective study, 167 women with hirsutism due to polycystic ovary syndrome (PCOS) were randomly assigned to the following treatment protocols: Group A (n = 72): spironolactone 100 mg-norgestimate 250 mcg-ethinyl estradiol 35 microg; Group B (n = 70): cyproterone acetate 12 mg-ethinyl estradiol 35 microg; Group C (n = 25): norgestimate 250 microg-ethinyl estradiol 35 microg. RESULTS The decrease in the hirsutism score was higher in group A than in the other groups (p < 0.001) and comparable in groups B and C. The decrease in acne score, androgen and estradiol levels, and ovary volume was similar in groups A and B. C-reactive protein increase was similar in all groups, but the augmentation of fibrinogen (p = 0.04), triglycerides (p < 0.01), monocyte count (p = 0.04), platelet number (p < 0.001) and mean volume (p = 0.01) was more pronounced in group B than in group A. Low-density lipoprotein/high-density lipoprotein cholesterol ratio decreased in groups A and C. CONCLUSION Spironolactone-norgestimate-ethinyl estradiol is an effective and well-tolerated combination for the treatment of hirsutism in PCOS, with a favorable influence on lipids and indices of low-grade inflammation.
Hitting the sweet spot: Automatic optimization of energy transfer during tool-held hits

Tool-held hitting tasks, like hammering a nail or striking a ball with a bat, require humans, and robots, to purposely collide and transfer momentum from their limbs to the environment. Due to the vibrational dynamics, every tool has a location where a hit is most efficient results in minimal tool vibrations, and consequently maximum energy transfer to the environment. In sports, this location is often referred to as the “sweet spot” of a bat, or racquet. Our recent neuroscience study suggests that humans optimize hits by using the jerk and torque felt at their hand. Motivated by this result, in this work we first analyze the vibrational dynamics of an end-effector-held bat to understand the signature projected by a sweet spot on the jerk and torque sensed at the end-effector. We then use this analysis to develop a controller for a robotic “baseball hitter”. The controller enables the robot-hitter to iteratively adjust its swing trajectory to ensure that the contact with the ball occurs at the sweet spot of the bat. We tested the controller on the DLR LWR III manipulator with three different bats. Like a human, our robot hitter is able to optimize the energy transfer, specifically maximize the ball velocity, during hits, by using its end effector position and torque sensors, and without any prior knowledge of the shape, size or material of the held bat.
A Novel Three‐Dimensional Computer‐Assisted Method for a Quantitative Study of Microvascular Networks of the Human Cerebral Cortex

Objective: Detailed information on microvascular network anatomy is a requirement for understanding several aspects of microcirculation, including oxygen transport, distributions of pressure, and wall shear stress in microvessels, regulation of blood flow, and interpretation of hemodynamically based functional imaging methods, but very few quantitative data on the human brain microcirculation are available. The main objective of this study is to propose a new method to analyze this microcirculation.
Tomato SlSnRK1 Protein Interacts with and Phosphorylates βC1, a Pathogenesis Protein Encoded by a Geminivirus β-Satellite1[C][W][OA]

The βC1 protein of tomato yellow leaf curl China β-satellite functions as a pathogenicity determinant. To better understand the molecular basis of βC1 in pathogenicity, a yeast two-hybrid screen of a tomato (Solanum lycopersicum) cDNA library was carried out using βC1 as bait. βC1 interacted with a tomato SUCROSE-NONFERMENTING1-related kinase designated as SlSnRK1. Their interaction was confirmed using a bimolecular fluorescence complementation assay in Nicotiana benthamiana cells. Plants overexpressing SnRK1 were delayed for symptom appearance and contained lower levels of viral and satellite DNA, while plants silenced for SnRK1 expression developed symptoms earlier and accumulated higher levels of viral DNA. In vitro kinase assays showed that βC1 is phosphorylated by SlSnRK1 mainly on serine at position 33 and threonine at position 78. Plants infected with βC1 mutants containing phosphorylation-mimic aspartate residues in place of serine-33 and/or threonine-78 displayed delayed and attenuated symptoms and accumulated lower levels of viral DNA, while plants infected with phosphorylation-negative alanine mutants contained higher levels of viral DNA. These results suggested that the SlSnRK1 protein attenuates geminivirus infection by interacting with and phosphorylating the βC1 protein.
Escherichia coli RcsA, a Positive Activator of Colanic Acid Capsular Polysaccharide Synthesis, Functions To Activate Its Own Expression

ABSTRACT Capsule (cps) gene expression in Escherichia coli is controlled by a complex network of regulators. Transcription of the cps operon is controlled by at least two positive regulators, RcsA and RcsB. We show here that RcsA functions to activate its own expression, as seen by the 100-fold-increased expression of arcsA::lacZ transcriptional fusion in strains with high levels of RcsA protein, either due to a mutation inlon or due to overexpression of RcsA from a multicopy plasmid. Expression of the rcsA::lacZfusion is increased by but not dependent on the presence of RcsB. In addition, the effects of H-NS and RcsB on the expression ofrcsA are independent of each other. A sequence motif, conserved between the E. coli cps promoter and theErwinia amylovora ams promoter and previously shown to be the RcsA-RcsB binding site, was identified in the rcsApromoter region and shown to be required for high-level expression ofrcsA.
Morphometric and immunohistochemical study of the omasum of red deer during prenatal development

The red deer is an important study species because of its value in the national economy and because it provides a wealth of genetic material. To date, there has been little research into the prenatal development of the stomach of ruminants, and none of the red deer. We therefore performed a histological evaluation of the ontogenesis of the omasum in the red deer. Histomorphometric and immunohistochemical analyses were carried out on 50 embryos and fetuses of deer from the initial stages of prenatal life until birth. For test purposes, the animals were divided into five experimental groups: Group I (1.4–3.6 cm crown–rump length, CRL; 30–60 days, 1–25% of gestation); Group II (4.5–7.2 cm CRL; 67–90 days, 25–35% of gestation); Group III (8–19 cm CRL; 97–135 days, 35–50% of gestation); Group IV (21–33 cm CRL; 142–191 days, 50–70% of gestation); and Group V (36–40 cm CRL; 205–235 days, 75–100% of gestation). At 67 embryonic days, the omasum wall was differentiated, and comprised three layers: the epithelial layer, pluripotential blastemic tissue and serosa. The stratification of the epithelial layer was accompanied by changes in its structure, with the appearance of four laminae of different sizes; in order of appearance these were: primary at 67 days, secondary at 90 days, tertiary at 97 days and quaternary at 135 days. At around mid‐gestation, lateral evaginations were formed from the stratum basale of the primary and secondary smaller laminae. These were the primitive corneum papillae. From 205 days, the corneum papillae were present in all four sizes of laminae. The histodifferentiation of the lamina propia‐submucosa, tunica muscularis and serosa showed patterns of development similar to those reported for the rumen and reticulum of red deer. The omasum of red deer during prenatal life, especially from 67 days of gestation, was shown to be an active structure with full secretory capacity. Its histological development, its secretory capacity (detected by the presence of neutral mucopolysaccharides) and its neuroendocrine nature (detected by the presence of positive non‐neuronal enolase cells and the neuropeptides vasoactive intestinal peptide and neuropeptide Y) were parallel to the development of the rumen and the reticulum. However, its prenatal development was later than that of the omasum in sheep, goat and cow.
Mathematical modelling of cylindrical electromagnetic vibration energy harvesters

In this paper the first steps for the derivation of a mathematical model to describe the mechanical behaviour of a cylindrical electromagnetic vibration energy harvester, designed to extract energy from human gait to power biomedical implantable devices, are provided. As it is usual, in the modelling of such devices, the proposed mechanical model is also based on the solution of Newton's second law, but here a nonlinear closed-form expression is used for the resulting magnetic force of the system, unlike what has been done in previous works where, traditionally, that expression is a linear or is a nonlinear approximation of the real one. The main feature of this mechanical model is that it depends on several parameters which are related to the main characteristics of this kind of devices, which constitutes a major advantage with respect to the usual models available in the literature since these characteristics can always be changed in order to optimize the device.
SENSORY DISORDERS IN CEREBRAL PALSY; TWO‐POINT DISCRIMINATION

Two‐point discrimination (TPD) was measured on eight points of the upper extremities of 220 children with cerebral palsy aged between seven and 14 years. 46 had classical diplegia, 23 had mildly spastic diplegia (without adductor spasms), 86 had hcmiplegia, 26 had generalized dyskinesia, 10 had right‐ and four had left‐sided. hemiathetosis and 25 had quadriplegia. TPD was decreased in all cases compared with normal controls: slightly more for the classical forms of diplegia and on the paretic side of those with hemiplegia, slightly less in athetoid children. This adds further evidence to the authors' previous observations that sensory disorder is an integral part of the clinical picture of cerebral palsy.
Identification of Conserved miRNAs in Solanum Lycopersicum Response to Long-term RPM-treatment

 Abstract—T o identify the miRNAs associated with the simulated microgravity response in plants and to ascertain the regulation network mediated by miRNAs under simulated microgravity conditions, we constructed a miRNA library by direct cloning method and analyzed the library. Six conserved Solanum lycopersicum miRNAs were identified for the first time in Solanum lycopersicum under simulated microgravity condition. Gene ontology analysis showed that most of the predicted targeted genes were involved in organelle part, transcription factor, signal transduction and metabolic process, implying a complicated relationship among the external signal, internal transduction and final phenotype. Cis-elements located in the upstream sequences of each miRNA were identified and their roles in gene regulation were investigated. In the study, miRNAs were identified in S. lycopersicum for the first time under long-term simulated microgravity condition, which will help reveal the regulation mechanism mediated by miRNAs under simulated microgravity condition and adaptation to Earth’s gravity.