Miracle-dz/UniFAR-FTUs huggingface dataset:
Brain histamine H1 receptor occupancy of orally administered antihistamines, bepotastine and diphenhydramine, measured by PET with 11C-doxepin.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT 'Bepotastine besilate' is a novel second-generation antihistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies. However, only a few clinical studies regarding its sedative property are available. In addition, histamine H(1) receptor occupancy (H(1)RO) of this new antihistamine has never been measured by positron emission tomography (PET). WHAT THIS STUDY ADDS This paper provides the first measurement result of cerebral H(1)RO of bepotastine besilate (approximately 15%) as determined by PET. This result is in accordance with the clinical classification of bepotastine as a second-generation antihistamine. In addition, the relationship between subjective sleepiness and cerebral H(1)RO of this second-generation antihistamine is demonstrated for the first time using a placebo-controlled crossover study design. AIMS Antihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H(1) receptor occupancy (H(1)RO) in the brain using positron emission tomography (PET). The aim was to measure H(1)RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine. METHODS Eight healthy male volunteers (mean age +/- SD 24.4 +/- 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with (11)C-doxepin in a crossover study design. Binding potential ratio and H(1)ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antihistamine was measured, and its correlation to H(1)RO was examined. RESULTS H(1)RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H(1)ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H(1)ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001). CONCLUSION Oral bepotastine (10 mg), with its relatively low H(1)RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders.
ABCB1 polymorphisms may have a minor effect on ciclosporin blood concentrations in myasthenia gravis patients.

AIMS Ciclosporin (CsA), which is widely used in autoimmune disease and transplantation, has a narrow therapeutic index. It also shows considerable interindividual variability in its pharmacokinetics, which may be attributable to polymorphisms of the multidrug efflux pump P-glycoprotein, encoded by MDR-1. The aim was to determine the role of genetic polymorphisms in MDR-1 with respect to interindividual variability of CsA blood concentrations in myasthenia gravis (MG) patients. METHODS MG patients (n = 129) receiving CsA were genotyped for MDR-1 1236C-->T (exon 12), 2677G-->T (exon 21) and 3435C-->T (exon 26). Trough blood and peak blood concentrations were determined to see if there was correlation with the corresponding genotype. RESULTS We observed a trend for CsA blood concentrations, especially peak blood concentrations, to be higher with the wild-type allele compared with minor alleles in genotype and haplotype. Furthermore, under the same CsA regimen, it was found that the trough concentrations of variant genotype (ABCB1 1236TT or ABCB1 2677TT) were significant greater than those of wild-type (ABCB1 1236CC or ABCB1 2677GG, respectively) (P = 0.0222 and 0.0081). The trough concentrations of wild-type haplotype pair group were significantly lower those that of the mutant type pair group (TT-TT-TT) (P = 0.007). CONCLUSIONS ABCB1 polymorphisms in both genotype and haplotype may have a minor effect on the CsA blood concentrations.
Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers

Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-Å X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.
Separation of stem cell maintenance and transposon silencing functions of Piwi protein

Piwi-interacting RNAs (piRNAs) and Piwi proteins have the evolutionarily conserved function of silencing of repetitive genetic elements in germ lines. The founder of the Piwi subfamily, Drosophila nuclear Piwi protein, was also shown to be required for the maintenance of germ-line stem cells (GSCs). Hence, null mutant piwi females exhibit two types of abnormalities, overexpression of transposons and severely underdeveloped ovaries. It remained unknown whether the failure of GSC maintenance is related to transposon derepression or if GSC self-renewal and piRNA silencing are two distinct functions of the Piwi protein. We have revealed a mutation, piwiNt, removing the nuclear localization signal of the Piwi protein. piwiNt females retain the ability of GSC self-renewal and a near-normal number of egg chambers in the ovarioles but display a drastic transposable element derepression and nuclear accumulation of their transcripts in the germ line. piwiNt mutants are sterile most likely because of the disturbance of piRNA-mediated transposon silencing. Analysis of chromatin modifications in the piwiNt ovaries indicated that Piwi causes chromatin silencing only of certain types of transposons, whereas others are repressed in the nuclei without their chromatin modification. Thus, Piwi nuclear localization that is required for its silencing function is not essential for the maintenance of GSCs. We suggest that the Piwi function in GSC self-renewal is independent of transposon repression and is normally realized in the cytoplasm of GSC niche cells.
POLITECNICO DI TORINO Repository ISTITUZIONALE Copper-containing mesoporous bioactive glass nanoparticles as multifunctional agent for bone regeneration /

The application of mesoporous bioactive glasses (MBGs) containing controllable amount of different ions, with the aim to impart antibacterial activity, as well as stimulation of osteogenesis and angiogenesis, is attracting an increasing interest. In this contribution, in order to endow nano-sized MBG with additional biological functions, the framework of a binary SiO2-CaO mesoporous glass was modified with different concentrations of copper ions (2 and 5% mol.), through a one-pot ultrasound-assisted sol-gel procedure. The Cu-containing MBG (2% mol.) showed high exposed surface area (550 m g ), uniform mesoporous channels (2.6 nm), remarkable in vitro bioactive behaviour and sustained release of Cu ions. Cu-MBG nanoparticles and their ionic dissolution extracts exhibited antibacterial effect against three different bacteria strains, E. coli, S. aureus, S. epidermidis, and the ability to inhibit and disperse the biofilm produced by S. epidermidis. The obtained results suggest that the developed material, which combines in single multifunctional agent excellent bioactivity and antimicrobial ability, offers promising opportunities for the prevention of infectious diseases and the effective treatment of bone defects. Statement of Significance In order to endow mesoporous bioactive glass, characterized by excellent bioactive properties, with additional biological functions, Cu-doped mesoporous SiO2-CaO glass (Cu-MBG) in the form of nanoparticles was prepared by an ultra-sound assisted one pot synthesis. Statement of Significance: The analysis of the bacterial viability, using different bacterial strains, and the morphological observation of the biofilm produced by the Staphylococcus epidermidis, revealed the antimicrobial effectiveness of the Cu-MBG and the relative ionic extracts against both the bacterial growth and the biofilm formation/dispersion, providing a true alternative to traditional antibiotic sys-
Motor Speech Disorders

The authors have limited consideration of motor speech disorders to dysarthrias of neurogenic nature. Aphasias (defined by the authors as problems of processing and symbolic formulation of the language code) are excluded. So are the deviant patterns of speech, such as developmental disorders of articulation and those disorders arising from structural impairments, such as cleft palate. A short but useful review of the basic motor process of speech production and its evaluation by clinical and other techniques is included. A more detailed description of relatively unfamiliar methods, such as palatography and videofluoroscopy would have been desirable. The neurologist will find the chapters on principles of neurologic function and hierarchy of motor organization rather basic. Other specialists may find these useful. On the other hand, many speech pathologists may find the section on motor speech examination somewhat devoid of detail. A disproportionately large space is allotted to the examination of the
Factors Predicting Total Free Flap Loss after Microsurgical Reconstruction Following the Radical Ablation of Head and Neck Cancers

Background. With greater experience in microsurgical reconstruction, free tissue transfer has become common and reliable. However, total flap necrosis after microsurgical reconstruction is sometimes seen in patients who have undergone radical ablation of head and neck malignancies. We investigated factors predicting free flap loss in head and neck reconstruction. Methods. We reviewed the records of 111 free flap reconstructions carried out among 107 patients with head and neck cancer who required radical resection and microsurgical reconstruction in our unit from 2004 through 2010. Among these patients, 6 showed total flap necrosis postoperatively. We investigated the associations between primary or recurrent tumor, type of flaps, chemotherapy, and radiotherapy and flap loss. Results. Five of 20 (25.0%) patients who underwent radiotherapy developed flap necrosis: among the 91 patient who did not undergo radiotherapy, only one (1.1%) developed. Preoperative radiotherapy was statistically identified as the most important risk factor for postoperative flap failure. Conclusions. Patients receiving radiation treatment are more likely to develop total flap failure when they undergo reconstructive surgery with free flaps after tumor ablation, because the combination of endarteritis and chronic ischemia caused by radiation damaged endothelial membrane in the recipient vessels, consequently, thrombosis tends to develop.
In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release

Understanding the molecular principles of synaptic vesicle fusion is a long-sought goal. It requires the development of a synthetic system that allows manipulations and observations not possible in vivo. Here, we report an in vitro system with reconstituted synaptic proteins that meets the long-sought goal to produce fast content release in the millisecond time regime upon Ca2+ triggering. Our system simultaneously monitors both content and lipid exchange, and it starts from stable interacting pairs of donor and acceptor vesicles, mimicking the readily releasable pool of synaptic vesicles prior to an action potential. It differentiates between single-vesicle interaction, hemifusion, and complete fusion, the latter mimicking quantized neurotransmitter release upon exocytosis of synaptic vesicles. Prior to Ca2+ injection, the system is in a state in which spontaneous fusion events between donor and acceptor vesicles are rare. Upon Ca2+ injection, a rapid burst of complete fusion events emerges, followed by a biphasic decay. The present study focuses on neuronal SNAREs, the Ca2+ sensor synaptotagmin 1, and the modulator complexin. However, other synaptic proteins could be added and their function examined. Ca2+ triggering is cooperative, requiring the presence of synaptotagmin, whereas SNAREs alone do not produce a fast fusion burst. Manipulations of the system mimic effects observed in vivo. These results also show that neuronal SNAREs alone do not efficiently produce complete fusion, that the combination of SNAREs with synaptotagmin lowers the activation barriers to full fusion, and that complexin enhances this kinetic control.
Piezosurgery And Its Applications In Periodontology And Implantology

ABSTRACT: The piezosurgery instrument, developed in 1988, uses a modulated ultrasonic frequency that permits highly precise and safe cutting of hard tissue. Nerves, vessels, and soft tissue are not injured by the microvibrations (60 to 200 mm/sec), which are optimally adjusted to target only mineralized tissue. The selective and thermally harmless nature of the piezosurgery instrument results in a low bleeding tendency. The precise nature of the instrument allows exact, clean, and smooth cut geometries during surgery. Postoperatively, excellent wound healing, with no nerve and soft tissue injuries, is observed. Because of its highly selective and accurate nature, with its cutting effect exclusively targeting hard tissue, its use may be extended to more complex oral surgery cases, as well as to other interdisciplinary problems. Key Words: Ultrasonic, microvibrations, piezoelectric, osteotomies, macrovibration
25th Anniversary Article: Semiconductor Nanowires – Synthesis, Characterization, and Applications

Semiconductor nanowires (NWs) have been studied extensively for over two decades for their novel electronic, photonic, thermal, electrochemical and mechanical properties. This comprehensive review article summarizes major advances in the synthesis, characterization, and application of these materials in the past decade. Developments in the understanding of the fundamental principles of “bottom‐up” growth mechanisms are presented, with an emphasis on rational control of the morphology, stoichiometry, and crystal structure of the materials. This is followed by a discussion of the application of nanowires in i) electronic, ii) sensor, iii) photonic, iv) thermoelectric, v) photovoltaic, vi) photoelectrochemical, vii) battery, viii) mechanical, and ix) biological applications. Throughout the discussion, a detailed explanation of the unique properties associated with the one‐dimensional nanowire geometry will be presented, and the benefits of these properties for the various applications will be highlighted. The review concludes with a brief perspective on future research directions, and remaining barriers which must be overcome for the successful commercial application of these technologies.
A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL

Abstract The role of Ribonuclease H1 (RNase H1) during primer removal and ligation at the mitochondrial origin of light-strand DNA synthesis (OriL) is a key, yet poorly understood, step in mitochondrial DNA maintenance. Here, we reconstitute the replication cycle of L-strand synthesis in vitro using recombinant mitochondrial proteins and model OriL substrates. The process begins with initiation of DNA replication at OriL and ends with primer removal and ligation. We find that RNase H1 partially removes the primer, leaving behind the last one to three ribonucleotides. These 5′-end ribonucleotides disturb ligation, a conclusion which is supported by analysis of RNase H1-deficient patient cells. A second nuclease is therefore required to remove the last ribonucleotides and we demonstrate that Flap endonuclease 1 (FEN1) can execute this function in vitro. Removal of RNA primers at OriL thus depends on a two-nuclease model, which in addition to RNase H1 requires FEN1 or a FEN1-like activity. These findings define the role of RNase H1 at OriL and help to explain the pathogenic consequences of disease causing mutations in RNase H1.
Trends in prescribing and self-poisoning in relation to UK regulatory authority warnings against use of SSRI antidepressants in under-18-year-olds.

AIMS To assess the impact of the UK Medicines and Healthcare products Regulatory Authority (MHRA) warning in December 2003 not to prescribe selective serotonin reuptake inhibitor (SSRI) antidepressants, except fluoxetine, to under-18-year-olds. METHODS Interrupted time series analysis of prescriptions (UK) and general hospital presentations for nonfatal self-poisoning (three centres in England) for 2000-2006. RESULTS Following the MHRA warning in December 2003 there were significant decreases in prescribing of SSRI antidepressants (conservative estimate 51%) to young people aged 12-19 years. Surprisingly, this decrease also affected fluoxetine (conservative estimate 20%) and tricyclics (conservative estimate 27%). Nonfatal self-poisoning in this age group following the warning also declined significantly for SSRIs (conservative estimate 44%), but not for fluoxetine, tricyclic antidepressants, or all drugs and other substances. Rates of nonfatal self-harm did not change significantly over the study period. CONCLUSIONS The reduction in both prescribing and self-poisoning with SSRI antidepressants (except fluoxetine) following the MHRA warning is in keeping with reduced availability of these drugs. There was some evidence of substitution from other SSRIs to fluoxetine for use in self-poisoning. Importantly, overall rates of nonfatal self-harm and self-poisoning did not change, indicating no substitution of method or increases in self-injury.
Investigation of endothelial function by pulse contour analysis: a protocol for drug administration and timing of pulse contour assessment.

AIMS Pulse contour analysis (PCA) obtained by finger photoplethysmography produces a digital volume pulse (DVP) including an inflection point in its down-slope. The reflection index (RI: ratio of the inflection point height over the maximal DVP) is responsive to vasodilatation. We aimed to optimize the drug dose and time interval for assessing endothelial function using PCA in healthy volunteers and patients with severe coronary artery disease. METHODS Time and dose to RI response relationships were constructed in 16 volunteers and nine patients to inhaled salbutamol (100-400 microg) or sublingual nitroglycerin (NTG; 25-400 microg). RESULTS For the volunteers, the time to maximum RI response to inhaled salbutamol and sublingual NTG was 10.73 +/- 0.41 and 3.66 +/- 0.21 min, respectively. A plateau in the RI response to salbutamol occurred between 5 and 15 min after inhalation and results were averaged over this period. A dose-dependent response was observed to inhaled salbutamol and sublingual NTG (P= 0.05 and P < 0.001 by repeated-measures anova, respectively) in healthy volunteers. By contrast, in patients with severe coronary artery disease inhaled salbutamol (100-400 microg) did not cause a significant change in RI. CONCLUSIONS In healthy volunteers the RI response to inhaled salbutamol (100-200 microg) averaged over 5-15 min after administration may be used to investigate endothelial function by PCA. The response to sublingual NTG (50 microg) should be determined at 4 min. This technique may not be suitable for the assessment of endothelial function in subjects with extensive coronary artery disease owing to the small responses observed and potential confounding effect of vasoactive medication.
Reconstruction of human elastic cartilage by a CD44+ CD90+ stem cell in the ear perichondrium

Despite the great demands for treating craniofacial injuries or abnormalities, effective treatments are currently lacking. One promising approach involves human elastic cartilage reconstruction using autologous stem/progenitor populations. Nevertheless, definitive evidence of the presence of stem cells in human auricular cartilage remains to be established. Here, we demonstrate that human auricular perichondrium, which can be obtained via a minimally invasive approach, harbors a unique cell population, termed as cartilage stem/progenitor cells (CSPCs). The clonogenic progeny of a single CD44+ CD90+ CSPC displays a number of features characteristic of stem cells. Highly chondrogenic CSPCs were shown to reconstruct large (>2 cm) elastic cartilage after extended expansion and differentiation. CSPC-derived cartilage was encapsulated by a perichondrium layer, which contains a CD44+ CD90+ self-renewing stem/progenitor population and was maintained without calcification or tumor formation even after 10 mo. This is a unique report demonstrating the presence of stem cells in auricular cartilage. Utilization of CSPCs will provide a promising reconstructive material for treating craniofacial defects with successful long-term tissue restoration.
Polymorphism of G4 associates: from stacks to wires via interlocks

Abstract We examined the assembly of DNA G-quadruplexes (G4s) into higher-order structures using atomic force microscopy, optical and electrophoretic methods, NMR spectroscopy and molecular modeling. Our results suggest that parallel blunt-ended G4s with single-nucleotide or modified loops may form different types of multimers, ranging from stacks of intramolecular structures and/or interlocked dimers and trimers to wires. Decreasing the annealing rate and increasing salt or oligonucleotide concentrations shifted the equilibrium from intramolecular G4s to higher-order structures. Control antiparallel and hybrid G4s demonstrated no polymorphism or aggregation in our experiments. The modification that mimics abasic sites (1′,2′-dideoxyribose residues) in loops enhanced the oligomerization/multimerization of both the 2-tetrad and 3-tetrad G4 motifs. Our results shed light on the rules that govern G4 rearrangements. Gaining control over G4 folding enables the harnessing of the full potential of such structures for guided assembly of supramolecular DNA structures for nanotechnology.
Identification of Chinese plague foci from long-term epidemiological data

Carrying out statistical analysis over an extensive dataset of human plague reports in Chinese villages from 1772 to 1964, we identified plague endemic territories in China (i.e., plague foci). Analyses rely on (i) a clustering method that groups time series based on their time-frequency resemblances and (ii) an ecological niche model that helps identify plague suitable territories characterized by value ranges for a set of predefined environmental variables. Results from both statistical tools indicate the existence of two disconnected plague territories corresponding to Northern and Southern China. Altogether, at least four well defined independent foci are identified. Their contours compare favorably with field observations. Potential and limitations of inferring plague foci and dynamics using epidemiological data is discussed.