Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of ageing and senescence on pancreatic β‐cell function

Ageing is generally associated with deterioration of organ function and regenerative potential. In the case of pancreatic β‐cells, an age‐related decline in proliferative potential is well documented, and was proposed to contribute to the increased prevalence of type 2 diabetes in the elderly. The effects of ageing on β‐cell function, namely glucose‐stimulated insulin secretion (GSIS), have not been studied as extensively. Recent work revealed that, surprisingly, β‐cells of mature mice and humans secrete more insulin than young β‐cells in response to high glucose concentrations, potentially serving to counteract age‐related peripheral insulin resistance. This functional change appears to be orchestrated by p16Ink4A‐driven cellular senescence and downstream remodelling of chromatin structure and DNA methylation, enhancing the expression of genes controlling β‐cell function. We propose that activation of the cellular senescence program drives life‐long functional maturation of β‐cells, due to β‐cell hypertrophy, enhanced glucose uptake and more efficient mitochondrial metabolism, in parallel to locking these cells in a non‐replicative state. We speculate that the beneficial aspects of this process can be harnessed to enhance GSIS. Other age‐related mechanisms, which are currently poorly understood, act to increase basal insulin secretion levels also in low glucose conditions. This leads to an overall reduction in the amplitude of insulin secretion between low and high glucose at old age, which may contribute to a deterioration in metabolic control.
Ambient air pollutant concentrations during pregnancy and the risk of fetal growth restriction

Background: Previous studies of air pollution and birth outcomes have not evaluated whether complicated pregnancies might be susceptible to the adverse effects of air pollution. It was hypothesised that trimester mean pollutant concentrations could be associated with fetal growth restriction, with larger risks among complicated pregnancies. Methods: A multiyear linked birth certificate and maternal/newborn hospital discharge dataset of singleton, term births to mothers residing in New Jersey at the time of birth, who were white (non-Hispanic), African–American (non-Hispanic) or Hispanic was used. Very small for gestational age (VSGA) was defined as a fetal growth ratio <0.75, small for gestational age (SGA) as ⩾0.75 and <0.85, and ‘reference’ births as ⩾0.85. Using polytomous logistic regression, associations between mean pollutant concentrations during the first, second and third trimesters and the risks of SGA/VSGA were examined, as well as effect modification of these associations by several pregnancy complications. Results: Significantly increased risk of SGA was associated with first and third trimester PM2.5 (particulate matter <2.5 μm in aerodynamic diameter), and increased risk of VSGA associated with first, second and third trimester nitrogen dioxide (NO2) concentrations. Pregnancies complicated by placental abruption and premature rupture of the membrane had ∼two- to fivefold greater excess risks of SGA/VSGA than pregnancies not complicated by these conditions, although these estimates were not statistically significant. Conclusions: These findings suggest that ambient air pollution, perhaps specifically traffic emissions during early and late pregnancy and/or factors associated with residence near a roadway during pregnancy, may affect fetal growth. Further, pregnancy complications may increase susceptibility to these effects in late pregnancy.
Role of Ocean Model Formulation in Climate Response Uncertainty

Oceanic heat uptake (OHU) is a significant source of uncertainty in both the transient and equilibrium responses to increasing the planetary radiative forcing. OHU differs among climate models and is related in part to their representation of vertical and lateral mixing. This study examines the role of ocean model formulation—specifically the choice of the vertical coordinate and the strength of the background diapycnal diffusivity Kd—in the millennial-scale near-equilibrium climate response to a quadrupling of atmospheric CO2. Using two fully coupled Earth system models (ESMs) with nearly identical atmosphere, land, sea ice, and biogeochemical components, it is possible to independently configure their ocean model components with different formulations and produce similar near-equilibrium climate responses. The SST responses are similar between the two models (r2 = 0.75, global average ~4.3°C) despite their initial preindustrial climate mean states differing by 0.4°C globally. The surface and interior responses of temperature and salinity are also similar between the two models. However, the Atlantic meridional overturning circulation (AMOC) responses are different between the two models, and the associated differences in ventilation and deep-water formation have an impact on the accumulation of dissolved inorganic carbon in the ocean interior. A parameter sensitivity analysis demonstrates that increasing the amount of Kd produces very different near-equilibrium climate responses within a given model. These results suggest that the impact of the ocean vertical coordinate on the climate response is small relative to the representation of subgrid-scale mixing.
Factors Determining the Specificity of Signal Transduction by Guanine Nucleotide-binding Protein-coupled Receptors

To define the integration of multiple signals by different types of adenylyl cyclase (AC) within the cell, we altered the population of enzymes expressed in the cell and determined the subsequent processing of stimulatory and inhibitory input. DDT1-MF2 cells expressed AC VI–IX and were stably transfected with AC II, III, or IV. Enzyme expression was confirmed by RNA blot analysis and functional assays. Basal enzyme activity was only increased in AC II transfectants (6-fold). Maximum stimulation of enzyme activity was increased in each of the AC transfectants to varying extents. α2A/D-AR activation elicited enzyme type-specific responses. α2-AR activation inhibited the effect of isoproterenol in control transfectants, and this action was magnified in AC III transfectants. In AC II and AC IV transfectants, α2-AR activation initiated both positive (Gβγ) and negative signals (Giα) to the Gsα-stimulated enzyme, and both types of signals were blocked by cell pretreatment with pertussis toxin. The negative input to AC II from the α2-AR was blocked by protein kinase C activation in AC II transfectants, but it was the positive input to AC IV that was compromised by protein kinase C activation. These data indicate that the integration of multiple signals by adenylyl cyclases is a dynamic process depending upon the enzyme type and phosphorylation status.
The Coconino Sandstone (Permian, Arizona, USA): Implications for the origin of ancient cross-bedded sandstones

The Permian Coconino Sandstone is one of the most prominent layers of rock in the Grand Canyon and is important to creationists because it has often been used by conventional scientists to discredit the Bible since it is a supposed windblown (eolian) deposit. Their argument is that deposits like this would be impossible to form in the midst of a global flood as described in Genesis. Over the past forty years, new data has been collected by us and others that we believe indisputably identifies the Coconino as a subaqueous sandstone--data that will be difficult for our critics to counter. These data include evidence from petrology, fossil footprint studies, sedimentology, regional stratigraphy and soft sediment deformation features. In our studies we found that there are many misconceptions or “urban myths” about the Coconino Sandstone including its grain roundness, grain sorting, grain frosting and angle of cross-bed dips. There are no modern analogs that match the precise sedimentology of the Coconino, but we believe that subaqueous sand waves may be a start in the right direction to understand how the Coconino was deposited. Instead of the Coconino being a problem for creationists, it can be one of our most powerful arguments in support of the biblical account of the Flood. There are many other similar cross-bedded sandstones around the world; the Coconino may be the key to unlocking their origin as well.
Distinct activation of an E2 ubiquitin-conjugating enzyme by its cognate E3 ligases

Significance Ubiquitin (Ub) conjugation triggers protein degradation by the proteasome. Here we describe an unexplored feature of the Ub conjugation system that entails differential activation of an E2-conjugating enzyme by its cognate E3 Ub ligases. In vitro and in vivo analyses of activity-reducing mutants of the yeast Ub-conjugating (Ubc) enzyme, Ubc7, demonstrated selective activation by one of its two cognate E3 ligases, Hrd1, but not by the other, Doa10. Supported by structural modeling of the RING:Ubc7∼Ub complex, these findings are consistent with a model whereby the E2∼Ub transition state depends on noncovalent interactions between helix α2 of Ubc7 and Ub that are differentially stabilized by the two E3 RING domains. This differential activation represents a previously unidentified mechanism for regulating protein ubiquitylation. A significant portion of ubiquitin (Ub)-dependent cellular protein quality control takes place at the endoplasmic reticulum (ER) in a process termed “ER-associated degradation” (ERAD). Yeast ERAD employs two integral ER membrane E3 Ub ligases: Hrd1 (also termed “Der3”) and Doa10, which recognize a distinct set of substrates. However, both E3s bind to and activate a common E2-conjugating enzyme, Ubc7. Here we describe a novel feature of the ERAD system that entails differential activation of Ubc7 by its cognate E3s. We found that residues within helix α2 of Ubc7 that interact with donor Ub were essential for polyUb conjugation. Mutagenesis of these residues inhibited the in vitro activity of Ubc7 by preventing the conjugation of donor Ub to the acceptor. Unexpectedly, Ub chain formation by mutant Ubc7 was restored selectively by the Hrd1 RING domain but not by the Doa10 RING domain. In agreement with the in vitro data, Ubc7 α2 helix mutations selectively impaired the in vivo degradation of Doa10 substrates but had no apparent effect on the degradation of Hrd1 substrates. To our knowledge, this is the first example of distinct activation requirements of a single E2 by two E3s. We propose a model in which the RING domain activates Ub transfer by stabilizing a transition state determined by noncovalent interactions between the α2 helix of Ubc7 and Ub and that this transition state may be stabilized further by some E3 ligases, such as Hrd1, through additional interactions outside the RING domain.
Accidental Injections of Dexamethasone Intravitreal Implant (Ozurdex®) into the Crystalline Lens

Purpose To describe the side effects and management after inadvertent injection of a dexamethasone implant (Ozurdex®) into the crystalline lens. Methods Two case reports. Results Two patients with macular edema due to unilateral retinal vein occlusion were scheduled for an intravitreal injection of Ozurdex®. During the procedure, the implant was accidentally injected into the crystalline lens. Both patients developed cataracts during the course of several weeks and in both there was an intraocular pressure (IOP) increase, which required treatment with topical hypotensives. Macular edema improved only slightly. Cataract surgery with uneventful removal of the implant was performed 3 (case 1) and 6 months (case 2) after the injection. Conclusions After inadvertent injection of Ozurdex® into the crystalline lens, cataract surgery with removal of the implant should be performed as soon as possible in order to avoid IOP increase and so that the underlying condition may be treated adequately.
Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen.

BACKGROUND The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). PATIENTS AND METHODS This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). RESULTS The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2-4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P<0.03). CONCLUSIONS The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.
On the Voice-Activated Question Answering

Question answering (QA) is probably one of the most challenging tasks in the field of natural language processing. It requires search engines that are capable of extracting concise, precise fragments of text that contain an answer to a question posed by the user. The incorporation of voice interfaces to the QA systems adds a more natural and very appealing perspective for these systems. This paper provides a comprehensive description of current state-of-the-art voice-activated QA systems. Finally, the scenarios that will emerge from the introduction of speech recognition in QA will be discussed.
Trans-umbilical Laparoscopic Appendectomy for Acute Appendicitis without Raising Skin-flaps: An Easy-to-use Modification Applied to the Series of 164 Patients from a Rural Institute of Central India

Background: Laparoscopic appendectomy (LA) is widely used and generally an accepted method for managing appendicitis. And the recent invention of laparoscopic trans-umbilical-appendectomy is a further improvement of LA. However, it requires expensive instruments with the requisite expertise. We discuss a useful modification of trans-umbilical appendectomy for acute appendicitis using routine instruments. Materials and Methods: From August 2009 to March 2011, 164 patients were operated by this method at our rural center. Out of them, 102 were males and 62, females. Mean age for males was 27.5 years (range, 14-51) and females, 31.2 years (range, 17-48). Mean body mass index was 21.7 kg/m2 (range, 16.2-29) and 23.2 kg/m2 (range, 17.4-30) for males and females respectively. Acute appendicitis patients wherein surgery was deemed essential were offered this technique. Three umbilical ports (one 10 mm and two 5 mm) were strategically placed to dissect out appendix. Routine laparoscopic instruments were used for all. Results: Mean operativetime was 45 min (range, 30-90) with 1.8% conversion-rate to conventional laparoscopy. Average blood-loss was 15 ml (range, 10-25). We had one caecal electrosurgical injury, which was managed expectantly. Umbilical sepsis and seroma were 3% and 6.1% respectively. Patients were discharged after an average 1.3 days (range, 1-4). The scars had receded in the umbilicus giving a near-scarless abdomen. Discussion: Recently developed technique of single-port appendectomy has primarily been used for chronic appendicitis. Moreover, >1 inch incision inducted per-umbilicum rises the attendant morbidity. We study a surgeon-friendly simple technique applied to acute appendicitis. Conclusion: Method described here is feasible and safe for managing acute appendicitis. It can be learnt rather easily (learning curve of 15 cases) by a laparoscopic surgeon and avoids expensive instrumentation. Thus, it may stand out in providing benefits of modern surgery to population of developing countries.
Contrasting degrees of recrystallization of carbonaceous material in the Nelson aureole, British Columbia and Ballachulish aureole, Scotland, with implications for thermometry based on Raman spectroscopy of carbonaceous material

The degree of recrystallization of carbonaceous material (CM), as monitored by Raman microspectroscopy, was examined as a function of metamorphic grade in two well‐studied contact aureoles containing carbonaceous pelites: the Nelson aureole, British Columbia and the Ballachulish aureole, Scotland. Here, we use (a) the R2 ratio extracted from the Raman spectrum of CM as a proxy for the degree of graphitization (0.0 in perfect graphite then increasing with structural defects) and (b) the second‐order S1 band (~2,700 cm−1) as a marker for the tridimensional ordering of CM. The Nelson aureole (garnet–staurolite–andalusite–sillimanite–K‐feldspar sequence, ~550–650°C, 3.5–4.0 kbar) was developed in rocks that were unmetamorphosed prior to contact metamorphism, whereas the Ballachulish aureole (cordierite–andalusite–K‐feldspar–sillimanite sequence, ~550–700°C, ~3.0 kbar) was developed in rocks that had been metamorphosed to garnet grade conditions (~7 kbar, ~500°C) c. 45 Ma before contact metamorphism. Thirty‐one samples were examined from Nelson and 29 samples from Ballachulish. At Nelson, the R2 ratio steadily decreases from ~0.25 to 0.0 as the igneous contact is approached, whereas at Ballachulish, the R2 ratio remains largely unchanged from regional values (~0.20–0.25) until less than 100 m from the igneous contact. The second‐order S1 band reveals that carbonaceous material (CM) was transformed to highly “ordered” locally tridimensional graphitic carbon at Ballachulish by regional metamorphism prior to contact metamorphism, whereas CM was still a disordered turbostratic (bidimensional) material before contact metamorphism in the case of Nelson. Pretexturation of CM likely induced sluggish recrystallization of CM and delayed graphitization in the Ballachulish aureole. Temperatures of recrystallization of the CM in the two aureoles were estimated using different published calibrations of the thermometry based on Raman Spectroscopy of Carbonaceous Material (RSCM), with differences among the calibrations being minor. In the Nelson aureole, temperatures are in reasonable agreement with those indicated by the metapelitic phase equilibria (all within 50°C, most within 25°C). In the Ballachulish aureole, the retarded crystallization noted above results in increasing underestimates of temperatures compared to the metapelitic phase equilibria (up to ~75°C too low within 200 m of the igneous contact). Our study calls for careful attention when using RSCM thermometry in complexly polymetamorphosed rocks to assess properly the meaning of the calculated temperature.
Production of Native Bispecific Antibodies in Rabbits

Background A natural bispecific antibody, which can be produced by exchanging Fab arms of two IgG4 molecules, was first described in allergic patients receiving therapeutic injections with two distinct allergens. However, no information has been published on the production of natural bispecific antibody in animals. Even more important, establishment of an animal model is a useful approach to investigate and characterize the naturally occurring antibody. Methodology/Principal Findings We demonstrated that a natural bispecific antibody can also be generated in New Zealand white rabbits by immunization with synthesized conjugates. These antibodies showed bispecificity to the components that were simultaneously used to immunize the animals. We observed a trend in our test animals that female rabbits exhibited stronger bispecific antibody responses than males. The bispecific antibody was monomeric and primarily belonged to immunoglobulin (Ig) G. Moreover, bispecific antibodies were demonstrated by mixing 2 purified monospecific antibodies in vivo and in vitro. Conclusions/Significance Our results extend the context of natural bispecific antibodies on the basis of bispecific IgG4, and may provide insights into the exploration of native bispecific antibodies in immunological diseases.
Directly characterizing the relative strength and momentum dependence of electron-phonon coupling using resonant inelastic x-ray scattering

T. P. Devereaux,1, 2 A. M. Shvaika,3 K. Wu,1 K. Wohlfeld,4 C. J. Jia,1 Y. Wang,1 B. Moritz,1 L. Chaix,1 W. -S. Lee,1 Z. -X. Shen,1, 2, 5 G. Ghiringhelli,6 and L. Braicovich6 Stanford Institute for Materials and Energy Sciences, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025. Geballe Laboratory for Advanced Materials, Stanford University, CA 94305. Institute for Condensed Matter Physics of the National Academy of Sciences of Ukraine, Lviv, 79011 Ukraine. Institute of Theoretical Physics, Faculty of Physics, University of Warsaw, Pasteura 5, PL-02093 Warsaw, Poland Dept. of Physics and Applied Physics, Stanford University, CA 94305. CNR-SPIN and Dipartimento di Fisica, Politecnico di Milano, I-20133 Milano, Italy. (Dated: May 11, 2016)
Animal Models of CNS Viral Disease: Examples from Borna Disease Virus Models

Borna disease (BD), caused by the neurotropic RNA virus, Borna Disease virus, is an affliction ranging from asymptomatic to fatal meningoencephalitis across naturally and experimentally infected warmblooded (mammalian and bird) species. More than 100 years after the first clinical descriptions of Borna disease in horses and studies beginning in the 1980's linking Borna disease virus to human neuropsychiatric diseases, experimentally infected rodents have been used as models for examining behavioral, neuropharmacological, and neurochemical responses to viral challenge at different stages of life. These studies have contributed to understanding the role of CNS viral injury in vulnerability to behavioral, developmental, epileptic, and neurodegenerative diseases and aided evaluation of the proposed and still controversial links to human disease.