Miracle-dz/UniFAR-FTUs huggingface dataset:
Explorer The developmental regulator Pax 6 is essential for maintenance of islet cell function in the adult mouse pancreas

The transcription factor Pax6 is a developmental regulator with a crucial role in development of the eye, brain, and olfactory system. Pax6 is also required for correct development of the endocrine pancreas and specification of hormone producing endocrine cell types. Glucagon-producing cells are almost completely lost in Pax6-null embryos, and insulin-expressing beta and somatostatin-expressing delta cells are reduced. While the developmental role of Pax6 is well-established, investigation of a further role for Pax6 in the maintenance of adult pancreatic function is normally precluded due to neonatal lethality of Pax6-null mice. Here a tamoxifen-inducible ubiquitous Cre transgene was used to inactivate Pax6 at 6 months of age in a conditional mouse model to assess the effect of losing Pax6 function in adulthood. The effect on glucose homeostasis and the expression of key islet cell markers was measured. Homozygous Pax6 deletion mice, but not controls, presented with all the symptoms of classical diabetes leading to severe weight loss requiring termination of the experiment five weeks after first tamoxifen administration. Immunohistochemical analysis of the pancreata revealed almost complete loss of Pax6 and much reduced expression of insulin, glucagon, and somatostatin. Several other markers of islet cell function were also affected. Notably, strong upregulation in the number of ghrelin-expressing endocrine cells was observed. These findings demonstrate that Pax6 is essential for adult maintenance of glucose homeostasis and function of the endocrine pancreas. Citation: Hart AW, Mella S, Mendrychowski J, van Heyningen V, Kleinjan DA (2013) The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas. PLoS ONE 8(1): e54173. doi:10.1371/journal.pone. 0054173 Editor: Renping Zhou, Rutgers University, United States of America Received August 23, 2012; Accepted December 7, 2012; Published January 11, 2013 Copyright: 2013 Hart et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Work at the IGMM Human Genetics Unit is supported by core funding from the Medical Research Council UK (http://www.mrc.ac.uk/). SM was supported by an EU FP6 collaborative grant LSHG-CT-2005-512036. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Dirk-Jan.Kleinjan@igmm.ed.ac.uk
Double minutes arise from circular extrachromosomal DNA intermediates which integrate into chromosomal sites in human HL-60 leukemia cells.

Amplification of oncogenes has been found to be an important prognostic factor in behavior of patients' malignancies. In this study we have used new gel electrophoresis techniques to follow the location of amplified c-myc oncogene sequences in HL-60 promyelocytic leukemia cells. In passages 46-62 of the cells, the cells contain amplified c-myc sequences on submicroscopic circular extrachromosomal DNA (episomes). With increased passages in culture (passages 63-72) the cells lose the episome c-myc sequences with a shift of those sequences to double minutes. With additional passage in culture, the c-myc shifts from the double minutes to a chromosomal site der(5)t(5;17)(q11.2;q? 11.2). Concomitant with the shift of the c-myc sequences into the chromosomal compartment is a phenotypic change of a shortened cell-doubling time. These studies provide the first molecular evidence of a progression from a submicroscopic location for amplified oncogene sequences to a chromosomal location for the amplified sequences. This molecularly documented model can now be used to test various strategies to prevent incorporation of extrachromosomally located oncogene sequences into chromosomal sites. Prevention of integration of the oncogene sequences into chromosomal sites could modulate progression of patients' tumors.
Lateral transmission of tension in frog myofibers: A myofibrillar network and transverse cytoskeletal connections are possible transmitters

The extensibility of the sarcolemma of single myofibers can be reduced locally by leaving a segment covered by a sleeve of surrounding tissue composed of cut myofibers, blood vessels, and connective tissue, hereafter referred to as “the splint. ” Splinted fibers from frog semitendinosus muscle were used to study mechanical connections (transverse coupling) between myofibrillar components and sarcolemma. The transverse coupling is strong enough to insure a tight correlation between myofibril length and overlying sarcolemma length in both resting and activated fibers and to transmit nearly maximum isometric tension to the splint. Lateral transmission of active tension was demonstrated with a preparation which had the distal two‐thirds of an intact fiber covered by a splint and the proximal third dissected clean. When the outer end of the splint was pinned down and only the distal tendon was held, tension generated in the splinted fiber was transmitted to, and recorded from, the splint. Parameters of isometric tension transmitted laterally were not significantly different from those of tension transmitted longitudinally. Myofibrils branch profusely and form a network that may act as a unitary force generator and transmitter. In splinted fibers its output is possibly picked up circumferentially and transmitted across the sarcolemma by a microfilament network. A cap of relatively inextensible sarcolemma “splints” myofiber ends. Resting tension is transmitted to and from the myofibrils by transverse coupling beyond the cap and the region of short sarcomere spacing it covers. Transverse cytoskeletal connections at Z and M regions are described. Immobilization of the sarcolemma allows study of myofibril‐sarcolemma linkage in intact libers. Both active and resting tension were transmitted laterally.
On Optimizing Multicarrier-Low-Density Codebook for GMAC With Finite Alphabet Inputs

Multicarrier-low-density spreading multiple access (MC-LDSMA) is a novel non-orthogonal multiple access scheme, which exploits a multidimensional codebook based on the sparse spreading technique. In this letter, instead of assuming the ideal Gaussian inputs, we contribute to design the sparse spreading codebook with the finite alphabet inputs in an information-theoretic framework. Single user mutual information (SMI) for the system with a generic detection is first derived. Different from the traditional method for maximizing the sum rate, we propose a fairness balanced criterion to maximize the minimal SMI in Gaussian multiple access channels. The modified multistart interior-point algorithm is proposed to obtain the optimal codebook. With the proposed codebook, MC-LDSMA achieves significant performance gains over the previously known schemes in terms of the SMI and bit-error rate.
Reliability and accuracy of a goniometer mobile device application for video measurement of the functional movement screen deep squat test.

BACKGROUND/PURPOSE The squat is a fundamental movement of many athletic and daily activities. Methods to clinically assess the squat maneuver range from simple observation to the use of sophisticated equipment. The purpose of this study was to examine the reliability of Coach's Eye (TechSmith Corp), a 2-dimensional (2D) motion analysis mobile device application (app), for assessing maximal sagittal plane hip, knee, and ankle motion during a functional movement screen deep squat, and to compare range of motion values generated by it to those from a Vicon (Vicon Motion Systems Ltd) 3-dimensional (3D) motion analysis system. METHODS Twenty-six healthy subjects performed three functional movement screen deep squats recorded simultaneously by both the app (on an iPad [Apple Inc]) and the 3D motion analysis system. Joint angle data were calculated with Vicon Nexus software (Vicon Motion Systems Ltd). The app video was analyzed frame by frame to determine, and freeze on the screen, the deepest position of the squat. With a capacitive stylus reference lines were then drawn on the iPad screen to determine joint angles. Procedures were repeated with approximately 48 hours between sessions. RESULTS Test-retest intrarater reliability (ICC3,1) for the app at the hip, knee, and ankle was 0.98, 0.98, and 0.79, respectively. Minimum detectable change was hip 6°, knee 6°, and ankle 7°. Hip joint angles measured with the 2D app exceeded measurements obtained with the 3D motion analysis system by approximately 40°. Differences at the knee and ankle were of lower magnitude, with mean differences of 5° and 3°, respectively. Bland-Altman analysis demonstrated a systematic bias in the hip range-of-motion measurement. No such bias was demonstrated at the knee or ankle. CONCLUSIONS The 2D app demonstrated excellent reliability and appeared to be a responsive means to assess for clinical change, with minimum detectable change values ranging from 6° to 7°. These results also suggest that the 2D app may be used as an alternative to a sophisticated 3D motion analysis system for assessing sagittal plane knee and ankle motion; however, it does not appear to be a comparable alternative for assessing hip motion. LEVEL OF EVIDENCE 3.
Bilobed Flap for Full‐Thickness Nasal Defect: A Common Flap for an Uncommon Indication

A 60-year-old woman was referred to the Mohs surgery unit of the Sant Pau Hospital in March 2000 for the treatment of a tumor of the alar rim and tip of the nose. Histopathological examination showed a sclerodermiform basal cell carcinoma. Four stages of Mohs surgery were needed to excise the entire tumor, which involved part of the nasal cartilage and nasal mucosa, resulting in a fullthickness defect (Figure 1). How would you proceed in this case?
Movements of Na and K in single muscle fibres

The aim of the experiments described here was to investigate the movements of labelled sodium and potassium ions through the surface membrane of single muscle fibres, and to determine the effect of activity on these movements. The advantages of using a single fibre are that the surface area can be measured fairly accurately and that radioactive ions have rapid access to the surface. The second point is important because frog muscle fatigues in a few minutes if stimulated at more than about 3 c/s. Activity can be maintained for long periods at low frequencies but the changes in ionic flux are then too small to be measured accurately. For this reason it is desirable to collect or apply tracer over well-defined periods lasting only a few minutes. This condition is difficult to satisfy with whole muscle. Other disadvantages of whole muscle are the variation in fibre diameter within the muscle and the difficulty of distinguishing between extracellular and intracellular sodium ions. Complications may also arise from the presence of muscle spindles, slow fibres and blood vessels. The disadvantages of the single fibre are the low counting rate associated with the small quantity of tracer inside the fibre and the difficulty of isolating fibres which will survive for long periods of time. However, since neither difficulty is insuperable it seemed desirable to attempt a quantitative analysis of ionic movements along lines similar to those followed in investigating giant nerve fibres (Keynes, 1951). The results agree with the observations of Fenn & Cobb (1936) on mammalian muscle in showing that activity is associated with an entry of sodium ions and a somewhat smaller loss of potassium ions. They also show that labelled K+ and Na+ are lost exponentially from single muscle fibres and that the movements of these ions are of the kind expected in a system in which exchange is limited by a single barrier such as the surface membrane.
QTL for survival to UV-C radiation in Drosophila melanogaster

Abstract Purpose: The aim of this study was to investigate tolerance to UV-C (ultraviolet C, 280–100 nm) radiation in Drosophila melanogaster, implementing a quantitative trait locus (QTL) mapping approach. This is of interest to test for genetic variation in survival to UV (ultraviolet) radiation. Materials and methods: We performed a QTL scan in D. melanogaster recombinant inbred lines (RIL) constructed from parental stocks derived from a crossing between northern and southern hemisphere populations that segregated substantial genetic variation in thermal resistance in a previous study. Here, two experimental treatments were implemented: Continuous and cyclic UV-C radiation. Results: Significant QTL were detected on all three major chromosomes. Among these, multiple trait composite interval mapping revealed a significant QTL in the pericentromeric region of chromosome 2, a genome region consistently implicated in thermotolerance in previous studies. Conclusions: This study shows substantial genetic variation for UV-C radiation resistance in D. melanogaster, with QTL for survival to UV-C radiation generally overlapping with major thermotolerance QTL. The genetic architecture of UV-C radiation resistance appears to be more complex in continuously irradiated individuals.
Tooth Wear Inclination in Great Ape Molars

Primate dietary diversity is reflected in their dental morphology, with differences in size and shape of teeth. In particular, the tooth wear angle can provide insight into a species' ability to break down certain foods. To examine dietary and masticatory information, digitized polygon models of dental casts provide a basis for quantitative analysis of wear associated with tooth attrition. In this study, we analyze and compare the wear patterns of Pongo pygmaeus, Gorilla gorillagorilla and Pan troglodytes schweinfurthii lower molars, focusing on the degree of inclination of specific wear facets. The variation in wear angles appears to be indicative of jaw movements and the specific stresses imposed on food during mastication, reflecting thus the ecology of these species. Orangutans exhibit flatter wear angles, more typical of a diet consisting of hard and brittle foods, while gorillas show a wear pattern with a high degree of inclination, reflecting thus their more leafy diet. Chimpanzees, on the other hand, show intermediate inclinations, a pattern that could be related to their highly variable diet. This method is demonstrated to be a powerful tool for better understanding the relationship between food, mastication and tooth wear processes in living primates, and can be potentially used to reconstruct the diet of fossil species.
UHF RiverSonde Operation in a Tidal Marsh

A UHF RiverSonde radar system was deployed in a tidal marsh during November and December 2005 near Georgetown, South Carolina. The water flow in the marsh was dominated by tidal effects, and the flow pattern was complicated due to the sinuous water channels. A single radar was used, so only the radial component of velocity was observable, but one of the main channels was aligned nearly in the radial direction from the radar antenna so that interpretation of the flow in that channel is relatively straightforward. Acoustic flow measurements are also available for comparison. The radar system performed well, and usable data were obtained under wind speeds of 2–3 m/s. Occasionally some unexpected signals also were seen.
Interactions between bandwidth limited CPLs and MMC based MVDC supply

With the improvement in the power electronic technologies, medium voltage dc (MVDC) electrical distribution systems are being considered for on-shore and off-shore applications. These future MVDC electrical distribution systems are expected to provide the possibility of easy interfacing of the renewable energy sources, improving the dynamics of the system and also help in reducing the carbon footprint of energy sources. Modular multilevel converters (MMCs) are used in high voltage dc (HVDC) applications and are being considered for MVDC applications as well. In this paper, we present an MVDC electrical distribution system where the source converter is an MMC and the loads exhibit bandwidth limited constant power load (CPL) behaviour. An analysis is carried out on the dynamic interactions between the MMC source converter and CPLs, considering varying distribution cable lengths between the source and the load, the filtering effort at the load end and different loading conditions.
Increased medial olivocochlear reflex strength in normal-hearing, noise-exposed humans

Research suggests that college-aged adults are vulnerable to tinnitus and hearing loss due to exposure to traumatic levels of noise on a regular basis. Recent human studies have associated exposure to high noise exposure background (NEB, i.e., routine noise exposure) with the reduced cochlear output and impaired speech processing ability in subjects with clinically normal hearing sensitivity. While the relationship between NEB and the functions of the auditory afferent neurons are studied in the literature, little is known about the effects of NEB on functioning of the auditory efferent system. The objective of the present study was to investigate the relationship between medial olivocochlear reflex (MOCR) strength and NEB in subjects with clinically normal hearing sensitivity. It was hypothesized that subjects with high NEB would exhibit reduced afferent input to the MOCR circuit which would subsequently lead to reduced strength of the MOCR. In normal-hearing listeners, the study examined (1) the association between NEB and baseline click-evoked otoacoustic emissions (CEOAEs) and (2) the association between NEB and MOCR strength. The MOCR was measured using CEOAEs evoked by 60 dB pSPL linear clicks in a contralateral acoustic stimulation (CAS)-off and CAS-on (a broadband noise at 60 dB SPL) condition. Participants with at least 6 dB signal-to-noise ratio (SNR) in the CAS-off and CAS-on conditions were included for analysis. A normalized CEOAE inhibition index was calculated to express MOCR strength in a percentage value. NEB was estimated using a validated questionnaire. The results showed that NEB was not associated with the baseline CEOAE amplitude (r = -0.112, p = 0.586). Contrary to the hypothesis, MOCR strength was positively correlated with NEB (r = 0.557, p = 0.003). NEB remained a significant predictor of MOCR strength (β = 2.98, t(19) = 3.474, p = 0.003) after the unstandardized coefficient was adjusted to control for effects of smoking, sound level tolerance (SLT) and tinnitus. These data provide evidence that MOCR strength is associated with NEB. The functional significance of increased MOCR strength is discussed.
Optimal Sampling of Natural Images

We formulate the problem of optimizing the sampling of natural images using an array of linear filters. Optimization of information capacity is constrained by the noise levels of the individual channels and by a penalty for the construction of long-range interconnections in the array. At low signal-to-noise ratios the optimal filter characteristics correspond to bound states of a Schrodinger equation in which the signal spectrum plays the role of the potential. The resulting optimal filters are remarkably similar to those observed in the mammalian visual cortex and the retinal ganglion cells of lower vertebrates. The observed scale invariance of natural images plays an essential role in this construction.
Coupling between ATP hydrolysis and protein conformational change in maltose transporter

As the intracellular part of maltose transporter, MalK dimer utilizes the energy of ATP hydrolysis to drive protein conformational change, which then facilitates substrate transport. Free energy evaluation of the complete conformational change before and after ATP hydrolysis is helpful to elucidate the mechanism of chemical‐to‐mechanical energy conversion in MalK dimer, but is lacking in previous studies. In this work, we used molecular dynamics simulations to investigate the structural transition of MalK dimer among closed, semi‐open and open states. We observed spontaneous structural transition from closed to open state in the ADP‐bound system and partial closure of MalK dimer from the semi‐open state in the ATP‐bound system. Subsequently, we calculated the reaction pathways connecting the closed and open states for the ATP‐ and ADP‐bound systems and evaluated the free energy profiles along the paths. Our results suggested that the closed state is stable in the presence of ATP but is markedly destabilized when ATP is hydrolyzed to ADP, which thus explains the coupling between ATP hydrolysis and protein conformational change of MalK dimer in thermodynamics. Proteins 2017; 85:207–220. © 2016 Wiley Periodicals, Inc.
Functional identification of cancer-relevant genes through large-scale RNA interference screens in mammalian cells.

stranded RNA (Fire et al. 1998) has provided one of the most powerful tools to manipulate gene expression and this has revolutionized loss-of-function genetics in Caenorhabditis elegans and Drosophila (Ashrafi et al. 2003; Kamath et al. 2003; Lum et al. 2003). In most mammalian cells, however, the introduction of long double-stranded RNA provokes an interferon response, leading to a general shutoff of protein synthesis (Stark et al. 1998). This response can be bypassed by using chemically synthesized, 21-base-pair double-stranded short interfering RNA (siRNAs), which can cause strong, but transient, inhibition of gene expression in nearly all mammalian cells (Elbashir et al. 2001). Indeed, small-scale genetic screens with sets of in vitro synthesized siRNAs have recently been performed in mammalian cells to identify modulators of apoptosis (Aza-Blanc et al. 2003). However, the use of these siRNAs is limited by the transient inhibition of gene expression and their high cost. To circumvent these limitations of siRNAs, we and others have developed expression vectors that direct the synthesis of short hairpin RNAs (shRNAs), which are processed in vivo to siRNA-like molecules that can suppress gene expression over prolonged periods of time (Brummelkamp et al. 2002b; Miyagishi and Taira 2002; Paddison et al. 2002; Sui et al. 2002; Yu et al. 2002). We have recently shown the feasibility of using shRNA vectors to identify loss-of-function phenotypes in mammalian cells by creating a set of vectors to suppress nearly all members of the family of de-ubiquitinating enzymes. Using this approach, we identified the cylindromatosis tumor suppressor gene as a key regulator of the transcription factor NF-κB (Brummelkamp et al. 2003). More recently, we constructed a large set of shRNA vectors that together target some 8000 human genes for suppression (Berns et al. 2004). We discuss here several ways in which such shRNA vector libraries can be used to identify novel components of cancer-relevant pathways.