News Article | March 2, 2017
DUBLIN, Ireland, March 02, 2017 (GLOBE NEWSWIRE) -- Horizon Pharma plc (NASDAQ:HZNP), a biopharmaceutical company focused on improving patients’ lives by identifying, developing, acquiring and commercializing differentiated and accessible medicines that address unmet medical needs, today announced support of a program developed by the National Organization for Rare Disorders (NORD) to help people with Urea Cycle Disorders (UCDs) seeking assistance with high out-of-pocket costs associated with the purchase of medical foods and supplements for their low-protein dietary needs. “Patients' health care needs extend beyond medications and we commend Horizon for being willing to support programs that are aimed at overcoming obstacles to other important treatments,” said Catherine Blansfield, RN, vice president of patient services at NORD. “This donation provides financial support for products, which are essential for good health but, unfortunately, are not commonly covered by health insurance benefits.” The program is independently administered by NORD and available to all people living with UCDs in the United States who meet the NORD eligibility criteria. Horizon provided a charitable grant to help fund the program and has no involvement or input on its administration. “I have to significantly limit the amount of protein I consume to avoid elevated ammonia levels, but the flipside is that too little protein can deprive my body of core amino acids, and that can also lead to high ammonia levels,” said Denise Z., who lives with a type of UCD called Citrullinemia Type 1. “Medical foods and supplements that provide these core nutrients are vital to my health, and that is why this program is so important to those of us in the UCD community who struggle with the day-to-day challenges of living with a UCD.” UCDs are rare genetic disorders that affect approximately 1 in 35,000 people in the United States. It is caused by an enzyme deficiency in the urea cycle, a process that is responsible for converting excess ammonia from the bloodstream and ultimately removing it from the body. Because of this, people with a UCD experience hyperammonemia, or elevated ammonia levels in their blood that can then reach the brain where it can cause irreversible brain damage, coma or death. UCD symptoms may first occur at any age depending on the severity of the disorder, with more severe defects presenting earlier in life. Those with UCDs adhere to a low-protein diet to decrease the nitrogen load of the urea cycle, and receive essential nutrient supplementation to help achieve normal growth and metabolic stability.1 “At Horizon, we are always looking for ways to be supportive, beyond our therapies, for people with rare diseases,” said Robert Metz, senior vice president, business operations and external affairs, Horizon Pharma plc. “We’ve received feedback directly from people living with UCDs, their caregivers and health care professionals about the financial burden that those who require medical foods and supplements face, and are thrilled to support NORD’s UCDs Medical Foods and Supplements Financial Assistance Program.” To learn more about the UCDs Medical Foods and Supplements Financial Assistance Program, patients or their caregivers should contact NORD at 877-333-1860 or UCD@rarediseases.org. About Horizon Pharma plc Horizon Pharma plc is a biopharmaceutical company focused on improving patients' lives by identifying, developing, acquiring and commercializing differentiated and accessible medicines that address unmet medical needs. The Company markets 11 medicines through its orphan, rheumatology and primary care business units. For more information, please visit www.horizonpharma.com. Follow @HZNPplc on Twitter or view careers on our LinkedIn page.
News Article | February 21, 2017
City officials worldwide are bursting blood vessels trying to figure out how to create their own version of Silicon Valley. From the Silicon Hills in Austin, Texas to Silicon Alley in NYC, the Silicon Docks in Ireland’s capital city to Silicon “Wadi” in Israel, potential new global tech hubs are popping up everywhere. Having the right ingredients for innovation to flourish on a scale similar to Silicon Valley will take more than stealing the moniker. The formal elements — an open economy, regulation that supports enterprise, a creative culture and easy access to capital — are the parts of the puzzle that could be implemented anywhere. However, the key ingredient underpinning Silicon Valley’s success, many believe, has been the steady flow of skilled engineers — with an entrepreneurial mindset — coming out of Stanford University. “SV was largely driven by Stanford University — it has become a magnet for attracting the best talent in tech,” says Dr. Damien McLoughlin, professor of marketing and associate dean at University College Dublin (UCD) Michael Smurfit Graduate Business School in Ireland. “As an educator, it does make me wonder what universities elsewhere should be doing differently. Just a few decades ago, all the smartest people worked for universities. Today they’re all in startups.” For tech hubs to thrive, a city or region needs a nearby university, with a strong research and engineering tradition, providing a constant supply of skilled graduates. However, that isn’t enough. “There must also be a culture of tech commercialization within any nearby university,” says Chuck Eesley, assistant professor at Stanford’s Department of Management Science & Engineering and affiliated faculty member at the Stanford Technology Ventures Program. “There’s no place for the Ivory Tower academic mindset, or the idea that commercialization somehow gets your hands dirty.” University incubators are already responsible for the commercialization of academic research output. But, in most cases, their influence is minor and peripheral. “Perhaps the university of tomorrow should be more like one big incubator,” suggests McLoughlin. By fostering an environment where tech startups and tech entrepreneurs can engage with university academics and students openly, and ideas can be shared more fluidly by industry and academia, one can achieve greater levels of innovation. Universities used to be where the smartest people in the world went to exchange ideas. Some spent their whole lives there as faculty and helped steer the brightest and best young students who passed through during their tenure. The role of the 21st century educational institution has changed. “In the past, the most important academic questions focused around the meaning of life and why we exist,” says McLoughlin. “Today the questions have changed, with one of the most important being: how do we engage with tech to make society better? If you ask me where the ideal place would be to try and answer fundamental questions like this in a truly independent way, the university is the obvious location. Is Stanford an already existing example of one such great, big incubator? “There’s definitely a special set of ingredients that came together here for the kind of high-tech entrepreneurship to emerge in SV,” says Eesley. “There are other institutions with great engineering programs, like Caltech and Carnegie Mellon University, but they haven’t been able to achieve the same level of commercialization. They have great breakthroughs, but something is missing.” It’s also critical that university policy makes it simple for faculty members and/or students to commercialize research. If institution authorities are overly concerned with royalties and ensuring they negotiate the biggest piece of the IP pie for the alma mater, they’re unlikely to encourage entrepreneurship from within. “I have experience in this area at both MIT and Stanford,” says Eesley. “MIT used to focus on negotiating as good a deal as possible for the university in every situation. Now their focus is on maximizing the number of deals getting done on campus. That is key to enabling true entrepreneurship in an academic setting.” Bringing in former alumni who became entrepreneurs to mentor also has an impact. “We did studies of mentorship where we randomized which students were matched with entrepreneurs or with VCs, and various other alumni who may have had successful careers but who never actually started a business,” says Eesley. “The ones with entrepreneurs for mentors were far more likely to start an early-stage startup upon graduation.” Eesley isn’t suggesting what’s happened (and continues to happen) in the southern Bay Area isn’t possible elsewhere. “Tech hubs can emerge in almost any location,” he says. “We know this because the centers of innovation of the past in the U.S. were places like Detroit and Cleveland. Just a few short decades ago, if you were a young, talented engineer, these were the cities you were drawn to.” With little to ostensibly offer in an educational system driven even more by commercial interests, the arts and humanities would presumably suffer most, and be considered to have even less value than they already do. McLoughlin disagrees. “In this context, engaging more with tech startups only appears as a prioritization of business and commerce above all else on a superficial level. The arts give us access to our cultural life and the culture of society,” he says. “If the incubator model were to be adopted in an overall university setting, the arts would thrive. The social sciences, in particular, would be put to the fore in the development of new tech and people would think more about the consequences of new innovations. Many of the negative aspects of life in the digital age could be avoided or minimized if there were more independent input during the design stages of new tech. If innovation was driven as much by universities as it is by startups, we would all benefit.”
News Article | February 23, 2017
Asian Horned frogs account for approximately half of the ancient family of frogs called Megophryidae. This group was previously estimated to have originated 100-126 million years ago (mya). Frogs of this family hopped alongside the famed Velociraptors and other dinosaurs during the Cretaceous period (145-66 mya). Despite the fact that these animals have been around for a long time, little is known about their evolutionary history. Furthermore, unlike their dinosaur contemporaries, these frogs did not leave behind any known fossils. Methods using information from DNA sequences exist for estimating the age of origin for such groups of animals but these methods rely heavily on fossils of related animal groups, which could prove unreliable for these species. New research recently published in the scientific journal, Molecular Biology and Evolution, by a team of scientists from Ireland and India resolved a 195-year old confusion regarding relationships between the species of Asian Horned Frogs, an enigmatic group of frogs often with horn-like projections over their eyes. Using DNA sequences, they discovered many potentially new species in this group previously unknown to science. They also estimated the ages of species and groups of species using a method that had previously not been tried on amphibians and inadvertently discovered that until now scientists may have been overestimating the age of many frog families. Their discovery may open a new chapter on how scientists interpret the evolutionary history of many animals that currently have no known fossil record. "While this research particularly focused on frogs, many other animal groups also lack a fossil record, and so its very difficult to decipher their evolutionary histories. Our hope is that methods used here will prove beneficial for understanding how the distant ancestors of living animals may have coexisted in prehistoric times," explains lead author Dr. Stephen Mahony. The research team was led by Ireland's leading herpetologist, Dr. Stephen Mahony (previously of University College Dublin [UCD], Ireland and University of Delhi [DU], India), and a prominent mammal molecular evolutionary biologist, Prof. Emma Teeling (UCD). A PhD student of Prof. Teeling, Nicole Foley (UCD), and the "Frogman of India", Prof. SD Biju (DU) were co-authors on this research publication. The scientists demonstrated that a recently developed method called RelTime, that does not require fossil information, provided comparatively better age estimates for frogs. Their results correlate well with current knowledge on prehistoric biogeography--distribution of animals in space and time, considering tectonic plate movements, the rise of mountain ranges and palaeoclimatic changes--that may have influenced the evolutionary history of Asian Horned Frogs. This research project was envisaged by Dr. Mahony in 2006 after he discovered that one widely distributed 'species' appeared to represent several similar but scientifically 'new' distinct species. Six of these species from Thailand, Cambodia and India, were formally described as new to science between 2009 and 2013 from his (and his colleagues) previous research. Since then, Stephen embarked on the most extensive research to have ever been carried out on this group of frogs. He did so by examining and measuring hundreds of specimens from museums in Asia, Europe and the US, and used DNA gene sequences to determine how these species are related. These new results indicate that the Asian Horned Frogs family may have originated as recently as 77 million years ago in contrast to 100-126 mya as previously estimated, and suggest that scientists might have been also overestimating the age of many other families of frogs by up to 35%. The results have completely changed our understanding of how the different Asian Horned Frog species and their species groups are related. Many of the species that look similar, and so were considered to be closely related, were found to be distant relatives of each other, and those that look different were found to be closely related. Finally, the results of this research have identified numerous species in India, Vietnam and Laos that are very likely new to science, several of which may be restricted to small distributions in vulnerable habitats. This raises concerns for their continued survival as "having a name" is the bedrock for conservation. "It is well known that Amphibians are one of the most endangered animal groups. Our research further demonstrates that many species remain undiscovered. Sadly, with climate change and continuing habitat destruction, we are losing many species before we can learn anything about them, but the use of molecular techniques is dramatically speeding up the learning process." says Mahony. The research was funded by the Irish Research Council Embark Scholarship, European Research Council, Department of Science and Technology Purse Grant from the Government of India and Research and Development grants from the University of Delhi. Mahony, S., Foley, N.M., Biju, S.D., Teeling, E.C. (2017) Evolutionary History of the Asian Horned Frogs (Megophryinae): Integrative Approaches to Timetree Dating in the Absence of a Fossil Record. Molecular Biology and Evolution. DOI: https:/
News Article | October 25, 2016
Experiments were performed in accordance with the regulations of the Institutional Animal Care and Use Committee of the University of California, San Diego. We used the following mouse lines: VGAT–ChR2–EYFP31 (Jackson Labs #014548), PV–Cre32 (Jackson Labs #008069), Gad2–Cre33 (Jackson Labs #010802) and Hoxd10–GFP34 (MMRRC #032065-UCD). Mice were bred by crossing homozygous VGAT–ChR2–EYFP, PV–Cre or Gad2–Cre males (all lines with a C57BL/6 background) with wild-type ICR females or homozygous Hoxd10–GFP females (ICR background) to C57BL/6 males. Mice were housed in a vivarium with a reversed light cycle (12 h day–12 h night). Mice of both genders were used for experiments at postnatal ages of 2–6 months. We used the following adeno-associated viruses (AAV) and canine adenovirus (CAV2): For the Cre recombinase (Cre)-dependent expression of Channelrhodopsin2 (ChR2)35, 36: AAV2/9.CAGGS.Flex.ChR2.tdTomato.SV40 (Addgene 18917; UPenn Vector Core). For the Cre-dependent expression of tdTomato: AAV2/1.CAG.Flex.tdTomato.WPRE.bGH (Allen Institute 864; UPenn Vector Core). For the expression of Cre: AAV2/9.hSyn.HI.eGFP-Cre.WPRE.SV40 (UPenn Vector Core). For Cre-dependent expression of the diphtheria toxin receptor (DTR)37: AAV2/1.Flex.DTR.GFP (Jessell laboratory; produced at UNC Vector Core). AAV2/9.CAGGS.Flex.ChR2.tdTomato.SV40 was bilaterally injected into the visual cortex of newborn PV–Cre or Gad2–Cre pups (postnatal day (P) 0–2). The virus was loaded into a bevelled glass micropipette (tip diameter 20–40 μm) mounted on a Nanoject II (Drummond) attached to a micromanipulator. Pups were anaesthetized by hypothermia and secured in a molded platform. In each hemisphere the virus was injected at two sites along the medial–lateral axis of the visual cortex. At each site we made three bolus injections of 28 nl. Each were at three different depths between 300 and 600 μm. Protein expression was verified by epi-fluorescent illumination through a dissection microscope (Leica MZ10F). Experiments were performed on animals with expression over the entire extent of visual cortex. AAV2/9.hSyn.HI.EGFP-Cre.WPRE.SV40 and AAV2/9.CAGGS.Flex.ChR2.tdTomato were mixed in 1:20 ratio. The mixture was injected into the visual cortex of newborn C57BL/6 pups (as described above). Protein expression was verified by epi-fluorescent illumination. Adult Hoxd10–GFP mice were anaesthetized with ~2% isoflurane (vol/vol) in O . The depth of anaesthesia was monitored with the toe-pinch response. The eyes were protected from drying by artificial tears. We cut open the scalp and thinned the skull to create a window of ~300–500 μm diameter. The remaining layer of bone in the window was thin enough to allow the penetration of the beveled glass pipette. A bolus of retrograde fluorescent microspheres (RetroBeads, Lumafluor Inc.) or CAV2.Cre virus (40 nl RetroBeads or 20 nl CAV2 virus) was injected into the NOT-DTN (coordinates (anteroposterior axis (AP) relative to bregma; mediolateral axis (ML) relative to the midline): AP: −1,260 μm; ML: 3,080 μm; depth: 1,960 μm; coordinates were adjusted based on the distance between bregma and lambda on mouse skull) using an UltraMicroPump (UMP3, WPI). The wound was sutured with a few stitches of 6-0 suture silk (Fisher Scientific NC9134710). Mice were perfused 3 days after the retrobead injection or 2 weeks after the CAV2 injection. AAV2/1.Flex.DTR.GFP was bilaterally injected into the visual cortex of VGAT–ChR2–EYFP pups between P0 and P2. CAV2.Cre virus was subsequently stereotactically injected into the NOT-DTN (same coordinates as above) bilaterally in mice of 2–6 months of age. Three to four weeks later we injected diphtheria toxin (DT 40 ng/g) intraperitoneally three times on alternate days. The OKR was assessed 11 or 12 days after the first diphtheria toxin injection. In control experiments, diphtheria toxin was replaced with PBS or diphtheria toxin was injected into mice that had not been infected with AAV2/1.Flex.DTR.GFP. Mice were implanted with a T-shaped head bar for head fixation. Mice were anaesthetized using ~2% isoflurane. The scalp and fascia were removed and a metal head bar was mounted over the midline using dental cement (Ortho-Jet powder; Lang Dental) mixed with black paint (iron oxide). We created a cranial window of ~3 × 3 mm (1.5–4.5 mm lateral to midline and 2.3–5.2 mm posterior to bregma) over the visual cortex on each hemisphere by gently thinning the skull until it appeared transparent when wetted by saline solution. The window was then covered with a thin layer of crazy glue. Following the surgery animals were injected subcutaneously with 0.1 mg/kg buprenorphine and allowed to recover in their home cage for at least 1 week. Several days before the test, mice were familiarized with head fixation in the recording setup. No visual stimulation was given. The horizontal OKR was elicited by a ‘virtual drum’ system39. Three computer LED monitors (Viewsonic VX2450wm-LED, 60-Hz refresh rate, gamma-corrected) were mounted orthogonally to each other to form a square enclosure that covered ~270° of visual field along the azimuth. The mouse head was immobilized at the centre of the enclosure with the nasal and temporal corners of the eye leveled. Visual stimuli were generated with Psychophysics Toolbox 3 running in Matlab (Mathworks). To ensure synchronized updating across multiple monitors we used AMD Eyefinity Technology (ATI FirePro V4800). The monitors displayed a vertical sinusoidal grating whose period (spacing between stripes) was adjusted throughout the azimuthal plane such that the projection of the grating on the eye had constant spatial frequency. In other words, the spatial frequency of the grating was perceived as constant throughout the visual field, as if the grating was drifting along the surface of a virtual drum. The dependence of pixel brightness on monitor coordinates was obtained by using this equation: B = L + L × C × sin(2π × x × SF), where B is the brightness of pixels, L is the luminance in cd/m2, C is the contrast, SF is the spatial frequency and x is the azimuth of pixels in degrees, which is transformed from the Cartesian coordinates of the monitor into the cylindrical coordinates of the virtual drum by the following formula: x = tan−1(x /D), where x is the horizontal pixel position in Cartesian coordinates and D is the distance from the centre of the monitors to the eye (Extended Data Fig. 1a). The grating drifted clockwise or counterclockwise in an oscillatory manner7, 11 (oscillation amplitude ± 5°; grating spatial frequency: 0.04–0.45 cpd; oscillation frequency 0.2–1 Hz, corresponding to a peak velocity of the stimulus of 6.28–31.4° s−1; contrast: 80%; mean luminance: 40 cd/m2). We chose the duration of the visual stimulus to allow the presentation of an integral number of oscillatory cycles (10 or 15 s for OKR test only; 7.5 s for simultaneous NOT-DTN electrophysiology and OKR test). Trials were spaced by an inter-stimulation interval of at least 8 s. The inter-stimulation interval following trials of cortical silencing was increased to 20 s. To measure the oscillation frequency tuning, spatial frequency was kept constant at 0.08 cpd; to measure the spatial frequency tuning oscillation, the frequency was kept at 0.4 Hz. To obtain the transfer function, we varied the spatial frequency of the visual stimulus rather than the oscillation frequency because OKR peak velocity is strongly modulated by spatial frequency and much less so by the oscillation frequency (consistent with previous observations7, 40; Extended Data Fig. 9a). The spatial frequency was varied from 0.04 to 0.45 cpd, and the oscillation frequency was kept constant at 0.4 Hz. To evaluate the directional preference of NOT-DTN neurons, one monitor was positioned 20 cm from the eye contralateral to the side of recording. Full-field sinusoidal drifting gratings (oscillation frequency: 1 Hz; spatial frequency: 0.08 cpd; mean luminance: 50 cd/m2; contrast: 100%) were used. Gratings were randomly presented at 12 equally spaced positions. The duration of the visual stimulus was 2 s and the inter-trial interval was 2.2 s. To visualize NOT-DTN with c-Fos immunostaining (c-Fos is an immediate early gene expressed in response to neuronal activity), OKR was elicited by drum stimulation of various spatial frequencies (0.04–0.45 cpd) with oscillation frequency 0.4 Hz, contrast 100% and luminance 50 cd/m2. Trials of oscillatory motion lasted for 15 s and were followed by an inter-trial interval of 8 s. The whole stimulation procedure took 60 min. The movement of the right eye was monitored through a high speed infrared (IR) camera (Imperx IPX-VGA 210; 100 Hz). The camera captured the reflection of the eye on an IR mirror (transparent to visible light, Edmund Optics #64-471) under the control of custom labview software and a frame grabber (National Instrument PCIe-1427). The pupil was identified online by thresholding pixel values or post hoc by combining thresholding and morphology operation and its profile was fitted with an ellipse to determine the centre. The eye position was measured by computing the distance between the pupil centre and the corneal reflection of a reference IR LED placed along the optical axis of the camera. To calibrate the measurement of the eye position, the camera and the reference IR LED were moved along a circumference centred on the image of the eye by ± 10° (Extended Data Fig. 1b). Three mouse lines (VGAT–ChR2–EYFP, PV–Cre and Gad2–Cre) were used in experiments involving optogenetic silencing of the visual cortex. They are equally efficient in silencing activity of visual cortex and interchangeable. VGAT–ChR2–EYFP mice were used in most of the silencing experiments, except in experiments illustrated in Extended Data Fig. 2a (PV–Cre line) and Extended Data Fig. 3b (all 3 lines). To photostimulate ChR2-expressing cortical inhibitory neurons in vivo, a 470-nm blue fibre-coupled LED (1 mm diameter, Doric Lenses) was placed ~5–10 mm above the cranial windows of each hemisphere. We restricted the illumination to the tissue under the cranial window by covering neighbouring areas with dental cement. An opaque shield of black clay prevented LED light from directly reaching the eyes. The total light power out of the LED fibre was 15–20 mW. Trials were alternated between visual stimulus alone and visual stimulus plus LED. The LED was turned on during the whole period of visual stimulation and turned off by ramping down the power over 0.5 s to limit rebound activation of the visual cortex. To photostimulate cortical input to the NOT-DTN in vivo, blue light illuminated only the visual cortex ipsilateral to the NOT-DTN where the probe was inserted. We dissected out the tissue overlying the horizontal semicircular canal in mice under ~2% isoflurane anaesthesia. A small hole was drilled in the canal with a miniature Busch Bur (0.25 mm, Gesswein) and the endolymph was partially drained. The horizontal semicircular canal was plugged with bone wax (FST 19009-00) to seal the opening and reduce the flow of the endolymph within the canal. The wound was sutured with a few stitches of 6/0 suture. Mice recovered for two days in their home cages before being tested for OKR. Sham lesions were done in the same way except that no hole was drilled and no wax was introduced in the semicircular canal. OKR gain (spatial frequency: 0.1 cpd; oscillation frequency: 0.4 Hz; contrast: 100%; mean luminance: 35 cd/m2) was assessed 1 day before and 1 h before OKR training. Two sessions (12 min) were used to minimize the effect of visual stimulation during OKR evaluation on OKR gain. During continuous OKR stimulation, a drum of the same visual parameters ran continuously for 38 min. OKR gain was then assessed again 12 min after OKR stimulation was finished. Mice were implanted with a T-shaped head bar for head fixation in the same way as described above for the OKR assessment, except that the procedure was done stereotactically with the help of an inclinometer (Digi-Key electronics 551-1002-1-ND). The inclinometer allowed us to calibrate the inclination of the two axis of the T bar relative to the anteroposterior (AP) and mediolateral (ML) axes of the skull before fixing it to the skull with dental cement. Three reference points with known coordinates were marked on the mouse skull because both bregma and lambda were inevitably masked by the dental cement holding the head bar. The head post on the recording rig was also calibrated with the same inclinometer to ensure that the recording probes were in register with the skull. Recordings from awake animals were performed using a method similar to that described previously43. One to two weeks before recording, mice were familiarized with head fixation within the recording setup over the course of two to four 50-min sessions. One day before recording, mice were anaesthetized with ~2% isoflurane. Whiskers and eyelashes contralateral to the recording side were trimmed to prevent interference with infrared video-oculography. To access the NOT-DTN we made an elongated, anteroposteriorly oriented craniotomy (~0.4 × 0.8 mm) around the coordinates of −3 mm (anteroposterior) and 1.3 mm (mediolateral). The coordinates were adjusted based on the distance between bregma and lambda on mouse skull. The craniotomy was then covered by Kwik-Cast Sealant (WPI). On the day of recording, after peeling off the Kwik-Cast cover, a drop of artificial cerebrospinal fluid (ACSF; in mM, 140 NaCl, 2.5 KCl, 2.5 CaCl , 1.3 MgSO , 1.0 NaH PO , 20 HEPES and 11 glucose, pH 7.4) was placed in the well of the craniotomy to keep the exposed brain moist. A 16-channel linear silicon probe (NeuroNexus a1x16-5mm-25-177) mounted on a manipulator (Luigs &Neumann) was slowly advanced into the brain to a depth of 2,000–2,200 μm. The occurrence of direction modulated activity upon visual stimulation was used to identify the NOT-DTN (see data analysis below). The probe was stained by lipophilic DiI to label the recording track for post hoc verification of successful targeting of the NOT-DTN. Recordings were not started until 20 min after insertion of the probe into the NOT-DTN. Signals were amplified 400-fold, band-pass filtered (0.3–5,000 Hz, with the presence of a notch filter) with an extracellular amplifier (A-M Systems 3600) and digitized at 32 kHz (National Instrument PCIe-6259) with custom-written software in Matlab. Raw data were stored on a computer hard drive for offline analysis. At the end of the recording session, brains were fixed by transcardial perfusion of 4% paraformaldehyde for histological analysis. Recordings from the superior colliculus or vLGN were done in the same way except that the coordinates of the craniotomy were 3.5 mm (anteroposterior) and 1 mm (mediolateral) for the superior colliculus and 2.5 mm (anteroposterior) and 2.3 mm (mediolateral) for the vLGN. For recordings from anaesthetized mice we used the same procedures as described above except that (1) the familiarization step was omitted and the craniotomy was performed immediately before recording; (2) animals were anaesthetized with urethane (1.2 g/kg, intraperitoneal) and given the sedative chlorprothixene (0.05 ml of 4 mg/ml, intramuscular), as previously described44; (3) body temperature was maintained at 37 °C using a feedback-controlled heating pad (FHC 40-90-8D); (4) a uniform layer of silicone oil was applied to the eyes to prevent drying; and (5) lactated Ringer’s solution was administrated at 3 ml/kg/h to prevent dehydration. Mice at postnatal days 15–30 were anaesthetized by intraperitoneal injection of ketamine and xylazine (100 mg/kg and 10 mg/kg, respectively), perfused transcardially with cold (0–4 °C) slice cutting solution ((in mM) 80 NaCl, 2.5 KCl, 1.3 NaH PO , 26 NaHCO , 20 d-glucose, 75 sucrose, 0.5 sodium ascorbate, 4 MgCl and 0.5 CaCl , 315 mOsm, pH 7.4, saturated with 95% O2/5% CO ) and decapitated. Brains were sectioned into coronal slices of 300–400 μm in cold cutting solution with a Super Microslicer Zero1 (D.S.K.). Slices containing the NOT-DTN were incubated in a submerged chamber at 34 °C for 30 min and then at room temperature (~21 °C) until used for recordings. During the whole procedure, the cutting solution was bubbled with 95% O /5% CO . Whole-cell recordings were done in ACSF (in mM: 119 NaCl, 2.5 KCl, 1.3 NaH PO , 26 NaHCO , 20 d-glucose, 0.5 sodium ascorbate, 4 MgCl , 2.5 CaCl , 300 mOsm, pH 7.4, saturated with 95% O /5% CO ). The ACSF was warmed to ~30 °C and perfused at 3 ml/min. NOT-DTN neurons were visualized with DIC infrared video-microscopy under a water immersion objective (40×, 0.8 NA) on an upright microscope (Olympus BX51WI) with an IR CCD camera (Till Photonics VX44). Whole-cell voltage-clamp recordings were performed with patch pipettes (borosilicate glass; Sutter Instruments) using a caesium-based internal solution ((in mM) 115 CsMeSO , 1.5 MgCl , 10 HEPES, 0.3 Na GTP, 4 MgATP, 10 Na -phosphocreatine, 1 EGTA, 2 QX-314-Cl, 10 BAPTA-tetracesium, 0.5% biocytin, 295 mOsm, pH 7.35). AMPA receptor-mediated EPSCs were recorded at the reversal potential for IPSCs (~−65 mV) and NMDA receptor-mediated EPSCs were recorded at +40 mV in the presence of the GABA receptor antagonist gabazine (5 μM, Tocris 1262) and the AMPA receptor antagonist NBQX (10 μM, Tocris 1044). To verify monosynaptic connectivity, we isolated NMDA receptor-mediated EPSCs in the presence of NBQX and high Mg2+ concentration (4 mM) or monosynaptic AMPA receptor-mediated EPSCs by a modified sCRACM approach45 in the presence of tetrodotoxin (TTX; 1 μM, Tocris 1069), 4-aminopyridine (4-AP; 1.5 mM, Abcam ab120122) and tetraethylammonium (TEA; 1.5 mM, ab120275). EPSCs were acquired and filtered at 4 kHz with a Multiclamp 700B amplifier, and digitized with a Digidata 1440A at 10 kHz under the control of Clampex 10.2 (Molecular Devices). Data were analysed offline with Clampfit 10.2 (Molecular Device). To photostimulate ChR2-expressing cortico-fugal axons, we delivered blue light using a collimated LED (470 nm) and a T-Cube LED Driver (Thorlabs) through the fluorescence illuminator port and the 40× objective. Light pulses of 10 ms and 5.5 mW/mm2 were given with a 20 s inter-stimulus interval. After recordings, slices were fixed by 4% paraformaldehyde for histology. After implanting the head bar, under anaesthesia (2% isoflurane), we dissected out part of the skull and removed, by aspiration, the area of the cortex and hippocampus overlaying the NOT-DTN. The identity of the NOT-DTN was assessed visually by its anatomy and stereotactic coordinates and verified electrophysiologically (see data analysis below). After the surgery, the mice were head-fixed and isoflurane was withdrawn. For at least the next 45 min, OKR performance and NOT-DTN activity were recorded. The GABA receptor agonist muscimol (0.2–1 mM in ACSF) was applied on top of the NOT-DTN. It took ~30 min for muscimol to silence the NOT-DTN, as assessed electrophysiologically. Pupillary dilation, as a side effect of silencing the olivary pretectal nucleus, was counteracted by topical application of 2% pilocarpine hydrochloride (agonist of muscarinic receptor, Tocris 0694) in saline to both eyes. Mice were perfused transcardially first with phosphate buffered saline (PBS, pH 7.4) and then with 4% paraformaldehyde in PBS (pH 7.4) under anaesthesia (ketamine 100 mg/kg and xylazine10 mg/kg; intraperitoneal injection). Brains were removed from the skull, post-fixed overnight in 4% paraformaldehyde and then immersed in 30% sucrose in PBS until they sank. Brains were subsequently coronally sectioned (40–60 μm sections) with a sliding microtome (Thermo Scientific HM450). Slices were incubated in blocking buffer (PBS, 5% goat serum (Life Technologies 16210-072), 1% Triton X-100) at room temperature for 2 h and then incubated with primary antibodies in blocking buffer at 4 °C overnight. The following primary antibodies were used: rabbit anti-GFP (1:1,000, Life Technologies A6455) and rabbit anti-c-Fos (1:1,000, Santa Cruz Biotechnology sc-52). The slices were washed three times with blocking buffer for 30 min each and then incubated with secondary antibodies conjugated with Alexa Fluor 488, 594 or 633 (1:800, Life Technologies A11008, A11012 or A21070, respectively) in blocking buffer for 2 h at room temperature. After being washed three times with blocking buffer for 10 min each, slices were mounted in Vectashield mounting medium containing DAPI (Vector Laboratories H1500). For c-Fos immunostaining, 90 min after the beginning of OKR stimulation (30 min after 60-min OKR simulation was finished), animals were perfused transcardially first with PBS and then with 4% paraformaldehyde in PBS. Brains were coronally sectioned into slices of 40 μm. To reveal the morphology of NOT-DTN neurons filled with biocytin, following fixation and blocking (see above), we incubated the slices with streptavidin conjugated with Alexa Fluor 647 (1:500, Life Technologies s32357) in blocking buffer overnight and then washed the slices three times. Images were acquired on a Leica SP5 confocal microscope, a Zeiss Axio Imager A1 epifluorescence microscope or an Olympus MVX10 stereoscope, and processed using ImageJ (National Institutes of Health). Analysis of eye tracking and in vivo electrophysiology was performed using custom-written codes in Matlab. Analysis of in vitro electrophysiology was done with Clampfit 10.2 (Molecular Devices). Saccade-like fast eye movements were removed from the recorded eye trajectory before computing OKR amplitude (Extended Data Fig. 1c). Saccades were detected as ‘spikes’ in the temporal derivative of the eye position (velocity) and replaced by linear interpolation. To derive the amplitude of the OKR we used the Fourier transform of the eye position as a function of time. The eye trajectories illustrated in this study are the averages of several cycles. The gain of the OKR was expressed as OKR gain = Amp /Amp , where Amp is the amplitude of eye movement and Amp the amplitude of drum movement. The OKR gain derived in the space domain is similar to that derived in the velocity domain (Extended Data Fig. 1f). In this study, we computed the gain in the space domain because deriving eye velocity from eye position introduces noise. Therefore, the OKR gain is 1 if the eye perfectly tracks the trajectory of the virtual drum and 0 if it does not track. The cortical contribution to the OKR gain is expressed as the percentage reduction in OKR gain caused by cortical silencing and calculated as ΔV (%) = (V − V )/V , where V and V are the values of the OKR gain measured under control conditions or during optogenetic cortical silencing, respectively. OKR potentiation is calculated as V / V , where V and V are the values of the OKR gain measured before and after vestibular lesion, respectively. The cortical contribution to OKR potentiation is expressed as PI = (ΔV − ΔV )/(ΔV − ΔV ), where ΔV and ΔV are the cortical contribution to the OKR gain before and after vestibular lesioning, respectively, and ΔV is the maximum possible cortical contribution to the OKR gain assuming that the entire amount of OKR potentiation depends on visual cortex. ΔV = (V − V )/V . Hence PI is 1 if the entire amount of OKR potentiation depends on visual cortex and is 0 if the cortical contribution to OKR gain before vestibular lesion is the same as the cortical contribution to OKR gain after vestibular lesion (ΔV = ΔV ) (Extended Data Fig. 3c, d). The cortical contribution to NOT-DTN activity is expressed as the cortical contribution to OKR gain but V and V are the firing rates of NOT-DTN neurons under control conditions or during optogenetic cortical silencing, respectively. Single units were isolated using spike-sorting Matlab codes, as described previously43. The raw extracellular signal was band-pass filtered between 0.5 and 10 kHz. Spiking events were detected with a threshold at 3.5 or 4 times the standard deviation of the filtered signal. Spike waveforms of four adjacent electrode sites were clustered using a k-means algorithm. After initial automated clustering, clusters were manually merged or split with a graphical user interface in Matlab. Unit isolation quality was assessed by considering refractory period violations and Fisher linear discriminant analysis. All units were assigned a depth according to the electrode sites at which their amplitudes were largest. Multi-unit spiking activity was defined as all spiking events exceeding the detection threshold after the removal of electrical noise or movement artefacts by the sorting algorithm. Individual spiking events were also assigned to one of the 16 recording sites according to where they showed the largest amplitude. For both single-unit activity and multi-unit activity, the visual response was computed as the mean firing rate during visual stimulation without baseline subtraction. Units recorded from visual cortex were assigned as regular-spiking neurons or fast-spiking putative inhibitory neurons based on the trough-to-peak times of spike waveforms43. A threshold of 0.4 ms was used to distinguish fast-spiking from regular-spiking units. The boundary of the NOT-DTN was determined by the appearance of a temporonasal directional bias in the multi-unit response to the visual stimulus. The preferred direction of an isolated NOT-DTN unit was determined by summing response vectors of 12 evenly spaced directions. The direction selectivity index (DSI) was calculated along the sampled orientation axis closest to the preferred direction according to the formula DSI = (R − R )/(R + R ), where R is the response at the preferred direction and R is the response at the opposite direction. The DSI of the response evoked by oscillatory drum movement was calculated as DSI = (R − R )/(R + R ), where R is the response during the temporonasal phase of drum movement and R is the response during the nasotemporal phase. The onset latency of optogenetically evoked activity of NOT-DTN neurons was determined as the time lag between the beginning of the LED illumination and the time point at which the firing rate reached three times the standard deviation of spontaneous activity. Similarly, the onset latency of optogenetically evoked EPSCs in NOT-DTN neurons was determined as the time lag between the beginning of the LED illumination and the time point at which the EPSC amplitude reached three times the standard deviation of baseline noise. Trial-by-trial jitter of optogenetically evoked EPSCs was calculated as the standard deviation of the onset latency. Analysis of c-Fos immunohistochemistry was performed with ImageJ (National Institutes of Health). c-Fos-positive cells were identified as continuous pixels after thresholding and counted automatically. To quantify the extent of overlap between arborization of GFP-expressing RGC axons and c-Fos expression in the NOT-DTN, their boundaries were manually drawn and the overlap coefficient r was calculated as where S1 is 1 if pixel i is within the domain of RGC axons, otherwise 0; and S2 is 1 if pixel i is within the domain of c-Fos immunohistochemistry, otherwise 0 (Extended Data Fig. 5c). For each animal, NOT-DTN multiunit activity was normalized to the average firing rate evoked by optimal spatial frequency. Data points of transfer functions from all animals were pooled, binned and averaged. The vectors (arrows in Extended Data Fig. 9g–i) start at the centre of mass of data points obtained at a given spatial frequency under control conditions (grey) and end at the centre of mass of data points obtained at the same spatial frequency during cortical silencing trials (blue). The x-axis value of the centre of mass is the NOT-DTN multiunit firing rate averaged over trials obtained at a given spatial frequency, normalized by the average firing rate evoked by the best spatial frequency. The y-axis value of the centre of mass is the average OKR gain obtained during the same trials. All samples or animals were included in the analysis except for the following exclusions: (1) in the analysis of OKR gain, trials in which video-oculography failed as a result of eye blinking or tears were excluded from analysis; (2) in Fig. 1g, h, one mouse was excluded from the analysis because its value of OKR potentiation was less than the threshold of 0.1; (3) in Fig. 3, two mice were excluded from the analysis because they were sick and lost a lot in body weight during experiments; (4) in Figs. 4, 5, one mouse was excluded because the identification of NOT-DTN failed; and (5) in statistics of the activities of superior colliculus and vLGN, recordings which were identified post hoc as missing the target structures were excluded from the analysis. These criteria were pre-established. Statistical analyses were done using statistics toolbox in Matlab. All data are presented as mean ± s.e.m. unless otherwise noted. Statistical significance was assessed using paired or unpaired t-tests and further confirmed with nonparametric Wilcoxon signed rank test or Wilcoxon rank sum test unless otherwise noted. Estimated sample sizes were retrospectively determined to achieve 80% power to detect expected effect sizes using Matlab. We did not intentionally select particular mice for treatment group or control group. No blinding was used. Owing to the limited sample size, the assumption of normal distribution was not tested. Nonparametric tests were used to confirm statistical significances reported by paired or unpaired t-tests. Thus, the conclusions of statistical tests were validated regardless of whether the data were normally distributed. The variance was not compared between groups. In t-tests, we assumed that samples were from distributions of unknown and unequal variances. The experiments were not randomized.
News Article | November 25, 2016
The amount of a particular chemical in a particular part of your brain predicts your ability to simultaneously hang onto several bits of information in your working memory, a Stanford University School of Medicine scientist and his University of California-Davis collaborators have learned. The discovery helps to clarify at least one aspect of the brain’s mysterious ways, and could someday help guide therapies for those whose working memory could stand improvement. Working memory is the brain function that lets you carry on a phone conversation while adding three numbers in your head and remembering that you need to steer the car onto the freeway exit in about two minutes — all this time not forgetting who you’re talking to. Like a computer’s RAM, working memory serves as a buffer where information, derived from the senses or retrieved from long-term memory, can be temporarily placed so the conscious brain can process it. It’s tied to assessments of cognitive capacity such as IQ, and to real-world outcomes such as academic performance. As most people eventually find out, working memory declines with age. “Deficits in working memory also characterize various neuropsychiatric conditions and are particularly evident in schizophrenia,” said Jong Yoon, M.D., an assistant professor of psychiatry and behavioral sciences at Stanford and a psychiatrist at the Palo Alto Veterans Affairs Health Care System who sees numerous patients with this disorder. Yoon is the lead author of the study, published Nov. 16 in the Journal of Neuroscience. The study teases apart three key components of working memory and shows that one component, but not the other two, is tied to the amount of a chemical called GABA in a brain area known as the dorsolateral prefrontal cortex, or DLPFC. Richard Maddock, M.D., a professor of psychiatry at UCD, is senior author of the study. This component, referred to as load, is a measure of the number of separate bits of information a person’s working memory can store at the same time. A second component, maintenance, denotes how long information can be stored in working memory before it’s lost. A third, distraction resistance, gauges how well an individual’s working memory holds onto information in the face of interfering stimuli. The DLPFC, a broad swath of neural tissue on the forebrain surface, has been shown in animal studies and in observations of brain-damaged patients to be integral to high-level executive functions in the brain, such as planning, prioritizing and avoiding distractions. It has likewise been strongly implicated in working memory. The DLPFC orchestrates activity in numerous distant centers throughout the brain, including the visual cortex, which is located near the brain’s surface but in the hindbrain. “No previous study has ever pinpointed GABA’s link with working memory in humans,” said Yoon. “Working memory is a complex process, requiring coordinated activity in centers throughout the brain. Yet, remarkably, the amount of this one chemical in a single part of the brain accounts for close to one-third of the variance in individuals’ load capacity.” In the study, 23 healthy participants ages 19-32 were subjected to batteries of tests of working memory. Yoon reasoned that different components of working memory would involve different neurotransmitter inputs. So he devised working-memory tests that separated the measurement of load, maintenance and distraction resistance. Participants repeated several related tasks. In the simplest, they were shown a drawing of a face and then, after a two-second delay, shown a second face and asked whether it was the same as or different from the first one. Variations of this task — initially presenting two faces instead of just one; lengthening the intervening delay; or displaying a different, irrelevant face between the initial and final displays — tested load, maintenance and distraction resistance, respectively. The investigators compared individuals’ error rates on the simple version of the task with outcomes on tasks taxing one or another working-memory component more heavily. The smaller the deterioration in performance on a test of a particular working-memory component, the greater the individual’s capacity regarding that component was judged to be. Using an advanced imaging method, the scientists measured GABA levels in the DLPFC and, for comparison, in the visual cortex. GABA, secreted by nerve cells, is an inhibitory neurotransmitter: Its uptake by other nerve cells inhibits their firing. Yoon and his associates also measured levels of an excitatory neurotransmitter, glutamate. By far the two most abundant neurotransmitters in the brain, GABA and glutamate are considered to be that organ’s stop and go signals. Individuals with higher levels of GABA in their DLPFC performed better on tests of their load capacity — the ability to juggle more bits of information — the researchers found. In contrast, no significant association emerged linking GABA levels in the DLPFC to maintenance or to distraction resistance, or tying participants’ load capacity to GABA levels in the visual cortex. Nor did imaging reveal any connection between performance on tests of load capacity and levels of glutamate in the DLPFC. Schizophrenic patients, Yoon said, are known to be deficient in an enzyme essential to GABA production. So, drugs that boost GABA levels or function in the brain might prove helpful in restoring their impaired working memory. He plans to test this hypothesis.
News Article | April 6, 2016
An MIT spinout, Synlogic, is aiming to create a new class of medicines, by re-programming bacteria found in the gut as “living therapeutics.” Based on research by its co-founders, MIT professors Tim Lu and Jim Collins, Synlogic creates so-called synthetic biotics, which sense and correct metabolic abnormalities that underlie some major diseases and rare genetic disorders. Human intestines are filled with trillions of bacteria, collectively called the microbiota, that carry out vital health functions. Synlogic’s synthetic biotics — capsules, liquid suspensions, or other dosage forms that can be taken regularly — augment the microbiota with new metabolic capabilities or complement lost functionality in organs such as the liver. “Over the past decade or so, the intricate connections between microbes and our bodies have become clearer and clearer, and it’s well known now that the bacteria that live in our gut have a major influence on human health,” said Lu, an associate professor of electrical engineering and computer science and of biological engineering, and head of MIT’s Synthetic Biology Group, who serves as scientific advisor for Synlogic. “We leverage that interface as a way of treating human disease.” Last month, Synlogic raised an additional $40 million in venture capital and secured its first industry partnership with pharmaceutical giant AbbVie. For the partnership, Synlogic will collaborate with AbbVie to develop synthetic biotics for the potential treatment of inflammatory bowel disease, which may include probiotic microbes programmed to detect intestinal inflammation, and produce anti-inflammatory molecules or break down pro-inflammatory effectors. Two of Synlogic’s main candidate drugs, expected to enter clinical trials during the next 12 months, treat rare genetic metabolic disorders. One drug candidate is for treating urea cycle disorder (UCD), which is caused by an enzyme deficiency that leads to a buildup of toxic ammonia in the blood. The other is for treating phenylketonuria (PKU), which involves a dangerous excess of the amino acid phenylalanine due to a mutation in another metabolic enzyme. In both cases, Synlogic’s drugs process and flush out the toxic metabolites from the body. Think of Synlogic’s drugs like biological thermostats, said Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Department of Biological Engineering and Institute for Medical Engineering and Science, who also chairs Synlogic’s scientific advisory board. Instead of identifying and regulating the temperature of a room, he said, “The synthetic biotics detect and regulate the amount of an enzyme or metabolic byproduct in a patient’s body.” For more than a decade at Boston University and MIT, Collins and Lu (who is Collins’ former student) have been developing “genetic circuits” for bacteria, which include on/off switches made with synthetic DNA or RNA sequences that instruct the bacteria to count, store memory, and even perform logic. Collins and Lu have used these genetic circuits to program bacteria to seek and cure infection. In 2011, this approach earned Collins funding from the Bill and Melinda Gates Foundation to engineer bacteria to detect cholera and produce targeted antimicrobial peptides to treat it. A few years ago, Lu and Collins, along with several venture capitalists, launched Synlogic to focus on commercializing “a new class of therapeutics based on living cells,” Collins said. In 2014, Synlogic came out of stealth mode, securing $30 million in funding from venture firms and the Gates Foundation. Since then, Synlogic has worked primarily on programming E. coli Nissle, a strain of bacteria derived from the gut that is also used widely and safely as a probiotic. The programmed E. coli Nissle, Lu said, provides greater precision, safety, and efficacy for disease treatment, compared with traditional methods. For inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, for instance, current treatments include small-molecule drugs or antibodies with anti-inflammatory properties. But the challenge is getting the right dosage, Lu said. “If you apply too little, it’s not going to work. If you apply too much, you have a chance you may immunosuppress the patient and cause side effects,” he said. Synlogic can “program microbes to detect inflammation and make anti-inflammation molecules at the site of inflammation, as well as produce molecules that positively impact immune system function,” Collins said. Then there’s the more rare but debilitating urea cycle disorder, which affects 2,000 to 6,000 people in the United States and impairs their ability to processes ammonia. If ammonia builds up too much and reaches the brain, it can lead to brain damage, coma, and death. The best available treatment option for people with UCD today is a liver transplant. Synlogic aims to treat UCD with a daily biotic that functions in a surprising way: “It can decrease the ammonia in the bloodstream, without even contacting the blood,” Lu said. Ammonia levels in the bloodstream, he explains, are dependent on ammonia production in the large intestine. Synlogic’s biotic converts intestinal ammonia into an amino acid, which is flushed out of the body through the stool, thereby dramatically reducing the flow of ammonia to the blood and reducing ammonia levels in the bloodstream. Synlogic’s biotic for PKU, which affects 13,000 people in the United States, functions in a similar way, to regulate the processing and extraction of phenylalanine. PKU patients must adhere to a lifelong, extremely low-protein diet that can result in serious developmental disorders, because they can’t eat normal foods that contain phenylalanine — including many meat, dairy, and seafood products. “If we can degrade phenylalanine with convenient administration of this probiotic, that will change the course of this disease,” Lu said. Collins said Synlogic has potential to treat many other rare genetic metabolic disorders. But the recent AbbVie deal, he said, also “opens up possibilities of using these microbes to produce biologics or other small molecules to treat a range of conditions.” These include cardiovascular disease and autoimmune, oncology, and central nervous system disorders, which have been linked to metabolic dysregulation. Part of the reason that probiotic treatments are not used for serious diseases is their lack of clinically validated efficacy. Synlogic, on the other hand, aims to overcome these efficacy issues with potent and precision-programmed synthetic biotics, Lu said. For example, in engineering the safe and easily programmable E. coli Nissle, Synlogic engineers have designed the microbe to consume a massive amount of toxic metabolites. The E. coli Nissle strain that forms the basis of Synlogic’s UCD program, for instance, can consume orders of magnitude more ammonia than natural E. coli can, Lu said. “For this treatment to work for patients, you want the max performance you can squeeze out of any one of these biotics,” he said. Based on their preclinical data, Synlogic’s treatments have the potential to reach “clinical levels” of efficacy not seen often in synthetic biology, said Collins: “Synlogic is programming these probiotic microbes to consume ammonia or phenylalanine for example, and they are reaching levels that are expected to be clinically meaningful, which is quite remarkable.”
News Article | February 28, 2017
NEW YORK--(BUSINESS WIRE)--Kroll Bond Rating Agency (KBRA) announced today the appointment of Stephen Kemmy to the role of Director within KBRA’s European RMBS group. Stephen previously worked as a Director at Fitch Ratings in London, within the Structured Finance group and covered bonds. He was primarily responsible for newly issued and existing ratings from the UK, Netherlands, Ireland and the Nordic countries. In addition, he worked on developing criteria for assessing Irish, Danish and Norwegian rating methodologies. Prior to working in structured finance, Stephen spent nearly 3 years working in KBC Bank Ireland plc as an Executive within the Credit Risk team and Treasury. Stephen holds an MBS in Finance from UCD Michael Smurfit School of Business and a BS in Accounting and Finance from Dublin Institute of Technology. “Stephen brings reputable knowledge in the market as KBRA continues to expand its footprint globally and to grow its business lines. Stephen will be focused on mortgage and housing finance across Europe helping us execute our existing pipeline and develop new ratings and research,” said Mauricio Noé, who is leading KBRA’s expansion into Europe. Please visit www.kbra.com for more details. KBRA is registered with the U.S. Securities and Exchange Commission as a Nationally Recognized Statistical Rating Organization (NRSRO). In addition, KBRA is recognized by the National Association of Insurance Commissioners (NAIC) as a Credit Rating Provider (CRP).
News Article | November 7, 2016
Urinary collection device (UCD) is a medical product helps in managing urinary output, hygiene required for long term medical care and collection of urine sample for urinalysis which include detection of various disorders such as urinary tract infection. Urinary collection device is used as a backup to bladder urine collection system or to prevent accidental leakage primarily among patients who stay in the hospital for long time and need bed rest. Urinary collection device is also used during spaceflight, in military fighter aircraft that are not equipped with toilets help pilots to empty their bladder who are required to fly aircraft for several hours, and among patients suffering from urinary incontinence disorder. Urinary collection device also helps in minimizing the contamination of urine specimen with bacterial flora from the patients and minimize the risk of urine leakage and odor. Urinary collection device is useful during travel or where the accessibility to a toilet is difficult. Increasing aging population along with risk of urological disorders such as urinary incontinence, rising demand for hygiene products and reimbursement policies are the factors expected to drive the growth of global urinary collection device market. Increasing prevalence of chronic kidney disease, rising demand for cost effective reusable products and self-monitoring devices are some other factors expected to fuel the growth of global urinary collection device market. However, complications associated with wear of device, difficulty in device maintenance, increasing in the risk of urinary tract infections during urinary drainage, difficulty in disposal of product, chances of skin irritation are the factors that may hamper the growth of urinary collection device market. The global urinary collection device market has been classified on the basis of product type, raw material and end user. Based on product type, the global urinary collection device market is divided into following: Based on raw material type, the global Urinary Collection Device Market is divided into following: Based on end user type, the global Urinary Collection Device Market is divided into following: Based on urine catheter product type segment, intermittent catheter is the most common type of catheter used to collect urine. On the other hand, external collection device is an alternative to Foley catheter used to manage urine output among patients. Enhancement in the standardization of device maintenance and fitting procedures helps in increasing the urine catheter drainage capacity along with less chances of injurious associated with catheter. The urinary collection devices are designed for precise groups of pathogens such as viral, chlamydia, bacterial and parasites. Urinary sample tubes helps in avoiding urine leakage during transportation and maintains urine sample from contamination for 48 hours without refrigeration. Also, helps in preventing from false positive or bacteria overgrowth. Based on urine collection bags, belly bag is the novel product introduced for both men and women who have a Foley catheter to collect urine. Belly bags are more effective than urine leg bags which helps in prevent from involuntary catheter extraction and enhance mobility of urine bag. Depending on geographic region, urinary collection device market is segmented into seven key regions: North America, Latin America, Eastern Europe, Western Europe, Asia Pacific, Japan, and Middle East & Africa. North America held largest share in the urinary collection device market followed by Europe, Japan and Asia Pacific owing to high incidence of chronic diseases, favorable reimbursement policy, rise in research & development activities and developed healthcare infrastructure. The developing nations in Asia Pacific, Middle East and Africa hold huge potential for growth in the urinary collection device market, due to increase in the awareness about hygiene care, rising per capita income and living standards along with increase healthcare expenditure. Some of the key players in global urinary collection device market are Teleflex, Medline Industries, Inc., Hollister Incorporated, Coloplast Ltd., Braun Melsungen AG, CR Bard Inc., Boston Scientific Corporation, Covidien Plc, CooK Medical, Thermo Fisher Scientific Inc. and BD.
News Article | February 27, 2017
Located some 116 million light years away, NGC 5044 is an early-type massive elliptical galaxy residing at the center of an X-ray bright group also named NGC 5044. This group contains about 150 members, most of which are dwarf galaxies. Although the group's center galaxy has been the subject of several past studies, its globular cluster and UCD system remain unexplored. UCDs are very compact galaxies with high stellar populations, containing about 100 million stars. They display masses, colors, and metallicities between those of globular clusters and early-type dwarf galaxies. These ultra-compact stellar systems could provide important insights on the formation and evolution of galaxies in the universe. That is why Faifer's team observed the NGC 5044 with the Gemini Multi-Object Spectrograph (GMOS) at the Gemini South telescope in Chile. They obtained deep images of several fields around NGC 5044, which allowed them to detect the presence of a UCD. "From the photometric and spectroscopic analysis of a deep field taken with Gemini+GMOS, we have been able to detect and confirm the first UCD in the NGC 5044 group," the researchers wrote in the paper. The radial velocity and angular proximity (2.83 arcmin) of this UCD indicate that this object is associated with galaxy NGC 5044. The newly discovered UCD was designated NGC 5044-UCD1. The researchers found that the metallicity of NGC 5044-UCD1 is within the range displayed by other UCD detected in constellations Virgo and Fornax, but considerably lower than that of the confirmed stripped nuclei described in previous studies. They also studied the star formation history of this UCD and found that this object is approximately 11.7 billion years old. Although the origin of UCDs is still widely debated, the most plausible hypotheses suggest that they are massive star clusters or the nuclei of tidally stripped dwarf galaxies. The scientists assume that NGC 5044-UCD1 could be such an unusually massive globular cluster. They note that the object's luminosity is well above the usual upper cut for "classical" globular clusters. Furthermore, NGC 5044-UCD1 presents a supersolar α-element abundance of [α/Fe] = 0.30, suggesting rapid star formation, typical for most globular clusters. "All the lines of evidence would point toward NGC 5044-UCD1 being an unusually massive globular cluster of the NGC 5044 system," the paper reads. Further spectroscopic observations could reveal more insights on the true nature of NGC 5044-UCD1. Currently, the team prepares an analysis of the complete photometric dataset, what will be presented in a forthcoming paper. More information: First confirmed ultra-compact dwarf galaxy in the NGC 5044 group, arXiv:1702.06472 [astro-ph.GA] arxiv.org/abs/1702.06472 Abstract Context. Ultra-compact dwarfs (UCDs) are stellar systems displaying colours and metallicities between those of globular clusters (GCs) and early-type dwarf galaxies, as well as sizes of Reff
News Article | February 23, 2017
Asian Horned frogs account for approximately half of the ancient family of frogs called Megophryidae. This group was previously estimated to have originated 100-126 million years ago (mya). Frogs of this family hopped alongside the famed Velociraptors and other dinosaurs during the Cretaceous period (145-66 mya). Despite the fact that these animals have been around for a long time, little is known about their evolutionary history. Furthermore, unlike their dinosaur contemporaries, these frogs did not leave behind any known fossils. Methods using information from DNA sequences exist for estimating the age of origin for such groups of animals but these methods rely heavily on fossils of related animal groups, which could prove unreliable for these species. New research recently published in the scientific journal, Molecular Biology and Evolution, by a team of scientists from Ireland and India resolved a 195-year old confusion regarding relationships between the species of Asian Horned Frogs, an enigmatic group of frogs often with horn-like projections over their eyes. Using DNA sequences, they discovered many potentially new species in this group previously unknown to science. They also estimated the ages of species and groups of species using a method that had previously not been tried on amphibians and inadvertently discovered that until now scientists may have been overestimating the age of many frog families. Their discovery may open a new chapter on how scientists interpret the evolutionary history of many animals that currently have no known fossil record. "While this research particularly focused on frogs, many other animal groups also lack a fossil record, and so its very difficult to decipher their evolutionary histories. Our hope is that methods used here will prove beneficial for understanding how the distant ancestors of living animals may have coexisted in prehistoric times," explains lead author Dr. Stephen Mahony. The research team was led by Ireland's leading herpetologist, Dr. Stephen Mahony (previously of University College Dublin [UCD], Ireland and University of Delhi [DU], India), and a prominent mammal molecular evolutionary biologist, Prof. Emma Teeling (UCD). A PhD student of Prof. Teeling, Nicole Foley (UCD), and the "Frogman of India", Prof. SD Biju (DU) were co-authors on this research publication. The scientists demonstrated that a recently developed method called RelTime, that does not require fossil information, provided comparatively better age estimates for frogs. Their results correlate well with current knowledge on prehistoric biogeography—distribution of animals in space and time, considering tectonic plate movements, the rise of mountain ranges and palaeoclimatic changes—that may have influenced the evolutionary history of Asian Horned Frogs. This research project was envisaged by Dr. Mahony in 2006 after he discovered that one widely distributed 'species' appeared to represent several similar but scientifically 'new' distinct species. Six of these species from Thailand, Cambodia and India, were formally described as new to science between 2009 and 2013 from his (and his colleagues) previous research. Since then, Stephen embarked on the most extensive research to have ever been carried out on this group of frogs. He did so by examining and measuring hundreds of specimens from museums in Asia, Europe and the US, and used DNA gene sequences to determine how these species are related. These new results indicate that the Asian Horned Frogs family may have originated as recently as 77 million years ago in contrast to 100-126 mya as previously estimated, and suggest that scientists might have been also overestimating the age of many other families of frogs by up to 35%. The results have completely changed our understanding of how the different Asian Horned Frog species and their species groups are related. Many of the species that look similar, and so were considered to be closely related, were found to be distant relatives of each other, and those that look different were found to be closely related. Finally, the results of this research have identified numerous species in India, Vietnam and Laos that are very likely new to science, several of which may be restricted to small distributions in vulnerable habitats. This raises concerns for their continued survival as "having a name" is the bedrock for conservation. "It is well known that Amphibians are one of the most endangered animal groups. Our research further demonstrates that many species remain undiscovered. Sadly, with climate change and continuing habitat destruction, we are losing many species before we can learn anything about them, but the use of molecular techniques is dramatically speeding up the learning process." says Mahony. Explore further: Seven new species of night frogs from India including four miniature forms More information: Stephen Mahony et al, Evolutionary History of the Asian Horned Frogs (Megophryinae): Integrative Approaches to Timetree Dating in the Absence of a Fossil Record, Molecular Biology and Evolution (2017). DOI: 10.1093/molbev/msw267