A candidate super-Earth planet orbiting near the snow line of Barnard's star.

Barnard's star is a red dwarf, and has the largest proper motion (apparent motion across the sky) of all known stars. At a distance of 1.8 parsecs1, it is the closest single star to the Sun; only the three stars in the α Centauri system are closer. Barnard's star is also among the least magnetically active red dwarfs known2,3 and has an estimated age older than the Solar System. Its properties make it a prime target for planetary searches; various techniques with different sensitivity limits have been used previously, including radial-velocity imaging4-6, astrometry7,8 and direct imaging9, but all ultimately led to negative or null results. Here we combine numerous measurements from high-precision radial-velocity instruments, revealing the presence of a low-amplitude periodic signal with a period of 233 days. Independent photometric and spectroscopic monitoring, as well as an analysis of instrumental systematic effects, suggest that this signal is best explained as arising from a planetary companion. The candidate planet around Barnard's star is a cold super-Earth, with a minimum mass of 3.2 times that of Earth, orbiting near its snow line (the minimum distance from the star at which volatile compounds could condense). The combination of all radial-velocity datasets spanning 20 years of measurements additionally reveals a long-term modulation that could arise from a stellar magnetic-activity cycle or from a more distant planetary object. Because of its proximity to the Sun, the candidate planet has a maximum angular separation of 220 milliarcseconds from Barnard's star, making it an excellent target for direct imaging and astrometric observations in the future.

COVID-19: public health management of the first two confirmed cases identified in the UK.

We report key learning from the public health management of the first two confirmed cases of COVID-19 identified in the UK. The first case imported, and the second associated with probable person-to-person transmission within the UK. Contact tracing was complex and fast-moving. Potential exposures for both cases were reviewed, and 52 contacts were identified. No further confirmed COVID-19 cases have been linked epidemiologically to these two cases. As steps are made to enhance contact tracing across the UK, the lessons learned from earlier contact tracing during the country's containment phase are particularly important and timely.

The effects of CO2 pressure and pH on the Suzuki coupling of basic nitrogen containing substrates.

The Suzuki coupling reaction of basic nitrogen containing substrates (2-bromo- and 2-chloro-4-aminopyridine, and 2-bromo and 2-chloropyridine) with phenylboronic acid using Pd(TPP)2Cl2/K3PO4 in acetonitrile-water biphasic solvent systems under a CO2 or a N2 atmosphere is discussed. It was observed that 2-halo-4-aminopyridine produced quantitative yields of coupled products under a CO2 atmosphere while the yields for the 2-halopyridines were poor. In contrast, the yields of coupled products for the 2-halopyridines substrates were quantitative under a N2 atmosphere while only poor yields were realized for the 2-halo-4-aminopyridines under the same conditions. Evidence is presented which suggests that the presence of CO2 alters the pH of the aqueous phase of the reaction system and the accompanying efficiency of the coupling process. Using a series of buffers to adjust the pH of the aqueous phase, the pH dependence associated with the efficiency of the coupling process is illustrated.

Global cost of correcting vision impairment from uncorrected refractive error.

OBJECTIVE: To estimate the global cost of establishing and operating the educational and refractive care facilities required to provide care to all individuals who currently have vision impairment resulting from uncorrected refractive error (URE). METHODS: The global cost of correcting URE was estimated using data on the population, the prevalence of URE and the number of existing refractive care practitioners in individual countries, the cost of establishing and operating educational programmes for practitioners and the cost of establishing and operating refractive care facilities. The assumptions made ensured that costs were not underestimated and an upper limit to the costs was derived using the most expensive extreme for each assumption. FINDINGS: There were an estimated 158 million cases of distance vision impairment and 544 million cases of near vision impairment caused by URE worldwide in 2007. Approximately 47 000 additional full-time functional clinical refractionists and 18 000 ophthalmic dispensers would be required to provide refractive care services for these individuals. The global cost of educating the additional personnel and of establishing, maintaining and operating the refractive care facilities needed was estimated to be around 20 000 million United States dollars (US$) and the upper-limit cost was US$ 28 000 million. The estimated loss in global gross domestic product due to distance vision impairment caused by URE was US$ 202 000 million annually. CONCLUSION: The cost of establishing and operating the educational and refractive care facilities required to deal with vision impairment resulting from URE was a small proportion of the global loss in productivity associated with that vision impairment.

Bioaugmentation of pilot-scale slow sand filters can achieve compliant levels for the micropollutant metaldehyde in a real water matrix.

Metaldehyde is a polar, mobile, low molecular weight pesticide that is challenging to remove from drinking water with current adsorption-based micropollutant treatment technologies. Alternative strategies to remove this and compounds with similar properties are necessary to ensure an adequate supply of safe and regulation-compliant drinking water. Biological removal of metaldehyde below the 0.1 µg•L-1 regulatory concentration was attained in pilot-scale slow sand filters (SSFs) subject to bioaugmentation with metaldehyde-degrading bacteria. To achieve this, a library of degraders was first screened in bench-scale assays for removal at micropollutant concentrations in progressively more challenging conditions, including a mixed microbial community with multiple carbon sources. The best performing strains, A. calcoaceticus E1 and Sphingobium CMET-H, showed removal rates of 0.0012 µg•h-1•107 cells-1 and 0.019 µg•h-1•107 cells-1 at this scale. These candidates were then used as inocula for bioaugmentation of pilot-scale SSFs. Here, removal of metaldehyde by A. calcoaceticus E1, was insufficient to achieve compliant water regardless testing increasing cell concentrations. Quantification of metaldehyde-degrading genes indicated that aggregation and inadequate distribution of the inoculum in the filters were the likely causes of this outcome. Conversely, bioaugmentation with Sphingobium CMET-H enabled sufficient metaldehyde removal to achieve compliance, with undetectable levels in treated water for at least 14 d (volumetric removal: 0.57 µg•L-1•h-1). Bioaugmentation did not affect the background SSF microbial community, and filter function was maintained throughout the trial. Here it has been shown for the first time that bioaugmentation is an efficient strategy to remove the adsorption-resistant pesticide metaldehyde from a real water matrix in upscaled systems. Swift contaminant removal after inoculum addition and persistent activity are two remarkable attributes of this approach that would allow it to effectively manage peaks in metaldehyde concentrations (due to precipitation or increased application) in incoming raw water by matching them with high enough degrading populations. This study provides an example of how stepwise screening of a diverse collection of degraders can lead to successful bioaugmentation and can be used as a template for other problematic adsorption-resistant compounds in drinking water purification.

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

Potential lost productivity resulting from the global burden of uncorrected refractive error.

OBJECTIVE: To estimate the potential global economic productivity loss associated with the existing burden of visual impairment from uncorrected refractive error (URE). METHODS: Conservative assumptions and national population, epidemiological and economic data were used to estimate the purchasing power parity-adjusted gross domestic product (PPP-adjusted GDP) loss for all individuals with impaired vision and blindness, and for individuals with normal sight who provide them with informal care. FINDINGS: An estimated 158.1 million cases of visual impairment resulted from uncorrected or undercorrected refractive error in 2007; of these, 8.7 million were blind. We estimated the global economic productivity loss in international dollars (I$) associated with this burden at I$ 427.7 billion before, and I$ 268.8 billion after, adjustment for country-specific labour force participation and employment rates. With the same adjustment, but assuming no economic productivity for individuals aged > 50 years, we estimated the potential productivity loss at I$ 121.4 billion. CONCLUSION: Even under the most conservative assumptions, the total estimated productivity loss, in $I, associated with visual impairment from URE is approximately a thousand times greater than the global number of cases. The cost of scaling up existing refractive services to meet this burden is unknown, but if each affected individual were to be provided with appropriate eyeglasses for less than I$ 1000, a net economic gain may be attainable.

Basal and Evoked Neurotransmitter Levels in Parkin, DJ-1, PINK1 and LRRK2 Knockout Rat Striatum.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of neurons in the substantia nigra that project to the striatum and release dopamine (DA), which is required for normal movement. Common non-motor symptoms likely involve abnormalities with other neurotransmitters, such as serotonin, norepinephrine, acetylcholine, glycine, glutamate and gamma-aminobutyric acid (GABA). As part of a broad effort to provide better PD research tools, the Michael J. Fox Foundation for Parkinson's Research funded the generation and characterization of knockout (KO) rats for genes with PD-linked mutations, including PINK1, Parkin, DJ-1 and LRRK2. Here we extend the phenotypic characterization of these lines of KO rats to include in vivo microdialysis to measure both basal and potassium-induced release of the above neurotransmitters and their metabolites in the striatum of awake and freely moving rats at ages 4, 8 and 12 months compared to wild-type (WT) rats. We found age-dependent abnormalities in basal DA, glutamate and acetylcholine in PINK1 KO rats and age-dependent abnormalities in basal DA metabolites in Parkin and LRRK2 KO rats. Parkin KO rats had increased glycine release while DJ-1 KO rats had decreased glutamate release and increased acetylcholine release compared to WT rats. All lines except DJ-1 KO rats showed age-dependent changes in release of one or more neurotransmitters. Our data suggest these rats may be useful for studies of PD-related synaptic dysfunction and neurotransmitter dynamics as well as studies of the normal and pathogenic functions of these genes with PD-linked mutations.

Reduced epithelial adhesion after extended contact lens wear correlates with reduced hemidesmosome density in cat cornea.

Reduced epithelial adhesion in cat corneas after continuous wear of thick hydrogel contact lenses has been reported previously. To investigate the mechanism(s) underlying this observed loss of epithelial adhesion further, the corneas of both eyes of cats that had worn low-oxygen-transmissible thick parallel-design hydrogel contact lenses only in one eye for 8-121 days were examined using both light and transmission electron microscopy (TEM). Contact lens wear induced many changes in the epithelium, including a decrease in the number of cell layers and appearance of cuboidal rather than columnar basal cell shapes. In addition, TEM revealed that the number of hemidesmosomes (HDs) per micrometer of basement membrane was reduced significantly after contact lens wear. Anchoring fibrils in lens-wearing corneas appeared normal, and the reduction in epithelial adhesion occurred without obvious epithelial edema. Decreased epithelial adhesion after contact lens wear appears to be directly related to the reduced numbers of HDs. Possible reasons for decreased HD density, such as loss of basal cell shape and chronic epithelial hypoxia after contact lens wear, are discussed.

Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses.

The relationship between corneal edema and hydrogel lens oxygen transmissibility was examined for both daily and extended contact lens wear by measuring the corneal swelling response induced by a variety of contact lenses over a 36-hr wearing period. The relationships derived enable average edema levels that occur with daily and extended wear in a population of normal young adults to be predicted to within +/- 1.0%. The critical lens oxygen transmissibilities required to avoid edema, for the group as a whole, for daily and extended contact lens wear were obtained from the derived curves. It was found under daily wear conditions that lenses having an oxygen transmissibility of at least 24.1 +/- 2.7 X 10(-9) (cm X ml O2)/(sec X ml X mmHg), an Equivalent Oxygen Percentage (EOP) of 9.9%, did not induce corneal edema. This level of oxygen transmissibility can be achieved (1) in standard, low water content, poly-HEMA lenses by using an average lens thickness of 33 microns or less, or (2) in a higher water content material, such as Duragel 75, by using an average thickness of 166 microns or less. The critical hydrogel lens oxygen transmissibility needed to limit overnight corneal edema to 4% (the level experienced without a contact lens in place) was found to be 87.0 +/- 3.3 X 10(-9) (cm X ml O2)/(sec X ml X mmHg)--an EOP of 17.9%. This ideal level of oxygen transmissibility cannot, at present, be provided with hydrogel materials.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term changes in corneal endothelial morphology following wounding in the cat.

The cat eye was used to determine the long-term morphological changes in the corneal endothelium that occur after central endothelial wounding. Central corneal thickness was measured using ultrasonic pachometry. Specular microscopy and computer-assisted morphometry was used to quantify central and peripheral endothelial cell density (ECD), coefficient of variation (COV) and the mean and standard deviation of the shape factor (S) over an 18-month period. After endothelial wounding, there was a rapid increase in corneal thickness followed by a rapid nonlinear decline, reaching presurgical levels 35 days after wounding. Central cell density had decreased by 25% at 4 weeks after wounding. During the following 18 months, endothelial cell density in the central cornea increased slightly. The coefficient of variation had increased by 60% at 4 weeks after wounding. This recovered slowly and had reached control levels by 18 months. The mean shape factor was higher in the wounded eye throughout the 18 months, whereas the standard deviation of the shape factor recovered after 12 months. Peripheral ECD had decreased significantly by 12 months after wounding, while COV and the mean shape factor was not significantly affected. The standard deviation of the shape factor had also increased significantly in the peripheral cornea after 18 months. These findings suggest that following endothelial wounding in the cat, changes in endothelial morphology occur over the entire cornea. Endothelial cell density and the shape factor have not recovered to control values, even 18 months after wounding. This pattern of endothelial repair supports the mechanisms of cell movement suggested by Honda et al and confirm the similarities in endothelial response between cat and man.

Diurnal variation of corneal thickness in the cat.

Central corneal thickness of both eyes of seven cats was measured hourly for 72 hr using ultrasonic pachometry. The mean corneal thickness was 569 +/- 36 micron (mean +/- SD), and the diurnal variation was 49 +/- 14 micron (8.6% of corneal thickness). In a separate experiment, the corneal thickness of one eye of each of five cats was measured following 2 hr of natural sleep; 2 1/4 hr after eye opening, the corneas had thinned an average of 43 +/- 22 micron. The authors conclude that corneal swelling induced by eye closure during periods of sleep is the prime determinant of the diurnal variation in cat corneal thickness. In studies where corneal thickness is to be monitored over a period of time, it is possible to control against this large diurnal variation by ensuring that the cat is active for a period of two hours prior to pachometry measurements.

The etiology of transient endothelial changes in the human cornea.

To investigate the etiology of contact lens-induced transient endothelial changes (blebs) in the human cornea, the effects of five different stimuli on corneal thickness and the appearance of the corneal endothelium were assessed. The stimuli included: (1) a silicone contact lens; (2) a silicone contact lens in combination with anoxia; (3) anoxia alone; (4) a thick hydroxyethyl methacrylate (HEMA) contact lens; and (5) a gas mixture of 9.8% carbon dioxide, 20.5% oxygen, and the balance nitrogen. The silicone lens alone produced no significant alteration in endothelial appearance and little change in corneal thickness. However, when nitrogen gas was passed in front of the lens, a typical bleb response was observed. This indicates that the physical presence of a contact lens is insufficient by itself to produce transient endothelial changes. Anoxia alone induced corneal swelling and endothelial bleb formation, indicating a metabolic component in the bleb response. The gas mixture containing 9.8% carbon dioxide also altered the endothelial appearance but had no significant effect on corneal thickness. The thick HEMA lens produced changes in both the appearance of the endothelium and corneal thickness. The only factor common to the stimuli which induced blebs would appear to be their ability to change the pH in or near the corneal endothelial layer.

Corneal thickness profiles in rabbits using an ultrasonic pachometer.

An ultrasonic pachometer was used to measure the central, mid-peripheral, and peripheral thickness in 17 locations across the corneas of 12 adult New Zealand Albino rabbit eyes. The mean thickness at each location was entered into a microcomputer to generate a three-dimensional plot of corneal thickness. The rabbit cornea was found to have uniform thickness, with an average thickness variation of only 7 micrometers across the cornea. The average central corneal thickness was 407 +/- 20 micrometers. The three-dimensional representation of corneal thickness was useful in monitoring the surgical effects of cataract extraction and postoperative healing in rabbits. The ultrasonic pachometer was found to be well suited to animal studies. This study indicated that the velocity of sound in rabbit corneal tissue was approximately 1,580 m/sec.

Corneal swelling response of the aphakic eye.

Corneal swelling response was measured for 12 unilateral aphakic subjects wearing high-plus hydrogel contact lenses on both eyes. Significantly less corneal edema was measured for aphakic eyes than for phakic eyes after 2, 4, and 6 hr of lens wear. These results indicate that the cornea of the aphakic eye responds differently to a given physiologic challenge than does the cornea of the phakic eye. Previous estimates of oxygen permeability required of contact lens materials for extended wear may be artificially high for aphakic eyes.

The minimum precorneal oxygen tension to avoid corneal edema.

One eye of each of eight subjects was exposed to gases containing oxygen concentrations of 1.0%, 2.5%, 4.9%, 7.5%, 10.1%, and 21.4% (oxygen partial pressures ranging from 8 to 158 mmHg) for 8 hr. The precorneal oxygen concentration required to avoid corneal edema for the group as a whole was 10.1% (an oxygen tension of 74 mmHg). There was considerable individual variation both in the corneal swelling response with each of the various oxygen concentrations and in the atmospheric oxygen concentration required to avoid edema: one subject required 7.5%, four subjects required 10.1%, and three subjects required 21.4% oxygen concentration. The results of this study suggest that the cornea requires higher levels of atmospheric oxygen than previously considered necessary for normal function.

Surgical incision alters the swelling response of the human cornea.

The ocular characteristics and responses were examined in patients who had undergone extracapsular cataract extraction (ECCE), intracapsular cataract extraction (ICCE) and penetrating keratoplasty (PKP) in one eye only. In each of the three groups, corneal sensitivity (the inverse of corneal touch threshold), oxygen uptake rate, and endothelial cell density were lower in the operated eye than in the normal healthy fellow eye. For the subjects as a whole, the differences in ocular characteristics between the two eyes were proportional to the angular size of the corneal incision, with ECCE patients (33 degrees incision) showing the least differences and PKP patients (360 degrees incision) showing the greatest differences. Five patients from the ICCE group were subjected to an osmotic stress test. There was no statistically significant difference in the corneal swelling response between the operated eye (5.1%) and the unoperated eye (4.7%), indicating that surgically induced scar tissue does not restrict the swelling properties of the cornea. When subjected to a hypoxic stress test, all three groups manifested less corneal edema in the operated eye (ECCE -0.7%, ICCE -4.0%, and PKP -3.3%). The reduction in hypoxic corneal swelling could not be attributed to removal of the crystalline lens since a similar reduction was seen in the PKP group who had phakic eyes. The corneal swelling response correlated inversely with the corneal touch threshold and directly with epithelial oxygen uptake, but did not correlate with endothelial cell density.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cataract surgery on corneal function.

Recent reports suggest that the aphakic eye develops less corneal edema than the phakic eye during hydrogel contact lens wear. Measurements were made of several ocular characteristics that might account for this difference in nine unilateral aphakic subjects. The measurements showed that compared with the phakic eye, the aphakic eye averaged a 15% lower epithelial oxygen uptake rate, 18% fewer endothelial cells, 85% loss of corneal sensitivity, and 8% thinner corneal epithelium. Both eyes of each subject were exposed to a reduced oxygen environment for 2 hr in separate experiments: (1) by wearing a thick hydrogel contact lens and closing the eyes, and (2) by exposing the eye to 100% nitrogen gas. In the gel lens-closed eye experiment the aphakic cornea swelled an average of 7.5%, compared with 11.0% for the phakic cornea. For the nitrogen gas experiment the results were 4.3% and 6.2%, respectively. Eighty-five percent of the edema was in the stromal layer. The lower swelling response for the aphakic eye was significant (p less than 0.01) in both experiments. Corneal swelling after hypoxia is considered to be caused by an increase in corneal osmolarity resulting from an increase in the rate of production of lactic acid. The reduced corneal swelling in the aphakic eye, when compared with the phakic eye, could therefore be the result of either (1) a reduction in the overall metabolic activity of the epithelium, as indicated by the lower epithelial oxygen uptake rate and the thinner corneal epithelium in the aphakic eye, or (2) an increased efflux of lactic acid from the cornea resulting from an increased endothelial permeability to lactate.

Long-term neural regeneration in the rabbit following 180 degrees limbal incision.

Penetrating 180 degrees superior limbal incisions were made on the right eye of four adult New Zealand albino rabbits. The contralateral eye served as control. Corneal touch thresholds (CTT) for the central, superior and inferior cornea (2-3 mm from limbus) were determined 3, 9, 15, 24 and 30 months after surgery. In all animals, the CTT was significantly elevated in the superior region of the cornea throughout the measurement period. CTT was elevated in the central and inferior cornea 3 months following surgery and was not affected in the inferior cornea on all other occasions. The animals were then sacrificed and the corneas subjected to histochemical demonstration of acetylcholinesterase corneal nerves. All rabbits showed a reduction in the number of histochemically detectable stromal nerve trunks in the operated region. These stromal nerve trunks showed regenerative changes including abnormally curved course and a subnormal number of axons within a nerve trunk. Epithelial nerve fiber defects included absence or distorted architecture of the basal epithelial plexus and intra-epithelial terminals. These results indicate that although extensive stromal reinnervation had occurred, the extent and quality of stromal nerves was inadequate to restore a normal epithelial plexus and corneal sensitivity.