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.

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.

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.

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.

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.

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.

Practical applications to modify and control the development of ametropia.

For many individuals, the developmental trend of lessening hyperopia from birth continues past emmetropia towards myopia during childhood. The global pattern for prevalence of refractive errors indicates that the prevalence of hyperopia is low; in contrast, the burden of myopia is on the rise because of rising prevalence and magnitude of myopia. This review highlights the need to lessen the global burden of myopia by intervening with the development and/or slowing the progression of myopia. Further, outcomes from human clinical trials of pharmaceutical, optical, and environmental approaches to control myopia will be summarised. Pharmaceutical treatments are effective in controlling eye growth but are associated with deleterious side effects. Optical strategies that induce myopic defocus at the retina such as peripheral defocus reducing lenses, simultaneous defocus lenses, bifocals, and orthokeratology as well as environmental influences such as increased outdoor activity show promise and provide a substantially risk-free environment in which to control eye growth.

Myopia, an underrated global challenge to vision: where the current data takes us on myopia control.

Myopia is the most frequent cause of distance impairment in the world and is creating an alarming global epidemic with deleterious ramifications for the quality of life and economic health of individuals and nations as a whole. In addition to being immediately disadvantageous, myopia increases the risk of serious disorders such as myopic macular degeneration, retinal detachment, glaucoma, and cataract and is a leading cause of visual impairment and blindness across many countries. The reduction in age of onset of myopia is of great concern since the earlier the onset, the more myopic the individual will become, with all the attendant increased risks of accompanying debilitating eye conditions. The economic burden is great; both in consequences of uncorrected refractive error and also in the provision of devices for correcting visual acuity. Earlier onset of myopia increases the lifetime economic burden related to loss of productivity and independence, leading to a reduced quality of life. Recent data suggest addressing accommodation per se has little direct amelioration of myopia progression. Pharmacological interventions that effect changes in the sclera show promising efficacy, whereas optical interventions based on a myopic shift in the retinal image are proving to effect up to 55% reduction in the rate of progression of myopia. Early contact lens and spectacle interventions that reduce the rate of progression of myopia are able to significantly reduce the burden of myopia. These non-pharmacological interventions show profound promise in reducing the overall associated morbidity of myopia.

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.

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.

Low energy ballasted flotation.

A novel process which involves the replacement or supplementation of bubbles in the dissolved air flotation process with low density beads is presented. The work comprised a series of bench-scale flotation trials treating three commonly encountered algal species (Microcystis, Melosira and Chlorella) that were removed in a flotation cell configured as either: conventional dissolved air flotation (DAF); ballasted flotation using low density 70 microm glass beads with a density of 100 kg m(-3); or a hybrid process of ballasted flotation combined with conventional DAF. Results indicated that the bead only system was capable of achieving better residual turbidity than standard DAF at bead concentrations of 500 mg L(-1). Addition of beads in combination with standard DAF reduced turbidity further to even lower residual turbidity levels. Algae removal was improved when glass beads were dosed, but removal was dependent on algal species. Microcystis was removed by 97% for bead only systems and this removal did not change significantly with the addition of air bubbles. Melosira was the next best removed algae with bead only dosed systems giving similar removals to that achieved by standard DAF using a 10% air recycle ratio (81 and 76% removal respectively). Chlorella was the least well removed algae by bead only systems (63% removal). However, removal was rapidly improved to 86% by the addition of air bubbles using only a 2% recycle ratio. Energy estimations suggested that at least a 50% energy reduction could be achieved using the process offering a potential route for future development of low energy separation processes for algae removal.

HIV, sexually transmitted infections, and risk behaviours in male sex workers in London over a 10 year period.

OBJECTIVES: To describe changing characteristics of men who sold sex in London between 1994 and 2003. METHODS: A baseline survey of 823 male sex workers attending a specialist clinic, plus follow up of 628 men for 1379 person years. RESULTS: Men recruited earlier (1994 to 1996) were more likely than those recruited later (2000 to 2003) to be UK born and to self define as homosexual. Later recruits included more men from South/Central America and eastern Europe and a higher proportion reported regular female partners. Baseline prevalence of HIV was 9% (59/636), and multivariate analysis showed an associated with injecting drug use and unprotected sex with a casual partner. During follow up there were 49 incident cases of HIV. Survival analysis showed earlier recruitment (1994-6) to be associated with a higher incidence of HIV. The prevalence of gonorrhoea increased over time. CONCLUSIONS: Men who sell sex are at risk of HIV and other STIs, but these risks do not appear to be directly linked to sex work. The changing demographics of these men is associated with different patterns of infection and poses challenges for service delivery.

Hepatitis B vaccination for male sex workers: the experience of a specialist GUM service.

BACKGROUND: Male sex workers are at risk of blood borne viruses but may have limited access to sexual health services, including vaccination. We explore factors associated with hepatitis B vaccination uptake among male sex workers in London METHODS: Follow up study of men attending the Working Men's Project, a specialist health project for men who sell sex, between 1994 and 2003. RESULTS: At baseline 797 men were screened for hepatitis B; 308 were not eligible for vaccination because of past or current infection (155, 19.4%) or previous vaccination 153 (19.2%). Of the 489 men eligible for a full course of vaccination 292 (59.8%) completed the course. Completion rates fell over time: men recruited up to 1999 were more likely to complete the course than those recruited more recently (177/259, 68.3% compared with 115/229, 50.2%, OR 2.14, 95% CI 1.48 to 3.09). CONCLUSION: This specialist service achieved a high rate of vaccine completion in the early years, but the decline is a concern. It may reflect wider availability of vaccination elsewhere and a more mobile population of sex workers. Shorter courses may achieve a higher completion.

Corneal and conjunctival sensitivity to air stimuli.

AIMS: To determine the repeatability of ocular surface sensitivity to mechanical stimulation using air stimuli and the effect of contact lens (CL) wear on sensitivity. METHODS: Repeatability: 14 subjects (24-39 years) participated. Mechanical sensitivity to warmed (34 degrees C) and ambient (20 degrees C) air was measured for the central cornea (CC), inferior cornea (IC), and inferior conjunctiva (ICON). Measurements were taken on 12 days; six morning and six afternoon measurements. Differences between sites, time of day, and stimulus temperature were evaluated. CL wear: 10 subjects (22-30 years) participated. Measurements were taken at the same time of day, either following no wear, wear of a CL of oxygen permeability [Dk] of 28 x 10(-9) [cm/s][ml O(2)/ml mm Hg] or wear of a CL of Dk 140 x 10(-9) [cm/s][ml O(2)/ml mm Hg]. Differences between sites and wear conditions were evaluated. RESULTS: Repeatability: Sensitivity varied between sites (p<0.01), time of day (p<0.05), and stimulus temperatures (p<0.01). There were no significant differences between days. Mean thresholds for eye temperature stimuli were; CC 64.4 (SD 28.6) ml/min; IC 84.6 (40.0) ml/min; ICON 120.6 (40.4) ml/min and for ambient temperature stimuli were CC 53.9 (16.0) ml/min, IC 59.0 (20.0) ml/min; ICON 72.6 (43.7) ml/min. CL wear: Sensitivity varied between sites and wear conditions (p<0.05). Conjunctival sensitivity was increased after wear of highly oxygen permeable CLs but unaffected by wear of low oxygen permeable CLs. CONCLUSIONS: The prototype gas aesthesiometer is able to repeatably measure ocular surface sensitivity and measurements are consistent with previously reported techniques.

The association between severity of intellectual disability and psychiatric symptomatology.

BACKGROUND: Mental illness is more prevalent in people with intellectual disabilities (ID) than in the normal population. The association between mental illness and severity of ID is also of importance in the understanding and treatment of maladaptive and challenging behaviours. The aim of this study was to investigate the association between severity of ID and prevalence of mental illness. METHODS: Using the Mini PAS-ADD, an instrument designed to identify psychiatric symptoms in people with ID, informants were interviewed about the presence of symptoms in 96 participants with moderate, severe and profound ID, and asked about the use of psychotropic medication. RESULTS: Mental illness, particularly anxiety, depression and psychosis, was far more prevalent in participants with moderate ID than in people with severe and profound ID. The use of psychotropic medication was not significantly different between the groups. CONCLUSIONS: The prevalence of psychiatric illness decreases with severity of ID. The usefulness of psychiatric illness models, in explaining maladaptive and challenging behaviours, also decreases with severity of ID. Drug treatment may become more complicated, and behavioural and environmental interventions may become relatively more important, as severity of ID increases.

ICEE/AHMRC NSW Aboriginal Eye and Visioncare Program, Australia.

CONTEXT: An astounding 50% of blindness and 70% of vision impairment in Australia is caused by conditions that are said to be preventable or treatable. Aboriginal people suffer 10 times the rate of blindness and attend eyecare practitioners in far lower numbers than other members of the Australian population. ISSUE: In order to combat this problem in New South Wales (NSW), Australia, the International Centre for Eyecare Education (ICEE), with the Aboriginal Health and Medical Research Council (AHMRC) and the Office of Aboriginal and Torres Strait Islander Health (OATSIH), and local Aboriginal communities, have set up eyecare clinics in Aboriginal Medical Services (AMS) around the State. These eye clinics provide eyecare and vision correction, including the provision of spectacles and other optical aids, as well as educational programs to increase health awareness among the Aboriginal population and Aboriginal eye health workers. The first eyecare clinic was opened in AMS Redfern (Sydney) in July 2000 and ICEE now has a presence in over 60 locations throughout NSW. There have already been over 8000 consultations and 6000 pairs of spectacles provided to Aboriginal communities during this time. The program has also demonstrated that an effective Aboriginal eyecare program can be self-sustainable. LESSONS: The key to the success of this program has been collaboration and cooperation. This has involved working through, and with, Aboriginal community-controlled health services, which has ensured that programs are developed in accordance with community needs and cultural sensitivities. It has also involved the harnessing of the contributions of a number of State, Federal, community and professional organisations and individuals. This has provided efficiencies in service and resource provision, which are essential to the sustainability of the program.

Epithelial split associated with wear of a silicone hydrogel contact lens.

PURPOSE: To describe the appearance and management of a superior epithelial arcuate lesion (SEAL) observed in association with the wear of a silicone hydrogel lens. METHODS: We present a case of a 30-year-old male who presented with a SEAL after 4 months of wear of a silicone hydrogel lens on a 30-day extended wear schedule. Bacteriological examination of the lenses and ocular adnexa was conducted at the time of the event. The clinical presentation and management are presented and compared to a review of cases associated with hydrogel lenses. RESULTS: The patient presented with symptoms of mild irritation. A linear splitwas noted in the superior peripheral cornea of the affected eye and was associated with limbal injection, stromal infiltrates, and fluorescein staining. Normal ocular biota was recovered from the lenses and eyelids of both eyes. Visual acuity remained unchanged and the lesion resolved following prophylactic treatment and discontinuation of lens wear for 8 days. CONCLUSIONS: The diagnosis and management of this SEAL case in a silicone hydrogel lens wearer mirrored that of previous events associated with hydrogel lenses. The possible etiologies of SEAL in this case are discussed and include mechanical irritation and dehydration of the lens surface.

Microcysts: clinical significance and differential diagnosis.

BACKGROUND: Microcysts are the most-distinctive and easily detectable indicator of contact lens-induced hypoxia. They should not be confused with cyst-like inclusions that occur in conditions such as Meesmann's dystrophy, bullous keratopathy, and Cogan's microcystic dystrophy, or with mucin balls, vacuoles, microcystic edema, and infiltrates. METHODS: Data from published literature and recent data from The Cornea and Contact Lens Research Unit (CCLRU) clinical trials involving low Dk and prototype high Dk soft contact lenses (SCLs) were examined. RESULTS: Extended wear with low Dk SCLs induces significant numbers of microcysts, whereas extended wear with high Dk SCLs does not. Subjects who transfer from low Dk to high Dk lenses have an initial increase in the number of microcysts after seven days that declines to normal levels over 1 to 3 months. Microcysts can be differentiated from other ocular conditions as they show reversed illumination, are 10- to 50-microm irregularly shaped dots, and are often associated with lens-induced hypoxia. CONCLUSIONS: Microcysts are easily observed and differentiated from other conditions in clinical practice. On average, fewer than ten microcysts per eye occur in nonhypoxic lens wear and, on average, more than 20 microcysts per eye are an indication of chronic hypoxia. The increase in microcyst numbers after transfer from low to high Dk lens wear is transitory and does not necessitate a period of no lens wear.

Giant left atrial intrapericardial aneurysm: noninvasive preoperative imaging.

Congenital giant intrapericardial aneurysms of the left atrium are rare. A 17-year-old boy presented with paroxysmal episodes of palpitations, chest pain, and dyspnea. A chest roentgenogram showed an enlarged left cardiac silhouette. Transthoracic echocardiography imaging showed an intrapericardial aneurysm of the left atrium. Cardiac magnetic resonance imaging confirmed the diagnosis and delineated adjacent structures to plan the surgical resection. We have found no previous reports of cases of diagnosis and preoperative assessment based solely on noninvasive imaging.