Drug discovery research in Ghana, challenges, current efforts, and the way forward

We have a long-term vision to develop drug discovery research capacity within Ghana, to tackle unmet medical needs in Ghana and the wider West African region. However, there are several issues and challenges that need to be overcome to enable this vision, including training, human resource, equipment, infrastructure, procurement, and logistics. We discuss these challenges from the context of Ghana in this review. An important development is the universities and research centres within Ghana working together to address some of these challenges. Therefore, while there is a long way to go to fully accomplish our vision, there are encouraging signs

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity

BACKGROUND: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported. METHODS: To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein. RESULTS:Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3' replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5'-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol. CONCLUSION: These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Identification of the top TESS objects of interest for atmospheric characterization of transiting exoplanets with JWST

Funding: Funding for the TESS mission is provided by NASA's Science Mission Directorate. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). MSIP is funded by NSF. This paper is based on observations made with the MuSCAT3 instrument, developed by the Astrobiology Center and under financial support by JSPS KAKENHI (grant No. JP18H05439) and JST PRESTO (grant No. JPMJPR1775), at Faulkes Telescope North on Maui, HI, operated by the Las Cumbres Observatory. This paper makes use of data from the MEarth Project, which is a collaboration between Harvard University and the Smithsonian Astrophysical Observatory. The MEarth Project acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering, the National Science Foundation under grant Nos. AST-0807690, AST-1109468, AST-1616624 and AST-1004488 (Alan T. Waterman Award), the National Aeronautics and Space Administration under grant No. 80NSSC18K0476 issued through the XRP Program, and the John Templeton Foundation. C.M. would like to gratefully acknowledge the entire Dragonfly Telephoto Array team, and Bob Abraham in particular, for allowing their telescope bright time to be put to use observing exoplanets. B.J.H. acknowledges support from the Future Investigators in NASA Earth and Space Science and Technology (FINESST) program (grant No. 80NSSC20K1551) and support by NASA under grant No. 80GSFC21M0002. K.A.C. and C.N.W. acknowledge support from the TESS mission via subaward s3449 from MIT. D.R.C. and C.A.C. acknowledge support from NASA through the XRP grant No. 18-2XRP18_2-0007. C.A.C. acknowledges that this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). S.Z. and A.B. acknowledge support from the Israel Ministry of Science and Technology (grant No. 3-18143). The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant No. PDR T.0120.21. The postdoctoral fellowship of K.B. is funded by F.R.S.-FNRS grant No. T.0109.20 and by the Francqui Foundation. H.P.O.'s contribution has been carried out within the framework of the NCCR PlanetS supported by the Swiss National Science Foundation under grant Nos. 51NF40_182901 and 51NF40_205606. F.J.P. acknowledges financial support from the grant No. CEX2021-001131-S funded by MCIN/AEI/ 10.13039/501100011033. A.J. acknowledges support from ANID—Millennium Science Initiative—ICN12_009 and from FONDECYT project 1210718. Z.L.D. acknowledges the MIT Presidential Fellowship and that this material is based upon work supported by the National Science Foundation Graduate Research Fellowship under grant No. 1745302. P.R. acknowledges support from the National Science Foundation grant No. 1952545. This work is partly supported by JSPS KAKENHI grant Nos. JP17H04574, JP18H05439, JP21K20376; JST CREST grant No. JPMJCR1761; and Astrobiology Center SATELLITE Research project AB022006. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to M.T. D.D. acknowledges support from TESS Guest Investigator Program grant Nos. 80NSSC22K1353, 80NSSC22K0185, and 80NSSC23K0769. A.B. acknowledges the support of M.V. Lomonosov Moscow State University Program of Development. T.D. was supported in part by the McDonnell Center for the Space Sciences. V.K. acknowledges support from the youth scientific laboratory project, topic FEUZ-2020-0038.JWST has ushered in an era of unprecedented ability to characterize exoplanetary atmospheres. While there are over 5000 confirmed planets, more than 4000 Transiting Exoplanet Survey Satellite (TESS) planet candidates are still unconfirmed and many of the best planets for atmospheric characterization may remain to be identified. We present a sample of TESS planets and planet candidates that we identify as “best-in-class” for transmission and emission spectroscopy with JWST. These targets are sorted into bins across equilibrium temperature Teq and planetary radius Rp and are ranked by a transmission and an emission spectroscopy metric (TSM and ESM, respectively) within each bin. We perform cuts for expected signal size and stellar brightness to remove suboptimal targets for JWST. Of the 194 targets in the resulting sample, 103 are unconfirmed TESS planet candidates, also known as TESS Objects of Interest (TOIs). We perform vetting and statistical validation analyses on these 103 targets to determine which are likely planets and which are likely false positives, incorporating ground-based follow-up from the TESS Follow-up Observation Program to aid the vetting and validation process. We statistically validate 18 TOIs, marginally validate 31 TOIs to varying levels of confidence, deem 29 TOIs likely false positives, and leave the dispositions for four TOIs as inconclusive. Twenty-one of the 103 TOIs were confirmed independently over the course of our analysis. We intend for this work to serve as a community resource and motivate formal confirmation and mass measurements of each validated planet. We encourage more detailed analysis of individual targets by the community.Peer reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

The Lancet Global Health Commission on Global Eye Health: vision beyond 2020

Eye health and vision have widespread and profound implications for many aspects of life, health, sustainable development, and the economy. Yet nowadays, many people, families, and populations continue to suffer the consequences of poor access to high-quality, affordable eye care, leading to vision impairment and blindness. In 2020, an estimated 596 million people had distance vision impairment worldwide, of whom 43 million were blind. Another 510 million people had uncorrected near vision impairment, simply because of not having reading spectacles. A large proportion of those affected (90%), live in low-income and middle-income countries (LMICs). However, encouragingly, more than 90% of people with vision impairment have a preventable or treatable cause with existing highly cost-effective interventions. Eye conditions affect all stages of life, with young children and older people being particularly affected. Crucially, women, rural populations, and ethnic minority groups are more likely to have vision impairment, and this pervasive inequality needs to be addressed. By 2050, population ageing, growth, and urbanisation might lead to an estimated 895 million people with distance vision impairment, of whom 61 million will be blind. Action to prioritise eye health is needed now. This Commission defines eye health as maximised vision, ocular health, and functional ability, thereby contributing to overall health and wellbeing, social inclusion, and quality of life. Eye health is essential to achieve many of the Sustainable Development Goals (SDGs). Poor eye health and impaired vision have a negative effect on quality of life and restrict equitable access to and achievement in education and the workplace. Vision loss has substantial financial implications for affected individuals, families, and communities. Although high-quality data for global economic estimates are scarce, particularly for LMICs, conservative assessments based on the latest prevalence figures for 2020 suggest that annual global productivity loss from vision impairment is approximately US$410·7 billion purchasing power parity. Vision impairment reduces mobility, affects mental wellbeing, exacerbates risk of dementia, increases likelihood of falls and road traffic crashes, increases the need for social care, and ultimately leads to higher mortality rates. By contrast, vision facilitates many daily life activities, enables better educational outcomes, and increases work productivity, reducing inequality. An increasing amount of evidence shows the potential for vision to advance the SDGs, by contributing towards poverty reduction, zero hunger, good health and wellbeing, quality education, gender equality, and decent work. Eye health is a global public priority, transforming lives in both poor and wealthy communities. Therefore, eye health needs to be reframed as a development as well as a health issue and given greater prominence within the global development and health agendas. Vision loss has many causes that require promotional, preventive, treatment, and rehabilitative interventions. Cataract, uncorrected refractive error, glaucoma, age-related macular degeneration, and diabetic retinopathy are responsible for most global vision impairment. Research has identified treatments to reduce or eliminate blindness from all these conditions; the priority is to deliver treatments where they are most needed. Proven eye care interventions, such as cataract surgery and spectacle provision, are among the most cost-effective in all of health care. Greater financial investment is needed so that millions of people living with unnecessary vision impairment and blindness can benefit from these interventions. Lessons from the past three decades give hope that this challenge can be met. Between 1990 and 2020, the age-standardised global prevalence of blindness fell by 28·5%. Since the 1990s, prevalence of major infectious causes of blindness—onchocerciasis and trachoma—have declined substantially. Hope remains that by 2030, the transmission of onchocerciasis will be interrupted, and trachoma will be eliminated as a public health problem in every country worldwide. However, the ageing population has led to a higher crude prevalence of age-related causes of blindness, and thus an increased total number of people with blindness in some regions. Despite this progress, business as usual will not keep pace with the demographic trends of an ageing global population or address the inequities that persist in each country. New threats to eye health are emerging, including the worldwide increase in diabetic retinopathy, high myopia, retinopathy of prematurity, and chronic eye diseases of ageing such as glaucoma and age-related macular degeneration. With the projected increase in such conditions and their associated vision loss over the coming decades, urgent action is needed to develop innovative treatments and deliver services at a greater scale than previously achieved. Good eye health at the community and national level has been marginalised as a luxury available to only wealthy or urban areas. Eye health needs to be urgently brought into the mainstream of national health and development policy, planning, financing, and action. The challenge is to develop and deliver comprehensive eye health services (promotion, prevention, treatment, rehabilitation) that address the full range of eye conditions within the context of universal health coverage. Accessing services should not bring the risk of falling into poverty and services should be of high quality, as envisaged by the WHO framework for health-care quality: effective, safe, people-centred, timely, equitable, integrated, and efficient. To this framework we add the need for services to be environmentally sustainable. Universal health coverage is not universal without eye care. Multiple obstacles need to be overcome to achieve universal coverage for eye health. Important issues include complex barriers to availability and access to quality services, cost, major shortages and maldistribution of well-trained personnel, and lack of suitable, well maintained equipment and consumables. These issues are particularly widespread in LMICs, but also occur in underserved communities in high-income countries. Strong partnerships need to be formed with natural allies working in areas affected by eye health, such as non-communicable diseases, neglected tropical diseases, healthy ageing, children's services, education, disability, and rehabilitation. The eye health sector has traditionally focused on treatment and rehabilitation, and underused health promotion and prevention strategies to lessen the impact of eye disease and reduce inequality. Solving these problems will depend on solutions established from high quality evidence that can guide more effective implementation at scale. Evidence-based approaches will need to address existing deficiencies in the supply and demand. Strategic investments in discovery research, harnessing new findings from diverse fields, and implementation research to guide effective scale up are needed globally. Encouragingly, developments in telemedicine, mobile health, artificial intelligence, and distance learning could potentially enable eye care professionals to deliver higher quality care that is more plentiful, equitable, and cost-effective. This Commission did a Grand Challenges in Global Eye Health prioritisation exercise to highlight key areas for concerted research and action. This exercise has identified a broad set of challenges spanning the fields of epidemiology, health systems, diagnostics, therapeutics, and implementation. The most compelling of these issues, picked from among 3400 suggestions proposed by 336 people from 118 countries, can help to frame the future research agenda for global eye health. In this Commission, we harness lessons learned from over two decades, present the growing evidence for the life-transforming impact of eye care, and provide a thorough understanding of rapid developments in the field. This report was created through a broad consultation involving experts within and outside the eye care sector to help inform governments and other stakeholders about the path forward for eye health beyond 2020, to further the SDGs (including universal health coverage), and work towards a world without avoidable vision loss. The next few years are a crucial time for the global eye health community and its partners in health care, government, and other sectors to consider the successes and challenges encountered in the past two decades, and at the same time to chart a way forward for the upcoming decades. Moving forward requires building on the strong foundation laid by WHO and partners in VISION 2020 with renewed impetus to ultimately deliver high quality universal eye health care for all

The TESS–Keck Survey. I. A Warm Sub-Saturn-mass Planet and a Caution about Stray Light in TESS Cameras

We report the detection of a Saturn-size exoplanet orbiting HD 332231 (TOI 1456) in light curves from the Transiting Exoplanet Survey Satellite (TESS). HD 332231 - an F8 dwarf star with a V-band magnitude of 8.56 - was observed by TESS in Sectors 14 and 15. We detect a single-transit event in the Sector 15 presearch data conditioning (PDC) light curve. We obtain spectroscopic follow-up observations of HD 332231 with the Automated Planet Finder, Keck I, and SONG telescopes. The orbital period we infer from radial velocity (RV) observations leads to the discovery of another transit in Sector 14 that was masked by PDC due to scattered light contamination. A joint analysis of the transit and RV data confirms the planetary nature of HD 332231 b, a Saturn-size (0.867-0.025+0.027RJ), sub-Saturn-mass (0.244±0.021MJ) exoplanet on a 18.71 day circular orbit. The low surface gravity of HD 332231 b and the relatively low stellar flux it receives make it a compelling target for transmission spectroscopy. Also, the stellar obliquity is likely measurable via the Rossiter-McLaughlin effect, an exciting prospect given the 0.14 au orbital separation of HD 332231 b. The spectroscopic observations do not provide substantial evidence for any additional planets in the HD 332231 system, but continued RV monitoring is needed to further characterize this system. We also predict that the frequency and duration of masked data in the PDC light curves for TESS Sectors 14-16 could hide transits of some exoplanets with orbital periods between 10.5 and 17.5 days

The TESS Objects of Interest Catalog from the TESS Prime Mission

We present 2241 exoplanet candidates identified with data from the Transiting Exoplanet Survey Satellite (TESS) during its 2 yr Prime Mission. We list these candidates in the TESS Objects of Interest (TOI) Catalog, which includes both new planet candidates found by TESS and previously known planets recovered by TESS observations. We describe the process used to identify TOIs, investigate the characteristics of the new planet candidates, and discuss some notable TESS planet discoveries. The TOI catalog includes an unprecedented number of small planet candidates around nearby bright stars, which are well suited for detailed follow-up observations. The TESS data products for the Prime Mission (sectors 1-26), including the TOI catalog, light curves, full-frame images, and target pixel files, are publicly available at the Mikulski Archive for Space Telescopes