While chiral allylic organophosphorus compounds are widely utilized in asymmetric catalysis and for accessing bioactive molecules, their synthetic methods are still very limited. We report the ...development of asymmetric nickel/Brønsted acid dual-catalyzed hydrophosphinylation of 1,3-dienes with phosphine oxides. This reaction is characterized by an inexpensive chiral catalyst, broad substrate scope, and high regio- and enantioselectivity. This study allows the construction of chiral allylic phosphine oxides in a highly economic and efficient manner. Preliminary mechanistic investigations suggest that the 1,3-diene insertion into the chiral Ni-H species is a highly regioselective process and the formation of the chiral C-P bond is an irreversible step.
Asymmetric hydrophosphinylation of 1,3-dienes with phosphine oxides using an inexpensive chiral catalyst has been demonstrated, providing access to chiral allylic phosphine oxides with broad substrate scope and high regio- and enantioselectivity.
The public view on antibiotics as reliable medicines changed when reports about “resistant superbugs” appeared in the news. While reasons for this resistance development are easily spotted, solutions ...for re‐establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.
Fit for the future: The discovery of novel antibacterials is a highly interdisciplinary field which relies on input from various research areas. This Review encompasses several aspects of antibiotic development—from very early strategies to mature drugs in clinical trials. An overview is given of methods suitable for mining novel antibacterials and for the elucidation of their bacterial targets.
In 2012 human African trypanosomiasis (HAT), also known as sleeping sickness, was targeted for elimination as a public health problem, set to be achieved by 2020. The World Health Organization (WHO) ...provides here the 2018 update on the progress made toward that objective. Global indicators are reviewed, in particular the number of reported cases and the areas at risk. Recently developed indicators for the validation of HAT elimination at the national level are also presented.
With 977 cases reported in 2018, down from 2,164 in 2016, the main global indicator of elimination is already well within the 2020 target (i.e. 2,000 cases). Areas at moderate or higher risk (i.e. ≥ 1 case/10,000 people/year) are also steadily shrinking (less than 200,000 km2 in the period 2014-2018), thus nearing the 2020 target i.e. 90% reduction (638,000 km2) from the 2000-2004 baseline (709,000 km2). Health facilities providing diagnosis and treatment of gambiense HAT continued to increase (+7% since the previous survey), with a better coverage of at-risk populations. By contrast, rhodesiense HAT health facilities decreased in number (-10.5%) and coverage. At the national level, eight countries meet the requirements to request validation of gambiense HAT elimination as a public health problem (i.e. Benin, Burkina Faso, Cameroon, Côte d'Ivoire, Ghana, Mali, Rwanda, and Togo), while for other endemic countries more efforts are needed in surveillance, control, or both.
The 2020 goal of HAT elimination as a public health problem is within grasp, and eligible countries are encouraged to request validation of their elimination status. Beyond 2020, the HAT community must gear up for the elimination of gambiense HAT transmission (2030 goal), by preparing for both the expected challenges (e.g. funding, coordination, integration of HAT control into regular health systems, development of more adapted tools, cryptic trypanosome reservoirs, etc.) and the unexpected ones.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the 20th century, epidemics of human African trypanosomiasis (HAT) ravaged communities in a number of African countries. The latest surge in disease transmission was recorded in the late 1990s, ...with more than 35,000 cases reported annually in 1997 and 1998. In 2013, after more than a decade of sustained control efforts and steady progress, the World Health Assembly resolved to target the elimination of HAT as a public health problem by 2020. We report here on recent progress towards this goal.
With 992 and 663 cases reported in 2019 and 2020 respectively, the first global target was amply achieved (i.e. fewer than 2,000 HAT cases/year). Areas at moderate or higher risk of HAT, where more than 1 case/10,000 people/year are reported, shrunk to 120,000 km2 for the five-year period 2016-2020. This reduction of 83% from the 2000-2004 baseline (i.e. 709,000 km2) is slightly below the target (i.e. 90% reduction). As a result, the second global target for HAT elimination as a public health problem cannot be considered fully achieved yet. The number of health facilities able to diagnose and treat HAT expanded (+9.6% compared to a 2019 survey), thus reinforcing the capacity for passive detection and improving epidemiological knowledge of the disease. Active surveillance for gambiense HAT was sustained. In particular, 2.8 million people were actively screened in 2019 and 1.6 million in 2020, the decrease in 2020 being mainly caused by COVID-19-related restrictions. Togo and Côte d'Ivoire were the first countries to be validated for achieving elimination of HAT as a public health problem at the national level; applications from three additional countries are under review by the World Health Organization (WHO).
The steady progress towards the elimination of HAT is a testament to the power of multi-stakeholder commitment and coordination. At the end of 2020, the World Health Assembly endorsed a new road map for 2021-2030 that set new bold targets for neglected tropical diseases. While rhodesiense HAT remains among the diseases targeted for elimination as a public health problem, gambiense HAT is targeted for elimination of transmission. The goal for gambiense HAT is expected to be particularly arduous, as it might be hindered by cryptic reservoirs and a number of other challenges (e.g. further integration of HAT surveillance and control into national health systems, availability of skilled health care workers, development of more effective and adapted tools, and funding for and coordination of elimination efforts).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human African trypanosomiasis (HAT) is a neglected tropical disease targeted for elimination 'as a public health problem' by 2020. The indicators to monitor progress towards the target are based on ...the number of reported cases, the related areas and populations exposed at various levels of risk, and the coverage of surveillance activities. Based on data provided by the National Sleeping Sickness Control Programmes (NSSCP), Non-Governmental Organizations (NGOs) and research institutions-and assembled in the Atlas of HAT-the World Health Organization (WHO) provides here an update to 2016 for these indicators, as well as an analysis of the epidemiological situation.
Trends for the two primary indicators of elimination are on track for the 2020 goal: 2,164 cases of HAT were reported in 2016 (as compared to the milestone of 4,000 cases), and for the period 2012-2016 280,000 km2 are estimated to be at moderate risk or higher (i.e. ≥ 1 case/10,000 people/year), as compared to the milestone of 230,000 km2. These figures correspond to reductions of 92% and 61% as compared to the respective baselines (i.e. 26,550 HAT cases in the year 2000, and 709,000 km2 exposed at various levels of risk for the period 2000-2004). Among the secondary indicators, an overall improvement in the coverage of at risk populations by surveillance activities was observed. Regarding passive surveillance, the number of fixed health facilities providing gambiense HAT diagnosis or treatment expanded, with 1,338 enumerated in endemic countries in 2017 (+52% as compared to the survey completed only sixteen months earlier). Concerning rhodesiense HAT, 124 health facilities currently provide diagnosis or treatment. The broadening of passive surveillance is occurring in a context of fairly stable intensity of active case finding, with between 1.8 million and 2.4 million people screened per year over the period 2012-2016.
Elimination of HAT as a public health problem by 2020 seems within reach, as the epidemiological trends observed in previous years are confirmed in this latest 2016 monitoring update. However, looking beyond 2020, and in particular to the 2030 goal of elimination of transmission as zero cases for the gambiense form of the disease only, there is no room for complacency. Challenges still abound, including ensuring the effective integration of HAT control activities in the health system, sustaining the commitment of donors and HAT endemic countries, and clarifying the extent of the threat posed by cryptic reservoirs (e.g. human asymptomatic carriers and the possible animal reservoirs in gambiense HAT epidemiology). WHO provides through the network for HAT elimination the essential coordination of the wide range of stakeholders to ensure synergy of efforts.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
African animal trypanosomosis (AAT) is a major livestock disease in Kenya. Even though, over the years various organizations have collected a vast amount of field data on tsetse and AAT in different ...parts of the country, recent national-level maps are lacking. To address this gap, a national atlas of tsetse and AAT distribution is being developed by the Kenya Tsetse and Trypanosomosis Eradication Council (KENTTEC) and partners.
All data collected by KENTTEC from 2006 to 2019 were systematically assembled, georeferenced and harmonized. A comprehensive data repository and a spatially-explicit database were created. Input data were collected mainly in the context of control activities, and include both baseline surveys (i.e. pre-intervention) and the subsequent monitoring during and after interventions. Surveys were carried out in four regions (i.e. Western, Rift Valley, Central and Coast), and in 21 of the 47 counties in Kenya. Various devices were used for entomological data collection (i.e. biconical, NGU and H traps, and sticky panels), while the buffy-coat technique was the method used to detect AAT.
Tsetse trapping was carried out in approximately 5000 locations, and flies (> 71,000) were caught in all four investigated regions. Six species of Glossina were detected: G. pallidipes (87% of the catches); G. brevipalpis (8%); G. fuscipes fuscipes (4%); G. longipennis (< 1%); G. austeni (< 1%); and G. swynnertoni (< 1%). A total of 49,785 animals (98% of which cattle) were tested for AAT in approximately 500 locations. Of these, 914 animals were found to be infected. AAT was confirmed in all study regions, in particular caused by Trypanosoma vivax (48% of infections) and T. congolense (42%). Fewer cases of T. brucei were found.
The development and regular update of a comprehensive national database of tsetse and AAT is crucial to guide decision making for the progressive control of the disease. This first version of the atlas based on KENTTEC data has achieved a remarkable level of geographical coverage, but temporal and spatial gaps still exist. Other stakeholders at the national and international level will contribute to the initiative, thus improving the completeness of the atlas.
Plants have evolved a sophisticated defense system that employs various hormone pathways to defend against attacks by insect pests. Cytokinin (CK) plays an important role in plant growth and stress ...tolerance, but the role of CKs in plant-insect interaction remains largely unclear. Here, we report that CKs act as a positive regulator in rice resistance against brown planthopper (BPH), a devastating insect pest of rice. We found that BPH feeding promotes CK biosynthesis and signaling in rice. Exogenous application of CKs significantly increased the rice resistance to BPH. Increasing endogenous CKs by knocking out
/
(
) led to enhanced resistance to BPH. Moreover, the levels of the plant hormone jasmonic acid (JA) and the expression of JA-responsive genes were elevated by CK treatment and in
knockout plants. Furthermore, JA-deficient mutant
was more susceptible to BPH, and CK-induced BPH resistance was suppressed in
. These results indicate that CK-mediated BPH resistance is JA-dependent. Our findings provide the direct evidence for the novel role of CK in promoting insect resistance, and demonstrate that CK-induced insect resistance is JA-dependent. These results provide important guidance for effective pest management strategies in the future.
Sleeping sickness, or human African trypanosomiasis (HAT), is transmitted by tsetse flies in endemic foci in sub-Saharan Africa. Because of international travel and population movements, cases are ...also occasionally diagnosed in non-endemic countries.
Antitrypanosomal medicines to treat the disease are available gratis through the World Health Organization (WHO) thanks to a public-private partnership, and exclusive distribution of the majority of them enables WHO to gather information on all exported cases. Data collected by WHO are complemented by case reports and scientific publications. During 2011-2020, 49 cases of HAT were diagnosed in 16 non-endemic countries across five continents: 35 cases were caused by Trypanosoma brucei rhodesiense, mainly in tourists visiting wildlife areas in eastern and southern Africa, and 14 cases were due to T. b. gambiense, mainly in African migrants originating from or visiting endemic areas in western and central Africa.
HAT diagnosis in non-endemic countries is rare and can be challenging, but alertness and surveillance must be maintained to contribute to WHO's elimination goals. Early detection is particularly important as it considerably improves the prognosis.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vibrio is a model organism for the study of quorum sensing (QS) signaling and is used to identify QS‐interfering drugs. Naturally occurring fimbrolides are important tool compounds known to affect QS ...in various organisms; however, their cellular targets have so far remained elusive. Here we identify the irreversible fimbrolide targets in the proteome of living V. harveyi and V. campbellii via quantitative mass spectrometry utilizing customized probes. Among the major hits are two protein targets with essential roles in Vibrio QS and bioluminescence. LuxS, responsible for autoinducer 2 biosynthesis, and LuxE, a subunit of the luciferase complex, were both covalently modified at their active‐site cysteines leading to inhibition of activity. The identification of LuxE unifies previous reports suggesting inhibition of bioluminescence downstream of the signaling cascade and thus contributes to a better mechanistic understanding of these QS tool compounds.
Studies in Vibrio: Fimbrolides represent natural products that interfere with quorum sensing in various organisms. Despite their importance in biological studies their cellular mechanisms have remained unknown. Chemical proteomics have been utilized to identify proteins involved in autoinducer biosynthesis (LuxS) and luciferase activity (LuxE) as molecular targets.
With the largest cattle population in Africa and vast swathes of fertile lands infested by tsetse flies, trypanosomosis is a major challenge for Ethiopian farmers. Managing the problem strategically ...and rationally requires comprehensive and detailed information on disease and vector distribution at the national level. To this end, the National Institute for Control and Eradication of Tsetse and Trypanosomosis (NICETT) developed a national atlas of tsetse and African animal trypanosomosis (AAT) for Ethiopia.
This first edition of the atlas focused on the tsetse-infested areas in western Ethiopia. Data were collected between 2010 and 2019 in the framework of national surveillance and control activities. Over 88,000 animals, mostly cattle, were tested with the buffy-coat technique (BCT). Odour-enhanced traps were deployed in approximately 14,500 locations for the entomological surveys. Animal- and trap-level data were geo-referenced, harmonized and centralized in a single database.
AAT occurrence was confirmed in 86% of the districts surveyed (107/124). An overall prevalence of 4.8% was detected by BCT in cattle. The mean packed cell volume (PCV) of positive animals was 22.4, compared to 26.1 of the negative. Trypanosoma congolense was responsible for 61.9% of infections, T. vivax for 35.9% and T. brucei for 1.7%. Four tsetse species were found to have a wide geographic distribution. The highest apparent density (AD) was reported for Glossina pallidipes in the Southern Nations, Nationalities and People's Region (SNNPR) (3.57 flies/trap/day). Glossina tachinoides was the most abundant in Amhara (AD 2.39), Benishangul-Gumuz (2.38), Gambela (1.16) and Oromia (0.94) regions. Glossina fuscipes fuscipes and G. morsitans submorsitans were detected at lower densities (0.19 and 0.42 respectively). Only one specimen of G. longipennis was captured.
The atlas establishes a reference for the distribution of tsetse and AAT in Ethiopia. It also provides crucial evidence to plan surveillance and monitor control activities at the national level. Future work on the atlas will focus on the inclusion of data collected by other stakeholders, the broadening of the coverage to tsetse-free areas and continuous updates. The extension of the atlas to data on control activities is also envisaged.
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