Natural variation in abiotic stress responsive gene expression and local adaptation to climate in Arabidopsis thaliana.

Gene expression varies widely in natural populations, yet the proximate and ultimate causes of this variation are poorly known. Understanding how variation in gene expression affects abiotic stress tolerance, fitness, and adaptation is central to the field of evolutionary genetics. We tested the hypothesis that genes with natural genetic variation in their expression responses to abiotic stress are likely to be involved in local adaptation to climate in Arabidopsis thaliana. Specifically, we compared genes with consistent expression responses to environmental stress (expression stress responsive, "eSR") to genes with genetically variable responses to abiotic stress (expression genotype-by-environment interaction, "eGEI"). We found that on average genes that exhibited eGEI in response to drought or cold had greater polymorphism in promoter regions and stronger associations with climate than those of eSR genes or genomic controls. We also found that transcription factor binding sites known to respond to environmental stressors, especially abscisic acid responsive elements, showed significantly higher polymorphism in drought eGEI genes in comparison to eSR genes. By contrast, eSR genes tended to exhibit relatively greater pairwise haplotype sharing, lower promoter diversity, and fewer nonsynonymous polymorphisms, suggesting purifying selection or selective sweeps. Our results indicate that cis-regulatory evolution and genetic variation in stress responsive gene expression may be important mechanisms of local adaptation to climatic selective gradients

An investigation of the 27 July 2018 bolide and meteorite fall over Benenitra, southwestern Madagascar

Several dozen stones of an ordinary chondrite meteorite fell in and around the town of Benenitra in southwestern Madagascar during the early evening of 27 July 2018, minutes after a widely observed meteor fireball (bolide) transit and detonation. The event was confirmed by low-frequency infrasound recordings received at ~17h15 UTC (Coordinated Universal Time; 19h15 local time) at the Comprehensive Nuclear Test Ban Treaty Organization (CTBTO) infrasound station I33MG near Antananarivo, 542 km north-northeast of Benenitra. An energy release equivalent to 2.038 kt of TNT was calculated from the infrasound signals. Seismograph readings at the SKRH station 77 km north-northwest of Benenitra recorded a twostage signal consistent with the arrivals of an initial air-coupled ground wave at 16h48:08 UTC and a stronger pulse at 16h49:22 UTC linked directly to the atmospheric pressure wave. The infrasound and seismic signal arrival times suggest that the bolide entry and detonation occurred at approximately 18h46 local time (16h46 UTC), entry was from the northwest, and the detonation hypocentre was located within ~20 km of Benenitra. Despite meteorite debris being found among buildings within Benenitra, there was no damage to structures or injuries reported. Eyewitness accounts and photographic records indicate that approximately 75 mostly intact stones were collected; however, the remoteness of the area, the rugged nature of the terrain and sales of fragments to meteorite collectors have limited scientific analysis of the fall and the extent of the strewn field. The total mass of recovered stones is estimated at between 20 kg and 30 kg, with one fragment of 11.2 kg and several of ~1 kg. Petrographic and mineral chemical analyses indicate that the stones belong to the L6 class of ordinary chondrites. Cosmogenic radionuclide analysis confirms that the fall is linked to the bolide event. The name Benenitra has been officially accepted by the Meteoritical Bulletin Database.Significance: Eyewitness reports, CTBTO infrasound records, seismograph records and cosmogenic radionuclide analysis confirm a meteorite fall over Benenitra on 27 July 2018. Petrographic and geochemical analyses confirm that the meteorite is an L6 ordinary chondrite. Recovery of meteorite falls is rare; this is Madagascar’s second known meteorite fall and the first that can be linked to a bolide. Regional and global science monitoring networks can be interrogated to improve the understanding of bolide events. Interaction of scientists with local communities is important to dispel misunderstandings around scientific phenomena, and can improve collection of data

Drug-Resistant Tuberculosis--Current Dilemmas, Unanswered Questions, Challenges and Priority Needs

Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis–specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed

Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics

Fine-Scale Population Recombination Rates, Hotspots, and Correlates of Recombination in the Medicago truncatula Genome

Recombination rates vary across the genome and in many species show significant relationships with several genomic features, including distance to the centromere, gene density, and GC content. Studies of fine-scale recombination rates have also revealed that in several species, there are recombination hotspots, that is, short regions with recombination rates 10–100 greater than those in surrounding regions. In this study, we analyzed whole-genome resequence data from 26 accessions of the model legume Medicago truncatula to gain insight into the genomic features that are related to high- and low-recombination rates and recombination hotspots at 1 kb scales. We found that high-recombination regions (1-kb windows among those in the highest 5% of the distribution) on all three chromosomes were significantly closer to the centromere, had higher gene density, and lower GC content than low-recombination windows. High-recombination windows are also significantly overrepresented among some gene functional categories—most strongly NB–ARC and LRR genes, both of which are important in plant defense against pathogens. Similar to high-recombination windows, recombination hotspots (1-kb windows with significantly higher recombination than the surrounding region) are significantly nearer to the centromere than nonhotspot windows. By contrast, we detected no difference in gene density or GC content between hotspot and nonhotspot windows. Using linear model wavelet analysis to examine the relationship between recombination and genomic features across multiple spatial scales, we find a significant negative correlation with distance to the centromere across scales up to 512 kb, whereas gene density and GC content show significantly positive and negative correlations, respectively, only up to 64 kb. Correlations between recombination and genomic features, particularly gene density and polymorphism, suggest that they are scale dependent and need to be assessed at scales relevant to the evolution of those features

Drug-Resistant Tuberculosis—Current Dilemmas, Unanswered Questions, Challenges, and Priority Needs

Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discusse

Tuberculosis Diagnostics and Biomarkers: Needs, Challenges, Recent Advances, and Opportunities

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostic

How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting

The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non-spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the Hemachatus + Naja and again independently in the king cobras (Ophiophagus). There was a significant increase of cytotoxicity in the Asian Naja linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African Naja, once within the Asian Naja, and once in the Hemachatus genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra Naja annulata, which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa

Optimising perioperative care for hip and knee arthroplasty in South Africa: a Delphi consensus study

Background A structured approach to perioperative patient management based on an enhanced recovery pathway protocol facilitates early recovery and reduces morbidity in high income countries. However, in low- and middle-income countries (LMICs), the feasibility of implementing enhanced recovery pathways and its influence on patient outcomes is scarcely investigated. To inform similar practice in LMICs for total hip and knee arthroplasty, it is necessary to identify potential factors for inclusion in such a programme, appropriate for LMICs. Methods Applying a Delphi method, 33 stakeholders (13 arthroplasty surgeons, 12 anaesthetists and 8 physiotherapists) from 10 state hospitals representing 4 South African provinces identified and prioritised i) risk factors associated with poor outcomes, ii) perioperative interventions to improve outcomes and iii) patient and clinical outcomes necessary to benchmark practice for patients scheduled for primary elective unilateral total hip and knee arthroplasty. Results Thirty of the thirty-three stakeholders completed the 3 months Delphi study. The first round yielded i) 36 suggestions to preoperative risk factors, ii) 14 (preoperative), 18 (intraoperative) and 23 (postoperative) suggestions to best practices for perioperative interventions to improve outcomes and iii) 25 suggestions to important postsurgical outcomes. These items were prioritised by the group in the consecutive rounds and consensus was reached for the top ten priorities for each category. Conclusion The consensus derived risk factors, perioperative interventions and important outcomes will inform the development of a structured, perioperative multidisciplinary enhanced patient care protocol for total hip and knee arthroplasty. It is anticipated that this study will provide the construct necessary for developing pragmatic enhanced care pathways aimed at improving patient outcomes after arthroplasty in LMICs