Evidence for Megalake Chad, north-central Africa, during the late Quaternary from satellite data

The existence of a very large Lake Chad during the late Quaternary, Megalake Chad, has long been questioned. A Megalake Chad would present strong evidence for climatic fluctuations of great magnitude during the Holocene in tropical Africa. In this paper we used satellite data from Landsat and Modis sensors to collect and analyse new information on landforms in a 2 000 000 km² region of the Lake Chad Basin. We detected 2300 km of remains marking the ancient shoreline of Megalake Chad. The satellite data also indicated many Saharan rivers and relict deltas leading to the long paleoshoreline. Large dunefield flattenings were observed and interpreted as the result of wave-cut erosion by the paleolake. Similarities were noticed between the landforms observed along the paleoshoreline of Megalake Chad and that of the former Aral Sea. This finding has significant consequences for reconstructing paleohydrology and paleoenvironments through the Lake Chad basin, and continental climate change.     

Peer Review of Grant Applications: Criteria Used and Qualitative Study of Reviewer Practices

Background

Peer review of grant applications has been criticized as lacking reliability. Studies showing poor agreement among reviewers supported this possibility but usually focused on reviewers’ scores and failed to investigate reasons for disagreement. Here, our goal was to determine how reviewers rate applications, by investigating reviewer practices and grant assessment criteria.

Methods and Findings

We first collected and analyzed a convenience sample of French and international calls for proposals and assessment guidelines, from which we created an overall typology of assessment criteria comprising nine domains relevance to the call for proposals, usefulness, originality, innovativeness, methodology, feasibility, funding, ethical aspects, and writing of the grant application. We then performed a qualitative study of reviewer practices, particularly regarding the use of assessment criteria, among reviewers of the French Academic Hospital Research Grant Agencies (Programmes Hospitaliers de Recherche Clinique, PHRCs). Semi-structured interviews and observation sessions were conducted. Both the time spent assessing each grant application and the assessment methods varied across reviewers. The assessment criteria recommended by the PHRCs were listed by all reviewers as frequently evaluated and useful. However, use of the PHRC criteria was subjective and varied across reviewers. Some reviewers gave the same weight to each assessment criterion, whereas others considered originality to be the most important criterion (12/34), followed by methodology (10/34) and feasibility (4/34). Conceivably, this variability might adversely affect the reliability of the review process, and studies evaluating this hypothesis would be of interest.

Conclusions

Variability across reviewers may result in mistrust among grant applicants about the review process. Consequently, ensuring transparency is of the utmost importance. Consistency in the review process could also be improved by providing common definitions for each assessment criterion and uniform requirements for grant application submissions. Further research is needed to assess the feasibility and acceptability of these measures.     

Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)–negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.     

Preliminary Study of the Fungal Ecology at the Haematology and Medical-Oncology Ward in Bamako,Mali

Data on fungal epidemiology in sub-Saharan African countries are scarce. This exploratory study aimed to characterize the fungal flora at the Onco-Haematology ward of the National Teaching Hospital of Point G in Bamako, Mali. A cross-sectional survey was conducted in the dry and in the rainy seasons. Nasal swab and sputum samples were collected from the hospitalized patients while airborne fungal spores were collected using electrostatic dust-fall collectors. Fungi were identified by their morphological characteristics and MALDI-TOF mass spectrometry. Candida albicans was the most frequent yeast species colonizing patients; Aspergillus species were isolated in 86 % of the patients and were the main airborne environmental contaminants. Overall, airborne fungal contamination rates increased from 33.8 % in the dry to 66.2 % in the rainy season (p < 0.001). The most frequent Aspergillus species were Aspergillus niger (36.6 %) and Aspergillus flavus (32.92 %). In contrast, Aspergillus fumigatus (5.43 %) was relatively rare. This high level of fungal exposure raises concern regarding the management of at-risk patients in this Onco-Haematology ward and stresses the need for strengthening the mycological diagnostic capacities to accompany the implementation of adapted fungal infection prevention and management policies.     

Reconstructive surgery for giant penoscrotal elephantiasis: about one case

Elephantiasis of the external genitalia is characterized by lymphedema and thickening of the subcutaneous tissues. This gives the skin an appearance similar to a pachyderm skin. This pathology is invalidating for the patient. Reconstructive surgery is often the only way to restaure aesthetic and functional aspects of the external genitalia. We aim to report a 52 year man with huge penoscrotal elephantiasis who underwent excision and penoscrotal reconstruction at the department of Urology, Yalgado Ouedraogo Teaching Hospital at Ouagadougou.     

Exclusion of livestock grazing and wood collection in dryland savannah: an effect on long‐term vegetation succession

Sahelian savannah faces increasing pressure from human activities, leading to its degradation. The aim of this study was to investigate the possibility of restoration of dryland savannah vegetation by the elimination of disturbance factors on the ecosystem. Is degraded dryland savannah vegetation able to be restored by means of natural succession? What is the timescale for its recovery? The study took place in the Bandia Reserve, 65 km south‐east of Dakar (Senegal), a unique site with two successional stages due to the elimination of uncontrolled exploitation. The vegetation structure of 15 years (15YRS) and 5 years (5YRS) after fencing was compared with vegetation exposed to continuous livestock grazing and wood collection outside the fenced area. Calculated by redundancy analysis, a significant effect of selected areas on the cover of all species was revealed and successional stage explained more than 45% of data variability. Perennial forbs, annual forbs and perennial grasses achieved the highest cover in 5YRS, woody species in 15YRS and annual grasses in the area outside of the fenced reserve. The dominant woody species Acacia seyal, A. ataxacantha, A. nilotica subsp. adstringens and Balanites aegyptiaca reconstituted the dense formation of Acacia bushland by means of natural succession in the 15YRS area.     

Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death

Activation of proteolytic cell death pathways may circumvent drug resistance in deadly protozoan parasites such as Plasmodium falciparum and Leishmania. To this end, it is important to define the cell death pathway(s) in parasites and thus characterize proteases such as metacaspases (MCA), which have been reported to induce cell death in plants and Leishmania parasites. We, therefore, investigated whether the cell death function of MCA is conserved in different protozoan parasite species such as Plasmodium falciparum and Leishmania major, focusing on the substrate specificity and functional role in cell survival as compared to Saccharomyces cerevisae. Our results show that, similarly to Leishmania, Plasmodium MCA exhibits a calcium-dependent, arginine-specific protease activity and its expression in yeast induced growth inhibition as well as an 82% increase in cell death under oxidative stress, a situation encountered by parasites during the host or when exposed to drugs such as artemisins. Furthermore, we show that MCA cell death pathways in both Plasmodium and Leishmania, involve a z-VAD-fmk inhibitable protease. Our data provide evidence that MCA from both Leishmania and Plasmodium falciparum is able to induce cell death in stress conditions, where it specifically activates a downstream enzyme as part of a cell death pathway. This enzymatic activity is also induced by the antimalarial drug chloroquine in erythrocytic stages of Plasmodium falciparum. Interestingly, we found that blocking parasite cell death influences their drug sensitivity, a result which could be used to create therapeutic strategies that by-pass drug resistance mechanisms by acting directly on the innate pathways of protozoan cell death.     

A molecular map of chloroquine resistance in Mali

Plasmodium falciparum chloroquine resistance (CQR) transporter point mutation (PfCRT 76T) is known to be the key determinant of CQR. Molecular detection of PfCRT 76T in field samples may be used for the surveillance of CQR in malaria-endemic countries. The genotype-resistance index (GRI), which is obtained as the ratio of the prevalence of PfCRT 76T to the incidence of CQR in a clinical trial, was proposed as a simple and practical molecular-based addition to the tools currently available for monitoring CQR in the field. In order to validate the GRI model across populations, time, and resistance patterns, we compiled data from the literature and generated new data from 12 sites across Mali. We found a mean PfCRT 76T mutation prevalence of 84.5% (range 60.9–95.1%) across all sites. CQR rates predicted from the GRI model were extrapolated onto a map of Mali to show the patterns of resistance throughout the participating regions. We present a comprehensive map of CQR in Mali, which strongly supports recent changes in drug policy away from chloroquine.