Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, ...is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Understanding the survival needs of neglected or underutilized species (NUS) in agroforestry can offer valuable insights to mitigate climate change and biodiversity loss. This paper analyses the ...habitat heterogeneity of Buxus balearica populations (palaeorelict of the Mediterranean Basin) using a methodology that integrates four approaches: ecological profiling, multivariate analysis, and the clustering of populations according to environmental variables and suitability. The habitat analysis was conducted on 240 occurrence points, integrating open-source databases and germplasm collection field work. Results reveal that the distribution of B. balearica in the south of the Iberian Peninsula is mainly conditioned by thermal variations, the humidity regime, and microtopography, which makes it very vulnerable to current and future climate change scenarios. The analysis of habitat heterogeneity demonstrates its capacity to estimate genetic diversity, which provides a solid basis for future research and conservation actions. The rapid extinction process of these boxwoods is evident by comparing the suitability model under different climate scenarios. There is an urgent need to improve the current status of the species and associated landscapes, considering B. balearica as an underutilized species, and establishing a sound management plan to reinforce its populations and protect its natural habitat.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Key message
The argan ex-situ collections help its crop breeding and conservation in the Mediterranean basin, specifically in the southern Iberian Peninsula, where climatic refuges and new ...cultivation areas could be established.
A. spinosa
(L.) Skeels, hereafter argan, is a tree species naturally distributed in Morocco and Algeria, introduced mainly for productive purposes in countries, such as Tunisia, Israel, and Spain. This promising species has a more extensive potential cultivation and use due to its economic prospects in human food and cosmetics. These reasons and its great aridity adaptation have raised the strategic value of argan and its ex-situ collections, compared to other more sensitive to climate change crops. From this perspective, this study aims to evaluate the genetic diversity of an ex-situ, 10-year-old collection on more than 600 specimens raised in southern Iberian Peninsula, and to promote its cultivation in the most suitable regions for its introduction throughout the Mediterranean basin. To this end, the genetic and morphological diversity of a subset of selected specimens was compared, and six MaxENT models were trained using 96 occurrence points in both wild and cultivated localities (ex-situ collections), together with six bioclimatic variables in a current timeframe and under two climate change scenarios (optimist and pessimist). Surprisingly, this Iberian collection’s genetic diversity was highly representative of the wild population’s diversity in their natural range. Given this representativeness, these cultivars could be a complementary conservation tool as well as a starting point for domestication, breeding, and cultivation programs in a wide environmental range in these territories. The natural distribution of argan will be considerably reduced and shift towards northern habitats by 2050 and 2080, where climatic refuges and new cultivation areas could be established.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance ...mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Argania spinosa
L. Skeels is an Algerian-Moroccan endemic tree. This species is part of various plant communities consisting of Mediterranean, Macaronesian and Saharan floristic elements. It has been ...introduced and perhaps sometimes naturalized in various regions of the Mediterranean basin. Due to its role in combating desertification, high socio-economic value, and traditional use as fodder and food, the southwestern Moroccan argan grove (Arganeraie) was declared Biosphere Reserve. It had already been subject to conservation and reforestation programs a century earlier. Its cultivation for oil production could be, besides an economic objective, an effective method to conserve its genetic diversity. Therefore, this study aims to estimate its potential distribution and establish efficient breeding programs by determining its ecological requirements, identifying its different habitats, and predicting habitat suitability models for Morocco, Algeria, Tunisia, and Spain. Using 53 occurrence points, wind speed and direction data, and 29 bioclimatic variables, multivariate methods were applied to describe the ecological profiles and characterize the heterogeneity of its habitat to subsequently, train a Maxent model that establishes, besides Morocco and Algeria, suitable cultivation areas in Tunisia and Spain. The North African potential area is limited to the western Mediterranean coast of Algeria and flat and coastal areas of eastern Tunisia. The increased likelihood of suitability remains in the southeast Iberian Peninsula. A high probability of argan cultivation is also evident in the Canary Islands. These results provide possibilities for future expansion of argan crop and a window of opportunity to improve its genetic diversity and conservation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal
different modes of action. IL-6 by classical signalling has anti-inflammatory ...and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.
Experiments suggest that biodiversity enhances the ability of ecosystems to maintain multiple functions, such as carbon storage, productivity, and the buildup of nutrient pools (multifunctionality). ...However, the relationship between biodiversity and multifunctionality has never been assessed globally in natural ecosystems. We report here on a global empirical study relating plant species richness and abiotic factors to multifunctionality in drylands, which collectively cover 41% of Earth's land surface and support over 38% of the human population. Multifunctionality was positively and significantly related to species richness. The best-fitting models accounted for over 55% of the variation in multifunctionality and always included species richness as a predictor variable. Our results suggest that the preservation of plant biodiversity is crucial to buffer negative effects of climate change and desertification in drylands.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Multiple ecosystem functions need to be considered simultaneously to manage and protect the several ecosystem services that are essential to people and their environments. Despite this, cost ...effective, tangible, relatively simple and globally relevant methodologies to monitor in situ soil multifunctionality, that is, the provision of multiple ecosystem functions by soils, have not been tested at the global scale.
We combined correlation analysis and structural equation modelling to explore whether we could find easily measured, field‐based indicators of soil multifunctionality (measured using functions linked to the cycling and storage of soil carbon, nitrogen and phosphorus). To do this, we gathered soil data from 120 dryland ecosystems from five continents.
Two soil surface attributes measured in situ (litter incorporation and surface aggregate stability) were the most strongly associated with soil multifunctionality, even after accounting for geographic location and other drivers such as climate, woody cover, soil pH and soil electric conductivity. The positive relationships between surface stability and litter incorporation on soil multifunctionality were greater beneath the canopy of perennial vegetation than in adjacent, open areas devoid of vascular plants. The positive associations between surface aggregate stability and soil functions increased with increasing mean annual temperature.
Synthesis and applications. Our findings demonstrate that a reduced suite of easily measured in situ soil surface attributes can be used as potential indicators of soil multifunctionality in drylands world‐wide. These attributes, which relate to plant litter (origin, incorporation, cover), and surface stability, are relatively cheap and easy to assess with minimal training, allowing operators to sample many sites across widely varying climatic areas and soil types. The correlations of these variables are comparable to the influence of climate or soil, and would allow cost‐effective monitoring of soil multifunctionality under changing land‐use and environmental conditions. This would provide important information for evaluating the ecological impacts of land degradation, desertification and climate change in drylands world‐wide.
Our findings demonstrate that a reduced suite of easily measured in situ soil surface attributes can be used as potential indicators of soil multifunctionality in drylands world‐wide. These attributes, which relate to plant litter (origin, incorporation, cover), and surface stability, are relatively cheap and easy to assess with minimal training, allowing operators to sample many sites across widely varying climatic areas and soil types. The correlations of these variables are comparable to the influence of climate or soil, and would allow cost‐effective monitoring of soil multifunctionality under changing land‐use and environmental conditions. This would provide important information for evaluating the ecological impacts of land degradation, desertification and climate change in drylands world‐wide.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND:Various recent outbreaks of hepatitis A virus (HAV) have been described in men who have sex with men despite the availability of an effective vaccine. This study aimed to determine the ...current rates of seroconversion after receiving HAV vaccine (HAV-V) in HIV-infected patients under real-life conditions.
SETTING:Patients were selected from a Southern Spanish multicentric cohort of HIV-infected subjects.
METHODS:Retrospective analysis of all patients who received 2 doses (standard scheme) from April 2008 to May 2016 or from June 2016 to February 2018 facing an HAV outbreak with shortage of HAV-V, 1 single dose of HAV-V. Response to HAV-V was defined as positive anti-HAV IgG between 1 and 12 months after the last vaccination dose.
RESULTS:A total of 522 patients were included, mainly men who have sex with men (86.2%). In the standard-dose group, 303/343 88.3%; 95% confidence interval (CI)84.5 to 91.5 patients showed seroconversion as compared with 149/179 (83.2%; 95% CI76.9 to 88.4) of the single-dose group (P = 0.107). Undetectable baseline HIV-RNA (adjusted odds ratio4.86; 95% CI1.86 to 12.75; P = 0.001) and a CD4 T-cell count ≥350/μL (adjusted odds ratio, 3.96; 95% CI1.26 to 12.49; P = 0.019) were independently associated with response to both regimens. A higher CD4/CD8 ratio was also associated with response after a single dose.
CONCLUSIONS:HIV-infected patients should be encouraged to undergo HAV-V with 2 standard doses 6 months apart; a single dose achieves a high rate of seroconversion in those patients with favorable response factors and may be enough to limit future outbreaks in case of HAV-V shortage until supply is reestablished.
The QoLKAMON study evaluated quality of life, efficacy and treatment safety in HIV patients receiving lopinavir/ritonavir in monotherapy (MT) versus continuing combined antiretroviral triple ...treatment with a boosted protease inhibitor (TT).
This was a 24-week, open-label, multicentre study in virologically-suppressed HIV-infected participants (N = 225) with a 2:1 randomization: 146 patients who switched to MT were compared with 79 patients who remained on a TT regimen. The primary endpoint was change in patient-reported outcomes in quality of life as measured by the MOS-HIV and EQ-5D questionnaires. Secondary endpoints included treatment adherence, patient satisfaction, incidence of adverse events and differences in plasma HIV-1 RNA viral load (VL) and CD4 cell counts.
Baseline quality of life, measured with the MOS-HIV score, was very good (overall score of 83 ± 10.5 in the MT arm and 82.3 ± 11.3 in the TT arm) and suffered no change during the study in any of the arms (at week 24, 83.5 ± 12.2 in MT arm and 81.9 ± 12.7 in TT arm), without statistically significant differences when compared. In regards to adherence to therapy and patient satisfaction, some aspects (number of doses forgotten in the last week and satisfaction of treatment measured with the CESTA score, dimension 1) improved significantly with MT. There were also no differences in the incidence and severity of adverse events, even though 22.8% of those in the MT arm switched their treatment when they were included in the study. Moreover, there was also no significant difference between the immunological and virological evolution of MT and TT. In the MT arm, the VL was always undetectable in 83% of patients (vs 90.7% in the TT arm) and there were only 6.7% of virological failures with VL > 50 copies/mL (vs 2.3% in the TT arm), without resistance mutations and with resuppression of VL after switching back to TT.
In a new clinical trial, monotherapy as a treatment simplification strategy in HIV-1 infected patients with sustained viral suppression has demonstrated quality of life, safety and efficacy profiles comparable to those of conventional triple therapy regimens.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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