Search

In this work, we used the rock phosphate Tahoua sample. It underwent several processing steps before obtaining the raw phosphate powder. However it presents a weak solubility and this weakness is due to the presence of metal oxides in the phosphate. Indeed, rock phosphate is the raw material of the fertilizer industry and it is rarely used directly as is, because of its low assimilability by plants. To solve this problem, we have transformed merchantable phosphate into phosphate fertilizers directly and easily assimilated. The objective of this work is to manufacture a simple superphosphate fertilizer (SSP) and study its solubility in perchloric acid and water. We manufactured a simple superphosphate based on crushed and ground Tahoua merchant phosphate. The studied granulometries are: (inferior to 63µm; 63µm; 100µm; 160µm). The attack was made with sulfuric acid (H2SO4) with a variation of temperatures (40°C; 60°C and 80°C) in order to determine the effects of the granulometrys and temperatures. The results obtained for granulometries (inferior to 63µm; 63µm; 100µm; 160µm) with ripening times (5th day, 12 days) and at these different temperatures are respectively 40°C (15.79%; 14.77%; 17.35%; 15.93%); 60°C (18.58% ; 8.32%; 8.32%; 12.67%); 80°C (16.40%; 19.73%; 16.54%; 21.56%) in the perchloric acid solution and 40°C (5.74%; 8.32%; 8.32%; 12.67%); 60°C (7.64%; 8.32%; 8.73%; 7.91%); 80°C (11.86%; 12.67%; 11.04%; 6.55%) in water These results allowed us to conclude that Tahoua rock phosphate is suitable for the manufacture of simple superphosphate fertilizer at 80°C (total P2O5 equals 21.54%) and at 60°C (and a soluble P2O5 equal to 12.87%) for a particle size of 160µm.

The objective of this study is to determine the surface functions and the pH at the point of zero charges (pHPCN) of powdered activated carbons (PAC) produced from two biomasses (nucleus shell ofBalanites aegyptiacaand nucleus shell ofZizyphus mauritiana) with a particle size between 60 and 80 µm. The methodology is based on immediate analyzes of the biomasses (ash rate, humidity rate, volatile matter rate and the actual density), the chemical activation of the biomasses by H3PO4and KOH activating agents at concentrations of (5%, 15%, 25%) and (10%, 15%, 20%) respectively, followed by pyrolysis at 400 °C and 600 °C for 2 hours. The CAPs obtained were characterized for their surface chemistry, by Boehm titration and pHPCNmeasurements and for their quantity, by yield calculation. The characterized PACs were compared to a commercial activated carbon. These analyzes reveal that the best PACs were obtained using a concentration of 25% H3PO4 and 10% KOH with a pyrolysis temperature of 400 °C. The surface functions of the PACs produced are acidic with a total absence of basic functions and exceed those of commercial activated carbon (CAC). The pHPCNsof PACs resulting from acid activation are acidic and those resulting from basic activation are neutral and basic. Thus, the pHPCNof the CAC is closer to the pHPCNof the PACs resulting from the impregnation with KOH. These biomasses are potentially promising for the production of PACs.

This study aims to determine the textural (specific surface, pore volume and pore size) and mineralogical characteristics of Tanout red clay of Zinder region (Niger) in order to have textural data allowing its use as an adsorbent. The methodology is based on textural analyzes (adsorption of N2at 77 K by the Brunauer-Emmett-Teller method), mineralogical (X-ray fluorescence, X-ray diffraction, thermo-gravimetric analysis, scanning electron microscopy) and physicochemical (preliminary analyses). The results obtained show that the red clay has a specific surface of 418.4 m2.g-1and 967.7 m2.g-1calculated according to the BET and Langmuir methods respectively and a microporous surface of 540 m2.g- 1, with pore volume varying from 0.0389 to 0.2535 cm3.g-1and pore size varying from 0.3675 to 5.423 nm calculated according to the methods (Barrett-Joyner-Halenda, Dubinin-Radushkevich, Dubinin -A, Horvath-Kawazoe and Saito-Foley). It has slit and cylindrical micro- pores. It has a slightly neutral pH in an aqueous medium and a high cation exchange capacity with low humidity and density, and is mainly composed of SiO2(83.2%), Al2O3(7.04%) and Fe2O3(3.35%) with trace elements, the main ones being: Zr (2490 ppm), Sr (310.21 ppm), Cu (310.1 ppm), V (290.1 ppm) and Zn (140ppm). It consists essentially of Montmorillonite, illite and Kaolinite with impurities such as quartz and rutile. This clay has a high degree of crystallinity. These characteristics make it a promoter material that can be used as an adsorbent.

Background Outcomes of retreatment for rifampicin-resistant tuberculosis (RR-TB) are rarely reported. We report ‘definitive outcomes’ after a cascade approach to RR-TB treatment. After a bacteriologically adverse outcome for the 9-months fluoroquinolone-based Short Treatment Regimen (STR), patients were retreated with a bedaquiline-based regimen (BDQ-regimen). Methods A Retrospective cohort study of RR-TB patients treated with the STR during 2012–2019 and retreated with a BDQ-regimen in case of failure or relapse was conducted. Definitive relapse-free cure took into account BDQ-regimen outcomes. Results Of 367 patients treated with the STR, 20 (5.4%) experienced failure or relapse. Out of these 20 patients, 14 started a BDQ-regimen, of whom none experienced failure or relapse. Definitive end of treatment outcomes of STR after revising with third-line BDQ-regimen outcomes, 84.7% (311/367) were cured relapse-free, 10.6% (39/367) died during treatment and 3.0% (11/367) were lost to follow-up during treatment with either the STR or BDQ-regimen. Six patients (1.6%; 6/367) with STR failure/relapse died before starting a BDQ-regimen. No patient had definitive treatment failure or relapse and remained without treatment. Conclusions If fluoroquinolone resistance is excluded or rare, it is beneficial to use fluoroquinolone as the core drug for a first RR-TB treatment regimen and to safeguard bedaquiline for those in need of retreatment.

If in several countries of the world, artificial insemination is a common practice in the management of animal herds, it is not the same for many of the nations of the Sahelian African zone such as Niger where several factors complicate its development. One of the annoying situations would be the very high cost of the technique for the breeder. Thus, to reduce this cost related to the cost of heat-inducing hormones, this study aims to search for an alternative solution to the use of the artificial insemination technique which is very inaccessible to African breeders. This study involves first listing all plant species that induce heat in sheep-goats, and then testing their effectiveness in vivo in the Red goat of Maradi. The administration of a semi-closed questionnaire to a sample of 63 nomadic breeders from North Maradi made it possible to identify 81 plant species. These plant species are used either alone, in association or in a mixture with other non-plant products. Thus, the survey made it possible to list 71 heat-inducing recipes, 77% of which consist exclusively of plant extracts. The preselected goats were randomly divided into four comparable and different groups of 6 to 7 individuals receiving recipe R1 (group 1, n=7), recipe R2 (group 2, n=7), recipe R3 (group 3, n=7) and recipe R4 (control group, n=6). Two of these recipes, tested on two groups of goats, had allowed ≈ 42.85 and ≈ 57.14% to give birth against only ≈ 33.33% in the control group and 0% in the goats treated with pigeon droppings. Thus, this study has made it possible to highlight a good knowledge of heat-inducing plants in goats by the nomadic population of North Maradi. It also revealed a trend in the effectiveness of the in vivo use of two of these plants in fertility in the Red goat of Maradi. This practice could constitute an alternative way to small ruminants’ artificial insemination for breeders in sub-Saharan Africa.

The objective of this study is to identify the different mechanisms involved in the phenomenon of adsorption of fluoride ions (F-) on raw and activated clays through some empirical models. The methodology is based on the application of a few kinetic (pseudo first order and pseudo second order), isothermal (Langmuir and Freundlich) and thermodynamic models on the experimental data of the adsorption of F-ions by plotting linear regression lines for determine the different characteristic parameters of each model. The results obtained show that the pseudo second order kinetic model better describes the adsorption kinetics of F-ions on raw and activated clays with correlation coefficients close to unity (range from 0.9994 to 0.9999) and similar values between experimental (0.37 to 0.676 mg.g-1) and theoretical (0.387 to 0.684 mg.g-1) capacities. The Freundlich model better describes the adsorption isotherm of F-ions on raw and activated clays with constants (KF) less than unity (0.175 to 0.953) and value of n (heterogeneity factor) which tend towards unity (0.399 to 0.921) with the exception of Arg1-2C and Arg3-2C. The thermodynamic model shows an endothermic, spontaneous process and an adsorption of physical and electrostatic type. The models used therefore apply well to the experimental data on the adsorption of F-ions on raw and activated clays because they have made it possible to identify the kinetics and the isotherm of this adsorption.

The objective of this study is to identify the different mineral phases, the structural and textural properties of natural clay of Tanout in Zinder region (Niger) in order to have mineralogical data allowing its valuation. The methodology is based on a physicochemical characterization by coupling several analysis techniques (preliminary analyses, X-ray fluorescence, X-ray diffraction, thermos- gravimetric analysis, scanning electron microscopy, Brunauer-Emmett-Teller by adsorption of N2at 77 K). The results from these analyzes show that this clay has a low humidity rate, a low density, a slightly neutral pH in an aqueous medium and a high cation exchange capacity and is mainly composed of SiO2(68.1%), Al2O3(17.02%) and Fe2O3(7.6%) with trace elements, the most important of which are: Zr (4150.6 ppm), Sr (470 ppm), Cu (380.2 ppm) and V (320ppm). It essentially consists of Kaolinite and Montmorillonite with impurities such as quartz and microclines. It has a specific surface of 441.1 m2.g-1and 2288 m2.g-1calculated according to the BET and Langmuir methods respectively, with porous volume varying from 0.0157 to 0.2597 cm3.g-1and of pore size which varies from 1.847 to 6.182 nm calculated according to the methods (Barrett-Joyner-Halenda, Dubinin-Radushkevich, Dubinin-A, Horvath-Kawazoe and Saito-Foley). This clay has an important degree of crystallinity. These characteristics make it a potential material that can be used in water pollution control.

Nowadays, one of the sectors to valorization of waste is their transformation in nobler materials rather than in energy. This study is about the valorization of agricultural waste (Parinari Macrophyllashells) for the development of active carbons, the characterization of porous materials gotten and the kinetic study for adsorption of gold (I) cyanide complex ion. The development is made by impregnation in KOH followed of a pyrolysis under flux of N2or CO2. The characteristics determined for adsorption are iodine index, methylene blue index, pH to point of zero charge (pHPZC) as well as the textures characteristics gotten by adsorption of nitrogen at 77 K. For adsorption of gold (I) cyanide complex ion , the kinetics model’s pseudo-order 1, pseudo-order 2, the model of Elovich and those diffusions of Boyd and Weber-Morris are studied. The results of the characterization showed that samples are basic (pHPZC> 7), present the specific surfaces of 1008 m2/g and 1063 m2/g with percentages in microporous surface more than 78% and for microporous volume more than 71%. The kinetics of adsorption of gold (I) cyanide complex ion (Au(CN)2-) obeys more to pseudo-order 2 model and a multi-linearity of the models of Elovich and diffusions during adsorption.

Summary Background Risk of mortality following surgery in patients across Africa is twice as high as the global average. Most of these deaths occur on hospital wards after the surgery itself. We aimed to assess whether enhanced postoperative surveillance of adult surgical patients at high risk of postoperative morbidity or mortality in Africa could reduce 30-day in-hospital mortality. Methods We did a two-arm, open-label, cluster-randomised trial of hospitals (clusters) across Africa. Hospitals were eligible if they provided surgery with an overnight postoperative admission. Hospitals were randomly assigned through minimisation in recruitment blocks (1:1) to provide patients with either a package of enhanced postoperative surveillance interventions (admitting the patient to higher care ward, increasing the frequency of postoperative nursing observations, assigning the patient to a bed in view of the nursing station, allowing family members to stay in the ward, and placing a postoperative surveillance guide at the bedside) for those at high risk (ie, with African Surgical Outcomes Study Surgical Risk Calculator scores ≥10) and usual care for those at low risk (intervention group), or for all patients to receive usual postoperative care (control group). Health-care providers and participants were not masked, but data assessors were. The primary outcome was 30-day in-hospital mortality of patients at low and high risk, measured at the participant level. All analyses were done as allocated (by cluster) in all patients with available data. This trial is registered with ClinicalTrials.gov , NCT03853824 . Findings Between May 3, 2019, and July 27, 2020, 594 eligible hospitals indicated a desire to participate across 33 African countries; 332 (56%) were able to recruit participants and were included in analyses. We allocated 160 hospitals (13 275 patients) to provide enhanced postoperative surveillance and 172 hospitals (15 617 patients) to provide standard care. The mean age of participants was 37·1 years (SD 15·5) and 20 039 (69·4%) of 28 892 patients were women. 30-day in-hospital mortality occurred in 169 (1·3%) of 12 970 patients with mortality data in the intervention group and in 193 (1·3%) of 15 242 patients with mortality data in the control group (relative risk 0·96, 95% CI 0·69–1·33; p=0·79). 45 (0·2%) of 22 031 patients at low risk and 309 (5·6%) of 5500 patients at high risk died. No harms associated with either intervention were reported. Interpretation This intervention package did not decrease 30-day in-hospital mortality among surgical patients in Africa at high risk of postoperative morbidity or mortality. Further research is needed to develop interventions that prevent death from surgical complications in resource-limited hospitals across Africa. Funding Bill & Melinda Gates Foundation and the World Federation of Societies of Anaesthesiologists. Translations For the Arabic, French and Portuguese translations of the abstract see Supplementary Materials section.

Background Perioperative management in digestive surgery is a challenge in sub-Saharan Africa. Objective: To describe the process and outcomes of perioperative management in gastrointestinal surgery. Materials and methods This was a single center cross-sectional study over a 4-month period from June 1 to September 30, 2017, in a Nigerien hospital (West Africa). This study included caregivers and patients operated on gastrointestinal surgery. Results We collected data for 56 caregivers and 253 patients underwent gastrointestinal surgery. The average age of caregivers was 38.6 ± 8.7. The median length of professional practice was 9 years. Almost 52% of caregivers (n = 29) did not know the standards of perioperative care. The median age of patients was 24 years, and male gender constituted 70% of cases (n = 177) with a sex ratio of 2.32. Patients came from rural areas in 78.2% (n = 198). Emergency surgery accounted for 60% (n = 152). The most surgical procedure was digestive ostomies performed in 28.9% (n = 73), followed by hernia repair and appendectomy in 24.5% (n = 62) and 13.9% (n = 35) respectively. The postoperative course was complicated in 28.1% (n = 71) among which 13 deaths. In the group of caregivers, the poor practice of perioperative management was associated with poor professional qualification, insufficient equipment, insufficient motivation (p, Highligth • Perioperative care in gastrointestinal surgery in a challenge in Sub-Saharan countries. • This setting is characterised by the difficulty of geographical access to hospital, lack of equipment. • Risk factors for complications are multifactorial. • This study can be a draft for improvement the quality of care in low resource settings.

We evaluated the removal capacity of a coupled microalgal-bacterial biofilm (CMBB) to eliminate three recalcitrant pharmaceuticals. The CMBB's efficiency, operating at different biofilm concentrations, with or without light, was compared and analyzed to correlate these parameters to pharmaceutical removal and their effect on the microorganism community. Removal rates changed with changing pharmaceutical and biofilm concentrations: higher biofilm concentrations presented higher removal. Removal of 82-94% venlafaxine and 18-51% carbamazepine was obtained with 5 days of CMBB treatment. No iohexol removal was observed. Light, microorganism composition, and dissolved oxygen concentration are essential parameters governing the removal of pharmaceuticals and ammonia. Chlorophyll concentration increased with time, even in the dark. Three bacterial phyla were dominant: Proteobacteria, Bacteroidetes and Firmicutes. The dominant eukaryotic supergroups were Archaeplastida, Excavata and SAR. A study of the microorganisms' community indicated that not only do the species in the biofilm play an important role; environment, concentration and interactions among them are also important. CMBB has the potential to provide low-cost and sustainable treatment for wastewater and recalcitrant pharmaceutical removal. The microenvironments on the biofilm created by the microalgae and bacteria improved treatment efficiency.

Planar chiral halogenated ferrocenes have come in useful as synthetic intermediates over the years, allowing for the preparation of functionalized derivatives for catalysis, material science, optoelectronics, and medicinal chemistry. Despite their chemical interest, few halogenated planar chiral ferrocenes have been prepared in enantiopure form by asymmetric synthesis so far. Enantioselective HPLC on polysaccharide-based chiral stationary phases (CSPs) has been used for resolving planar chiral ferrocenes making both enantiomers available. However, the enantioseparation of derivatives containing halogens or alkyl groups exclusively remains rather challenging. Given this context, in this study the enantioseparation of eleven dihalogenated planar chiral ferrocenes was systematically explored by using five polysaccharide-based CSPs under multimodal elution conditions. Baseline enantioseparations were achieved for nine analytes with separation factors (?) ranging from 1.15 to 1.66. Thermodynamic quantities associated with the enantioseparations were derived from van't Hoff plots, and for 1-halo-2-(iodoethynyl)ferrocenes (1-halogen = F, Cl, Br) halogen-dependent thermodynamic profiles were identified on a cellulose tris(3,5-dimethylphenylcarbamate)-based column. The impact of CSP structure and mobile phase (MP) polarity on the enantioseparation was evaluated. In addition, with the aim to unravel the functions of halogen substituents in mechanisms and noncovalent interactions underlying selector-selectand complex formation at molecular level, local electron charge density of specific molecular regions of the interacting partners were evaluated in terms of calculated electrostatic potential (V) and related source function (SF) contributions. On this basis, the impact of halogen type and position on the enantioseparation was investigated by correlating theoretical and experimental data.

International audience; Chalcogen bonding results from non-covalent interactions occurring between electrodeficient chalcogen atoms and Lewis bases. Among the chalcogens, tellurium is the strongest Lewis acid, but Te-based compounds are scarcely used as organocatalysts. For the first time, telluronium cations demonstrated impressive catalytic properties at low loadings in three benchmark reactions: the Friedel–Crafts bromination of anisole, the bromolactonization of ω-unsaturated carboxylic acids and the aza-Diels–Alder between Danishefsky's diene and imines. The ability of telluronium cations to interact with a Lewis base through chalcogen bonding was demonstrated on the basis of multi-nuclear (17O, 31P, and 125Te) NMR analysis and DFT calculations.

Objectives To assess: 1—the spousal concordance of lifestyle and anthropometric characteristics between partners of infertile couples in which the woman is obese; and 2—in men, the influence of these characteristics on their conventional seminal parameters. Design Cross-sectional study. Setting Fertility clinic of the Centre hospitalier universitaire de Sherbrooke, Canada, between January 2012 and February 2015. Patients 97 infertile heterosexual couples in which women were obese and seeking fertility treatments. Intervention Not applicable. Main outcome measures Weight and percentage of fat mass were evaluated using a scale with foot-to-foot bio-impedance. Abdominal obesity was estimated with waist circumference and lifestyle habits, by a self-reported questionnaire. Seminal parameters were analysed and collected according to the WHO guidelines (Kruger’s strict criteria for seminal morphology). Results There was a significant spousal concordance for the percentage of fat mass, leisure activities and overall nutritional quality. Accordingly, male participants displayed anthropometric and lifestyle characteristics at higher risk than Canadian men of similar age. Moreover, BMI, daily consumption of fruits & vegetables and sleeping hours in men were independently associated to the total motile sperm count. Conclusion This is the first study to report concordance for anthropometric and lifestyle characteristics between partners of infertile couples in which the woman is obese. These characteristics in men were more adverse than in the general population and were associated with reduced sperm quality. Altogether, our results suggest that male partners of infertile couples could benefit from participating in the lifestyle intervention that is already recommended for their spouse affected by obesity. Capsule Because partners of subfertile couples in which the woman is obese share adverse anthropometric and lifestyle characteristics, male partners should be implicated in lifestyle interventions already indicated for their spouse.

Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that were similarly associated with acute SARS-CoV-2 infection and non–COVID-19-related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that were associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1(+) mature/activated neutrophils, ALCAM(+) monocytes, and CD38(+)CD8(+) T cells). A subset of SARS-CoV-2–specific immune alterations correlated with disease severity, disease outcome at 30 days, and mortality. Our data provide an understanding of the immune dysregulation specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2–positive patients at risk of unfavorable outcomes and to uncover candidate molecules to investigate from a therapeutic perspective.

Actinometers are physical or chemical systems that can be employed to determine photon fluxes. Chemical actinometers are photochemical systems with known quantum yields that can be employed to determine accurate photon fluxes for specific photochemical reactions. This review explores in detail several practical chemical actinometers (ferrioxalate, iodide-iodate, uranyl oxalate, nitrate, uridine, hydrogen peroxide and several actinometers for the vacuum ultraviolet). Each actinometer is described with recommended conditions for its use.

International audience; Thromboembolic complications related to SARS-CoV-2 have been extensively reported. They include deep vein thrombosis, pulmonary embolism, ischemic stroke, and acute coronary syndrome. Penile thrombosis has not been reported as a thrombotic complication of SARS-CoV-2 infection with hypercoagulability. Here we describe a case of priapism as a thromboembolic complication in a patient with COVID-19 who recovered from acute respiratory distress syndrome (ARDS). We discuss the underlying pathophysiological mechanisms mainly related to an hypercoagulability state. Emergency management consisted on an intracavernosal injection of the sympathomimetic agent ethylephrine and cavernosal blood aspiration. The patient experienced no recurrences under thromboprophylaxis by enoxaparin 40 mg twice daily.

International audience; The halogen bond (XB) is a noncovalent interaction involving a halogen acting as electrophile and a Lewis base. In the last decades XB has found practical application in several fields. Nevertheless, despite the pivotal role of noncovalent interactions in separation science, investigations of XB in this field are still in their infancy, and so far a limited number of studies focusing on solid phase extraction, liquid-liquid microextraction, liquid-phase chromatography, and gas chromatography separation have been published. In addition, in the last few years, our groups have been systematically studying the potentiality of XB for HPLC enantioseparations. On this basis, in the present paper up-to-date results emerging from focused experiments and theoretical analyses performed by our laboratories are integrated with a descriptive presentation of XB features and the few studies published until now in separation science. Then, the aim of this article is to provide a comprehensive and critical discussion of the topic, and account for some still open issues in the application of XB to separate chemical mixtures.

International audience; The chromatographic performances of four coated and immobilized amylose phenylcarbamate-based chiral columns were evaluated and compared under normal phase (NP) elution conditions by using chiral 4,4'-bipyri-dine derivatives as analytes. n-Hexane/2-propanol 90:10 and n-hexane/2-propanol/methanol 90:5:5 mixtures were employed as mobile phases (MPs), and the effect of adding methanol in the MP on retention and selectivity was considered. The effect of temperature on retention and selectivity was also evaluated, and overall thermo-dynamic parameters associated with the analyte adsorption onto the CSP surface were derived from van't Hoff plots. Interesting cases of enantiomer elution order (EEO) reversal, which are dependent on the nature of polar modifier, analyte structure, column-type, and temperature, were observed. The impact of substitution pattern and electronic properties of analytes and selectors on the separation behaviour was investigated by correlating chro-matographic parameters and molecular properties determined by using density functional theory (DFT) calculations. Both coated and immobilized amylose tris(3,5-dimethylphenylcarbamate) columns allowed for the baseline enantioseparation (2.0 ≤ R S ≤ 4.9) of all 4,4'-bipyridines considered in this study. These results appear particularly useful because both enantiomers of these 4,4'-bipyridine derivatives are currently under investigation as new inhibitors of transthyretin fibrillogenesis, a biochemical phenomenon which is implicated to cause amyloid diseases.

International audience; Designed more than thirty years ago in order to improve and maximize the discrimination capability of native polysaccharides, cellulose-and amylose-based selectors have shown excellent and unequalled performances for the enantioseparation of chiral compounds. The successful story of these chiral selectors relies on a multi-site high-ordered chiral platform which is held up by intramolecular hydrogen bonds (HBs), and makes the polymer able to host and discriminate enantiomers. In this environment, both achiral and stereoselective intermolecular noncovalent interactions play a pivotal role, and HBs, halogen bonds (XBs), dipole-dipole, π-π stacking, steric repulsive, and van der Waals interactions underlie adsorption process and formation of transient diastereomeric assemblies between the polymer and the enantiomer pair. In the last decades, advances in computational chemistry and spectroscopic techniques have improved knowledge of noncovalent interactions, contributing to decode their functions in chemical systems. Significantly, over time the growing interplay between experimental and theoretical approaches has contributed to unravel intermolecular forces underlying selector-selectand association and to understand recognition patterns. On this basis, this review summarizes seminal and representative studies dealing with noncovalent interactions that function in HPLC enantioseparations promoted by cellulose benzoates and phenylcarbamates of amylose and cellulose. The importance of integrating theoretical and experimental approaches to profile mechanisms and interaction patterns is highlighted by discussing focused case studies. In particular, the advantageous utilization of electrostatic potential (V) analysis and molecular dynamics (MD) simulations in this field is evidenced. A systematic compilation of all published literature has not been attempted.

Recent studies have shown the efficiency of hydroxyl radicals generated via ultraviolet (UV)-based advanced oxidation processes (AOPs) combined with hydrogen peroxide (UV/H2O2) as a treatment process in water. The effects of AOP treatments on bacterial gene expression was examined using Pseudomonas aeruginosa strain PAO1 as a model-organism bacterium. Many bacterial genes are not expressed all the time, but their expression is regulated. The regulation is at the beginning of the gene, in a genetic region called “promoter” and affects the level of transcription (synthesis of messenger RNA) and translation (synthesis of protein). The level of expression of the regulated genes can change as a function of environmental conditions, and they can be expressed more (induced, upregulated) or less (downregulated). Exposure of strain PAO1 to UV/H2O2 treatment resulted in a major change in gene expression, including elevated expression of several genes. One interesting gene is PA3237, which was significantly upregulated under UV/H2O2 as compared to UV or H2O2 treatments alone. The induction of this gene is probably due to formation of radicals, as it is abolished in the presence of the radical scavenger tert-butanol (TBA) and is seen even when the bacteria are added after the treatment (post-treatment exposure). Upregulation of the PA3237 promoter could also be detected using a reporter gene, suggesting the use of such genetic constructs to develop biosensors for monitoring AOPs in water-treatment plants. Currently biosensors for AOPs do not exist, consequently impairing the ability to monitor these processes on-line according to radical exposure in natural waters.

This study demonstrates the potential of a new BiOCl0.875 Br0.125 photocatalyst to disinfect Escherichia coli in water under simulated solar irradiation. Photocatalytic efficiency was examined for different photocatalyst loadings, solar wavelengths, exposure times, photocatalyst concentration × contact time (Ct) concept and with the use of scavengers. To elucidate the inactivation mechanism, we examined DNA damage, membrane damage, lipid peroxidation and protein release. Both photolysis and photocatalysis were negligible under visible irradiation, but enhanced photocatalytic activity was observed under solar UVA (λ > 320 nm) and UVB (λ > 280 nm), with 1.5 and 3.6 log inactivation, respectively, after 40 min of irradiation. The log inactivation vs Ct curve for E. coli by UVA/BiOCl0.875 Br0.125 was fairly linear, with Ct = 10 g L-1 × min, resulting in 2 log inactivation. Photocatalytic treatment led to membrane damage, but without lipid peroxidation. Accordingly, protein was released from the cells after UVA or UVA/BiOCl0.875 Br0.125 treatment. Photocatalysis also increased endonuclease-sensitive sites vs photolysis alone, by an unknown mechanism. Finally, E. coli inactivation was not influenced by the addition of tert-butanol or l-histidine, implying that neither hydroxyl radicals nor singlet oxygen reactive species are involved in the inactivation process.

There is controversy about the anti- or pro-oxidative effects of the nitric oxide (NO)-donor sodium nitroprusside (SNP). Hence, the activity of the antioxidant enzyme catalase (CAT) and the status of malondialdehyde (MDA) were investigated after a 2.5 mg/kg dose of SNP had been i.p. administered to different and comparable groups of mice (n = 48). The drug was administered at two different circadian times (1 and 13 h after light onset [HALO]). There were, irrespectively of sampling time, no significant differences in the means of CAT activity and MDA status between control and SNP-treated groups, no matter the treatment time. However, CAT activity was significantly (Student's t-test, p < 0.001) increased 1 h following SNP administration at 1 HALO, whereas the significant (p < 0.001) increase in the enzyme activity was found only 3 h after injection at 13 HALO. The drug dosing either at 1 or 13 HALO resulted in no significant differences of MDA status between control and treated groups regardless to the sampling time. Two-way analysis of variance (ANOVA) detected a significant (F0.05(7,88)= 5.3; p < 0.0006) interaction between sampling time and treatment in mice injected at 1 HALO, suggesting the influence of treatment on sampling-time-related changes in CAT activity. However, ANOVA validated no interaction between the two factors in mice treated at 13 HALO, illustrating that the sampling-time differences in enzyme activity were greater. Furthermore, two-way ANOVA revealed no interaction in the variation of MDA status in animals treated either at 1 or 13 HALO. This study indicates that SNP significantly affected the anti-oxidant system.

A chalcogen bond (ChB) is a sigma-hole-based noncovalent interaction between a Lewis base and an electrophilic element of Group VI (O, S, Se, Te), which behaves as a Lewis acid. Recently, we demonstrated that halogen bond, the more familiar ?-hole-based interaction, is able to promote the enantioseparation of chiral compounds in HPLC environment. On this basis, an investigation to detect ChBs, functioning as stereoselective secondary interactions for HPLC enantioseparations, was started off and the results of this study are described herein. Our investigation also focused on the impact of the perfluorinated aromatic ring as a -hole donor recognition site. For these purposes, seven atropisomeric fluorinated 3-arylthio-4,4'-bipyridines were designed, synthesized and used as potential ChB donors (ChBDs) with two cellulose-based chiral stationary phases (CSPs) containing carbonyl groups as ChB acceptors (ChBAs). In addition, one and two analogues lacking fluorine and sulphur, respectively, were prepared as terms of comparison. The design of the test analytes was computationally guided. In this regard, electrostatic potentials (EPs) associated with sigma and -holes were computed and the atomic contributions to the sulphur EP maxima were derived using a molecular space partitioning in terms of Bader's atomic basins. This procedure is akin to the Bader-Gatti electron density source function (SF) decomposition, yet suitably extended to the EP field. For five 3-substituted-4,4'-bipyridines, thermodynamic parameters were derived from van't Hoff plots. Finally, the use of molecular dynamic (MD) simulation to model ChB in cellulose-analyte complexes was explored. Evidences that sigma and -hole interactions can jointly drive HPLC enantioseparations through recognition sites generated by electronic charge depletion emerged from both experimental results and theoretical data.

Halogen bond (XB)-driven enantioseparations involve halogen-centred regions of electronic charge depletion (sigma-hole) as electrophilic recognition sites. The knowledge in this field is still in its infancy. Indeed, although the influence of halogens on enantioseparation have been often considered, only recently the function of electrophilic halogens (Cl, Br, I) as enantioseparations 'drivers' has been demonstrated by our groups. Further to these studies, in this paper we focus on some unexplored issues. First, as XB-driven chiral recognition mechanisms are at an early stage of comprehension, a theoretical investigation based on a series of 32 molecular dynamic (MD) simulations was performed by using polyhalogenated 4,4'-bipyridines and polysaccharide-based polymers as ligands and receptors, respectively. Enantiomer elution orders (EEOs) were derived from calculations and the theoretical model accounted for some analyte- and chiral stationary phase (CSP)-dependent experimental EEO inversions. Then, the function of halogen-centred sigma-holes in competitive systems, presenting also hydrogen bond (HB) centres as recognition sites, was considered. In this regard, Pirkle's enantioseparations of halogenated compounds performed on Whelk-O1 were theoretically re-examined and electrostatic potentials (EPs) associated with both sigma-holes on halogens and HB centres were computed and compared. Then, the enantioseparation of halogenated 2-nitro-1-arylethanols was performed on cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) and the influence of halogen substituents on the chromatographic results was evaluated by correlating theoretical and experimental data.

Biological rhythmicity has been extensively studied in animals for many decades. Although temporal patterns of physical activity have been identified in humans, no large-scale, multi-national study has been published, and no comparison has been attempted of the ubiquity of activity rhythms at different time scales (such as daily, weekly, monthly, and annual).Using individually worn actigraphy devices, physical activity of 2,328 individuals from five different countries (adults of African descent from Ghana, South Africa, Jamaica, Seychelles, and the United States) was measured for seven consecutive days at different times of the year.Analysis for rhythmic patterns identified daily rhythmicity of physical activity in all five of the represented nationalities. Weekly rhythmicity was found in some, but not all, of the nationalities. No significant evidence of lunar rhythmicity or seasonal rhythmicity was found in any of the groups.These findings extend previous small-scale observations of daily rhythmicity to a large cohort of individuals from around the world. The findings also confirm the existence of modest weekly rhythmicity but not lunar or seasonal rhythmicity in human activity. These differences in rhythm strength have implications for the management of health hazards of rhythm misalignment.

The use of Aspergillus niger (A. niger) fungal spores as challenge organism for UV reactor validation studies is attractive due to their high UV-resistance and non-pathogenic nature. However A. niger spores UV dose-response was dependent upon sporulation conditions and did not follow the Bunsen-Roscoe Principle of time-dose reciprocity. Exposure to 8 h of natural sunlight for 10 consecutive days increased UV resistance when compared to spores grown solely in dark conditions. Application of 250 mJ cm(-2) at high irradiance (0.11 mW cm(-2)) resulted in a 2-log inactivation; however, at low irradiance (0.022 mW cm(-2)) a 1-log inactivation was achieved. In addition, surface electron microscopy (SEM) images revealed morphological changes between the control and UV exposed spores in contrast to other well accepted UV calibrated test organisms, which show no morphological difference with UV exposure.

The impact of climate variability on Maradi and Dosso agriculture was estimated taking into account farmer adaptations. The study used a Ricardian analysis of 200 farms to explore the effects of climate variability on net revenue. It also simulates the impact of different climate scenarios on agriculture incomes. This analysis bespeaks that if temperature increases 1°C annually, the annual crop net revenues for both frameworks will decrease up to 582170.7 FCFA2 for model without adaptation (M1) and up to 1316 FCFA for model with adaptation (M2). An increase of Precipitation of 1 mm/month will increase crop receipts for the frameworks up to 721,917 FCFA for M1 and 1,861,455 FCFA for M2. In order to predict climate change impacts for these regions, the RCP 4.5 and RCP 8.5 of IPCC scenarios were examined. The crop net receipts will fall between 10% and 26% if the scenarios happen. Another finding of this study is that each farmer who is practicing adaptation is able to cover the potential loss from climate variability up to 8.95% and 12.71% per ha respectively in Maradi and in Dosso. The study proposes that these regions should start planning measures for unexpected event of climate conditions. Irrigated systems need to be encouraged in order to minimize the vulnerability of the agricultural sector.

Rhodamine B (RhB) is a water-soluble fluorescent dye that is often used to determine flux and flow direction in biotechnological and environmental applications. In the current research, RhB in soluble (termed free) and virus-bound (termed nano-bound) forms was used as an efficiency indicator for three environmental processes. The degradation of free and nano-bound RhB by (i) direct UV photolysis and (ii) UV/H2O2 advanced oxidation process (AOP) was studied in a collimated beam apparatus equipped with medium-pressure mercury vapor lamp. The degradation by (iii) solar light-induced photocatalysis was studied in a solar simulator with titanium dioxide and bismuth photocatalysts. Results showed negligible RhB degradation by direct UV and solar light, and its nearly linear degradation by UV/H2O2 and photocatalysis/photosensitization in the presence of a solid catalyst. Considerable adsorption of free RhB on bismuth-based catalyst vs. no adsorption of nano-bound RhB on this catalyst or of any form of the dye on titanium dioxide produced two important conclusions. First, the better degradation of free RhB by the bismuth catalyst suggests that close proximity of a catalyst hole and the decomposing molecule significantly influences degradation. Second, the soluble form of the dye might not be the best option for its use as an indicator. Nano-bound RhB showed high potential as an AOP indicator, featuring possible separation from water after the analysis.

Lignocellulosic biomass is a promising feedstock for ethanol production, but lignin, a polyphenol, hampers the use of enzymes for its saccharification; pretreatment is thus key to preparing such feedstock. Ozonation was previously demonstrated as an effective pretreatment, but claimed to be uneconomical due to the assumed need for lignin mineralization. We analyzed, for the first time, ozonation of highly concentrated tannic acid (TA) solution (60g/L) as a lignin model. Most of the TA disappeared within 3.5h, following triple-phase kinetics with two transition points: at 7min and 60min of ozonation for 0.4L ozone reactor. Maximal enzymatic activity was found at the first transition point, demonstrating that very short ozonation that results in partial decomposition of TA, is enough to remediate TA's negative effect on cellulase activity. Short ozonation could decrease energy input by up to 97%, making ethanol production more economically competitive.

In order to forecast consumption, electric power generation, transmission and distribution companies need model to predict short-term demand for electric power load so that they can use their electricity infrastructure efficiently, safely and economically. The short-term forecast of electrical energy demand is the forecast of consumption over time interval ranging from one hour to few days. For optimal use of electricity grid, energy production must keep pace with demand. To this end, prediction errors can lead to risks and shortcomings in the generation and distribution of electrical load to users. This paper is part of electrical charge prediction of Niamey city. Several are being carried out in this field, but prediction techniques based on artificial neural networks have recently been developed. This work focused on two (2) neural approaches such as the multilayer Perceptron (MLP) and the non-linear autoregressive network with exogenous inputs (NARX). Several configurations of these two models have been developed and tested on actual electrical load data. We carried out the short-term forecast (hourly basis) of electrical load of Niamey city. All configurations have been implemented in MATLAB software. The statistical indicators MAPE (Mean Absolute Average Error in Percent), R2 (the correlation coefficient) and RMSE (Square Root of Mean Square Error) were used to evaluate the performance of the models. Thus, with MAPE of 5.1765%, R2 of 95.3013% and RMSE of 5.6014%, the [ABCD] configuration of NARX model converges better compared to the MLP model with MAPE of 7.1874%, R2 of 92.0622% and RMSE of 7.2199%. Where A is the data charge of the same time of the previous day, B is the charge data of the same time of the previous week, C is the charge data of same time of previous year and D is the average of last 24 charge values. So the NARX model is the most efficient and can be used for future predictions on Niamey city network.

Le nombre et la durée de survie des patients transplantés cardiaque sont en augmentation. Une partie de ces patients se présentent régulièrement pour une chirurgie générale en dehors de la transplantation cardiaque. L’anesthésie chez ces patients peut être difficile en raison des particularités physiologiques du cœur dénervé et de la gestion du traitement immunosuppresseur avec le risque de rejet et d’infection. Nous discutons la prise en charge anesthésique à travers un cas d’un patient âgé de 60 ans transplanté cardiaque devant subir une chirurgie de cure d’éventration abdominale et une revue de la littérature. The Pan African Medical Journal. 2016;24

The preparation of 27 isomers of chiral hexahalogeno-4,4′-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.

Treatment ofAcinetobacter baumanniimeningitis is an important challenge due to the accumulation of resistance of this bacteria and low meningeal diffusion of several antimicrobial requiring use of an antimicrobial effective combination to eradicate these species. We report a case ofAcinetobacter baumanniimultidrug-resistant nosocomial meningitis which was successfully treated with intravenous and intrathecal colistin associated with rifampicin.

The high performance liquid chromatography (HPLC) enantioseparation of eleven atropisomeric 4,4′-bipyridines was performed in the normal and polar organic phase mode using three cellulose-based chiral stationary phases (CSPs), namely Lux ® Cellulose-1, Lux ® Cellulose-2, Lux ® Cellulose-4, and two amylose-based CSPs, Chiralpak ® AD-H and Lux ® Amylose-2. n -Hexane/2-propanol mixtures and pure ethanol were employed as mobile phases. The combined use of Chiralpak ® AD-H and Lux ® Cellulose-2 allowed to enantioseparate all the considered bipyridines. Ten bipyridines were enantioseparated at the multimilligram level allowing the elution sequence determination of the enantiomers as well as their future use for the preparation of homochiral metal organic frameworks (MOFs). Moreover, the performance of the CSPs regarding the same bipyridine was different and dependent on the backbone as well as on the side chain of the polymer. The impact of substitution pattern, shape and electronic properties of the molecules on the separation behavior was investigated through the evaluation of retention factors ( k ), separation factors ( α ), resolution ( R s ) and molecular properties determined using density functional theory (DFT) calculations. In this regard, the substituents at the 3,3′,5,5′ positions of the 4,4′-bipyridyl rings exhibited a pivotal role on the enantioseparation.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces a deleterious effect on several organs, including the heart, eventually leading to septic shock and death. Endotoxemia-induced cardiotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation, inducing DNA, protein, and membrane lipid damage. Resveratrol (trans-3,5,4' trihydroxystilbene; RVT) is a phytoalexin polyphenol that exhibits antioxidant and -inflammatory properties. We investigated the putative effect of a subacute treatment with this natural compound on LPS-induced cardiotoxicity in the rat. We found that resveratrol counteracted LPS-induced lipoperoxidation and decreased superoxide dismutase (SOD) activity, but had no effect on the LPS-induced decrease in catalase (CAT) nor on the increase in peroxidase (POD) activity. Resveratrol also reversed LPS-induced myocardial nitric oxide (NO) elevation. More important, LPS-induced iron depletion from plasma to the myocardial compartment was abolished upon resveratrol treatment. All these data suggest that resveratrol is capable of alleviating LPS-induced cardiotoxicity, and that its mode of action may involve iron-shuttling proteins.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of gram-negative bacteria inducing deleterious effects on several organs including the liver and eventually leading to septic shock and death. Endotoxemia-induced hepatotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation inducing DNA, proteins and membrane lipid damages. Resveratrol (trans-3,5,4' trihydroxystilbene) is a phytoalexin polyphenol exhibiting antioxidant and anti-inflammatory properties. In this study, we investigated the effect of subacute pre-treatment with this natural compound on LPS-induced hepatotoxicity in rat. Resveratrol counteracted LPS-induced lipoperoxidation and depletion of antioxidant enzyme activities as superoxide dismutase (SOD) and catalase (CAT) but slightly glutathione peroxidase (GPx) activity. The polyphenol also abrogated LPS-induced liver and plasma nitric oxide (NO) elevation and attenuated endotoxemia-induced hepatic tissue injury. Importantly resveratrol treatment abolished LPS-induced iron sequestration from plasma to liver compartment. Our data suggest that resveratrol is capable of alleviating LPS-induced hepatotoxicity and that its mode of action may involve differential iron compartmentalization via iron shuttling proteins.

Lipopolysaccharide (LPS), a glycolipid component of the cell wall of gram-negative bacteria can elicit a systemic inflammatory process leading to septic shock and death. Acute phase response is characterized by fever, leucocytosis, thrombocytopenia, altered metabolic responses and redox balance by inducing excessive reactive oxygen species (ROS) generation. Resveratrol (trans-3,5,4' trihydroxystilbene) is a natural polyphenol exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effect of resveratrol on endotoxemia-induced acute phase response in rats. When acutely administered by i.p. route, resveratrol (40 mg/kg b.w.) counteracted the effect of a single injection of LPS (4 mg/kg b.w.) which induced fever, a decrease in white blood cells (WBC) and platelets (PLT) counts. When i.p. administered during 7 days at 20 mg/kg per day (subacute treatment), resveratrol abrogated LPS-induced erythrocytes lipoperoxidation and catalase (CAT) activity depression to control levels. In the plasma compartment, LPS increased malondialdehyde (MDA) via nitric monoxide (NO) elevation and decreased iron level. All these deleterious LPS effects were reversed by a subacute resveratrol pre-treatment via a NO independent way. Resveratrol exhibited potent protective effect on LPS-induced acute phase response in rats.

Rhodanese (thiosulfate sulfurtransferase) is a ubiquitous enzyme that accelerates the transformation of cyanide into the very less toxic thiocyante. Influence of cerebral rhodanese level on cyanide toxicity has already been shown in mice. However, age-related changes in rhodanese activity have not been previously examined. The aim of the experiments was to investigate age-related changes of cerebral rhodanese activity in male and female mice maintained from birth to age 16 weeks under 12:12 light:dark (LD) cycle conditions. The rhythm of enzyme activity was quantified by Cosinor test programme in 2-, 4-, 8-, 12-, and 16-week-old mice. Significant ultradian (tau =1 2h) rhythms were validated both by ANOVA (P0.05) and Cosinor analyses (Por = 0.01) in 2- and 4-week-old mice. However, in addition to the ultradian rhythm, a significant (Por = 0.01) prominent circadian (tau = 24h) rhythm, whose peak time located at approximately 9 Hours After Light Onset (HALO), was detected in 4-week-old females. In 8-, 12-, and 16-week-old mice, the Cosinor validated significant (Por = 0.0001) circadian rhythms in both genders. The circadian peak time initially located at approximately 5 HALO in 8-week-old mice, moved to approximately 9 HALO and then to be stabilized at approximately 17 HALO in 12- and 16-week-old mice, respectively. Furthermore, the ultradian components were detected in 8- and 12-week-old females. On the other hand, at age 16 weeks, no significant ultradian rhythm was detected in males or in females. The enzyme activity was greater in females compared to males during the first 8 postnatal weeks. Two-way ANOVA revealed a significant (P0.02) interaction between circadian time and gender in 4-, 8-, 12-, and 16-week-old mice, suggesting the influence of gender on time-related changes in rhodanese activity. However, though ANOVA validated significant changes related to both sampling-time and gender, no interaction was detected between the two factors in 2-week-old mice, illustrating the gender-related difference in enzyme activity was greater. Moreover, the obtained results showed that rhodanese activity significantly increased with age during the postnatal development (PND). However, this increase would be limited by age in old mice as early as 12 weeks after birth. The data also showed a 12h phase-shift of the circadian rhodanese peak time during PND, suggesting that the rhythm stabilization is age dependent. The main findings of this study indicated that the increased sensitivity to cyanide, generally reported in old mice, may be due in part to a decrease in the activity of brain rhodanese.

Le bon fonctionnement de la cellule dépend du contrôle fin des mécanismes transcriptionnels et traductionnels. De nombreuses études ont établi que les dérèglements transcriptionnels peuvent être à l’origine de maladies telles que le cancer, l’obésité et le diabète. Depuis une décennie, le rôle de la traduction des ARNm dans certaines de ces pathologies et son contrôle par la voie PI3K/Akt/mTOR a été démontré. La rapamycine, inhibiteur spécifique de mTOR, présente une forte activité anti-proliférative dans plusieurs types de cancer. De récentes études démontrent qu’elle pourrait potentiellement être efficace dans le traitement de l’obésité et du diabète. La rapamycine et ses analogues semblent donc destinés à un avenir prometteur., Gene regulation by transcriptional and post-translational mechanisms is implicated in the regulation of cellular homeostasis. Transcriptional deregulation has been largely documented in the etiology of diseases such as cancer, obesity and diabetes. During the past decade, the control of translation initiation by the PI3K/Akt/mTOR pathway in the development of these pathologies has been documented. Rapamycin, a specific inhibitor of mTOR, demonstrates considerable anti-proliferative activity against numerous cancer types. Recent studies also demonstrated that rapamycin may be beneficial in the treatment of obesity and diabetes. Rapamycin and its analogs seem destined for a promising future and will help in the development of novel therapeutic strategies.