Looking back and moving forward: 50 years of soil and soil fertility management research in sub-Saharan Africa

Article purchased; Published online: 02 Nov 2017Low and declining soil fertility has been recognized for a long time as a major impediment to intensifying agriculture in sub-Saharan Africa (SSA). Consequently, from the inception of international agricultural research, centres operating in SSA have had a research programme focusing on soil and soil fertility management, including the International Institute of Tropical Agriculture (IITA). The scope, content, and approaches of soil and soil fertility management research have changed over the past decades in response to lessons learnt and internal and external drivers and this paper uses IITA as a case study to document and analyse the consequences of strategic decisions taken on technology development, validation, and ultimately uptake by smallholder farmers in SSA. After an initial section describing the external environment within which soil and soil fertility management research is operating, various dimensions of this research area are covered: (i) ‘strategic research’, ‘Research for Development’, partnerships, and balancing acts, (ii) changing role of characterization due to the expansion in geographical scope and shift from soils to farms and livelihoods, (iii) technology development: changes in vision, content, and scale of intervention, (iv) technology validation and delivery to farming communities, and (v) impact and feedback to the technology development and validation process. Each of the above sections follows a chronological approach, covering the last five decades (from the late 1960s till today). The paper ends with a number of lessons learnt which could be considered for future initiatives aiming at developing and delivering improved soil and soil fertility management practices to smallholder farming communities in SSA

Human cerebrospinal fluid monoclonal CASPR2 autoantibodies induce changes in electrophysiology, functional MRI, and behavior in rodent models

Anti-contactin associated protein receptor 2 (CASPR2) encephalitis is a severe autoimmune encephalitis with a variable clinical phenotype including behavioral abnormalities, cognitive decline, epileptic seizures, peripheral nerve hyperexcitability and neuropathic pain. The detailed mechanisms of how CASPR2 autoantibodies lead to synaptic dysfunction and clinical symptoms are largely unknown. Aiming for analyses from the molecular to the clinical level, we isolated antibody-secreting cells from the cerebrospinal fluid of two patients with CASPR2 encephalitis. From these we cloned four anti-CASPR2 human monoclonal autoantibodies (mAbs) with strong binding to brain and peripheral nerves. All were highly hypermutated and mainly of the IgG4 subclass. Mutagenesis studies determined selective binding to the discoidin domain of CASPR2. Surface plasmon resonance revealed affinities with dissociation constants K D in the pico- to nanomolar range. CASPR2 mAbs interrupted the interaction of CASPR2 with its binding partner contactin 2 in vitro and were internalized after binding to CASPR2-expressing cells. Electrophysiological recordings of rat hippocampal slices after stereotactic injection of CASPR2 mAbs showed characteristic afterpotentials following electrical stimulation. In vivo experiments with intracerebroventricular administration of human CASPR2 mAbs into mice and rats showed EEG-recorded brain hyperexcitability but no spontaneous recurrent seizures. Behavioral assessment of infused mice showed a subtle clinical phenotype, mainly affecting sociability. Mouse brain MRI exhibited markedly reduced resting-state functional connectivity without short-term structural changes. Together, the experimental data support the direct pathogenicity of CASPR2 autoantibodies. The minimally invasive EEG and MRI techniques applied here may serve as novel objective, quantifiable tools for improved animal models, in particular for subtle neuropsychiatric phenotypes or repeated measurements

Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures

Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients' symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies

Regulation of vascular tone, molecular mechanisms

The goal of this survey was to review briefly the molecular mechanisms that regulate vascular smooth muscle function. Components of the machinery involved in the contraction and relaxation of vascular smooth muscle include the following.Contractile proteins. The force generated by vascular smooth muscle is the result of thin (actin) and thick (myosin) filaments being pulled by one another so that the cell tends to shorten. The processes by which this intereaction is regulated are a matter of some debate. However, most observations indicate that the process that initiates contraction is a calcium-dependent phosphorylation of the myosin light chain.Cellular sites for the regulation of myoplasmic calcium concentration. The final event that initiates the contractile process is an increase in the intracellular concentration of ionized calcium. Cellular sites that may contribute to the raising and lowering of ionized calcium include the following: (A) cell membrane, (B) sarcoplasmic reticulum, and (C) mitochondria.Membrane electrical events. The electrical state of the cell membrane influences contractile responses of vascular smooth muscle. Over the physiologic range, an elevation in the membrane potential has a reciprocal influence on muscle excitability. The membrane potential is the sum of the diffusion potentials and the electrogenic pump.Excitation-contraction coupling. The excitatory events of the cell membrane (changes in membrane potential and the generation of action potentials) are coupled to the interaction of the contractile proteins by an increase in myoplasmic ionized calcium.Cyclic nucleotides and calcium. Cyclic AMP and cyclic GMP may link contraction and relaxation to the release and uptake of activator calcium by subcellular organelles. These nucleotides also influence the level of phosphorylation of the myosin light chain.Energy metabolism and hypoxia. The chemical energy source for cellular processes in vascular smooth muscle is ATP. Vascular tone, or maintenance of a contractile force, in this muscle is a relatively efficient process that may reflect a special noncycling link between myosin and actin. Current evidence suggests that hypoxic conditions influence vascular tone by altering the activity of the electrogenic sodium pump.This listing of statements is by no means the final word in molecular mechanisms that govern vascular tone. Indeed, vascular smooth muscle remains to be a constant source of surprises for the interested investigator.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24206/1/0000465.pd

Total Synthesis of (-)-Chokol A by an Asymmetric Domino Michael Addition-Dieckmann Cyclization

A convergent and asymmetric total synthesis of (-)-chokol A was accomplished in six steps starting from the α,β-unsaturated ester (E)-9 in an overall yield of 27% with an enantiomeric excess of 95%. The key step of this synthesis is the asymmetric tandem conjugate addition-Dieckmann cyclization of the higher-order cuprate 8 derived from vinyl bromide 7 with the α,β-unsaturated ester (E)-9

Synthesis of (±)-Chokol A by a Tandem Michael-Addition/Dieckmann Cyclization

A total synthesis of (±)-chokol A (rac-12) was accomplished in five steps by starting from the α,β-unsaturated ester (E)-2 in an overall yield of 24%. The key step of this synthesis is the tandem conjugate addition/Dieckmann cyclization of the cuprate derived from vinyl bromide 9 with the α,β-unsaturated ester (E)-2

3-Substituted and 2,3-Disubstituted Cyclopentanones via an Asymmetric Tandem 1,4-Addition/Dieckmann Cyclization

A new stereoselective method for the synthesis of 3-substituted and 2,3-disubstituted cyclopentanones is described. The key step is the 1,4-addition of a cuprate to a chilar Michael-acceptor derived from (-)-8-phenylmenthol or the Helmchen auxiliary followed by Dieckmann cyclization of the obtained chiral enolates. The resultant 2,3-cyclopentanones can be transformed after methanolysis and demethoxycarbonylation to the related 3-substituted ­cyclopentanones