We report a micro-fractionation device for high performance liquid chromatography-mass spectrometry to archive chromatographic separations on an array of optimized surface energy traps (SETs). The method has the potential to significantly alter nanoflow LC-MS workflow, decoupling separation and analysis. The wetting characteristics of the SETs cause the HPLC eluent stream to spontaneously split into droplet microfractions. The droplet mirofractions are then dried down to enable facile storage and transport of the archived separation. Discontinuously dewetting array parameters were explored to maximize array volume and resolution using a combination of SET design, shape, size, and spacing. Mass spectrometry analysis is performed utilizing a liquid micro-junction surface sampling probe to extract dried analytes from the surface of the SETs followed by electrospray ionisation. A reverse phase separation of pharmaceutical compounds is "recorded" using the micro-fractionation device followed by "reading" the chromatographic trace with a mass spectrometer 24 hours after the separation was performed/archived, demonstrating a true decoupling of LC, and MS. Additionally, we demonstrate the ability to collect microfractions with sub-one-second integration time, approaching the scan time of a mass spectrometer or UV-Vis detector. With further improvements to the device, sub-1-second micro-fractionation may enable seamless reconstruction of archived chromatograms indistinguishable from online LC-MS data, while also providing the benefits of easy storage and transport of archived separations.

To evaluate the role of vacuolar protein sorting 35 (VPS35) in α-synuclein (αS) degradation pathways using a novel retromer stabilizer, guanidine hydrazone (2a).

Ambient ionization methods have become important tools in mass spectrometry. The LMJ-SSP can significantly simplify/reduce lengthy sample preparation requirements associated with mass spectrometry analysis. Samples may be introduced through direct contact, insertion and droplet injection, enabling applications from drug discovery and surface analysis to tissue profiling and metabolic mapping. This review examines the underlying principles associated with the LMJ-SSP interface and highlights modifications of the original design that have extended its capability. We summarize different application areas that have exploited the method and describe potential future directions for the adaptable ambient ionization source.

Introduction Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale. Objectives This study was designed to identify cardiac metabolic changes in serum during the first 5 min following early myocardial ischaemia in humans, applying an untargeted metabolomics approach. Methods Peripheral venous samples were collected from 46 patients in a discovery study (DS) and a validation study (VS) (25 for DS, 21 for VS). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute myocardial ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Plasma samples were collected at baseline (prior to PCI) and at 1 and 5 min post-coronary occlusion. Samples were analyzed by Ultra Performance Liquid Chromatography-Mass Spectrometry in an untargeted metabolomics approach. Results The study observed changes in the circulating levels of metabolites at 1 and 5 min following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites as significant (P < 0.05) when compared to baseline levels, respectively. Fatty acid beta-oxidation and anaerobic respiration, lysoglycerophospholipids, arachidonic acid, docosahexaenoic acid, tryptophan metabolism and sphingosine-1-phosphate were identified as mechanistically important. Conclusion Using an untargeted metabolomics approach, the study identified important cardiac metabolic changes in peripheral and coronary sinus plasma, in a human model of controlled acute myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischemia and provide insights into diagnostic and interventional targets.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disease due to mutation of the VPS13A gene encoding the protein chorein. ChAc is a slowly progressive disorder that typically presents in early adulthood, and whose clinical features include chorea and dystonia with involuntary lip, cheek, and tongue biting. Some patients also have seizures. Treatment for ChAc is symptomatic. A small number of ChAc patients have been treated with bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi), and we now present an additional case. Patient chart, functional measures, and laboratory findings were reviewed from the time of ChAc diagnosis until 6 months after DBS surgery. Here, we present a case of ChAc in a 31-year-old male positive for VPS13A gene mutations who presented with chorea, tongue biting, dysarthria, weight loss, and mild cognitive dysfunction. DBS using monopolar stimulation with placement slightly lateral to the GPi was associated with significant improvement in chorea and dysarthria. This case adds to the current state of knowledge regarding the efficacy and safety of bilateral GPi-DBS for symptomatic control of drug-resistant hyperkinetic movements seen in ChAc. Controlled trials are needed to better assess the impact and ideal target of DBS in ChAc.

Metal clusters of gold and silver with highly tunable optical and electronic properties are attractive candidates for next generation medical imaging and therapy. Of these two most commonly studied metals, silver clusters often exhibit superior optical properties (i.e. stronger absorbance and higher emission quantum yield). The atomically precise synthesis of these clusters is essential before their use in biological applications can be realized. However, most cluster synthetic routes result in complex mixtures, where isolation and/or characterization can become incredibly challenging. Using photochemistry, we demonstrate a synthetic route for silver thiolate clusters resulting in the isolation of a pure eighteen-atom silver cluster capped by fourteen captopril ligands, Ag-18(Capt)(14). The facile control over the reduction of Ag(i) salt that this photochemical route affords can be readily applied as a general synthesis for isolating other new, atomically precise clusters.

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Silver and gold clusters have received a lot of recent attention for their use in biomedical imaging. However, crude solutions of clusters are often complex mixtures, leading to discrepancies in their identification and characterization; important factors in determining their utility in biological applications. In the present study, silver clusters were separated for analysis using reverse-phase high performance liquid chromatography, which has previously been implemented in the efficient separation of gold clusters. Using fluorescence excitation-emission matrix (EEM) spectroscopy, we have demonstrated that a certain family of glutathione-protected silver clusters, previously thought to be one optically distinct species, is better described as a complex mixture of at least three distinct silver cluster species, each possessing unique optical properties. Based on these findings, EEM spectroscopy can be implemented as a powerful technique for determining the purity of complex mixtures, especially when other techniques, including mass spectrometry, fail to provide adequate characterization of a given material.

Background We undertook this study to identify patients with Parkinson disease (PD) with no or rare falls who may progress to frequent falling by their next annual follow-up visit. Methods We analyzed data in the National Parkinson Foundation Quality Improvement Initiative database to identify factors predicting which patients with PD with no or rare falls at the baseline visit will report at least monthly falls at the annual follow-up visit. Multivariable models were constructed using logistic regression. Variables were introduced in 4 blocks: in the 1st block, variables present at or before the baseline visit were entered; in the 2nd, baseline visit assessments; in the 3rd, interventions implemented during baseline visit; and, in the 4th block, changes in comorbidities, living situation, and treatment between visits. Results Of 3,795 eligible participants, 3,276 (86.3%) reported no or rare falls at baseline visit, and of them, 382 (11.7%) reported at least monthly falls at follow-up visit. Predictors included female sex, <90% diagnostic certainty, motor fluctuations, levodopa treatment, antidepressant treatment, prior deep brain stimulation (DBS), worse quality of life, Hoehn & Yahr stage 2 or 3, worse semantic fluency, and, between visits, addition of amantadine, referral to occupational therapy, social services, or DBS, new diagnoses of cancer or osteoarthritis, and increased emergency visits. Conclusions This large-scale analysis identified several predictors of progression to falling in PD. Such identifiers may help target patient subgroups for falls prevention intervention. Some factors are modifiable, offering opportunities for developing such interventions.

After more than a century of colonial rule by Germany and then South Africa, Namibia finally gained its independence on 21 March 1990. Namibia has promoted a liberal, mixed economic system which encourages foreign direct investment and hopefully employment growth, while simultaneously seeking to redress the most oppressive and divisive legacies of apartheid. Before considering some of the principal economic policy issues facing Namibia since independence, this chapter outlines a series of fundamental economic, social and political parameters and features that should inform any policy or planning process. Despite the huge historical baggage and Namibian concerns that apartheid South Africa was still secretly planning to undermine the new South West Africa People's Organisation (SWAPO) government and Namibian independence, joint technical commissions were established and both disputes were resolved peacefully. Namibia's government has also sought to address the country's dependence on energy imports for all of its petroleum and coal and about half of its electricity requirements.

This chapter discusses two current issues concerning urban-rural interaction: the impact of returned international migrants from South Africa and Zimbabwe, and the national implications of rural development policies involving agrarian reform together with attempts to eliminate migrant labour. These illustrate well the centrality of rural-urban population mobility and attendant commodity and financial flows to national and international political economic analysis and development strategies throughout the region. Malawi and Mozambique are used as case studies because they have experienced the largest and most rapid reductions in labour exports. In view of the severe land pressure in many rural reserves, agrarian reform and resettlement are prerequisites for equitable development. State policy may also seek to reduce or eliminate migrant labour for moral and equity reasons. Whereas Malawi represented a most unusual case of rapidly increasing domestic labour demand due to labour-intensive economic development, Mozambique was less fortunate and suffered greatly in terms of both unemployment and its balance of payments.