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Bulk acoustic wave induced mixing in microfluidic systems has been studied by using a pair of small size ultrasonic transducers integrated into a prototype polydimethylsiloxane device. The acoustic properties of the integrated ultrasonic transducers were evaluated, demonstrating the generation of bulk acoustic wave in the mixing chamber when a low ac voltage is applied. Then, the mixing efficiency of the device was studied by using two stream laminar flows and taking into account the particular geometry of the mixing chamber. Because of the limited power consumption, the system should be compatible with the requirements of a number of applications in both analytical chemistry and biology. [ABSTRACT FROM AUTHOR]

Lead-free piezoelectric ceramics (1-x)K0.5Na0.5NbO3–xLiSbO3 have been fabricated by a conventional ceramic sintering technique. The results of x-ray diffraction suggest that Li+ and Sb5+ diffuse into the K0.5Na0.5NbO3 lattices to form a solid solution with a perovskite structure. The ceramics can be well sintered at 1070–1110 °C. The introduction of LiSbO3 into the Na0.5K0.5NbO3 solid solution decreases slightly the paraelectric cubic-ferroelectric tetragonal phase transition temperature (Tc), but greatly shifts the ferroelectric tetragonal-ferroelectric orthorhombic phase transition (TO–F) to room temperature. Coexistence of the orthorhombic and tetragonal phases is formed at 0.05

The dc-arc detection is essential for dc systems to operate reliably and safely. Due to the randomness of dc-arc faults, it is difficult to define their characteristics for detection. The magnetic-sensing-based methodology using tunnel magnetoresistance (TMR) sensor was developed to distinguish the dc arc accurately. However, the noise from the power electronics such as maximum power pointing tracking (MPPT) controllers could affect the dc-arc detection in a photovoltaic (PV) system. In this paper, the arc faults which may occur in PV systems under various conditions were emulated in the dc system of 9 kW. It was verified that the proposed methodology of measuring pink noise can distinguish the dc arc accurately for PV systems from 48 to 300 V and current up to 30 A. An off-grid PV system was established to experimentally demonstrate the arc-detection method in the practical system. The experimental results confirmed that the technique could identify the dc arc correctly with an extended working region despite the noise of power electronics in MPPT. It was verified that the arc-detection system is capable of discriminating the normal operation and arc fault in the PV system. This technique is applicable and promising for arc-faults detection in PV systems. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the case of a 56-year-old man diagnosed with B-chronic lymphocytic leukemia (B-CLL) and treated with alemtuzumab, who developed Epstein-Barr virus (EBV)-related cerebral lymphoma.

A response by J. J. A. Auwerda to a letter to the editor about his article on contemporaneous autoantibodies and alloantibodies is presented.

An arc fault establishes a current path in the air which may cause malfunction of direct current (dc) system and even a fire hazard. Arc fault detection is essential to improving the reliability, efficiency, and safety of the dc system. However, the randomness of dc arc faults makes it difficult to define their characteristics. In this paper, a magnetic-sensing-based technique is proposed to detect dc arc. This paper developed a promising dc-arcing detection technique based on the analysis of frequency-domain features of the magnetic field measured by a magnetic sensor. The effects of the supply voltage, load current, and electrode diameter on the frequency domain of the arc current were investigated. The experimental results show that the proposed detection technique could reliably discriminate the normal operation and arc fault. This technique is cost-effective because it can be implemented with low-cost magnetoresistive sensors and does not require an expensive current transformer. [ABSTRACT FROM AUTHOR]

In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology. [ABSTRACT FROM AUTHOR]

There are an estimated 1 billion cases of superficial fungal infection globally. Fungal pathogens form biofilms within wounds and delay the wound healing process. Miconazole and terbinafine are commonly used to treat fungal infections. They induce the accumulation of reactive oxygen species (ROS) in fungi, resulting in the death of fungal cells. ROS are highly reactive molecules, such as oxygen (O2), superoxide anion (O2•−), hydrogen peroxide (H2O2) and hydroxyl radicals (•OH). Although ROS generation is useful for killing pathogenic fungi, it is cytotoxic to human keratinocytes. To the best of our knowledge, the effect of miconazole and terbinafine on HaCaT cells has not been studied with respect to intracellular ROS stimulation. We hypothesized that miconazole and terbinafine have anti-wound healing effects on skin cells when used in antifungal treatment because they generate ROS in fungal cells. We used sulforhodamine B protein staining to investigate cytotoxicity and 2′,7′-dichlorofluorescein diacetate to determine ROS accumulation at the 50% inhibitory concentrations of miconazole and terbinafine in HaCaT cells. Our preliminary results showed that topical treatment with miconazole and terbinafine induced cytotoxic responses, with miconazole showing higher cytotoxicity than terbinafine. Both the treatments stimulated ROS in keratinocytes, which may induce oxidative stress and cell death. This suggests a negative correlation between intracellular ROS accumulation in keratinocytes treated with miconazole or terbinafine and the healing of fungi-infected skin wounds. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance remains a serious problem that results in high mortality and increased healthcare costs globally. One of the major issues is that resistant pathogens decrease the efficacy of conventional antimicrobials. Accordingly, development of novel antimicrobial agents and therapeutic strategies is urgently needed to overcome the challenge of antimicrobial resistance. A potential strategy is to kill pathogenic microorganisms via the formation of reactive oxygen species (ROS). ROS are defined as a number of highly reactive molecules that comprise molecular oxygen (O 2), superoxide anion (O 2 •−), hydrogen peroxide (H 2 O 2) and hydroxyl radicals (•OH). ROS exhibit antimicrobial actions against a broad range of pathogens through the induction of oxidative stress, which is an imbalance between ROS and the ability of the antioxidant defence system to detoxify ROS. ROS-dependent oxidative stress can damage cellular macromolecules, including DNA, lipids and proteins. This article reviews the antimicrobial action of ROS, challenges to ROS hypothesis, work to solidify ROS-mediated antimicrobial lethality hypothesis, recent developments in antimicrobial agents using ROS as an antimicrobial strategy, safety concerns related to ROS, and future directions in ROS research. • Reactive oxygen species (ROS) could combat antimicrobial resistance. • ROS are used as an antimicrobial strategy because of their toxicity to a broad range of microbial pathogens. • ROS exert antimicrobial activity via an induction of oxidative stress in microbial cells. • Oxidative stress caused by ROS leads to microbial DNA damage, and ultimately inducing cell death. [ABSTRACT FROM AUTHOR]

Within data gathered through passive monitoring of patients with Multiple Sclerosis (MS), there is a clear necessity for improved methodological approaches to match the emergence of continuous, objective, measuring technologies. As most gold standards measure infrequently and require clinician presence, fluctuations in the daily progression are not accounted for. Due to the underlying conditions of homogeneity and stationarity (the main tenets of ergodicity) not being met for the majority of the statistical methods employed in the clinical setting, alternative approaches should be investigated. A solution is to use a non-linear time series analysis approach. Here, Early-Warning Signals (EWS) in the form of critical fluctuations in Keystroke Dynamics (KD), collected using participant's smartphones, are investigated as indicators for a clinical change in three groups. These are patients with MS and changes in Magnetic Resonance Imaging (MRI), patients with MS but without changes in MRI, and healthy controls (HCs). Here, we report examples of EWS and changes in KD coinciding with clinically relevant changes in outcome measures in both patients with and without differences in the amount of MRI enhancing lesions. We also report no clinically relevant changes in EWS in the HC population. This study is a first promising step toward using EWS to identify periods of instability as measured by a continuous objective measure as a proxy for outcome measures in the field of MS. [ABSTRACT FROM AUTHOR]

Bismuth sodium titanate based lead-free ceramic fiber with the chemical formula of 0.885(Bi0.5Na0.5)TiO3–0.05(Bi0.5K0.5)TiO3–0.015(Bi0.5Li0.5)TiO3–0.05BaTiO3, BNKLBT-1.5, has been fabricated by a powder-based extrusion method. The ceramic fibers with 400 μm diameter were well crystallized after being calcined at 800 °C and sintered at 1170 °C. The piezoelectric and ferroelectric properties of the single fiber were found to be 155 pC/N and ∼34.5 μC/cm2, respectively, which is comparable with that in bulk sample. 1-3 ceramic/polymer composites were fabricated by two routes, including dice and filled method and fiber pick-and-place method. Theoretical models were used to calculate the piezoelectric properties of the composites and compared with experimental results. [ABSTRACT FROM AUTHOR]

Two complexes dichloro(9,9-dihexyl-4,5-diazafluorene)platinum(II) (Pt-DHF) and dichloro(9,9-dihexyl-4,5-diazafluorene)palladium(II) (Pd-DHF) were synthesized and their in vivo antitumour activity was investigated using an athymic nude mice model xenografted with human Hep3B carcinoma cells. Pt-DHF- and Pd-DHF-treated groups showed significant tumour growth inhibition (with about 9-fold and 3-fold tumour growth retardation) when compared with the vehicle control group. The liver toxicology effects on the animals of the two compounds were investigated. Pt-DHF and Pd-DHF-treated groups had a lower alanine transaminase and aspartate transaminase values than those of the vehicle treated group as the animals from the vehicle control group had very heavy hepatoma burden. We assume that both complexes could be further investigated as effective antitumour agents and it is worthwhile to study their underlying working mechanism. [ABSTRACT FROM AUTHOR]

Excretion of hazardous pharmaceutical residues causes the emergence of toxic potential to the environment. Nanomedicine is commonly associated with nanoparticulate drug delivery to offer the improved therapeutic effects at a lower dose for disease treatments. Green chemistry aims to reduce or exclude the utilisation or generation of toxic substances in the design, manufacture and application of chemical products. The use of non-toxic and biodegradable materials in pharmaceutical formulations could minimize the adverse effects of pharmaceutical residues entering the environment in the first place. In our study, bovine serum albumin, a non-toxic, biodegradable and biocompatible protein, was used in the formation of nanoparticulate drug delivery systems. Glucose was used instead of glutaraldehyde to modify albumin nanoparticles for berberine delivery in order to prevent the potential toxicity to humans and the environment. These nanoparticles highly inhibited LX-2 cell growth and exhibited stronger caspase 3 activation at a lower dose when compared with free drug in vitro. Nanoparticles with berberine at doses of 1 and 2 μg g−1 could rescue mice from CCl4-induced hepatotoxicity in vivo. Green glucose-bovine serum albumin nanoparticles could be safe and effective to deliver berberine at low doses in liver fibrosis treatment. [ABSTRACT FROM AUTHOR]

Highlights: [•] We develop d-glucose modified gelatin/collagen matrix and reservoir nanoparticles. [•] C. officinalis powder and oil were entrapped in matrix and reservoir systems. [•] C. officinalis powder nanoparticles greatly enhanced the anti-cancer activity. [•] Nanoparticles did not induce strong cytotoxicity towards normal human cell lines. [•] Therapeutic selectivity was found between cancer and normal cells. [Copyright &y& Elsevier]

A series of ruthenium(II) bis(2,2'-bipyridyl) complexes containing N-phenyl-substituted diazafluorenes (Ru-C1, Ru-C6, Ru-C7 and Ru-F) was synthesized and their potential antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) was investigated. The Ru-C7 complex showed significant improvement in both minimum inhibitory concentration (MIC, 6.25 μg mL-1) and minimum bactericidal concentration (MBC, 25 μg mL-1) towards MRSA when compared with those of methicillin (positive control) (MIC = 25 μg mL-1 and MBC = 100 μg mL-1). The Ru-C7 complex possessed much stronger antibacterial effects than the Ru-C6 complex (MIC, 25 μg mL-1, MBC, >100 μg mL-1). Both Ru-C6 and Ru-C7 complexes were also demonstrated to be biologically safe when tested on normal human skin keratinocytes. [ABSTRACT FROM AUTHOR]

A novel compound, (5-(dimethylamino)-N-(4-ethynylphenyl)-1-naphthalenesulfonamide), was prepared and characterized; it shows dual functional roles as an effective antitumor and a two-photon induced bio-imaging agent. [ABSTRACT FROM AUTHOR]

We report on the feasible fabrication of microfluidic devices for noncontact particle trapping. A half-wavelength resonator was constructed using standard soft lithography to generate ultrasonic standing waves through a miniature piezoelectric transducer. Microparticles (400 nm to 10 μm in diameter) flowing through polydimethylsiloxane microchannels were efficiently trapped to levitate in the middle depth of a resonance cavity. Such a device could potentially offer a flexible platform for particle-based assays for a large variety of applications. [ABSTRACT FROM AUTHOR]

Background: Given the opioid epidemic, fentanyl screening in urine has become increasingly important. Immunoassays remain the most common screening methodology due to the high throughput and ease of integration into automated chemistry systems. The fentanyl ARK II from Ark Diagnostics is a widely used immunoassay, while a novel fentanyl assay called FEN2 by Lin-Zhi has become available on the Roche platform. Here, we evaluate and compare their performance., Methods: Four hundred and thirty-four urine samples were analyzed for fentanyl across the Lin-Zhi FEN2 and ARK II assays on the Cobas c502 platform. Samples were analyzed immediately upon request for drug of abuse screening or frozen for subsequent analysis. For confirmation testing, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a limit of detection of 1 ng/mL for fentanyl/norfentanyl was used. Any sample with either fentanyl or norfentanyl above the LC-MS/MS cutoff was deemed positive., Results: The ARK II had 11 false negatives and 7 false positives, while the Lin-Zhi FEN2 had 12 false negatives and 2 false positives. This resulted in ARK II having a sensitivity and specificity of 90.4% and 97.8% respectively, while Lin-Zhi FEN2 had a sensitivity and specificity of 89.5% and 99.4%., Conclusions: Both the ARK II and Lin-Zhi FEN2 immunoassays detected fentanyl well. Overall, the Lin-Zhi assay had slightly better specificity than ARK II, in our data set. While some discrepant results were observed between the 2 immunoassay systems, most occurred near the immunoassay detection cutoffs., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Intratumoral heterogeneity can wreak havoc on current precision medicine strategies because of challenges in sufficient sampling of geographically separated areas of biodiversity distributed across centimeter-scale tumor distances. To address this gap, we developed a deep learning pipeline that leverages histomorphologic fingerprints of tissue to create "Histomic Atlases of Variation Of Cancers" (HAVOC). Using a number of objective molecular readouts, we demonstrate that HAVOC can define regional cancer boundaries with distinct biology. Using larger tumor specimens, we show that HAVOC can map biodiversity even across multiple tissue sections. By guiding profiling of 19 partitions across six high-grade gliomas, HAVOC revealed that distinct differentiation states can often coexist and be regionally distributed within these tumors. Last, to highlight generalizability, we benchmark HAVOC on additional tumor types. Together, we establish HAVOC as a versatile tool to generate small-scale maps of tissue heterogeneity and guide regional deployment of molecular resources to relevant biodiverse niches.

In vivo ultrasound imaging with phased array transducers is of great importance for both clinical application and biomedical research. In this work, relaxor ferroelectric PMN-0.28PT single crystal with very high piezoelectric constant d 33  ≥ 2000 pC/N and electromechanical coupling coefficient k 33  ∼ 0.92 is used to fabricate high-frequency phased array transducers. A 128-element 20-MHz phased array transducer is successfully fabricated, and the optimized performance of -6 dB average bandwidth of ∼ 84 % and insertion loss of -43 dB are achieved. The axial and lateral imaging resolutions of the transducer are determined to be 81 µm and 243 µm, respectively. With Verasonics image platform, in vivo fisheye images are acquired, demonstrating the potential application of our developed high-frequency phased array transducer for biomedical research on small animals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The human brain represents one of the most complex biological structures with significant spatiotemporal molecular plasticity occurring through early development, learning, aging, and disease. While much progress has been made in mapping its transcriptional architecture, more downstream phenotypic readouts are relatively scarce due to limitations with tissue heterogeneity and accessibility, as well as an inability to amplify protein species prior to global -OMICS analysis. To address some of these barriers, our group has recently focused on using mass-spectrometry workflows compatible with small amounts of formalin-fixed paraffin-embedded tissue samples. This has enabled exploration into spatiotemporal proteomic signatures of the brain and disease across otherwise inaccessible neurodevelopmental timepoints and anatomical niches. Given the similar theme and approaches, we introduce an integrated online portal, "The Brain Protein Atlas (BPA)" (www.brainproteinatlas.org), representing a public resource that allows users to access and explore these amalgamated datasets. Specifically, this portal contains a growing set of peer-reviewed mass-spectrometry-based proteomic datasets, including spatiotemporal profiles of human cerebral development, diffuse gliomas, clinically aggressive meningiomas, and a detailed anatomic atlas of glioblastoma. One barrier to entry in mass spectrometry-based proteomics data analysis is the steep learning curve required to extract biologically relevant data. BPA, therefore, includes several built-in analytical tools to generate relevant plots (e.g., volcano plots, heatmaps, boxplots, and scatter plots) and evaluate the spatiotemporal patterns of proteins of interest. Future iterations aim to expand available datasets, including those generated by the community at large, and analytical tools for exploration. Ultimately, BPA aims to improve knowledge dissemination of proteomic information across the neuroscience community in hopes of accelerating the biological understanding of the brain and various maladies., (© 2022 Wiley-VCH GmbH.)

Glioblastoma is often subdivided into three transcriptional subtypes (classical, proneural, mesenchymal) based on bulk RNA signatures that correlate with distinct genetic and clinical features. Potential cellular-level differences of these subgroups, such as the relative proportions of glioblastoma's hallmark histopathologic features (e.g. brain infiltration, microvascular proliferation), may provide insight into their distinct phenotypes but are, however, not well understood. Here we leverage machine learning and reference proteomic profiles derived from micro-dissected samples of these major histomorphologic glioblastoma features to deconvolute and estimate niche proportions in an independent proteogenomically-characterized cohort. This approach revealed a strong association of the proneural transcriptional subtype with a diffusely infiltrating phenotype. Similarly, enrichment of a microvascular proliferation proteomic signature was seen within the mesenchymal subtype. This study is the first to link differences in the cellular pathology signatures and transcriptional profiles of glioblastoma, providing potential new insights into the genetic drivers and poor treatment response of specific subsets of glioblastomas., (© 2022. The Author(s).)

Cerebral organoids have emerged as robust models for neurodevelopmental and pathological processes, as well as a powerful discovery platform for less-characterized neurobiological programs. Toward this prospect, we leverage mass-spectrometry-based proteomics to molecularly profile precursor and neuronal compartments of both human-derived organoids and mid-gestation fetal brain tissue to define overlapping programs. Our analysis includes recovery of precursor-enriched transcriptional regulatory proteins not found to be differentially expressed in previous transcriptomic datasets. To highlight the discovery potential of this resource, we show that RUVBL2 is preferentially expressed in the SOX2-positive compartment of organoids and that chemical inactivation leads to precursor cell displacement and apoptosis. To explore clinicopathological correlates of this cytoarchitectural disruption, we interrogate clinical datasets and identify rare de novo genetic variants involving RUVBL2 in patients with neurodevelopmental impairments. Together, our findings demonstrate how cell-type-specific profiling of organoids can help nominate previously unappreciated genes in neurodevelopment and disease., Competing Interests: Declaration of interests S.W.S. is on the Scientific Advisory Committees of Deep Genomics and Population Bio and serves as an academic consultant for the King Abdulaziz University., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Early detection and monitoring of cognitive dysfunction in multiple sclerosis (MS) may be enabled with smartphone-adapted tests that allow frequent measurements in the everyday environment., Objectives: The aim of this study was to determine the reliability, construct and concurrent validity of a smartphone-adapted Symbol Digit Modalities Test (sSDMT)., Methods: During a 28-day follow-up, 102 patients with MS and 24 healthy controls (HC) used the MS sherpa ® app to perform the sSDMT every 3 days on their own smartphone. Patients performed the Brief International Cognitive Assessment for MS at baseline. Test-retest reliability (intraclass correlation coefficients, ICC), construct validity (group analyses between cognitively impaired (CI), cognitively preserved (CP) and HC for differences) and concurrent validity (correlation coefficients) were assessed., Results: Patients with MS and HC completed an average of 23.2 ( SD = 10.0) and 18.3 ( SD = 10.2) sSDMT, respectively. sSDMT demonstrated high test-retest reliability (ICCs > 0.8) with a smallest detectable change of 7 points. sSDMT scores were different between CI patients, CP patients and HC (all p s < 0.05). sSDMT correlated modestly with the clinical SDMT (highest r = 0.690), verbal (highest r = 0.516) and visuospatial memory (highest r = 0.599)., Conclusion: Self-administered smartphone-adapted SDMT scores were reliable and different between patients who were CI, CP and HC and demonstrated concurrent validity in assessing information processing speed.

Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma's hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance., (© 2022. The Author(s).)

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing., Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS., Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures., Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760-0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale ( r  = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r  = -0.553, respectively), p s < 0.001., Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS.

Cyclosporins are an invaluable class of drug used to prevent the rejection of transplanted tissue. While the most popular drug in this group is cyclosporin A, several other analogues are available, including some enantiomeric and structurally isomeric forms. Unfortunately, the presence of such isomers can make the detection and identification of these drugs by mass spectrometry (MS) alone quite challenging. Here, we demonstrate the separation and analysis of six cyclosporin analogues using liquid chromatography (LC) and differential mobility spectroscopy (DMS) coupled to MS. Using DMS, we demonstrate the separation of three isomers: CycA and CycH (cyclosporin H), which are enantiomers, and isocyclosporin A (a structural isomer of CycA and CycH). For several of the cyclosporins, we can separate different conformers for each isomeric form. After DMS separation, tandem mass spectrometry (MS/MS) analyses of the separated isomers also distinguish these isomeric forms of cyclosporin. In addition, we have probed differences between each isomer by using gas-phase hydrogen-deuterium exchange (HDX) immediately after DMS separation, which reveals differences in the levels of intramolecular hydrogen bonding between each of the cyclosporins.