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Factors Impacting the Nuclear Magnetic Resonance Spectra of Electrolyte Adsorbed in Layered Metal-Organic Frameworks.
Get PDFElectrically conductive layered metal-organic frameworks (MOFs) have a wide range of electrochemical applications including in sensors, batteries, spintronics, magnetic semiconductors, and supercapacitors. In these devices, MOF structure strongly influences performance, often through MOF-electrolyte interactions. However, few studies have directly probed these interactions at the electrochemical interface. Recent work showed that 19F NMR spectroscopy can probe organic electrolyte environments in the layered MOF Ni3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene), revealing that the chemical shifts of in-pore anions are influenced by specific chemical interactions with the MOF functionality. Here, we expand this approach to study ion adsorption in a range of layered MOFs and study the factors influencing the in-pore chemical shifts. We find that all MOF-electrolyte systems display positively shifted in-pore electrolyte resonances, with calculations indicating that both aromatic ring currents and metal-center-induced currents significantly contribute to the observed shifts. We also find that paramagnetic MOFs exhibit additional paramagnetic shifts of the in-pore resonance when specific MOF-electrolyte interactions are present, with paramagnetic NMR calculations linking these to specific coordination geometries and revealing ion binding sites. Finally, MOF particle morphology also strongly affects the appearance of the NMR spectra, with rod-like morphologies leading to slower exchange and better peak resolution. Overall, our results reveal the key factors that influence the NMR spectra of electrolyte sorption in layered MOFs and demonstrate the power of NMR spectroscopy to probe electrochemical interfaces and guide materials design
Self-assembly of a gonadotropin-releasing hormone antagonist-Teverelix
No full textPeptide and protein aggregation (self-assembly) has been an important topic for many years,
since it is implicated in a range of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s
and Huntington’s Diseases. At the same time, it also represents a significant challenge for the
Pharmaceutical Industry, as many peptides and protein-based drugs have a propensity to self
assemble into amorphous or highly structured aggregates. Such processes can occur during the
manufacture, purification, processing or even storage of therapeutic peptides, as they are
exposed to different conditions (e.g., agitation and pH changes) which can enhance the intrinsic
aggregation propensity. Aggregation is associated with a number of adverse effects, including
loss of biological activity and gain of cytotoxicity and/or immunogenicity. Although most
aggregation processes are deleterious, there are a few examples where self-assembly can be
useful, for example, when the aggregates themselves can be used directly in drug delivery, as
slow-release depots thus enhancing drug half-life in vivo. In this work, the self-assembly of
teverelix, a synthetic peptide which has been shown to be an effective treatment for prostate
cancer, was studied. It was known that at high concentrations teverelix (in the form of a TFA
salt) forms a microcrystalline suspension, which is compatible with subcutaneous injection,
however, under other conditions it was known to form fibrillar structures. The mechanism of
formation of either state, and the factors affecting the stability and rate of formation of these
states was largely unknown.
Since the behaviour of Tv at low and high concentrations is significantly different, the studies
performed within this Thesis can be divided into two parts. First, low peptide concentrations
(< 10 mg/mL), were studied and fibrils found to be the main aggregated species. The amyloid
identity of Tv fibrils was shown by X-ray fibre diffraction and some structural information on
the Tv fibrils was extracted from the diffraction pattern. In parallel, the morphology and
dimensions of the Tv fibrils were studied by transmission electron microscopy. The kinetics of
fibril formation were investigated and factors including Tv concentration, pH, ionic strength
and TFA concentration were demonstrated to have a considerable effect. Oligomeric species
formed in freshly prepared solutions of Tv was studied by size-exclusion chromatography and
Tv molecules found to be largely dimeric with some slightly larger oligomers also populated.
By combining all the information obtained, a mechanism of Tv fibril formation is proposed.
At high Tv concentrations (~75 mg/mL), microcrystals were found to the main species. The
morphology and dimensions of the microcrystals was studied by transmission and scanning
electron microscopy. All microcrystals had the rectangular-shaped morphology with the width
varying from 500 nm to 2.5 m, length from 500 nm to 5 m. In addition, the stability of Tv
microcrystals was studied using dilution experiments and the subsequent rapid formation of
fibrils investigated. Considerable time and effort were put into determining the structure of Tv
in its crystalline state. Unfortunately, all the crystal screens and seeding experiments under a
wide variety of conditions did not produce crystals of sufficient size/stability to solve the
structure. One incomplete diffraction dataset was obtained but there was insufficient data for
structure determination.
Lastly, preliminary studies were performed on Tv-Ac samples at both low and high
concentrations (1 mg/mL & 75 mg/mL). At low concentration (pH 5.9-8.0), the behaviour of
Tv-Ac is similar to Tv-TFA, and fibrils were the main aggregated species observed. A similar
decrease in pH was observed after fibril formation by Tv-Ac and was attributed potentially to
the deprotonation of the lysine side chain. At 75 mg/mL (pH 5.1), the behaviour of Tv-Ac was
significantly different from Tv-TFA The cloudy microcrystalline suspension observed for Tv
TFA was not seen for Tv-Ac even when the pH value was adjusted to 2.0 similar to that of 75
mg/mL Tv-TFA samples (pH was 1.74). Therefore, the TFA counterions play an important role
in the formation of microcrystalline state of Tv
Emerging role of KDM5C in X-linked intellectual disability based on human genetic data and zebrafish models.
No full textINTRODUCTION: Claes-Jensen syndrome is a rare X-linked syndromic neurodevelopmental disorder by pathogenic variants in lysine specific demethylase 5C (KDM5C), a lysine-specific histone demethylase. METHODS: In this study, clinical evaluations were conducted in affected individuals and carrier females. X-chromosome inactivation (XCI) assays were performed to assess genotype-phenotype correlations. Functional studies evaluated variant effects on RNA transcription, protein expression, and stability. Zebrafish models were used for in vivo validation. RNA sequencing with KEGG and GO analyses identified dysregulated genes and pathways, further confirmed in zebrafish. RESULTS: Two novel KDM5C variants NM_004187.5:c.3019del and NM_004187.5:c.782-2A>T were identified in unrelated families with X-linked ID. Affected males presented with short stature, microcephaly, language delay, and intellectual disability, while carrier females showed milder features including learning difficulties and short stature. Skewed XCI in some carriers suggested a role in phenotypic variability. Both variants impair RNA transcription, protein expression and stability. Zebrafish models recapitulated neurodevelopmental and behavioral abnormalities. Transcriptomic analyses revealed disrupted antiviral and interferon-related signaling, implicating aberrant immune activation. Pharmacologic inhibition of the Toll-like receptor pathway ameliorated mutant phenotypes, highlighting neuroinflammation as a potential therapeutic target for KDM5C-related disorders. CONCLUSION: These findings expand the mutational spectrum of KDM5C-associated ID and uncover a novel pathogenic mechanism between KDM5C dysfunction, protein instability, and dysregulated inflammatory signaling
Measurements of differential cross-sections of WbWb production in the dilepton channel in pp collisions at s=13 TeV using the ATLAS detector
No full textAt the Large Hadron Collider, the WbWb final state is expected to be dominated by tt¯ production with a contribution from single-top processes. Differential cross-sections for WbWb production in the dilepton decay channel are measured at the particle level as a function of various kinematic variables. The analysis is based on data from proton-proton collisions at a centre-of-mass energy of s=13 TeV, recorded by the ATLAS detector at the Large Hadron Collider over the period from 2015 to 2018, corresponding to an integrated luminosity of 140 fb−1. Measurements are performed within the fiducial phase-space defined by the presence of two b-jets and one electron and one muon of opposite charges. The differential cross-sections are corrected for detector effects and unfolded to the particle level. Results are compared with predictions from Monte Carlo event generators at next-to-leading order in perturbative quantum chromodynamics; overall the measurements are in reasonable agreement with several generator setups, although no single prediction is able to describe all measured distributions simultaneously. These measurements provide valuable constraints on the modelling of WbWb production and the interference between doubly resonant and singly resonant WbWb production
Groups with conjugacy classes of coprime sizes
No full textSuppose that x, y are elements of a finite group G lying in conjugacy classes of coprime sizes. We prove that ⟨xG⟩∩⟨yG⟩ is an abelian normal subgroup of G and, as a consequence, that if x and y are π‐regular elements for some set of primes π, then xGyG is a π‐regular conjugacy class in G. The latter statement was previously known for π‐separable groups G and this generalisation permits us to extend several results concerning the common divisor graph on p‐regular conjugacy classes, for some prime p
Simplified flow cytometric quantification of human neutrophil extracellular traps (NETs).
No full textSeveral cellular pathways lead to the formation of neutrophil extracellular traps (NETs), a form of cell death (NETosis), distinct from apoptotic and necrotic cell death. Surprisingly, there remains a paucity of methods enabling efficient quantification of NETosis and associated pathways. Here, we describe the development of a simple, sensitive, reliable and flexible flow cytometry assay allowing efficient detection and quantification of NETosis. For the core assay, isolated primary human neutrophils were incubated with stimulants e.g. PMA/ionomycin with or without inhibitors prior to fixing. The fixed cells were then blocked and subsequently incubated in anti-DNA/Histone 1 and anti-histone H2A antibodies for dual detection of Histone 1 and Histone H2A. Cells with were H1-DNA/H2A double fluorescent were deemed NETotic. Imaging flow cytometry was used to validate the accuracy of NETosis detection/quantification. Several key pathways of NETosis were confirmed via the use of established NET-inducers in accordance with existing established methodologies. Importantly, our novel flow cytometry-based NETosis detection assay could efficiently discriminate NETosis from established neutrophil activation, as well as apoptotic and necrotic cell death. We believe our methodology will complement existing NETosis methodologies whilst concomitantly reducing human error, subjectivity and, indeed the false positivity (attained from neutrophil activation and other cell death processes) inherent in existing methodologies. Furthermore, the simplicity and flexibility of our methodology permit additional markers and pathways of NETosis to be investigated, highlighting it as an integral research tool for both general NETosis research and the pursuit to better understand the pathogenesis of NETosis-associated diseases
Broken Bones, Buried Bullets, and Honest Money: Peacemaking, Innovation, and History in Karamoja, Uganda
No full textAbstract A focus on indigenous mechanisms of conflict resolution and reconciliation has influenced many international peacebuilding and transitional justice interventions since the turn of the twenty-first century. Scholarly analyses and policy proposals concerning indigenous peacebuilding, however, tend to reproduce two-dimensional images of fossilized tradition, rather than reckoning with ongoing processes of adaptation and creativity. This article offers a longue durée analysis of changing modes of peacemaking among the Jie agropastoralists of the Karamoja region of northeastern Uganda, focusing on particular ‘peacemaking technologies’ that Jie people innovated and adopted over time. I conceive of peacemaking technologies not only as particular materials or rituals employed in processes of conflict resolution, but as ‘technologies-in-use’, which derive their meaning and efficacy from changing political, economic, and sociocultural realities. Each of these peacemaking technologies thus offers a window into moments of change and innovation in Jie history. In tracing the history of peacemaking in Karamoja, I urge scholars and practitioners of peacebuilding to treat indigenous forms of peacemaking as nuanced processes of adaptation rather than timeless, immutable traditions, and to engage with the context-specific understandings of peace that gave rise to these mechanisms of conflict resolution. Doing so reveals neither the collapse of indigenous systems of conflict resolution nor their failure to adapt to the demands of twenty-first-century life, but a process of adaptation, rooted in both indigenous ethics and pragmatic economic calculus
Sir Robert Clayton (1629–1707) and Two John Drydens, 1673–1680
No full textThe wealthy scrivener, banker, Royal African Company investor, and whig politician Sir Robert Clayton (1629-1707) appears as ‘extorting Ishban’ in lines 280-297 of John Dryden and Nahum Tate’s anonymously published The Second Part of Absalom and Achitophel (1682). Clayton, who served as Lord Mayor of London in 1679-80 and played a significant role in the Exclusion Crisis, was a natural target for Tate and Dryden, who portrayed him as usurious and socially ambitious, both fanatical in his politics and avid for a peerage. The precise division of authorship of the Second Part is still unresolved, although most accounts follow its publisher Jacob Tonson in firmly attributing the authorship of lines 310-509 to Dryden. Most critics therefore assume that Dryden himself did not write the section satirizing Clayton. Clayton’s customer ledger books, now dispersed between The London Archives (formerly the London Metropolitan Archives) and Surrey History Centre and Archives, reveal a more direct, but hitherto unnoticed, connection between the banker and the poet: Dryden and his wife Elizabeth held accounts with Clayton and his partner John Morris (c.1625-1683) between 1673 and 168
An emergent neural coactivity code for dynamic memory.
No full textNeural correlates of external variables provide potential internal codes that guide an animal's behavior. Notably, first-order features of neural activity, such as single-neuron firing rates, have been implicated in encoding information. However, the extent to which higher-order features, such as multineuron coactivity, play primary roles in encoding information or secondary roles in supporting single-neuron codes remains unclear. Here, we show that millisecond-timescale coactivity among hippocampal CA1 neurons discriminates distinct, short-lived behavioral contingencies. This contingency discrimination was unrelated to the tuning of individual neurons, but was instead an emergent property of their coactivity. Contingency-discriminating patterns were reactivated offline after learning, and their reinstatement predicted trial-by-trial memory performance. Moreover, optogenetic suppression of inputs from the upstream CA3 region during learning impaired coactivity-based contingency information in the CA1 and subsequent dynamic memory retrieval. These findings identify millisecond-timescale coactivity as a primary feature of neural firing that encodes behaviorally relevant variables and supports memory retrieval
Unsupervised Learning of Probably Symmetric Deformable 3D Objects from Images in the Wild
No full textWe propose a method to learn 3D deformable object categories from raw single-view images, without external supervision. The method is based on an autoencoder that factors each input image into depth, albedo, viewpoint and illumination. In order to disentangle these components without supervision, we use the fact that many object categories have, at least in principle, a symmetric structure. We show that reasoning about illumination allows us to exploit the underlying object symmetry even if the appearance is not symmetric due to shading. Furthermore, we model objects that are probably, but not certainly, symmetric by predicting a symmetry probability map, learned end-to-end with the other components of the model. Our experiments show that this method can recover very accurately the 3D shape of human faces, cat faces and cars from single-view images, without any supervision or a prior shape model. On benchmarks, we demonstrate superior accuracy compared to another method that uses supervision at the level of 2D image correspondences