Recent progress in solid-state NMR of spin-½ low-γ nuclei applied to inorganic materials.

Significant technological and methodological advances in solid-state NMR techniques in recent years have increased the accessibility of nuclei with small magnetic moments (hereafter termed low-γ) underpinning an increased range of applications of such nuclei. These methodological advances are briefly summarised, including improvements in hardware and pulse sequences, as well as important developments in associated computational methods (e.g. first principles calculations, spectral simulation). Here spin-½ nuclei are the focus, with this Perspective complementing a very recent review that looked at half-integer spin low-γ quadrupolar nuclei. Reference is made to some of the original reports of such spin-½ nuclei, but recent progress in the relevant methodology and applications to inorganic materials (most within the last 10 years) of these nuclei are the focus. An overview of the current state-of-the-art of studying these nuclei is thereby provided for both NMR spectroscopists and materials researchers.

Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.

Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.

Gastrointestinal Adenocarcinoma Incidence and Survival Trends in South Australia, 1990-2017.

BACKGROUND & AIMS: Globally, there has been a concerning rise in the incidence of young-onset cancers. The aim of this study was to provide trends in the incidence and survival of gastrointestinal adenocarcinomas (oesophagus, stomach, pancreas, and colorectal) in South Australia over a 27-year period. METHODS: This is a cross-sectional analysis of a prospective longitudinal database including all cases of gastrointestinal adenocarcinomas prospectively reported to the South Australian (State) Cancer Registry from 1990 to 2017. RESULTS: A total of 28,566 patients diagnosed with oesophageal, stomach, pancreatic, or colorectal adenocarcinoma between 1990 and 2017 were included in the study. While the overall incidence for gastrointestinal adenocarcinomas in individuals >50 years has decreased since 2000 (IRR of 0.97 (95% CI 0.94-1.00; p = 0.06)) compared to 1990-1999, the rate amongst individuals aged 18-50 has significantly increased (IRR 1.41 (95% CI 1.27-1.57; p < 0.001)) during the same reference time period. Although noted in both sexes, the rate of increase in incidence was significantly greater in males (11.5 to 19.7/100,000; p < 0.001). The overall survival from adenocarcinomas across all subsites improved in the >50-year cohort in the last decade (HR 0.89 (95% CI 0.86-0.93; p < 0.001)) compared to 1990-1999. In individuals aged 18-50 years, there has only been a significant improvement in survival for colorectal cancer (HR 0.82 (95% CI 0.68-0.99; p < 0.04)), but not the other subsites. A lower overall survival was noted for males in both age cohorts (18-50 years-HR 1.24 (95% CI 1.09-1.13; p < 0.01) and >50 years-HR 1.13 (95% CI 1.10-1.16; p < 0.001), respectively) compared to females. CONCLUSIONS: This study from South Australia demonstrates a significant increase in young-onset gastrointestinal adenocarcinomas over the last 28 years, with a greater increase in the male sex. The only significant improvement in survival in this cohort has been noted in colorectal cancer patients.

Mapping of N-C Bond Formation from a Series of Crystalline Peri-Substituted Naphthalenes by Charge Density and Solid-State NMR Methodologies.

A combination of charge density studies and solid state nuclear magnetic resonance (NMR) 1 JNC coupling measurements supported by periodic density functional theory (DFT) calculations is used to characterise the transition from an n-π* interaction to bond formation between a nucleophilic nitrogen atom and an electrophilic sp2 carbon atom in a series of crystalline peri-substituted naphthalenes. As the N⋅⋅⋅C distance reduces there is a sharp decrease in the Laplacian derived from increasing charge density between the two groups at ca. N⋅⋅⋅C = 1.8 Å, with the periodic DFT calculations predicting, and heteronuclear spin-echo NMR measurements confirming, the 1 JNC couplings of ≈3-6 Hz for long C-N bonds (1.60-1.65 Å), and 1 JNC couplings of <1 Hz for N⋅⋅⋅C >2.1 Å.

Labeling and Probing the Silica Surface Using Mechanochemistry and 17 O†NMR Spectroscopy*.

In recent years, there has been increasing interest in developing cost-efficient, fast, and user-friendly 17 O enrichment protocols to help to understand the structure and reactivity of materials by using 17 O NMR spectroscopy. Here, we show for the first time how ball milling (BM) can be used to selectively and efficiently enrich the surface of fumed silica, which is widely used at industrial scale. Short milling times (up to 15 min) allowed modulation of the enrichment level (up to ca. 5 %) without significantly changing the nature of the material. High-precision 17 O compositions were measured at different milling times by using large-geometry secondary-ion mass spectrometry (LG-SIMS). High-resolution 17 O NMR analyses (including at 35.2 T) allowed clear identification of the signals from siloxane (Si-O-Si) and silanols (Si-OH), while DNP analyses, performed by using direct 17 O polarization and indirect 17 O{1 H} CP excitation, agreed with selective labeling of the surface. Information on the distribution of Si-OH environments at the surface was obtained from 2D 1 H-17 O D-HMQC correlations. Finally, the surface-labeled silica was reacted with titania and using 17 O DNP, their common interface was probed and Si-O-Ti bonds identified.

Correction: Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis.

Correction for 'Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis' by Maurício Morais et al., Org. Biomol. Chem., 2017, 15, 2947-2952, DOI: .

A novel multinuclear solid-state NMR approach for the characterization of kidney stones.

The spectroscopic study of pathological calcifications (including kidney stones) is extremely rich and helps to improve the understanding of the physical and chemical processes associated with their formation. While Fourier transform infrared (FTIR) imaging and optical/electron microscopies are routine techniques in hospitals, there has been a dearth of solid-state NMR studies introduced into this area of medical research, probably due to the scarcity of this analytical technique in hospital facilities. This work introduces effective multinuclear and multidimensional solid-state NMR methodologies to study the complex chemical and structural properties characterizing kidney stone composition. As a basis for comparison, three hydrates (n=1, 2 and 3) of calcium oxalate are examined along with nine representative kidney stones. The multinuclear magic angle spinning (MAS) NMR approach adopted investigates the 1H, 13C, 31P and 31P nuclei, with the 1H and 13C MAS NMR data able to be readily deconvoluted into the constituent elements associated with the different oxalates and organics present. For the first time, the full interpretation of highly resolved 1H NMR spectra is presented for the three hydrates, based on the structure and local dynamics. The corresponding 31P MAS NMR data indicates the presence of low-level inorganic phosphate species; however, the complexity of these data make the precise identification of the phases difficult to assign. This work provides physicians, urologists and nephrologists with additional avenues of spectroscopic investigation to interrogate this complex medical dilemma that requires real, multitechnique approaches to generate effective outcomes.

Recent progress in solid-state nuclear magnetic resonance of half-integer spin low-γ quadrupolar nuclei applied to inorganic materials.

An overview is presented of recent progress in the solid-state nuclear magnetic resonance (NMR) observation of low-γ nuclei, with a focus on applications to inorganic materials. The technological and methodological advances in the last 20 years, which have underpinned the increased accessibility of low-γ nuclei for study by solid-state NMR techniques, are summarised, including improvements in hardware, pulse sequences and associated computational methods (e.g., first principles calculations and spectral simulation). Some of the key initial observations from inorganic materials of these nuclei are highlighted along with some recent (most within the last 10 years) illustrations of their application to such materials. A summary of other recent reviews of the study of low-γ nuclei by solid-state NMR is provided so that a comprehensive understanding of what has been achieved to date is available.

Direct 17O Isotopic Labeling of Oxides Using Mechanochemistry.

While 17O NMR is increasingly being used for elucidating the structure and reactivity of complex molecular and materials systems, much effort is still required for it to become a routine analytical technique. One of the main difficulties for its development comes from the very low natural abundance of 17O (0.04%), which implies that isotopic labeling is generally needed prior to NMR analyses. However, 17O-enrichment protocols are often unattractive in terms of cost, safety, and/or practicality, even for compounds as simple as metal oxides. Here, we demonstrate how mechanochemistry can be used in a highly efficient way for the direct 17O isotopic labeling of a variety of s-, p-, and d-block oxides, which are of major interest for the preparation of functional ceramics and glasses: Li2O, CaO, Al2O3, SiO2, TiO2, and ZrO2. For each oxide, the enrichment step was performed under ambient conditions in less than 1 h and at low cost, which makes these synthetic approaches highly appealing in comparison to the existing literature. Using high-resolution solid-state 17O NMR and dynamic nuclear polarization, atomic-level insight into the enrichment process is achieved, especially for titania and alumina. Indeed, it was possible to demonstrate that enriched oxygen sites are present not only at the surface but also within the oxide particles. Moreover, information on the actual reactions occurring during the milling step could be obtained by 17O NMR, in terms of both their kinetics and the nature of the reactive species. Finally, it was demonstrated how high-resolution 17O NMR can be used for studying the reactivity at the interfaces between different oxide particles during ball-milling, especially in cases when X-ray diffraction techniques are uninformative. More generally, such investigations will be useful not only for producing 17O-enriched precursors efficiently but also for understanding better mechanisms of mechanochemical processes themselves.

A soft-chemistry approach to the synthesis of amorphous calcium ortho/pyrophosphate biomaterials of tunable composition.

The development of amorphous phosphate-based materials is of major interest in the field of biomaterials science, and especially for bone substitution applications. In this context, we herein report the synthesis of gel-derived hydrated amorphous calcium/sodium ortho/pyrophosphate materials at ambient temperature and in water. For the first time, such materials have been obtained in a large range of tunable orthophosphate/pyrophosphate molar ratios. Multi-scale characterization was carried out thanks to various techniques, including advanced multinuclear solid state NMR. It allowed the quantification of each ionic/molecular species leading to a general formula for these materials: [(Ca2+y Na+z H+3+x-2y-z)(PO43-)1-x(P2O74-)x](H2O)u. Beyond this formula, the analyses suggest that these amorphous solids are formed by the aggregation of colloids and that surface water and sodium could play a role in the cohesion of the whole material. Although the full comprehension of mechanisms of formation and structure is still to be investigated in detail, the straightforward synthesis of these new amorphous materials opens up many perspectives in the field of materials for bone substitution and regeneration. STATEMENT OF SIGNIFICANCE: The metastability of amorphous phosphate-based materials with various chain length often improves their (bio)chemical reactivity. However, the control of the ratio of the different phosphate entities has not been yet described especially for small ions (pyrophosphate/orthophosphate) and using soft chemistry, whereas it opens the way for the tuning of enzyme- and/or pH-driven degradation and biological properties. Our study focuses on elaboration of amorphous gel-derived hydrated calcium/sodium ortho/pyrophosphate solids at 70 °C with a large range of orthophosphate/pyrophosphate ratios. Multi-scale characterization was carried out using various techniques such as advanced multinuclear SSNMR (31P, 23Na, 1H, 43Ca). Analyses suggest that these solids are formed by colloids aggregation and that the location of mobile water and sodium could play a role in the material cohesion.

Exploring pre-surgery donor-specific antibodies in the context of organ shortage in liver transplant.

BACKGROUND: There is a growing disparity between the number of liver transplant (LT) candidates and availability of suitable liver allografts. Antibody-mediated rejection (AMR), secondary to positive donor-specific antibodies (DSA), remains a concern in liver transplantation. This study aimed to correlate expression of DSA on pre-transplant screening and outcomes of LT, specifically development of AMR in liver allografts and liver function profile in the post-operative period. METHODS: Data of consecutive patients undergoing orthotopic LT (OLT) at the South Australian Liver Transplant Unit was analysed. All patients underwent DSA testing pre-transplant. RESULTS: Within a cohort of 96 patients, over a post-OLT median follow-up of 849 days, only 2 patients (2%) developed AMR. While both patients had a positive DSA test preoperatively, overall DSA positivity was noted in 31% patients, with a specificity for prediction of AMR of 0.708. No significant association was noted between AMR (p = 0.092), T cell-mediated rejection/TCMR (p = 0.797) or late hepatic artery thrombosis/LHAT (p = 0.521). There was no significant interaction effect between DSA positivity and serum bilirubin or transaminases over a period of 100 days. CONCLUSION: AMR following LT is uncommon. A positive DSA pre-transplant does not imply a definite risk of AMR. Also, there does not exist a significant interaction in time between DSA expression and serum bilirubin or transaminase levels. Until there emerges evidence to the contrary, it appears reasonable to consider DSA-positive donors within the broad context of marginal donors in the context of a worldwide shortage of LT donor allografts.

Direct solid state NMR observation of the 105Pd nucleus in inorganic compounds and palladium metal systems.

The ability to clearly relate local structure to function is desirable for many catalytically relevant Pd-containing systems. This report represents the first direct 105Pd solid state NMR measurements of diamagnetic inorganic (K2Pd(iv)Cl6, (NH4)2Pd(iv)Cl6 and K2Pd(iv)Br6) complexes, and micron- and nano-sized Pd metal particles at room temperature, thereby introducing effective 105Pd chemical shift and Knight shift ranges in the solid state. The very large 105Pd quadrupole moment (Q) makes the quadrupole parameters (CQ, ηQ) extremely sensitive to small structural distortions. Despite the well-defined high symmetry octahedral positions describing the immediate Pd coordination environment, 105Pd NMR measurements can detect longer range disorder and anisotropic motion in the interstitial positions. The approach adopted here combines high resolution X-ray pair distribution function (PDF) analyses with 105Pd, 39K and 35Cl MAS NMR, and shows solid state NMR to be a very sensitive probe of short range structural perturbations. Solid state 105Pd NMR observations of ∼44-149 µm Pd sponge, ∼20-150 nm Pd black nanoparticles, highly monodisperse 16 ± 3 nm PVP-stabilised Pd nanoparticles, and highly polydisperse ∼2-1100 nm biomineralized Pd nanoparticles (bio-Pd) on pyrolysed amorphous carbon detect physical differences between these systems based on relative bulk:surface ratios and monodispersity/size homogeneity. This introduces the possibility of utilizing solid state NMR to help elucidate the structure-function properties of commercial Pd-based catalyst systems.

Pushing the limits of sensitivity and resolution for natural abundance 43Ca NMR using ultra-high magnetic field (35.2 T).

Natural abundance 43Ca solid state NMR experiments are reported for the first time at ultra-high magnetic field (35.2 T) on a series of Ca-(pyro)phosphate and Ca-oxalate materials, which are of biological relevance in relation to biomineralization processes and the formation of pathological calcifications. The significant gain in both sensitivity and resolution at 35.2 T leads to unprecedented insight into the structure of both crystalline and amorphous phases.

A Combined 25 Mg Solid-State NMR and Ab Initio DFT Approach to Probe the Local Structural Differences in Magnesium Acetate Phases Mg(CH3 COO)2 ⋠nH2 O (n=0, 1, 4).

Multinuclear (1 H, 13 C, 25 Mg) solid-state NMR data is reported for a series of magnesium acetate phases Mg(CH3 COO)2 ⋅ nH2 O (n=0 (two polymorphs), 1, 4). The central focus here is 25 Mg as this set of compounds provides an expanded range of local magnesium coordinations compared to what has previously been reported in the literature using NMR. These four compounds provide 10 distinct magnesium sites with varying NMR interaction parameters. One of the anhydrous crystal structures (α) has an MgO7 site which is reported, to the best of our knowledge, for the first time. For those phases with a single crystal structure, a combination of magic angle spinning (MAS) NMR at high magnetic field (20 T) and first principles density functional theory (DFT) calculations demonstrates the value of including 25 Mg in NMR crystallography approaches. For the second anhydrate phase (ß), where no single crystal structure exists, the multinuclear NMR data clearly show the multiplicity of sites for the different elements, with 25 Mg satellite transition (ST) MAS NMR revealing four inequivalent magnesium environments, which is new information constraining future refinement of the structure. This study highlights the sensitivity of 25 Mg NMR to the local environment, an observation important for several sub-disciplines of chemistry where the structural chemistry of magnesium is likely to be crucial.

The Toxicogenome of Hyalella azteca: A Model for Sediment Ecotoxicology and Evolutionary Toxicology.

Hyalella azteca is a cryptic species complex of epibenthic amphipods of interest to ecotoxicology and evolutionary biology. It is the primary crustacean used in North America for sediment toxicity testing and an emerging model for molecular ecotoxicology. To provide molecular resources for sediment quality assessments and evolutionary studies, we sequenced, assembled, and annotated the genome of the H. azteca U.S. Lab Strain. The genome quality and completeness is comparable with other ecotoxicological model species. Through targeted investigation and use of gene expression data sets of H. azteca exposed to pesticides, metals, and other emerging contaminants, we annotated and characterized the major gene families involved in sequestration, detoxification, oxidative stress, and toxicant response. Our results revealed gene loss related to light sensing, but a large expansion in chemoreceptors, likely underlying sensory shifts necessary in their low light habitats. Gene family expansions were also noted for cytochrome P450 genes, cuticle proteins, ion transporters, and include recent gene duplications in the metal sequestration protein, metallothionein. Mapping of differentially expressed transcripts to the genome significantly increased the ability to functionally annotate toxicant responsive genes. The H. azteca genome will greatly facilitate development of genomic tools for environmental assessments and promote an understanding of how evolution shapes toxicological pathways with implications for environmental and human health.

EBV+ HHV-8+ Multicentric Castleman Disease With Plasmablastic Aggregates in an HIV+ Man: An Evolving Clinicopathologic Entity.

We report a case of EBV+ and HHV-8+ multicentric Castleman disease with plasmablastic aggregates in an HIV-positive individual. A 41-year-old man presented in early 2015 with fevers, sweats, weight loss, intractable itching, and on subsequent testing was found to be HIV positive. Investigations showed cervical lymphadenopathy and splenomegaly. He was treated for HIV and his symptoms resolved. His symptoms recurred in January 2016, and a provisional diagnosis of multicentric Castleman disease was entertained. The HHV-8 (human herpesvirus-8) and EBV (Epstein-Barr virus) viral load was elevated. A left supraclavicular lymph node core biopsy was performed, which showed features of multicentric Castleman disease with plasmablastic aggregates that are EBV (EBER) and HHV-8 positive. He responded well to rituximab treatment and remains well with no symptoms at recent follow-up.

Strong-coupling induced damping of spin-echo modulations in magic-angle-spinning NMR: Implications for J coupling measurements in disordered solids.

In the context of improving J coupling measurements in disordered solids, strong coupling effects have been investigated in the spin-echo and refocused INADEQUATE spin-echo (REINE) modulations of three- and four-spin systems under magic-angle-spinning (MAS), using density matrix simulations and solid-state NMR experiments on a cadmium phosphate glass. Analytical models are developed for the different modulation regimes, which are shown to be distinguishable in practice using Akaike's information criterion. REINE modulations are shown to be free of the damping that occurs for spin-echo modulations when the observed spin has the same isotropic chemical shift as its neighbour. Damping also occurs when the observed spin is bonded to a strongly-coupled pair. For mid-chain units, the presence of both direct and relayed damping makes both REINE and spin-echo modulations impossible to interpret quantitatively. We nonetheless outline how a qualitative comparison of the modulation curves can provide valuable information on disordered networks, possibly also pertaining to dynamic effects therein.

Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis.

Disulfide bridging offers a convenient approach to generate site-selective antibody conjugates from native antibodies. To optimise the reagents available to achieve this strategy, we describe here the use of dibromomaleimides designed to undergo accelerated post-conjugation hydrolysis. Conjugation and hydrolysis, which serve to 'lock' the conjugates as robustly stable maleamic acids, is achieved in just over 1 h. This dramatic acceleration is also shown to infer significant improvements in homogeneity, as demonstrated by mass spectrometry analysis.

Diffuse Gastric Carcinoma Undergoes Characteristic Phenotypic Changes in the Intravascular Environment: Evidence for a Reversal of the Epithelial-Mesenchymal Transition in Lymphovascular Metastasis.

This article reports differences between the properties of extravascular carcinoma, which generally forms the vast bulk of a tumor, and those of intravascular carcinoma, at both primary and metastatic lymph node sites. In a morphological and immunohistochemical study of 19 diffuse gastric adenocarcinomas, we report that in comparison to extravascular carcinoma, the intravascular tumor compartment showed frequent and profound phenotypic change, including increased tumor cell cohesion, differentiation and cadherin/catenin expression. For example, greatest cohesion was seen at the intravascular site in 78% ( P = .00006) of primary cancers and in 84% ( P = .000015) of their lymph node metastases. Pan cadherin showed a statistically significant increase at the intravascular metastatic site ( P = .031). We suggest that this change from an extravascular isolated cell phenotype to an intravascular cohesive phenotype represents reversal of the epithelial to mesenchymal transition. Since this proposed reversal of epithelial to mesenchymal transition in intravascular carcinoma is frequently conspicuous in routine histological sections of many types of cancer, as our previous publications have indicated, this process is likely to have widespread significance for the biology of metastasis.