Octahedra-Tilted Control of Displacement Disorder and Dielectric Relaxation in Mn-Doped SrTiO3 Single Crystals.

Strontium titanate SrTiO3 (STO) is a canonical example of a quantum paraelectric, and its doping with manganese ions unlocks its potential as a quantum multiferroic candidate. However, to date, the specifics of incorporation of the manganese ion into the perovskite lattice and its impact on structure-property relationships are debatable questions. Herein, using high-precision X-ray diffraction of a Mn (2 atom %)-doped STO single crystal, clear fingerprints of the displacement disorder of Mn cations in the perovskite B-sublattice are observed. Moreover, near the temperature of the antiferrodistortive transition, the off-center Mn position splits in two, providing the unequal potential barrier's distribution for possible local atomic hopping. A link with this was found via analysis of the dielectric response that reveals two Arrhenius-type relaxation processes with similar activation energies (35 and 43 meV) and attempt frequencies (1 × 1011 and ∼1.6 × 1010 Hz), suggesting similar dielectric relaxation mechanisms.

Synthesis of Perovskite-Type BiScO3 Ceramics and their Dielectric and Infrared Characterization.

BiScO3 compound was obtained in the form of dense ceramic with a perovskite-type structure, and its complex characterization was determined for the first time. The corresponding synthesis procedure is described in detail. It is demonstrated that the temperature region of the phase stability at atmospheric pressure lies at T < 700 °C (973 K). It is shown that the crystal structure of the BiScO3 ceramic is centrosymmetric. Dielectric measurements of the synthesized sample performed at frequencies 25 Hz to 1 MHz and at temperatures 10-340 K show no changes typical for phase transition. Room-temperature infrared (30-15600 cm-1) and Raman (90-2000 cm-1) spectra of the prepared BiScO3 ceramic are measured, and information on the parameters of phonon resonances is obtained. The number of infrared modes exceeds that predicted by the factor group analysis of the noncentrosymmetric space group C2. The reason for selection rules violation can be associated with the disorder of the crystal structure and local distortions induced by the lone pair of electrons of Bi3+.

The Early Changes in Emergency General Surgery Following Implementation of UK COVID-19 Policy: A Retrospective Cohort Study.

Introduction Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide. On 23rd March 2020, the UK introduced measures in an effort to curb the disease spread. The aim of this study was to analyse the effect of government and Royal College measures on the general surgical take. Materials and methods A retrospective analysis of patients referred to the acute general surgical take between 2nd March 2020 and 5th April 2020, including acuity at the time of referral, management, and patient outcomes, was undertaken. Data fit into a 'pre-COVID measures' cohort (prior to 23rd March 2020) and a 'post-COVID measures' cohort (on or after 23rd March 2020). Results A total of 465 patient referrals were included. There was a decrease in admissions rate in the post-COVID measures' cohort (p=0.001), but with an increase in patient acuity with white cell count (WCC) (p=0.024) and C-reactive protein (CRP) (p=0.036). Laparoscopic surgery decreased (p=0.004); however, the proportion of patients having an operation remained constant. There was no increase in short-term morbidity and mortality or length of stay (LOS). Discussion The data suggests that UK lockdown introduction influenced people's behaviour. Fewer patients presented to the surgical take; however, these patients were of higher acuity. Despite changes in royal college guidelines, there was no decrease in the proportion of patients undergoing operations; however, a higher proportion were open procedures. The change in national and college guidelines did not affect short-term morbidity, mortality or LOS.

Infraclavicular arterio-arterial prosthetic loop is a safe and effective vascular access technique for haemodialysis in frail patients: a prospective observational study.

Vascular access failure causes significant morbidity among end stage renal failure patients. With the increased life expectancy and frailty of those patients, maintaining vascular access became a great challenge. In this study, we assess the short and midterm outcomes of infraclavicular arterio-arterial prosthetic loop (IAAPL) as vascular access for haemodialysis in frail patients who have exhausted conventional vascular access methods. A prospective observational study of 43 patients undergoing IAAPL was conducted in a single centre between May 2017 and March 2020. Primary, assisted primary and secondary patency rates were recorded in addition to complications and patient compliance with access. The achieved primary, assisted primary and secondary patency rates at 6 months are 87.5%, 95%, 97.5% respectively, at one year, corresponding rates were 75%, 83.3%, 94.4% and at 18 months they were 68.6%, 77.1%, 85.7% respectively. There was no procedure related mortality and life-threatening complications during the study period. So we can assume that infraclavicular AAPL is a safe and effective method of obtaining alternative vascular access for hemodialysis in frail patients for whom the conventional vascular access for hemodialysis is not suitable or contraindicated.

In vivo assessment of glutamine anaplerosis into the TCA cycle in human pre-malignant and malignant clonal plasma cells.

BACKGROUND: Overexpression of c-Myc is required for the progression of pre-malignant plasma cells in monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cells in multiple myeloma (MM). c-Myc also increases glutamine anaplerosis into the tricarboxylic acid (TCA) cycle within cancer cells. Whether increased glutamine anaplerosis is associated with the progression of pre-malignant to malignant plasma cells is unknown. METHODS: Human volunteers (N = 7) and patients with MGUS (N = 11) and MM (N = 12) were prospectively recruited to undergo an intravenous infusion of 13C-labeled glutamine followed by a bone marrow aspiration to obtain bone marrow cells and plasma. RESULTS: Despite notable heterogeneity, stable isotope-resolved metabolomics (SIRM) revealed that the mean 13C-labeled glutamine anaplerosis into the TCA cycle was higher in malignant compared to pre-malignant bone marrow plasma cells relative to the remainder of their paired bone marrow mononuclear cells. RNA sequencing demonstrated a higher relative mRNA expression of c-Myc and glutamine transporters such as ASCT2 and SN2 in malignant compared to pre-malignant bone marrow plasma cells. Finally, higher quantitative levels of TCA cycle intermediates in the bone marrow plasma differentiated MM from MGUS patients. CONCLUSION: Measurement of the in vivo activity of glutamine anaplerosis into the TCA cycle provides novel insight into the metabolic changes associated with the transformation of pre-malignant plasma cells in MGUS to malignant plasma cells in MM. TRIAL REGISTRATION: NCT03384108 and NCT03119883.

Metabolomic and Lipidomic Profiling of Bone Marrow Plasma Differentiates Patients with Monoclonal Gammopathy of Undetermined Significance from Multiple Myeloma.

Oncogenic drivers of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) such as c-MYC have downstream effects on intracellular metabolic pathways of clonal plasma cells (PCs). Thus, extracellular environments such as the bone marrow (BM) plasma likely have unique metabolite profiles that differ from patients with MGUS compared to MM. This study utilized an untargeted metabolite and targeted complex lipid profiling of BM plasma to identify significant differences in the relative metabolite levels between patients with MGUS and MM from an exploratory cohort. This was followed by verification of some of the metabolite differences of interest by targeted quantification of the metabolites using isotopic internal standards in the exploratory cohort as well as an independent validation cohort. Significant differences were noted in the amino acid profiles such as decreased branch chain amino acids (BCAAs) and increased catabolism of tryptophan to the active kynurenine metabolite 3-hydroxy-kynurenine between patients with MGUS and MM. A decrease in the total levels of complex lipids such as phosphatidylethanolamines (PE), lactosylceramides (LCER) and phosphatidylinositols (PI) were also detected in the BM plasma samples from MM compared to MGUS patients. Thus, metabolite and complex lipid profiling of the BM plasma identifies differences in levels of metabolites and lipids between patients with MGUS and MM. This may provide insight into the possible differences of the intracellular metabolic pathways of their clonal PCs.

The Ecobiomics project: Advancing metagenomics assessment of soil health and freshwater quality in Canada.

Transformative advances in metagenomics are providing an unprecedented ability to characterize the enormous diversity of microorganisms and invertebrates sustaining soil health and water quality. These advances are enabling a better recognition of the ecological linkages between soil and water, and the biodiversity exchanges between these two reservoirs. They are also providing new perspectives for understanding microorganisms and invertebrates as part of interacting communities (i.e. microbiomes and zoobiomes), and considering plants, animals, and humans as holobionts comprised of their own cells as well as diverse microorganisms and invertebrates often acquired from soil and water. The Government of Canada's Genomics Research and Development Initiative (GRDI) launched the Ecobiomics Project to coordinate metagenomics capacity building across federal departments, and to apply metagenomics to better characterize microbial and invertebrate biodiversity for advancing environmental assessment, monitoring, and remediation activities. The Project has adopted standard methods for soil, water, and invertebrate sampling, collection and provenance of metadata, and nucleic acid extraction. High-throughput sequencing is located at a centralized sequencing facility. A centralized Bioinformatics Platform was established to enable a novel government-wide approach to harmonize metagenomics data collection, storage and bioinformatics analyses. Sixteen research projects were initiated under Soil Microbiome, Aquatic Microbiome, and Invertebrate Zoobiome Themes. Genomic observatories were established at long-term environmental monitoring sites for providing more comprehensive biodiversity reference points to assess environmental change.

A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma.

Monocarboxylate transporters (MCTs) support tumour growth by regulating the transport of metabolites in the tumour microenvironment. High MCT1 or MCT4 expression is correlated with poor outcomes in human patients with head and neck squamous cell carcinoma (HNSCC). Recently, drugs targeting these transporters have been developed and may prove to be an effective treatment strategy for HNSCC. Feline oral squamous cell carcinoma (OSCC) is an aggressive and treatment-resistant malignancy resembling advanced or recurrent HNSCC. The goals of this study were to investigate the effects of a previously characterized dual MCT1 and MCT4 inhibitor, MD-1, in OSCC as a novel treatment approach for feline oral cancer. We also sought to determine the potential of feline OSCC as a large animal model for the further development of MCT inhibitors to treat human HNSCC. In vitro, MD-1 reduced the viability of feline OSCC and human HNSCC cell lines, altered glycolytic and mitochondrial metabolism and synergized with platinum-based chemotherapies. While MD-1 treatment increased lactate concentrations in an HNSCC cell line, the inhibitor failed to alter lactate levels in feline OSCC cells, suggesting an MCT-independent activity. In vivo, MD-1 significantly inhibited tumour growth in a subcutaneous xenograft model and prolonged overall survival in an orthotopic model of feline OSCC. Our results show that MD-1 may be an effective therapy for the treatment of feline oral cancer. Our findings also support the further investigation of feline OSCC as a large animal model to inform the development of MCT inhibitors and future clinical studies in human HNSCC.

A diagnostic cohort study on the accuracy of 18-fluorodeoxyglucose (18FDG) positron emission tomography (PET)-CT for evaluation of malignancy in anterior mediastinal lesions: the DECiMaL study.

OBJECTIVES: The aim of this study is to collate multi-institutional data to determine the value by defining the diagnostic performance of fluorodeoxyglucose positron emission tomography (FDG PET)/CT for malignancy in patients undergoing surgery with an anterior mediastinal mass in order to ascertain the clinical utility of PET/CT to differentiate malignant from benign aetiologies in patients presenting with an anterior mediastinal mass SETTING: DECiMaL Study is a multicentre, retrospective, collaborative cohort study in seven UK surgical sites. PARTICIPANTS: Between January 2002 and June 2015, a total of 134 patients were submitted with a mean age (SD) of 55 years (16) of which 69 (51%) were men. We included all patients undergoing surgery who presented with an anterior mediastinal mass and underwent PET/CT. PET/CT was considered positive for any reported avidity as stated in the official report and the reference was the resected specimen reported by histopathology using WHO criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: Sensitivity, specificity, positive and negative predicted values of [18F]-FDG PET in determining malignant aetiology for an anterior mediastinal mass. RESULTS: The sensitivity and specificity of PET/CT to correctly classify malignant disease were 83% (95% CI 74 to 89) and 58% (95% CI 37 to 78). The positive and negative predictive values were 90% (95% CI 83% to 95%) and 42% (95% CI 26% to 61%). CONCLUSIONS: The results of our study suggest reasonable sensitivity but no specificity implying that a negative PET/CT is useful to rule out the diagnosis of malignant disease whereas a positive result has no value in the discrimination between malignant and benign diseases of the anterior mediastinum.

Polar Order and Frustrated Antiferromagnetism in Perovskite Pb2MnWO6 Single Crystals.

Single crystals of the multiferroic double-perovskite Pb2MnWO6 have been synthesized and their structural, thermal, magnetic and dielectric properties studied in detail. Pure perovskite-phase formation and stoichiometric chemical composition of the as-grown crystals are confirmed by X-ray single-crystal and powder diffraction techniques as well as energy-dispersive X-ray and inductively coupled plasma mass spectrometry. Detailed structural analyses reveal that the crystals experience a structural phase transition from the cubic space group (s.g.) Fm3̅m to an orthorhombic structure in s.g. Pn21a at about 460 K. Dielectric data suggest that a ferrielectric phase transition takes place at that same temperature, in contrast to earlier results on polycrystalline samples, which reported a transition to s.g. Pnma and an antiferroelectric low-temperature phase. Magnetic susceptibility measurements indicate that a frustrated antiferromagnetic phase emerges below 8 K. Density functional theory based calculations confirm that the cationic order between Mn and W is favorable. The lowest total energy was found for an antiferromagnetically ordered state. However, analyses of the calculated exchange parameters revealed strongly competing antiferromagnetic interactions. The large distance between the magnetic atoms, together with magnetic frustration, is shown to be the main reason for the low value of the ordering temperature observed experimentally. We discuss the structure-property relationships in Pb2MnWO6 and compare these observations to reported results on related Pb2BWO6 perovskites with different B cations.

Flexor digitorum lateralis tendon transposition for the repair of bilateral calcaneal tendon rupture in a cat with severe thermal injury.

OBJECTIVE: To describe a novel technique utilizing the flexor digitorum lateralis tendon to repair rupture of the common calcaneal tendon with a gap defect. CLINICAL REPORT: An eight-month-old male Domestic Shorthair cat with bilateral common calcaneal tendon rupture secondary to severe thermal injury underwent bilateral common calcaneal tendon repair performed in two stages. The first stage involved using the flexor digitorum lateralis tendon to reconstruct the common calcaneal tendon and a semitendinosus muscle flap for improved blood supply. A calcaneotibial screw was used for immobilization of the tarsocrural joint. The second surgery involved free skin grafting for complete wound closure. Twelve weeks after the calcaneotibial screws were placed, the calcaneotibial screws were removed and fibreglass splints were applied. The splints were removed after two weeks. RESULTS: Full recovery took five months between the surgery and the final follow-up examination. The cat had a functional gait with no lameness and was able to jump to a height of approximately 75 cm. CLINICAL SIGNIFICANCE: Use of the flexor digitorum lateralis tendon may be considered for repair of a common calcaneal tendon rupture when a gap exists and traditional tendon lengthening techniques are not feasible.

Expanded-ring N-heterocyclic carbenes efficiently stabilize gold(I) cations, leading to high activity in π-acid-catalyzed cyclizations.

A series of six- and seven-membered expanded-ring N-heterocyclic carbene (er-NHC) gold(I) complexes has been synthesized using different synthetic approaches. Complexes with weakly coordinating anions [(er-NHC)AuX] (X(-) = BF4(-), NTf2(-), OTf(-)) were generated in solution. According to their (13)C NMR spectra, the ionic character of the complexes increases in the order X(-) = Cl(-) < NTf2(-) < OTf(-) < BF4(-). Additional factors for stabilization of the cationic complexes are expansion of the NHC ring and the attachment of bulky substituents at the nitrogen atoms. These er-NHCs are bulkier ligands and stronger electron donors than conventional NHCs as well as phosphines and sulfides and provide more stabilization of [(L)Au(+)] cations. A comparative study has been carried out of the catalytic activities of five-, six-, and seven-membered carbene complexes [(NHC)AuX], [(Ph3 P)AuX], [(Me2S)AuX], and inorganic compounds of gold in model reactions of indole and benzofuran synthesis. It was found that increased ionic character of the complexes was correlated with increased catalytic activity in the cyclization reactions. As a result, we developed an unprecedentedly active monoligand cationic [(THD-Dipp)Au]BF4 (1,3-bis(2,6-diisopropylphenyl)-3,4,5,6-tetrahydrodiazepin-2-ylidene gold(I) tetrafluoroborate) catalyst bearing seven-membered-ring carbene and bulky Dipp substituents. Quantitative yields of cyclized products were attained in several minutes at room temperature at 1 mol % catalyst loadings. The experimental observations were rationalized and fully supported by DFT calculations.

Expanded ring diaminocarbene palladium complexes: synthesis, structure, and Suzuki-Miyaura cross-coupling of heteroaryl chlorides in water.

A series of new 6- and 7-membered N-heterocyclic carbene (NHC) complexes of palladium (NHC)Pd(cinn)Cl (cinn = cinnamyl = 3-phenylallyl) were synthesized and characterized structurally in the solid state. The influence of ring size (5, 6 or 7) and bulkiness of N-aryl substituents (Mes = 2,4,6-trimethylphenyl, or Dipp = 2,6-diisopropylphenyl) in carbenes on palladium catalysed Suzuki-Miyaura cross-coupling was revealed. Due to the unique stereoelectronic properties of expanded ring NHCs, a versatile, highly efficient green protocol of coupling of heteroaromatic chlorides and bromides with boronic acids has been developed. High quantitative yields of biaryls were achieved with water as solvent, under air, using low catalyst and phase transfer agent loadings, and with mild and environmentally benign base NaHCO3.

Structures of adnectin/protein complexes reveal an expanded binding footprint.

Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin (¹°Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three ¹°Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the ß strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these ß strand interactions, indicating that these nonloop residues can expand the available binding footprint.

Dual reactivity of N-heterocyclic carbenes towards copper(II) salts.

Complexes of N-heterocyclic carbenes (NHCs) with copper(II) halogenides are unstable. Upon formation, these complexes decompose to give haloamidinium salts. Contrastingly, O-substituted copper(II) NHC complexes are fairly stable. A series of new five-, six- and seven-membered ring NHC complexes of Cu(OAc)(2) have been synthesised and characterised in the solid state.

Distribution and diversity of archaeal and bacterial ammonia oxidizers in salt marsh sediments.

Diversity and abundance of ammonia-oxidizing Betaproteobacteria (beta-AOB) and archaea (AOA) were investigated in a New England salt marsh at sites dominated by short or tall Spartina alterniflora (SAS and SAT sites, respectively) or Spartina patens (SP site). AOA amoA gene richness was higher than beta-AOB amoA richness at SAT and SP, but AOA and beta-AOB richness were similar at SAS. beta-AOB amoA clone libraries were composed exclusively of Nitrosospira-like amoA genes. AOA amoA genes at SAT and SP were equally distributed between the water column/sediment and soil/sediment clades, while AOA amoA sequences at SAS were primarily affiliated with the water column/sediment clade. At all three site types, AOA were always more abundant than beta-AOB based on quantitative PCR of amoA genes. At some sites, we detected 10(9) AOA amoA gene copies g of sediment(-1). Ratios of AOA to beta-AOB varied over 2 orders of magnitude among sites and sampling dates. Nevertheless, abundances of AOA and beta-AOB amoA genes were highly correlated. Abundance of 16S rRNA genes affiliated with Nitrosopumilus maritimus, Crenarchaeota group I.1b, and pSL12 were positively correlated with AOA amoA abundance, but ratios of amoA to 16S rRNA genes varied among sites. We also observed a significant effect of pH on AOA abundance and a significant salinity effect on both AOA and beta-AlphaOmicronBeta abundance. Our results expand the distribution of AOA to salt marshes, and the high numbers of AOA at some sites suggest that salt marsh sediments serve as an important habitat for AOA.

An improved synthesis of some 5-substituted indolizines using regiospecific lithiation.

Various 2-substituted indolizines can be directly and selectively lithiated in the 5 position and subsequent reactions with different electrophiles lead to some novel classes of indolizines. In particular, previously unknown 5-formyl- and 5-iodoindolizine have been prepared by this way and the molecular structure of 5-formyl-2- phenylindolizine was confirmed by X-Ray analysis. The reactivity of the 5-CHO- and 5- COPh groups toward some nucleophiles has been examined, and some additional classes of derivatives (oximes and alcohols) have been obtained. The possibility of Suzuki cross- coupling of 5-iodoindolizines and boronic acids was proven.

Dakin-West trick in the design of novel 2-alkyl(aralkyl) derivatives of oxazolo[3,2-a]pyridines.

A series of previously unavailable derivatives of 2-alkyl- and 2-benzylderivatives of oxazolo[3,2-a]pyridines III were obtained via tandem ring opening and ring closure from stable mesoionic 3-acyloxazolo[3,2-a]pyridinium-2-olates I. The key intermediates of this tandem transformation are N-(b-oxoethyl)pyridones-2 II obtained by Dakin-West acylation of (pyridone-2-yl-1)acetic acid. An example of further utilization of this strategy is illustrated by preparation of unknown 2-benzylimidazo[1,2-a]pyridine from the salt I and ammonia.