Evidence for room temperature electric polarization in RMn(2)O(5) multiferroics.

It is established that the multiferroics RMn(2)O(5) crystallize in the centrosymmetric Pbam space group and that the magnetically induced electric polarization appearing at low temperature is accompanied by a symmetry breaking. However, both our present x-ray study-performed on compounds with R=Pr,Nd,Gd,Tb, and Dy-and first-principles calculations unambiguously rule out this picture. Based on structural refinements, geometry optimization, and physical arguments, we demonstrate in this Letter that the actual space group is likely to be Pm. This turns out to be of crucial importance for RMn(2)O(5) multiferroics since Pm is not centrosymmetric. Ferroelectricity is thus already present at room temperature, and its enhancement at low temperature is a spin-enhanced process. This result is also supported by direct observation of optical second harmonic generation. This fundamental result calls into question the actual theoretical approaches that describe the magnetoelectric coupling in this multiferroic family.

Polar and magnetic layered A-site and rock salt B-site-ordered NaLnFeWO6 (Ln = La, Nd) perovskites.

We have expanded the double perovskite family of materials with the unusual combination of layered order in the A sublattice and rock salt order over the B sublattice to compounds NaLaFeWO6 and NaNdFeWO6. The materials have been synthesized and studied by powder X-ray diffraction, neutron diffraction, electron diffraction, magnetic measurements, X-ray absorption spectroscopy, dielectric measurements, and second harmonic generation. At room temperature, the crystal structures of both compounds can be defined in the noncentrosymmetric monoclinic P2(1) space group resulting from the combination of ordering both in the A and B sublattices, the distortion of the cell due to tilting of the octahedra, and the displacement of certain cations. The magnetic studies show that both compounds are ordered antiferromagnetically below T(N) ≈ 25 K for NaLaFeWO6 and at ∼21 K for NaNdFeWO6. The magnetic structure of NaNdFeWO6 has been solved with a propagation vector k = ((1/2) 0 (1/2)) as an antiferromagnetic arrangement of Fe and Nd moments. Although the samples are potential multiferroics, the dielectric measurements do not show a ferroelectric response.

Emergent symmetry in a low-dimensional superconductor on the edge of Mottness.

Upon cooling, condensed-matter systems typically transition into states of lower symmetry. The converse-i.e., the emergence of higher symmetry at lower temperatures-is extremely rare. In this work, we show how an unusually isotropic magnetoresistance in the highly anisotropic, one-dimensional conductor Li0.9Mo6O17 and its temperature dependence can be interpreted as a renormalization group (RG) flow toward a so-called separatrix. This approach is equivalent to an emergent symmetry in the system. The existence of two distinct ground states, Mott insulator and superconductor, can then be traced back to two opposing RG trajectories. By establishing a direct link between quantum field theory and an experimentally measurable quantity, we uncover a path through which emergent symmetry might be identified in other candidate materials.

Upper critical magnetic field far above the paramagnetic pair-breaking limit of superconducting one-dimensional Li0:9Mo6O17 single crystals.

The upper critical field H(c2) of purple bronze Li0:9Mo6O17 is found to exhibit a large anisotropy, in quantitative agreement with that expected from the observed electrical resistivity anisotropy. With the field aligned along the most conducting axis, H(c2) increases monotonically with decreasing temperature to a value 5 times larger than the estimated paramagnetic pair-breaking field. Theories for the enhancement of H(c2) invoking spin-orbit scattering or strong-coupling superconductivity are shown to be inadequate in explaining the observed behavior, suggesting that the pairing state in Li0:9Mo6O17 is unconventional and possibly spin triplet.

Magnetic and structural studies of the multifunctional material SrFe(0.75)Mo(0.25)O(3-δ).

SrFe0.75Mo0.25O3-δ has been recently discovered as an extremely efficient electrode for intermediate temperature solid oxide fuel cells (IT-SOFCs). We have performed structural and magnetic studies to fully characterize this multifunctional material. We have observed by powder neutron diffraction (PND) and transmission electron microscopy (TEM) that its crystal symmetry is better explained with a tetragonal symmetry (I4/mcm space group) than with the previously reported orthorhombic symmetry (Pnma space group). The temperature dependent magnetic properties indicate an exceptionally high magnetic ordering temperature (TN ∼ 750 K), well above room temperature. The ordered magnetic structure at low temperature was determined by PND to be an antiferromagnetic coupling of the Fe cations. Mössbauer spectroscopy corroborated the PND results. A detailed study, with X-ray absorption spectroscopy (XAS), in agreement with the Mössbauer results, confirmed the formal oxidation states of the cations to be mixed valence Fe(3+/4+) and Mo(6+).

Micro and nano-scale compartments guide the structural transition of silk protein monomers into silk fibers.

Silk is a unique, remarkably strong biomaterial made of simple protein building blocks. To date, no synthetic method has come close to reproducing the properties of natural silk, due to the complexity and insufficient understanding of the mechanism of the silk fiber formation. Here, we use a combination of bulk analytical techniques and nanoscale analytical methods, including nano-infrared spectroscopy coupled with atomic force microscopy, to probe the structural characteristics directly, transitions, and evolution of the associated mechanical properties of silk protein species corresponding to the supramolecular phase states inside the silkworm's silk gland. We found that the key step in silk-fiber production is the formation of nanoscale compartments that guide the structural transition of proteins from their native fold into crystalline ß-sheets. Remarkably, this process is reversible. Such reversibility enables the remodeling of the final mechanical characteristics of silk materials. These results open a new route for tailoring silk processing for a wide range of new material formats by controlling the structural transitions and self-assembly of the silk protein's supramolecular phases.

Guidelines for the management of asthma in adults and adolescents: Position statement of the South African Thoracic Society - 2021 update.

Asthma prevalence is increasing worldwide, and surveys indicate that most patients in developed and developing countries, including South Africa, do not receive optimal care and are therefore not well controlled. Standard management guidelines adapted to in-country realities are important to support optimal care. The South African Thoracic Society (SATS) first published a guideline for the management of chronic persistent asthma in 1992, which has subsequently been revised several times. The main aim of the present document was to revise and update SATS' statement on the suggested management of chronic asthma, based on the need to promote optimal care and control of asthma, together with the incorporation of new concepts and drug developments. This revised document reinforces optimal care and incorporates the following primary objectives to achieve the recent advances in asthma care: continued emphasis on the use of inhaled corticosteroids (ICS) as the foundation of asthma treatmentto reduce the reliance on short-acting beta-2 agonist (SABA) monotherapy for asthma symptomsto incorporate the evidence and strategy for the use of the combination of an ICS and formoterol for acute symptom relief (instead of a SABA)to incorporate the evidence and strategy for the use of as-needed ICS-long-acting beta agonists (LABA) for patients with infrequent symptoms or 'mild' asthmato incorporate the evidence and strategy for the use of a long-acting muscarinic antagonist (LAMA) in combination with ICS-LABA; andto incorporate the evidence and strategy for the use of and management with a biologic therapy in severe asthma.

Scanning Tunneling Microscopy and Nanolithography on a Conducting Oxide, Rb0.3MoO3.

The scanning tunneling microscope has been used to image and modify the surface of a conducting oxide (Rb(0.3)MoO(3))in ambient atmosphere. Individual octahedral MoO(6) units of the oxide can be imaged, and under certain conditions defects can be created in the surface that are stable in air. The ability to produce nanometer-sized structures on the surface of an oxide is demonstrated and discussed with reference to nanolithographic applications.

Vascular endothelial growth factor pathway promotes osseointegration and CD31hiEMCNhi endothelium expansion in a mouse tibial implant model: an animal study.

AIMS: It is increasingly appreciated that coordinated regulation of angiogenesis and osteogenesis is needed for bone formation. How this regulation is achieved during peri-implant bone healing, such as osseointegration, is largely unclear. This study examined the relationship between angiogenesis and osteogenesis in a unique model of osseointegration of a mouse tibial implant by pharmacologically blocking the vascular endothelial growth factor (VEGF) pathway. MATERIALS AND METHODS: An implant was inserted into the right tibia of 16-week-old female C57BL/6 mice (n = 38). Mice received anti-VEGF receptor-1 (VEGFR-1) antibody (25 mg/kg) and VEGF receptor-2 (VEGFR-2) antibody (25 mg/kg; n = 19) or an isotype control antibody (n = 19). Flow cytometric (n = 4/group) and immunofluorescent (n = 3/group) analyses were performed at two weeks post-implantation to detect the distribution and density of CD31hiEMCNhi endothelium. RNA sequencing analysis was performed using sorted CD31hiEMCNhi endothelial cells (n = 2/group). Osteoblast lineage cells expressing osterix (OSX) and osteopontin (OPN) were also detected with immunofluorescence. Mechanical pull-out testing (n = 12/group) was used at four weeks post-implantation to determine the strength of the bone-implant interface. After pull-out testing, the tissue attached to the implant surface was harvested. Whole mount immunofluorescent staining of OSX and OPN was performed to determine the amount of osteoblast lineage cells. RESULTS: Flow cytometry revealed that anti-VEGFR treatment decreased CD31hiEMCNhi vascular endothelium in the peri-implant bone versus controls at two weeks post-implantation. This was confirmed by the decrease of CD31 and endomucin (EMCN) double-positive cells detected with immunofluorescence. In addition, treated mice had more OPN-positive cells in both peri-implant bone and tissue on the implant surface at two weeks and four weeks, respectively. More OSX-positive cells were present in peri-implant bone at two weeks. More importantly, anti-VEGFR treatment decreased the maximum load of pull-out testing compared with the control. CONCLUSION: VEGF pathway controls the coupling of angiogenesis and osteogenesis in orthopaedic implant osseointegration by affecting the formation of CD31hiEMCNhi endothelium. Cite this article: Bone Joint J 2019;101-B(7 Supple C):108-114.

Emergence of a real-space symmetry axis in the magnetoresistance of the one-dimensional conductor Li0.9Mo6O17.

We report on an emerging symmetry axis in the magnetoresistance of bulk single crystals of quasi-one-dimensional Li0.9Mo6O17 below T min = 25 K, the temperature at which the electrical resistivity experiences a minimum. Detailed angle-dependent magnetoresistance sweeps reveal that this symmetry axis is induced by the development of a negative magnetoresistance, which is suppressed only for magnetic fields oriented along the poles of the MoO6 octahedra that form the conducting chains. We show that this unusual negative magnetoresistance is consistent with the melting of dark excitons, composed of previously omitted orbitals within the t 2g manifold that order below T min. The unveiled symmetry axis in directional magnetic fields not only provides evidence for the crystallization of these dark excitons but also sheds new light on the long-standing mystery of the metal-insulator transition in Li0.9Mo6O17.

Recommendations for locus-specific databases and their curation.

Expert curation and complete collection of mutations in genes that affect human health is essential for proper genetic healthcare and research. Expert curation is given by the curators of gene-specific mutation databases or locus-specific databases (LSDBs). While there are over 700 such databases, they vary in their content, completeness, time available for curation, and the expertise of the curator. Curation and LSDBs have been discussed, written about, and protocols have been provided for over 10 years, but there have been no formal recommendations for the ideal form of these entities. This work initiates a discussion on this topic to assist future efforts in human genetics. Further discussion is welcome.

A structured simple form for ordering genetic tests is needed to ensure coupling of clinical detail (phenotype) with DNA variants (genotype) to ensure utility in publication and databases.

Researchers and clinicians ideally need instant access to all the variation in their gene/locus of interest to efficiently conduct their research and genetic healthcare to the highest standards. Currently much key data resides in the laboratory books or patient records around the world, as there are many impediments to submitting this data. It would be ideal therefore if a semiautomated pathway was available, with a minimum of effort, to make the deidentified data publicly available for others to use. The Human Variome Project (HVP) meeting listed 96 recommendations to work toward this situation. This article is planned to initiate a strategy to enhance the collection of phenotype and genotype data from the clinician/diagnostic laboratory nexus. Thus, the aim is to develop universally applicable forms that people can use when investigating patients for each inherited disease, to assist in satisfying many of the recommendations of the HVP Meeting [Cotton et al., 2007]. We call for comment and collaboration in this article.

3d-4f coupling and multiferroicity in frustrated Cairo Pentagonal oxide DyMn2O5.

In solid state science, multifunctional materials and especially multiferroics have attracted a great deal of attention, as they open the possibility for next generation spintronic and data storage devices. Interestingly, while many of them host coexisting 3d and 4f elements, the role of the coupling between these two magnetic entities has remained elusive. By means of single crystal neutron diffraction and inelastic neutron scattering experiments we shed light on this issue in the particular case of the multiferroic oxide DyMn2O5. This compound undergoes a first order magnetic transition from a high temperature incommensurate phase to a low temperature commensurate one. Our investigation reveals that although these two phases have very different magnetic structures, the spin excitations are quite similar indicating a fragile low temperature ground state with respect to the high temperature one. Such a rare scenario is argued to be a manifestation of the competition between the exchange interaction and 4f magnetic anisotropy present in the system. It is concluded that the magnetic structure, hence the ferroelectricity, can be finely tuned depending on the anisotropy of the rare earth.

Deletions and insertions in the p53 tumor suppressor gene in human cancers: confirmation of the DNA polymerase slippage/misalignment model.

We analyzed all published deletions and insertions in the p53 gene to assess the relevance of mutagenesis models. Almost all deletions and insertions can be explained by one or more of the following DNA sequence features: monotonic base runs, adjacent or nonadjacent repeats of short tandem sequences, palindromes, and runs of purines or pyrimidines (homocopolymer runs). Increased length of monotonic runs correlates positively with increased frequency of events. Complex frameshift mutations can be explained by the formation of quasi-palindromes, with mismatch excision and replication using one strand of the palindrome as a template. Deletions and insertions in the p53 tumor suppressor gene may reflect both spontaneous and carcinogen-induced mutagenesis.

TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution.

Several groups have studied the molecular pathology of inherited breast cancer. By combining several such studies, we show in this study that somatic TP53 abnormalities are more common in breast cancer associated with BRCA1 or BRCA2 germ-line mutations than in sporadic breast cancers (odds ratio, 2.8; P = 0.0003). Then, we compared the spectrum of TP53 mutations for breast cancers in the IARC TP53 mutation database with the 82 mutations reported in BRCA1/2-associated breast cancers. The spectrum differed significantly both in distribution (P < 1 x 10(-6)) and in base changes (P = 0.025). Mutations at A:T bp were more common in BRCA1/2-associated tumors and strand bias suggesting DNA repair abnormalities was found. Changes were common at TP53 codons that are not mutation hotspots. Structural modeling showed that most of these p53 non-hotspot amino acids characterized in breast tumors isolated from patients with deficient BRCA1/2 function are distributed in a region of the protein on the opposite side of the p53 DNA-binding surface. Our results suggest that BRCA1/2 mutations influence the type and distribution of TP53 mutations seen in breast cancer.

Integrity of p53 in hepatitis B x antigen-positive and -negative hepatocellular carcinomas.

Inactivation of the tumor suppressor p53 seems to be important to the pathogenesis of hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus infection. Although this inactivation may be due to mutations in the p53 gene, recent evidence suggests that the hepatitis B virus-encoded X antigen (HBxAg) binds to and inactivates wild-type p53. Hence, experiments were designed to test the hypothesis that there is a low frequency of p53 mutations in HBxAg-positive HCC. HBxAg and p53 were assayed by immunohistochemistry (IHC) in HCC and nontumor liver from 16 Chinese patients, half of whom were hepatitis B surface antigen carriers. HBxAg was detectable in tumor and/or nontumor cells from all patients by IHC; six of these samples also had detectable p53. To determine whether p53 detection by IHC, and hence stabilization, is associated with mutation, sequencing of p53 exons 5-8 was performed with each patient sample. Wild-type sequences were found in 13 of 16 HBxAg-positive cases (81%). Hence, HBxAg is a common marker of HCC that correlates with the persistence of wild-type p53 among both carriers and noncarriers. The low frequency of p53 mutations in HCC in these patients implies that p53 inactivation may occur predominantly by complex formation with HBxAg.

Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice.

We have examined the mutational spectrum in the Trp53 gene from UVB radiation-induced skin cancers in Trp53+/+ and Trp53+/- mutant mice of all three possible Xpc genotypes. Mutations were detected in exons 2-10 of the Trp53 coding region in approximately 90% of >80 different skin cancers examined. In contrast to Trp53+/+ mice in which most mutations in the Trp53 gene were located in exons 5-8, the majority of the mutations in Trp53+/- mice were at other exons. We observed a high predilection for C-->T transition mutations at a unique CpG site in codon 122 (exon 4) of the Trp53 gene in Xpc-/- Trp53+/- mice. This site is not part of a pyrimidine dinucleotide. Mutations at this codon, as well as in codons 124 and 210, were observed exclusively in Xpc-/- or Xpc+/- mice. Mutations at the corresponding codons (127 and 213) in the human p53 gene have been reported in skin tumors from human patients with xeroderma pigmentosum. Hence, mutations at codons 122 (125), 124 (127), and 210 (213) may constitute signatures for defective or deficient nucleotide excision repair in mice (humans). In Xpc-/- mice, the majority of mutations were located at C residues in CpG sites, in which the C is presumably methylated. A similar bias can be deduced from studies in human XP individuals.

Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants.

Deciding whether a missense allelic variant affects protein function is important in many contexts. We previously demonstrated that a detailed analysis of p53 intragenic conservation correlates with somatic mutation hotspots. Here we refine these evolutionary studies and expand them to the p16/Ink4a gene. We calculated that in order for 'absolute conservation' of a codon across multiple species to achieve P<0.05, the evolutionary substitution database must contain at least 3(M) variants, where M equals the number of codons in the gene. Codons in p53 were divided into high (73% of codons), intermediate (29% of codons), and low (0 codons) likelihood of being mutation hotspots. From a database of 263 somatic missense p16 mutations, we identified only four codons that are mutational hotspots at P<0.05 (8 mutations). However, data on function, structure, and disease association support the conclusion that 11 other codons with > or =5 somatic mutations also likely indicate functionally critical residues, even though P0.05. We calculated p16 evolution using amino acid substitution matrices and nucleotide substitution distances. We looked for evolutionary parameters at each codon that would predict whether missense mutations were disease associated or disrupted function. The current p16 evolutionary substitution database is too small to determine whether observations of 'absolute conservation' are statistically significant. Increasing the number of sequences from three to seven significantly improved the predictive value of evolutionary computations. The sensitivity and specificity for conservation scores in predicting disease association of p16 codons is 70-80%. Despite the small p16 sequence database, our calculations of high conservation correctly predicted loss of cell cycle arrest function in 75% of tested codons, and low conservation correctly predicted wild-type function in 80-90% of codons. These data validate our hypothesis that detailed evolutionary analyses help predict the consequences of missense amino-acid variants.

Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features.

Missense mutations in p53 frequently occur at 'hotspot' amino acids which are highly conserved and represent regions of structural or functional importance. Using the p53 mutation database and the p53 DNA sequences for 11 species, we more precisely defined the relationships among conservation, mutation frequency and protein structure. We aligned the p53 sequences codon-by-codon and determined the degree of substitution among them. As a whole, p53 is evolving at an average rate for a mammalian protein-coding gene. As expected, the DNA binding domain is evolving more slowly than the carboxy and amino termini. A detailed map of evolutionary conservation shows that within the DNA binding domain there are repeating peaks and valleys of higher and lower evolutionary constraint. Mutation hotspots were identified by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Seventy-three hotspots were identified; these 19% of codons account for 88% of all reported p53 mutations. Both high evolutionary constraint and mutation hotspots are noted at amino acids close to the protein-DNA interface and at others more distant from DNA, often buried within the core of the folded protein but sometimes on its surface. The results indicate that targeting highly conserved regions for mutational and functional analysis may be efficient strategies for the study of cancer-related genes.

Phase I evaluation of therapy with four schedules of 5-fluorouracil by continuous infusion combined with recombinant interferon alpha.

The purpose of this study was to determine the maximum tolerated dose and dose-limiting toxicities of 5-fluorouracil (5-FU) when administered concurrently with recombinant IFN-alpha using four continuous infusion (CI) dosing schedules of 5-FU. Forty-five patients with advanced or refractory cancers were treated with 5-FU by CI, plus IFN during the infusion only, by one of four schedules: schedule A: 24-h 5-FU infusion repeated weekly, 9 x 10(6) units IFN x 2 doses weekly; schedule B: 48-h 5-FU infusion repeated weekly, 9 x 10(6) units IFN x 4 doses weekly; schedule C: 5-day 5-FU infusion repeated every 3 weeks, 9 x 10(6) units IFN three times weekly; and schedule D: 21-day 5-FU infusion, repeated after 7 days off therapy, 9 x 10(6) units IFN three times weekly. At least three patients were treated at all dose levels. Doses of 5-FU were escalated to the next level if less than one half of the patients at a given level developed grades 2-4 toxicity. The maximum tolerated dose for 5-FU was 2150 mg/m2/week for schedule A (24-h CI), 2350 mg/m2/week for schedule B (48-h CI), 750 mg/m2/day for schedule C (5-day CI), and 175 mg/m2/day for schedule D (21-day CI). Median delivered dose intensities at these levels were 1788 mg/m2/week for schedule A, 2192 mg/m2/week for schedule B, 1250 mg/m2/week for schedule C, and 593 mg/m2/week for schedule D. The dose-limiting toxicities were hematological and gastrointestinal (stomatitis, diarrhea, nausea, anorexia) for schedules A and B and gastrointestinal (mostly stomatitis) for schedules C and D. Severe fatigue due to IFN was rare. Responses correlated with toxicity >/= grade 2, but not with increased dose intensity. Responses were noted in several tumor types on schedules A, B, and D. 5-FU can be combined with IFN using 24- and 48-h high-dose and long-term low-dose CI schedules, with large differences in dose intensity at maximum tolerated dose. Shorter infusions produce less mucosal and more hematological toxicity. Tumor responses were seen on both short- and long-term CI schedules. Future studies can establish the efficacies of these new schedules of 5-FU/IFN administration in specific tumor types.